U.S. flag

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

  • Publications
  • Account settings
  • Advanced Search
  • Journal List
  • Quant Imaging Med Surg
  • v.11(6); 2021 Jun

A case study of glycogen storage disease type Ia presenting with multiple hepatocellular adenomas: an analysis by gadolinium ethoxybenzyl-diethylenetriamine-pentaacetic acid magnetic resonance imaging

Xiaoming li.

1 Department of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China;

2 Department of Radiology, Shan Xi Medical University, Taiyuan, China;

3 Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China;

4 Magnetic Resonance Collaborations, Siemens Healthcare Ltd., Shanghai, China

Glycogen storage disease type Ia (GSD Ia) is a rare disease caused by a deficiency of hepatic glucose-6-phosphatase (G6Pase). Here, we report a 17-year-old Chinese boy with GSD Ia. Clinical manifestations of the patient included hepatomegaly, growth retardation, doll face, and biochemical abnormalities, including hypoglycaemia, hyperuricaemia, and hyperlipidaemia. The computed tomography (CT) and gadolinium ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA) magnetic resonance imaging (MRI) revealed multiple masses in the left and right hemiliver. These masses presented as different dynamic enhanced patterns in the Gd-EOB-DTPA MRI. In addition, a large amount of glycogen deposit was detected in the liver tissue biopsy. Liver puncture confirmed that the masses were hepatocellular adenomas (HCAs). Genetic analyses confirmed the presence of liver metabolic disease, and the final clinical diagnostic was GSD Ia. The patient’s clinical manifestations were significantly improved following regular treatment with raw corn starch for 9 months. Unfortunately, it was suspected that parts of the adenoma had undergone malignant transformation.


Glycogen storage disease type Ia (GSD Ia) is an extremely rare autosomal recessive inherited disorder affecting glycometabolism, with a prevalence of 1 in 100,000 ( 1 ). Deficiency of the enzyme glucose 6-phophatase (G6Pase) leads to abnormal glycogen metabolism, which then causes abnormal deposits of glycogen in the endoplasmic reticulum cavity. European research guidelines recommend that the diagnosis of GSD Ia should be based on clinical manifestations, imaging, and abnormal biochemical indicators ( 2 ). Diet and adjuvant drug therapy are the main forms of treatment for GSD type I. The objective is to maintain blood glucose levels and prevent long-term complications, including the development of hepatocellular adenomas (HCAs) and hepatocellular carcinomas (HCCs) ( 3 ). Although the use of magnetic resonance imaging (MRI) in the detection of HCAs has been reported in the literature ( 4 - 6 ), to our knowledge, this is the first case to include a comprehensive dataset, including clinical signs, laboratory tests, imaging manifestations, pathology, gene sequencing, and follow-up results.

Case presentation

A 17-year-old boy presented with growth retardation and was initially admitted for short stature. Physical examination revealed weight loss, lack of male sexual development, facial signs of chronic liver disease ( Figure 1A ), and an enlarged liver. Fasting blood glucose levels (3.57 mmol/L) were slightly decreased. Platelet count (374×10 9 g/L), alkaline phosphatase (274 IU/L), glutamyl transpeptidase (233 IU/L), glutamic oxaloacetic transaminase (115 IU/L), alanine transaminase (71 IU/L), triglycerides (5.76 mmol/L), total cholesterol (6.54 mmol/L), lactic acid (9.9 mmol/L), albumin (51.20 g/L), anion gap (24 mmol/L), and uric acid (477 µmol/L) levels were all elevated. He tested positive for ketone bodies. Other indicators, such as alpha fetoprotein and abnormal prothrombin, were normal. He also tested positive for hepatitis B virus (HBV) markers and had been undergoing antiretroviral therapy for the past 16 years.

An external file that holds a picture, illustration, etc.
Object name is qims-11-06-2785-f1.jpg

The computed tomography (CT) and magnetic resonance imagining (MRI) images of a 17-year-old male patient with Glycogen storage disease type Ia and hepatocellular adenomas. (A) A photograph of the patient presenting with doll face, growth retardation, and absence of male sexual development. (B,C,D,E,F) The contrast-enhanced CT results performed at time intervals of 15 months. Examination on July 1, 2015 showed a low-density nodule in segment II (white arrow, B). At the patient’s second examination, the number and diameter of the nodules had increased (white arrows, C). The lesion (no. 2, white triangle, D) was hyperintense on T2WI. The lesion was hyperintense on in-phase analysis (E). Perilesional signal (white triangles) was decreased on opposed-phase analysis (F). (G,H,I) The dynamic enhanced MRI. The lesion was significantly enhanced in the arterial phase (white arrow, G), and persisted to the delayed phase (white arrow, H) in comparison with adjacent hepatocytes. (I) Coronary hepatobiliary phase (HBP; white arrow) showed enlarged liver volume, and the nodule was hypointense but mixed with a slightly hyperintense interior.

The contrast-enhanced abdominal computed tomography (CT) examination at the time of admission ( Figure 1B ) showed multiple low-density nodules, and the largest nodule was located in segment II of the liver. Abdominal CT scans performed 15 months later ( Figure 1C ) revealed that the number and diameter of the nodules had increased.

The gadolinium ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA) MRI ( Figure 1D,E,F,G,H,I ) revealed an enlarged liver with fat infiltration. Thirteen abnormal rounded nodules were found in the left and right hemiliver with different diameters and signal features. Details of the Gd-EOB-DTPA MRI findings are shown in Table 1 . These hypervascular features are commonly observed in different histological types of liver tumors ( 7 ). Therefore, to establish an exact diagnosis of GSD, systematic clinical characteristics including the enlarged liver, developmental retardation, and laboratory examinations were used together with the same hypervascular MRI imaging presentations.

Liver puncture was performed vertically into the liver (about 3 cm deep), and soft liver tissues (1 cm) were rapidly extracted. Staining of the liver tissues with periodic acid-Schiff (PAS) showed large amounts of glycogen deposition in the hepatocytes ( Figure 2A ). The pathology of one of the nodules was confirmed to be HCA ( Figure 2B ). Analyses of the genes ( Figure 2C ) related to liver metabolic diseases suggested that there was a homozygous mutation of the glucose 6-phophatase catalytic ( G6PC ) gene on exon 5 (rs80356484), c.G648 T. This caused CTG to change to CTT (p. Leu216L) and created a new splicing site located 91 base pairs (bp) downstream of the authentic splice site. The patient’s parents were found to be heterozygous for c.G648 T. Therefore, the final clinical diagnosis for this patient was GSD Ia.

An external file that holds a picture, illustration, etc.
Object name is qims-11-06-2785-f2.jpg

Pathological examinations. (A) Periodic acid-Schiff (PAS) staining of the specimen showed a large amount of glycogen deposition in the hepatocytes (400× magnification). (B) Hematoxylin and eosin (HE) staining of the biopsy showed the presence of tumor cells (400× magnification). (C) The pathogenic mutation caused CTG to change to CTT in exon V at the 17th chromosome.

The patient was prescribed 50–100 g of raw corn starch four times a day (every 4–6 hours). After 9 months, the patient had grown by 10 cm in height, and secondary sexual characteristics had begun to develop, including facial hair, pubic hair, and seminal emission. However, Gd-EOB-DTPA MRI revealed that the diameter of the four lesions in segments II and III were larger than previously observed. In addition, two of the lesions were now hypointense, while in the previous hepatobiliary phase (HBP), they were hyperintense ( Figure 3 ).

An external file that holds a picture, illustration, etc.
Object name is qims-11-06-2785-f3.jpg

The gadolinium ethoxybenzyl-diethylenetriamine-pentaacetic acid magnetic resonance imaging (Gd-EOB-DTPA MRI) scans at the time of admission and at 9-month follow-up. (A,B) Scans taken on October 30th, 2016 at the time of admission and (C,D) scans taken on July 29, 2017 after 9 months of medical treatment. The lesion (white arrow, referred to as no. 4 adenoma in Table 1 ) presented with obvious enhancement in the arterial phase (A), and showed isointensity on hepatobiliary phase (HBP) in comparison with adjacent hepatocytes (B). After 9 months’ treatment, the diameter of the lesion (C) had grown larger in size compared to (A) and showed hypointensity on HBP (D).

GSD Ia is a rare inherited metabolic disorder. Due to the lack of G6Pases, glucose 6-phosphates cannot be further hydrolysed into glucose, and thus excessive amounts of glycogen are accumulated. This leads to hepatomegaly ( 8 ). Whole gene sequencing of the G6PC gene can be used to confirm the diagnosis of GSD Ia ( 9 ), which accounts for about 80% of GSD type I. Genetic mutations at certain sites of G6PC are related to different ethnic groups. For example, the mutation c.247C>T (p. Arg83Cys) has a high incidence in the Caucasian (32%) and Jewish (96%) communities, whereas the mutation of c.378_379dupTA (p. Tyr128Thrfs*3) is most common in the Hispanic population (50%). The genetic variation in our case study is a homozygous point mutation on exon V at the 17th chromosome (648G>T, p. Leu216L), and has a high prevalence in the Chinese (36–40%) and Japanese (85–88%) populations ( 3 ).

Based on the molecular types of HCA, it can be classified into four subgroups with different imaging features, including hepatocyte nuclear factor 1A HCA (HHCA), inflammatory HCA (IHCA), activating β-catenin HCA (β-catenin HCA), and unclassified HCA (UHCA) ( 10 ). Approximately 16–75% of HCAs are associated with GSD type I ( 3 ). The signal intensity of HCAs varies on T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI) MRI sequences, which may be explained by variations in adipose, hemorrhage, or glycogen deposition. Decreased signal intensity on T1WI opposed-phase images can be caused by intratumoral fat deposition presented in HHCAs. The “atoll sign” (peripheral high signal intensity) on T2WI has been proposed to be a characteristic finding of IHCAs ( 11 ). The obscure scar may be a possible sign of the BHCAs, but the specificity of these features remains very low ( 12 ). All types of HCAs show hypervascularization in the arterial phase. Different dynamic enhanced patterns, including wash-in, wash-out, and lasting enhancements, may be caused by different types of pathology. Generally, IHCAs and β-catenin HCAs show lasting enhancement, while HHCAs and UHCAs show wash-in and wash-out patterns ( 11 ). HCAs typically appear hypointense on HBP which is also correlated with a low level of organic anion transporting polypeptide (OATP) expression. Yet, several studies have reported HCAs showing iso- or hyperintensity on HBP, especially in IHCAs and BHCAs ( 13 ). This may be related to the uptake of the contrast agent due to the overexpression of OATP. Secondly, it may be explained by the combination of tumor hyperintensity on precontrast T1WI and underlying steatosis ( 12 ).

It is worth nothing that this disease should be differentiated from focal nodular hyperplasia (FNH), a highly differentiated HCC. While HCAs are easily confused with FNH, the treatments for HCAs and FNH are different. The majority of FNH cases only require follow-up observation, whereas HCAs require clinical intervention. Approximately 90% of FNH and some HCA cases show hyperintensity in the HBP. The signal of FNH on T2WI imaging is close to that of normal liver parenchyma and often associated with a central scar ( 14 ). Intratumoral fat deposition and the atoll sign are typical features in HCAs but seldom observed in FNH ( 11 ). Reizine and colleagues reported that the mean liver-to-lesion contrast enhancement ratio (LLCER) of FNH was significantly higher than that of HCAs (46.67%±26.58% and 22.14%±30.74%, respectively) ( 15 ). Clinical symptoms such as obesity, metabolic diseases, and the use of oral contraceptives or steroids, will increase the confidence in the diagnosis of HCAs. Also, attention should be given to the differential diagnosis of HCCs, as 10% of highly differentiated HCCs also show hyperintensity in the HBP, which may be related to the overexpression of OATP on the surface of cancer cells. However, a low signal ring can be observed around the HCCs, and the signal of HCCs in the HBP is mostly heterogeneous, which presents as “mosaic” or “nodule-in-nodule” appearance ( 16 ). Moreover, HCC patients have a history of hepatitis with increased alpha-fetoprotein or abnormal prothrombin level ( 17 ).

Unfortunately, HCAs may progress to malignant transformations even if clinical symptoms improve after treatment. It has been reported that 5% of HCAs are associated with a risk of malignant transformation, especially β-catenin HCAs ( 18 ). Compared with HCAs induced by oral contraceptives or steroids, GSD I HCAs show a higher potential to transform into HCCs ( 19 ), but the pathological mechanism for this unclear. Kishnani et al . ( 20 ) used a high-density single-nucleotide polymorphism (SNP) array to evaluate chromosomal aberrations in 10 cases of GSD I HCAs and 7 cases of the general HCA population. The authors speculated that the chromosomal loss of 6q and the gain of 6p is significant for the malignant transformation of GSD Ia HCAs, which suggests that a regular diet alone may not prevent malignant transformation.

In conclusion, for childhood patients presenting with hepatomegaly, growth retardation, and laboratory tests abnormalities including hypoglycaemia, hyperuricaemia, and hyperlipidaemia, a diagnosis of GSD should be considered. If T1WI, T2WI, and Gd-EOB-DTPA MRI detect multiple masses with different signal intensities and enhancement patterns, there is a strong likelihood that the patient has GSD I with multiple HCAs. Treatment should be commenced without delay, even before gene sequencing analyses and liver biopsies are performed.


The authors are grateful to the patient and his family for their kind cooperation.

Funding: This study was supported by funding from the Research and Development of New Technology for Accurate Diagnosis and Treatment of Liver Tumor based on Magnetic Resonance Imaging - Specific Imaging and its Application in Central Hospitals in Northeast and Southwest Chongqing (csct2019jscx-msxmX0200); Intelligent Assisted Diagnostic Model of Vascular Cognitive Dysfunction based on MRI Imaging Groupology (cstc2019jscx-msxmX0104); Nursery Talents of Army Medical University (2017MPRC-07); The Army Medical University’s Defense Innovation Program (2018XLC3008 rTMS); and the Military Medical Innovation Ability Improvement Plan of Medical Staff in the First Affiliated Hospital to Army Medical University (SWH2018QNWQ-04).

Ethical Statement: Approval from the institutional review board and ethics committee was obtained prior to the study. The patient and his parents agreed that his clinical data can be used for research and publication.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/ .

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-746 ).The authors have no conflicts of interest to declare.

Gene therapy for glycogen storage diseases


  • 1 Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
  • 2 Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
  • PMID: 31227835
  • PMCID: PMC6796997
  • DOI: 10.1093/hmg/ddz133

The focus of this review is the development of gene therapy for glycogen storage diseases (GSDs). GSD results from the deficiency of specific enzymes involved in the storage and retrieval of glucose in the body. Broadly, GSDs can be divided into types that affect liver or muscle or both tissues. For example, glucose-6-phosphatase (G6Pase) deficiency in GSD type Ia (GSD Ia) affects primarily the liver and kidney, while acid α-glucosidase (GAA) deficiency in GSD II causes primarily muscle disease. The lack of specific therapy for the GSDs has driven efforts to develop new therapies for these conditions. Gene therapy needs to replace deficient enzymes in target tissues, which has guided the planning of gene therapy experiments. Gene therapy with adeno-associated virus (AAV) vectors has demonstrated appropriate tropism for target tissues, including the liver, heart and skeletal muscle in animal models for GSD. AAV vectors transduced liver and kidney in GSD Ia and striated muscle in GSD II mice to replace the deficient enzyme in each disease. Gene therapy has been advanced to early phase clinical trials for the replacement of G6Pase in GSD Ia and GAA in GSD II (Pompe disease). Other GSDs have been treated in proof-of-concept studies, including GSD III, IV and V. The future of gene therapy appears promising for the GSDs, promising to provide more efficacious therapy for these disorders in the foreseeable future.

© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Clinical Trials as Topic
  • Combined Modality Therapy
  • Gene Editing
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Genetic Therapy* / adverse effects
  • Genetic Therapy* / methods
  • Genetic Vectors / genetics
  • Glycogen Storage Disease / genetics*
  • Glycogen Storage Disease / metabolism
  • Glycogen Storage Disease / therapy*
  • Immunomodulation
  • Liver / metabolism
  • Organ Specificity
  • Standard of Care
  • Transduction, Genetic
  • Treatment Outcome

Grants and funding

  • R01 AR065873/AR/NIAMS NIH HHS/United States
  • R01 DK105434/DK/NIDDK NIH HHS/United States
  • Open access
  • Published: 03 September 2021

Impact of glycogen storage disease type I on adult daily life: a survey

  • Sven F. Garbade 1 ,
  • Viviane Ederer 2 ,
  • Peter Burgard 1 ,
  • Udo Wendel 3 ,
  • Ute Spiekerkoetter 2 ,
  • Dorothea Haas 1 &
  • Sarah C. Grünert   ORCID: orcid.org/0000-0001-5986-0468 2  

Orphanet Journal of Rare Diseases volume  16 , Article number:  371 ( 2021 ) Cite this article

4780 Accesses

11 Citations

1 Altmetric

Metrics details

Glycogen storage disease type I (GSD I) is a rare autosomal recessive disorder of carbohydate metabolism characterized by recurrent hypoglycaemia and hepatomegaly. Management of GSD I is demanding and comprises a diet with defined carbohydrate intake and the use of complex carbohydrates, nocturnal tube feeding or night-time uncooked cornstarch intake, regular blood glucose monitoring and the handling of emergency situations. With improved treatment, most patients nowadays survive into adulthood. Little research has been performed on the impact of GSD I on daily life, especially in adult patients.

In this multi-centre study we assessed the impact of GSD I on adult daily life in 34 GSD I patients (27 GSD Ia, 7 GSD Ib) between 17 and 54 years (median 26 years) using a self-designed questionnaire that specifically focused on different aspects of daily life, such as job situation, social life, sports, travelling, composition of the household, night-time and day-time dietary management and disease monitoring as well as the patient’s attitude towards the disease. At the time of investigation, the majority of patients either attended school or university or were employed, while 3 patients (9%) were out of work. Most patients ranked GSD I as a disease with moderate severity and disease burden. Dietary treatment was considered challenging by many, but the vast majority of patients considered life with GSD I as well-manageable.


Although the management of GSD I poses a significant burden on daily life, most patients live an independent adult life, have a positive attitude towards their disease and seem to cope well with their situation.

Glycogen storage disease type I (GSD I, OMIM 613742) is a rare autosomal recessive disorder of carbohydate metabolism. Two subtypes are clinically and genetically distinguished: GSD Ia is caused by variations in G6PC resulting in deficiency of glucose-6-phosphatase (G6P), while GSD Ib is due to deficiency of the glucose-6-phophate transporter in the endoplasmatic reticulum, encoded by SLC37A4 [ 1 , 5 ]. GSD Ia/b are the most severe forms among hepatic GSDs, as G6P and the glucose-6-phosphate transporter are involved in both glycogenolysis and gluconeogenesis. The prevalence is approximately 1:100,000, with GSD Ia accounting for about 80% of cases [ 1 ].

GSD Ia is clinically characterised by severe fasting hypoglycaemia, hepatomegaly, failure to thrive, growth retardation, short stature, truncal obesity, doll-like facies, bleeding tendency, and hypotrophic muscles [ 1 ]. Laboratory findings include hyperuricemia, hyperlipidemia, and elevated lactate concentrations. Additionally, GSD Ib is associated with neutropenia and neutrophil dysfunction resulting in frequent and often severe bacterial infections and possible chronic inflammatory bowel disease [ 5 ]. Patients with GSD I generally appear normal at birth and usually present in infancy or early childhood. Treatment aims to prevent hypoglycaemia, thereby minimizing the secondary metabolic derangements and clinical symptoms. This requires regular meals with a defined carbohydrate intake and the use of complex carbohydrates. Fasting tolerance is significantly reduced but variable among patients and can improve with age. Nocturnal management is essential, either by continuous gastric tube feeding of carbohydrates or—depending on the age of the child and patient’s/family’s preference—by intake of calculated amounts of slowly resorbing uncooked cornstarch or Glycosade®, a hydrothermally treated starch with a high amylopectin content [ 5 ]. As patients are prone to hypoglycemic events, they usually have an emergency protocol, a sick-day regimen to prevent hypoglycaemia during intercurrent illnesses, and are trained to use specific measures before high-energy demanding physical activities. With optimal metabolic control, the hepatomegaly improves and growth normalizes [ 5 ]. The frequency of long-term complications such as hepatic adenomas, osteoporosis, focal segmental glomerulosclerosis, and small fiber neuropathy has markedly decreased with improvements in therapy and good metabolic control [ 5 ].

Life expectancy in GSD I is still unknown [ 21 ]. Prior to effective treatment most patients with GSDI died during childhood, some received a liver transplantation. Nowadays, with improved treatment, most patients survive into adulthood [ 16 ]. This requires not only that patients integrate treatment and management into activities of daily life like schooling and university training, professional training, work, social activities, sports, or travelling, but also to solve developmental tasks of adulthood including autonomy, romantic relationships, sexuality and family planning, and development of an attitude towards their condition. Medical conditions, particularly those requiring strict adherence to treatment recommendations or dietary restrictions, can be associated with impaired quality of live (QoL) and emotional functioning [ 2 , 6 , 8 , 11 , 13 , 23 , 26 ]. Only few studies have addressed the QoL of patients with GSD I so far [ 12 , 21 , 25 ], particularly data on adults are scarce. This has prompted us to assess the impact of GSD I on adult life in a study sample of 34 GSD Ia and Ib patients treated in different German metabolic centres.

Thirty-four adult patients with GSD Ia (n = 27) and GSD Ib (n = 7) were enrolled in the study. The median age of patients was 26 years (range 17–54 years). About 60% of the patients were male. Characteristics of the study participants are given in Table 1 . None of the patients has received liver transplantation.

Living situation

Of the 34 patients, 29.4% (n = 10) reported to live alone while 32.4% (n = 11) lived with their parents or at least one parent, 20.6% (n = 7) lived together with their partner, and 17.7% (n = 6) in a flat-sharing community.

Educational and professional status

Educational and professional status are displayed in Fig.  1 . The majority of patients either attended school or university or had a regular working life, while only 3 patients (9%) were unemployed. Among the working individuals, four patients (4/25; 16%) reported to work mainly physically, while 17/25 (68%) predominantly performed office work.

figure 1

Education and professional life of 34 adult GSD I patients. The majority of patients either attended school or university or had a normal working life, while only 3 patients (9%) were unemployed

Dietary management and preparation of the diet

The majority of patients (25/33; 75.8%) reported being responsible for the preparation of meals and the overall dietary management. In about one quarter of patients (8/33; 24.2%), the preparation of meals was still done by the patients’ parents. This was especially the case in younger patients: the median age of patients whose meals were prepared by their parents was 22 years (IQR 17.8–24.3 years), whereas the median age of patients preparing their meals themselves was 28 years (IQR 23–30 years, p  = 0.024, asymptotic Mann–Whitney test). While 21.2% (7/33) of patients reported to consume only self-prepared meals during the school or working day, 39.9% (13/33) and 24.2% (8/33) also ate at a canteen or restaurant, respectively.

Most patients (21/31; 67.7%) followed a dietary regimen with a defined amount of carbohydrates per hour, but were flexible in their choice of foods and carbohydrate sources to meet the dietary requirements. Fourteen of 34 patients (41.2%) had continuous nocturnal feeds, either by a nasogastric tube (11/34; 32.4) or a percutaneous endoscopic gastrostomy (PEG) tube (3/34; 8.8%), while 15/34 (44.1%) and 11/34 (32.4%) used uncooked corn starch or Glycosade® respectively. Half of the patients on continuous nocturnal feeds (7/14; 50%) reported to flexibly switch to corn starch or Glycosade during weekends, holidays or overnight stay outside their usual environment. Twenty-eight of 31 patients (90.3%) reported beeing responsible for their nocturnal dietary management, while 3 patients (3/31; 9.7%) received support by parents or partners. 28/32 patients (87.5%) considered their nocturnal dietary management as safe.

Metabolic control and hypoglycaemia

While 33/34 patients (97.1%) reported to possess a glucometer, one patient (1/34; 2.9%) did not have a functional device. Twelve patients (12/34; 35.3%) always carry a glucometer outside their home, 13 (13/34; 38.2%) only at times, and 9 (9/34; 26.5%) never.

Frequencies of diurnal and nocturnal blood glucose measurements are shown in Fig.  2 . Fifty percent of patients (17/34) reported always checking their blood glucose concentration when suspecting to be hypoglycemic, while 5 patients (5/34; 14.7%) never measured their blood glucose under these circumstances. The remaining 12 patients (12/34; 35.3%) only check their blood glucose level every now and then when suspecting hypoglycemia.

figure 2

Frequency of diurnal and nocturnal blood glucose measurements in 34 adult GSD I patients

Twenty-five patients (25/34; 73.5%) had a continuous glucose monitoring (CGM) or at least tested a CGM device in the past. The majority of them (19/25; 76.0%) experienced CGM as helpful, while 7 patients (7/26; 26.9%) considered it not helpful. Nine patients (9/33; 27.3%) recorded their daily blood sugar profile at least every 6 months, while the majority (24/33, 72.7%) recorded blood sugar profiles less often, mostly before an appointment in the outpatient clinic. Twenty-four patients (24/34; 70.6%) reported to have had at least one diurnal hypoglycaemia within the last six months. Of these, two (8.3%) reported daily hypoglycaemias, 12 patients (50%) had one hypoglycaemia per week, six patients about one per month (24%) and 4 patients (16.7%) less than one per month. Nocturnal hypoglycaemias had occurred in 20 patients (20/33; 60.6%) within the last six months. Of these 20 patients, 13 (13/20; 65%) had at least one hypoglycaemia per month.

Episodes of severe hypoglycaemia during which patients were dependent on external help had occurred in seven patients (7/34; 20.6%) within the last 6 months.

Visits to the outpatient clinic

Apart from 4 patients (4/34; 11.8%) of whom 2 (2/34; 5.9%) were no longer followed by a metabolic centre, all other patients were regularly seen in a metabolic outpatient clinic. The majority was followed regularly either every 6 months (12/34; 35.3%) or once per year (12/34; 35.3%). Most patients (25/31; 80.7%) attended their appointments alone, while 6 patients (6/31; 19.4%) were accompanied mainly by a parent or partner. Sixteen patients (16/30; 53.3%) expressed that they preferred to attend their medical appointments alone, while 14 (14/30; 46.7%) would be more comfortable to be accompanied. The reasons for this were diverse: Lack of confidence (1 patient), feeling more secure and comfortable (8 patients), need of transport (2 patients), out of habit (8 patients), interest of parents, partners or family members (13 patients), involvement of parents or partners in management and treatment (6 patients), to not miss important information (“four ears hear more than two”) (7 patients), and a feeling of security when the social environment is well-informed about the disease (9 patients).

Most patients (27/33; 81.8%) felt well-informed about their medical results including laboratory parameters and sonographic results, whereas 6 patients (6/33; 18.2%) denied this, mainly because the results were not explained to them by their metabolic physicians. Some patients complained that they usually do not receive the results before their next appointment in the outpatient clinic (5/21; 23.8%), or with a delay of at least one month (3/21; 14.3%).

Physical exercise and sports

About three-quarters of patients (25/34; 73.5%) reported to exercise regularly. Most patients (28/34; 82.4%) were used to take measures to prevent hypoglycaemia during physical activity and felt safe with these measures (24/28; 85.7%). On the other hand, 4 patients (4/24; 14.3%) did not feel fully confident with their dietary measures during sports.

Five patients (5/34; 14.7%) considered GSD I to have only little impact on their physical performance, while 14 patients (14/34; 41.2%) perceived a moderate, and 15 patients (15/34; 44.1%) a high impact of GSD on their physical fitness.

Emergency regimens

Only 10 patients (10/34; 29.4%) had a sick-day regimen that they followed at home during episodes of fever, diarrhoea or vomiting. However, 31 patients (31/33; 93.9%) had an emergency document that most of them always carried with them (25/30; 83.3%). Five patients (5/30; 16.7%) did not have an appropriate emergency card.

Four patients (4/34; 11.8%) reported to not be well informed about the risks of alcohol consumption in GSD I. Five patients had no alcohol consumption at all (5/34; 14.7%). Alcoholic beverages that were regularly consumed by the remainder of patients were wine (10/32; 31.3%), beer (14/32; 43.8%), liqueurs (4/32; 12.5%), spirits (11/32; 34.4%), and alcopops (3/32; 9.4%).

All patients stated that they had travelled in the past. The majority (29/34; 85.3%) had good experiences while 5 patients (5/34; 14.7%) reported rather negative experiences. Most patients (29/34; 85.3%) could cope well with the efforts and challenges associated with travelling and enjoyed participating in different activities (24/34; 70.6%), felt safe with their dietary management (12/34; 35.3%) and had no hypoglycaemias (18/34; 52.9%). Patients with negative experiences stated that they considered the efforts associated with travelling proportionately too high (1/34; 2.9%), felt insecure with their dietary management (1/34; 2.9%), had hypoglycaemias (3/34; 8.8%) or could not take part in certain activities (1/45; 2.9%).

Driving licence

Twenty-nine patients (29/33; 87.9%) reported to have a driving license, but two patients with a driving license (2/27; 7.4%) did usually not drive on their own.

Coping with the disease

Most patients communicated their disease openly with family members (others than parents and siblings, 33/34; 97.1%), partners (19/21; 90.5%), friends (32/32; 100%), sporting comrades (13/20; 65%), teachers (6/15; 40%), colleagues at work (22/28; 78.6%), and superiors at work (23/29; 79.3%). Most of these persons were considered well-informed and competent to help in case of a hypoglycaemic event.

When asked to rate GSD I on a 6-point ordinal severity scale (1 = GSD I is no severe disorder, 6 = GSD I is a very severe disorder), most patients ranked GSD I as a disease with moderate severity and disease burden (Fig.  3 A). Patients with GSD Ib perceived their disease as similarly severe as GSD Ia patients ( p  = 0.55, Mann–Whitney test; Fig.  3 A). The attitude toward the challenges of dietary treatment was highly variable among patients, however many individuals reported to consider treatment as rather challenging, independent of the GSD I subtype ( p  = 0.36, Mann–Whitney test; Fig.  3 B). Nevertheless, the vast majority of patients (31/34; 91.2%) thought that life with GSD I is well-manageable and patients with GSD are able to live a normal life if certain measures are taken (Fig.  3 C). Again, there were no marked differences between GSD Ia and Ib patients ( p  = 0.86, Mann–Whitney test).

figure 3

Evaluation of the severity of GSD I and the disease burden ( A ), challenges of dietary treatment ( B ), and the possibility to live a “normal life” with GSD I (C)  (n = 34). Most patients consider GSD I a disease with moderate severity and disease burden. Attitude toward the challenges of dietary treatment was highly variable among patients. The majority of patients thought that life with GSD I is well-manageable and patients with GSD I are able to live a normal life if certain measures are taken

The emotions that patients reported in association with their disease are shown in Fig.  4 . The most frequently mentioned negative emotions were anxiety, fear and rage.

figure 4

Feelings pronounced by patients in association with their disease. The most commonly mentioned negative feelings were anxiety, fear, and rage

The impact of GSD I perceived by the patients on different aspects of adult life is shown in Table 2 . Altogether, most patients had a rather positive view on their disease and their life with the disease.

Thanks to better treatment strategies the prognosis of GSD I has markedly improved within the last decades, and many patients reach adulthood without major complications. Nevertheless, GSD I remains a challenging disorder as treatment requires meticulous adherence and planning with high impact on daily life and QoL. Only little research has been performed on this topic in the past. This is especially true for adults with this rare metabolic disorder. We herein report data on the impact of GSD I on different aspects of adult life and perceived disease burden in 34 GSD I patients.

In most previous studies, QoL has been addressed with the use of standardized questionnaires: Storch et al. investigated psychosocial functioning of children with GSD Ia and Ib [ 25 ]. The authors studied 31 children and their parents using different questionnaires that addressed QoL, loneliness, family functioning, sibling relationship quality, parental distress, parenting stress, child adaptive behaviour, and child emotional and behavioural functioning. The authors showed that both types of GSD I were associated with reduced QoL and independent functioning, elevated levels of internalizing distress and parental stress relative to healthy peers. Based on these results, Sechi et al. [ 21 ] performed an Italian multicentre study on the QoL of adult GSD I patients using the standardized questionnaire SF-36 [ 21 ]. Thirty-eight patients over 16 years (median age 26.5 years) were included in this study. Their results showed that also adult patients with GSD I may have an impaired QoL. Especially patients with GSD type Ib, women, and those with renal complications were more likely to experience a poorer QoL [ 21 ]. Although patients with GSD I had lower median scores in general health perception and social functioning when compared to normative data, they had higher median scores for bodily pain and mental health which might be explained by good coping strategies. QoL data of adolescent and adult GSD I patients are also available from the Swiss hepatic glycogen storage disease registry [ 12 ]. This registry includes 27 GSD I patients between 14 and 29 years. QoL was assessed using the SF-12 questionnaire, and in contrast to the above mentioned studies, scores in this sample were within the normal range [ 12 ]. Additionally, most patients were well integrated into social and professional life.

Flanagan et al. studied eating attitudes, eating disorder symptoms, and body image among 64 patients with GSD ranging from 7 to 52 years and found a lower body esteem in children, adolescents and adults with GSD compared to population norms [ 7 ]. Interestingly, patients reported growing acceptance of their bodies with age associated with less negative attitudes and behaviours in adulthood.

Our study addressed several aspects of normative adult life events as well as the disease burden perceived by the patients. Different from the above-mentioned studies, we used a self-developed questionnaire that was tailored specifically to the challenges and burdens associated with GSD I, including aspects such as dietary management. Overall, our data demonstrate that most adult GSD I patients live an independent adult life. Concerning education and work, all but 3 unemployed patients (9%) either attended school or university or had a regular working life. Very similar findings were reported by Sechi et al. [ 21 ] with an unemployment rate of 11.4% in 38 adult GSD I patients. Data from the Swiss GSD registry comparably showed that most patients were employed or in vocational training with no need of supporting services [ 12 ].

In our study, we did not ask for the reason for unemployment, but it is of note that in the European Study on GSD I (ESGSD I) with more than 200 GSD I patients, 11% were reported to need a special education or work, while 6% were unable to have a profession because of mental disability [ 19 ]. However, it is important to bear in mind that the ESGSD study includes patients from the “pre-cornstarch aera”, and it is well-conceivable that poorer metabolic control and also possibly later diagnosis might have contributed to a poorer neurologic outcome.

At the time of the study, most patients lived an independent life, while about 32% still lived with their parents (median age of patients living with their parents was 22 years). In this respect, GSD I patients do not seem to differ significantly from the normal population, as German demographic data show that more than 28% of 25-year-olds still live with their parents [ 24 ]. About one quarter reported that parents were still mainly responsible for the preparation of meals and dietary management. Difficulty in becoming independent from parents has been observed in patients with inherited metabolic diseases in general [ 14 , 21 ]. This is well understandable considering the high level of parental involvement in disease management during infancy and childhood [ 14 , 21 ]. It is also of note, that almost half of the patients in our study preferred to be accompanied to visits in the metabolic outpatient clinic. Supporting patients’ personal responsibility should be one major aim in the transition process from adolescence to adulthood. This includes the early involvement of the patient in the treatment and disease monitoring together with age-appropriate communication and information by doctors during outpatient visits. Providing appropriate information empowers the individual, giving them confidence to manage their disorder in the future [ 14 ]. Several patients in our study stated that results of outpatient visits such as laboratory values and necessary therapeutic adaptions were often not well communicated to them.

Living with a chronic disease might not only impact QoL due to the disorder itself, but also due to the necessary treatment, which may be a major challenge. For patients with GSD I this includes frequent meals, strict planning of activities, loss of spontaneity as well as sleep disturbances due to night-time interruptions for nocturnal corn starch intake [ 7 , 20 ]. When asked for their opinion about the severity of GSD I, most patients ranked GSD I as a disease with moderate severity and disease burden, but rated the challenges of dietary treatment as rather high. The three negative emotions that more than 60% of patients felt with respect to their disease at least sometimes were anxiety, fear, and rage.

Among the aspects addressed in this study, the highest impact of GSD I was perceived on physical performance and fitness. More than 85% of patients either considered their physical fitness moderately or highly impaired. Additionally, some patients expressed at least some degree of uncertainty with respect to the risk of hypoglycaemia during sports. The impact of GSD I on partnership was rated low (53.6%) or moderate (35.7%) by most patients. Interestingly, Sechi et al. [ 21 ] reported a lower percentage of married patients with children in their sample of 38 Italian patients when compared to the age- and gender-matched Italian population and suggested that GSD I patients may have more difficulty in forming adult relationships and starting a family than healthy peers. Impact on free time activities and friendships was also considered low by the majority of the study patients. More than 30% of patients reported a high or very high financial impact due to their chronic disease. Studying families with a child affected by a urea cycle defect, Cederbaum et al. [ 4 ] reported financial stress as one of the greatest sources of stress in their study cohort. Financial stress affects a significant proportion of patients diagnosed with a chronic illness. In addition to costs for medication that are not all covered by insurance companies, a chronic disease may have an impact on education and professional choices, but also on the fitness for work, thereby affecting the economic status.

Overall, most patients in our study had a rather positive attitude towards their disease and felt able to live a normal life if certain measures are taken. Given the challenges and restrictions associated with GSD I this may reflect good coping strategies in most of the patients. Comparable to healthy subjects, successful coping enables individuals with a chronic illness to emphasize the positive aspects of their lives, thereby reducing general distress [ 3 , 22 ]. Coping strategies are highly variable, and the perceived disease burden of an individual patient does not automatically correlate with disease severity. This is reflected by the fact that we did not observe significant differences in the perceived disease burden between patients with GSD Ia and GSD Ib, although GSD Ib in adulthood is usually associated with additional problems such as inflammatory bowel disease and other complications linked to neutropenia. Sechi et al. reported that the personal evaluation of “ general health” given by GSD I patients was similar to that perceived by patients affected by type 2 diabetes, another chronic disease requiring a lifelong diet [ 15 , 21 ].

Most patients communicated their disorder openly to family members, partners, friends, sporting comrades, teachers and colleagues. In view of the fact that GSD I can lead to life-threatening hypoglycaemia and that in these situations, patients may depend on external help, information of the patients’ social environment and competency to react properly can be lifesaving. In fact, about 20% of patients at least had one severe hypoglycaemia within the last six months during which they required external help.

One might object that our study lacks normative data from healthy subjects and the sample possibly has selection bias only including individuals successfully coping with their condition. However, results clearly vary in all items and clearly demonstrate that participants are neither perfectly compliant nor a selection of relatively mild forms. Our aim was not to do a normative comparison with healthy adults, but to explore how disease-specific facets of GSD type I interfere with adult normative life-events and developmental tasks [ 17 ]. We see the significant strength of our study, that instead of using a standardised generic questionaire, describes the QoL of adults with GSD I in a way unfolding how they struggle and cope with their condition and how they live (day and night), thereby providing essential information for all disciplines of the treatment team. Our data also provide a basis for the development of a transition program for adolescents with GSD I that covers all relevant aspects adult life. The workshop based on the items of the questionnaire allows to postulate face validity, comprehensiveness, and comprehensibility of the questionnaire (see methods paragraph). Apart from linking the questionnaire to the theory of developmental tasks we do not postulate any theoretical construct why construct, convergent and discriminant validity is not claimed. However, in further studies the questionnaire can be linked to objective measures like long-term blood glucose concentrations or physical fitness. Participants also reported behaviour not recommended for individuals with GSD I (alcohol consumption) why social desirability may not be a critical issue in our data. A limitation can be raised regarding the representativeness of our sample. Members of patient organisations may be more active copers of their condition, but on the other hand non-members may feel sufficiently competent to master their condition alone.

Our study demonstrated that although GSD I is a severe disease that requires lifelong therapy with strict adherence, most patients live an independent adult life and cope well with their situation. Physicians involved in transition of GSD patients should support their patients in becoming autonomous as early as possible and address important topics such as medical monitoring, the risk of alcohol consumption, and family planning with their patients. Patient organisations that enable exchange with peers of the same age may not only contribute to better information of patients, but also provide emotional and psychosocial support.

A questionnaire was designed by two of the authors (UW, paediatrician and PB, psychologist), both having long-lasting clinical experience in treatment and care of individuals with GSD I as well as patient workshops dealing with self-mangement and coping with the condition, to address important aspects of daily life with GSD I in adulthood. Item construction followed Havidhurst’s theory of developmental tasks [ 9 ] originating from biology (e.g. physical changes and health related issues), the self (achieving emotional and practical everyday independence), and social expectations (preparing for a professional economic career, achieving sexual and romantic relations). The items cover school and professional education, the job situation, social life, sports, travelling, composition of the household, dietary management and disease monitoring as well as the patient’s attitude towards his/her disease. Pre-diagnosed psychological conditions such as anxiety or depression were not assessed by the questionnaire. An English translation of the questionnaire can be found in the Additional file 1 : Supplemental Material. For this study, subjects were recruited on the occasion of a workshop held at the Annual meeting of the German patient organisation for glycogen storage diseases (Duderstadt 2017) and via the Metabolic Centres Freiburg and Heidelberg. The workshop was divided in two parts. In part one participants filled in the pseudonymized questionnaire, in part two participants shared their experience with particular items of the questionnaire (e.g. travelling, night-time feeding). During the workshop no further issues were introduced and no difficulties of item comprehensibility was reported. The entire study population is referred to as “adults”, although two 17 year-old individuals were included. The study was approved by the ethics committees of the universities Freiburg and Heidelberg (EKFR Nr. 468/18, S-022/2019).

Statistical analysis

Data analysis was performed using the Software R ( https://www.r-project.org ) [ 18 ]. Descriptive and explorative analysis was used to describe the study sample. Continuous data is reported with mean and standard deviation, count data is presented as frequencies and percentages. No a-priori hypotheses are tested. We used asymptotic Mann–Whitney Test from R package ‘coin’ to compare medians between two groups [ 10 ].

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.


Continuous glucose monitoring

European study on GSD I

  • Glycogen storage disease type I
  • Glucose-6-phosphatase

Interquartile range

Percutaneous endoscopic gastrostomy

Quality of Life

Bali DS, Chen Y-T, Austin S, Goldstein JL, et al. Glycogen storage disease type I. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle: University of Washington; 1993.

Google Scholar  

Bösch F, Landolt MA, Baumgartner MR, et al. Health-related quality of life in paediatric patients with intoxication-type inborn errors of metabolism: analysis of an international data set. J Inherit Metab Dis. 2020. https://doi.org/10.1002/jimd.12301 .

Article   PubMed   PubMed Central   Google Scholar  

Carver CS, Connor-Smith J. Personality and coping. Annu Rev Psychol. 2010;61:679–704. https://doi.org/10.1146/annurev.psych.093008.100352 .

Article   PubMed   Google Scholar  

Cederbaum JA, LeMons C, Rosen M, et al. Psychosocial issues and coping strategies in families affected by urea cycle disorders. J Pediatr. 2001;138:S72-80. https://doi.org/10.1067/mpd.2001.111839 .

Article   CAS   PubMed   Google Scholar  

Chen MA, Weinstein DA. Glyogen storage diseases: diagnosis, treatment and outcome. Transl Sci Rare Dis. 2016;1:45–72.

Eminoglu TF, Soysal SA, Tumer L, et al. Quality of life in children treated with restrictive diet for inherited metabolic disease. Pediatr Int. 2013;55:428–33. https://doi.org/10.1111/ped.12089 .

Flanagan TB, Sutton JA, Brown LM, et al. Disordered eating and body esteem among individuals with glycogen storage disease. JIMD Rep. 2015;19:23–9. https://doi.org/10.1007/8904_2014_359 .

Ford S, O’Driscoll M, MacDonald A. Living with phenylketonuria: lessons from the PKU community. Mol Genet Metab Rep. 2018;17:57–63. https://doi.org/10.1016/j.ymgmr.2018.10.002 .

Havighurst RJ, Havighurst RJ. Developmental tasks and education. 3rd ed. New York: McKay; 1974.

Hothorn T, Hornik K, van de Wiel MA, Zeileis A. A lego system for conditional inference. Null. 2006;60:257–63. https://doi.org/10.1198/000313006X118430 .

Article   Google Scholar  

Hysing M, Elgen I, Gillberg C, et al. Chronic physical illness and mental health in children. Results from a large-scale population study. J Child Psychol Psychiatry. 2007;48:785–92. https://doi.org/10.1111/j.1469-7610.2007.01755.x .

Kaiser N, Gautschi M, Bosanska L, et al. Glycemic control and complications in glycogen storage disease type I: results from the Swiss registry. Mol Genet Metab. 2019;126:355–61. https://doi.org/10.1016/j.ymgme.2019.02.008 .

Khemakhem R, Dridi Y, Hamza M, et al. Living with type 1 diabetes mellitus: how does the condition affect children’s and adolescents’ quality of life? Arch Pediatr. 2020;27:24–8. https://doi.org/10.1016/j.arcped.2019.11.002 .

Lee PJ. Growing older: the adult metabolic clinic. J Inherit Metab Dis. 2002;25:252–60. https://doi.org/10.1023/a:1015602601091 .

Lloyd CE, Orchard TJ. Physical and psychological well-being in adults with Type 1 diabetes. Diabetes Res Clin Pract. 1999;44:9–19. https://doi.org/10.1016/s0168-8227(99)00004-2 .

Martens DHJ, Rake JP, Schwarz M, et al. Pregnancies in glycogen storage disease type Ia. Am J Obstet Gynecol. 2008;198:646.e1-7. https://doi.org/10.1016/j.ajog.2007.11.050 .

Article   CAS   Google Scholar  

McCormick CM, Kuo SI-C, Masten AS. Developmental tasks across the life span. In: Fingerman KL, Berg CA, Smith J, Antonucci TC, editors. Handbook of life-span development. Berln: Springer; 2011. p. 117–39.

R Core Team. R Core Team (2020): R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria; 2020. https://www.R-project.org/ .

Rake JP, Visser G, Labrune P, et al. Glycogen storage disease type I: diagnosis, management, clinical course and outcome Results of the European Study on Glycogen Storage Disease Type I (ESGSD I). Eur J Pediatr. 2002;161(Suppl 1):S20–34. https://doi.org/10.1007/s00431-002-0999-4 .

Rousseau-Nepton I, Huot C, Laforte D, et al. Sleep and quality of life of patients with glycogen storage disease on standard and modified uncooked cornstarch. Mol Genet Metab. 2018;123:326–30. https://doi.org/10.1016/j.ymgme.2017.09.003 .

Sechi A, Deroma L, Paci S, et al. Quality of life in adult patients with glycogen storage disease type I: results of a multicenter italian study. JIMD Rep. 2014;14:47–53. https://doi.org/10.1007/8904_2013_283 .

Segerstrom SC, Smith GT. Personality and coping: individual differences in responses to emotion. Annu Rev Psychol. 2019;70:651–71. https://doi.org/10.1146/annurev-psych-010418-102917 .

Simon E, Schwarz M, Roos J, et al. Evaluation of quality of life and description of the sociodemographic state in adolescent and young adult patients with phenylketonuria (PKU). Health Qual Life Outcomes. 2008;6:25. https://doi.org/10.1186/1477-7525-6-25 .

Statistisches Bundesamt. D-STATIS, Statistisches Bundesamt; 2020. https://www.destatis.de/DE/Presse/Pressemitteilungen/2020/08/PD20_N045_122.html .

Storch E, Keeley M, Merlo L, et al. Psychosocial functioning in youth with glycogen storage disease type I. J Pediatr Psychol. 2008;33:728–38. https://doi.org/10.1093/jpepsy/jsn017 .

Zeltner NA, Landolt MA, Baumgartner MR, et al. Living with intoxication-type inborn errors of metabolism: a qualitative analysis of interviews with paediatric patients and their parents. JIMD Rep. 2017;31:1–9. https://doi.org/10.1007/8904_2016_545 .

Download references


We are grateful to all patients for their participation in this study and for their motivation and trust. This work was supported by the Metabolic Division in the University Children’s Hospital, which is part of the Freiburg Center for Rare Diseases. Several authors of this publication are members of the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN)—Project ID No 739543.

Open Access funding enabled and organized by Projekt DEAL.

Author information

Authors and affiliations.

Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany

Sven F. Garbade, Peter Burgard & Dorothea Haas

Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center, University of Freiburg, Faculty of Medicine, Mathildenstraße 1, 79106, Freiburg, Germany

Viviane Ederer, Ute Spiekerkoetter & Sarah C. Grünert

Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

You can also search for this author in PubMed   Google Scholar


SFG performed the statistical analysis, was involved in interpretation of the data, and drafted the figures. VE was involved in data analysis. PB and UW designed the questionnaire, helped with data interpretation and drafted parts of the manuscript. US gave scientific input. DH recruited patients and collected patient data. SCG was responsible for patient recruitment, data collection, data analysis and interpretation and drafted the manuscript. All authors critically revised and proofread the manuscript prior to submission. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Sarah C. Grünert .

Ethics declarations

Ethics approval and consent to participate.

This study has been approved by the ethics committees of the University Hospitals Freiburg and Heidelberg (EKFR Nr. 468/18; S-022/2019). All patients gave their consent to participate in this study.

Consent for publication

All patients gave their consent for the publication.

Competing interests

All authors declare that they have no competing interests.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information


Additional file 1. English translation of the questionnaire used in this study to assess the impact of GSD I on adult daily life.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Cite this article.

Garbade, S.F., Ederer, V., Burgard, P. et al. Impact of glycogen storage disease type I on adult daily life: a survey. Orphanet J Rare Dis 16 , 371 (2021). https://doi.org/10.1186/s13023-021-02006-w

Download citation

Received : 19 April 2021

Accepted : 24 August 2021

Published : 03 September 2021

DOI : https://doi.org/10.1186/s13023-021-02006-w

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

  • Glucose-6-phosphate transporter
  • Quality of life
  • Disease burden

Orphanet Journal of Rare Diseases

ISSN: 1750-1172

  • Submission enquiries: Access here and click Contact Us
  • General enquiries: [email protected]

glycogen storage disease research paper

Pompe Disease: a Clinical, Diagnostic, and Therapeutic Overview

  • Neuromuscular Disorders (C Fournier, Section Editor)
  • Open access
  • Published: 04 August 2022
  • volume  24 ,  pages 573–588 ( 2022 )

You have full access to this open access article

  • David Stevens MD 1 ,
  • Shadi Milani-Nejad DO 1 &
  • Tahseen Mozaffar MD   ORCID: orcid.org/0000-0002-1230-0188 1 , 2 , 3  

4828 Accesses

7 Citations

Explore all metrics

Cite this article

Purpose of review.

This review summarizes the clinical presentation and provides an update on the current strategies for diagnosis of Pompe disease. We will review the available treatment options. We examine newly approved treatments as well as upcoming therapies in this condition. We also provide commentary on the unmet needs in clinical management and research for this disease.

Recent Findings

In March 2015, Pompe disease was added to the Recommended Uniform Screening Panel (RUSP) and since then a number of states have added Pompe disease to their slate of diseases for their Newborn Screening (NBS) program. Data emerging from these programs is revising our knowledge of incidence of Pompe disease. In 2021, two randomized controlled trials involving new forms of enzyme replacement therapy (ERT) were completed and one new product is already FDA-approved and on the market, whereas the other product will come up for FDA review in the fall. Neither of the new ERT were shown to be superior to the standard of care product, alglucosidase . The long-term effectiveness of these newer forms of ERT is unclear. Newer versions of the ERT are in development in addition to multiple different strategies of gene therapy to deliver GAA, the gene responsible for producing acid alpha-glucosidase, the defective protein in Pompe Disease. Glycogen substrate reduction is also in development in Pompe disease and other glycogen storage disorders.

There are significant unmet needs as it relates to clinical care and therapeutics in Pompe disease as well as in research. The currently available treatments lose effectiveness over the long run and do not have penetration into neuronal tissues and inconsistent penetration in certain muscles. More definitive gene therapy and enzyme replacement strategies are currently in development and testing.

Avoid common mistakes on your manuscript.


Pompe disease, also known as glycogen storage disease type II (GSD II) or acid maltase deficiency (AMD), is a genetic disorder caused by a deficiency of the acid alpha-glucosidase (GAA) enzyme, due to recessive mutations in the GAA gene, which leads to accumulation of lysosomal glycogen [ 1 ], diffusely but primarily affecting the skeletal and cardiac muscle tissue. More than 300 different mutations have been described in the GAA gene. The clinical presentation of Pompe disease is a spectrum between the cardiac and skeletal muscle dysfunction and has wide variability. It is divided into two forms which are referred to as infantile onset Pompe disease (IOPD), described by Johannes Pompe in the 1930s and late-onset Pompe disease (LOPD), described by Andrew Engel in 1969 [ 2 , 3 ]. IOPD has more severe cardiac involvement with hypertrophic cardiomyopathy, hypotonia, and respiratory insufficiency and is often fatal within 1 year of age without treatment. LOPD presents primarily as a muscle disease and has a more insidious course. LOPD can have onset anywhere from infancy to late adulthood. It presents with a pattern of symmetric limb-girdle muscle weakness and LOPD was till recently classified additional under the limb-girdle muscular dystrophy umbrella, with a designation of LGMD2V [ 4 ]. However, the revised classification system removed Pompe disease [ 5 •]. It is the severity of the enzyme deficiency that determines which phenotype (IOPD vs. LOPD) will result. Patients with IOPD have a severe or complete GAA deficiency with < 1% residual enzyme activity, whereas LOPD is caused by only a partial deficiency (< 30% residual activity) of GAA [ 6 ].


The traditional estimate of incidence is around 1/40,000 overall [ 7 , 8 ], with about 3/4 of the cases as LOPD and 1/4 as IOPD. Incidence can vary widely among different ethnic groups and has historically been based on retrospective data from carrier frequencies. The populations that appear to be at higher risk include people of African American, Taiwanese, Dutch, and Israeli descent. However, now that newborn screening protocols are being put in place, we are getting more definitive incidence frequencies.

Newborn screening (NBS) from California showed a birth prevalence of 1/25,200 [ 9 •]. NBS in Illinois, Pennsylvania, and Missouri have shown incidences of 1/23,596, 1/16,095, and 1/10,152 respectively [ 10 , 11 , 12 ]. Analysis of NBS data in Japan showed an overall incidence of ~ 1/37,000 from 2013 to 2020 [ 13 ]. Studies from Taiwan have shown birth prevalence rates of 1/26,466 or 1/20,114 for LOPD and 1/67,047 for IOPD [ 14 •, 15 ]. Overall, the incidences from these newer studies for Pompe disease are higher than the previously estimated 1/40,000 as above. For IOPD specifically, the data has been quite variable. The screening data from Japan, California, Pennsylvania, and Illinois has shown IOPD incidence ranging from around 1/200,000 to 1/300,000 [ 9 •, 11 , 12 , 13 ]. However, the incidence rates seen in Taiwan and Missouri are much higher at 1/67,047 and 1/46,700 respectively [ 12 , 15 ]. Further data collected with newborn screening in different parts of the world will be key in gaining a better understanding of the epidemiology of this disease.

The new data does raise an interesting conundrum. If the incidence is indeed so much higher, it approximates the incidence of relatively more common neuromuscular disorders such as facioscapulohumeral muscular dystrophy (FSHD) (1 in 15,000) [ 16 ] and myotonic dystrophy (DM1) (1 in 8000) [ 17 ]. The prevalence of Pompe disease in the Neuromuscular Clinics or the Muscular Dystrophy Association (MDA) clinics is nowhere close to those of FSHD or DM1, which begs the question whether these patients with Pompe disease are misdiagnosed as other musculoskeletal disorders or whether not all mutations have the same penetrance and may not manifest disease?


Acid alpha-glucosidase (GAA) facilitates the breakdown of glycogen to glucose within the lysosomes of cells throughout various tissues in the body [ 6 ]. With a deficiency of this enzyme, as seen in Pompe disease, there is abnormal accumulation of glycogen and progressive expansion of these glycogen-filled lysosomes. The skeletal and cardiac muscle are the most affected. Primary mechanisms of cellular injury are lysosomal rupture and autophagy. In 1970, Engel reported that autophagic function was abnormal in Pompe patients [ 3 ], and more recent mouse models showing accumulation of autophagosomes have supported this idea [ 6 ]. Typically, autophagy works in nutrient poor states by recycling intracellular material to supply amino acids for energy production. Additionally, autophagy helps clear out mis-folded proteins and other intracellular debris [ 6 ]. This process entails autophagosomes forming and collecting intracellular contents, after which they fuse with lysosomes to degrade the collected material. It is thought that this autophagic buildup may work in conjunction with the expanded lysosomes from glycogen build up, and their rupture spilling the contents into the sarcoplasm, to cause dysfunction and injury to muscle [ 6 ].

Diagnostic evaluation

The diagnosis of Pompe disease is ultimately confirmed with enzyme assays and genetic testing. Clinical history, exam, muscle enzymes, and electromyography (EMG) are the core of the initial workup and are used to help determine which patient should undergo further testing specific to Pompe disease, particularly in the setting of LOPD [ 1 ].

A clinical history of a limb-girdle pattern of weakness that is slowly progressive over years is the typical clinical phenotype of LOPD. Respiratory insufficiency is present in the majority of patients [ 18 ]. Examination will show a limb-girdle pattern of weakness with most prominent weakness typically affecting thigh adductors [ 18 ]. This is often accompanied by postural changes such as lumbar lordosis or camptocormia, with scapular winging. Laboratory workup is expected to show an elevated creatine kinase (CK) level in the majority of patients but can be normal. The CK level will typically not be higher than 2000 U/L, and average around 600–700 U/L [ 19 ]. Electromyography will classically show an irritable myopathy affecting the proximal muscles. One key feature often seen in Pompe disease on EMG is myotonic discharges in the paraspinals muscles. The IPANEMA study found that within patients with proximal muscle weakness and elevated CK levels presenting undiagnosed to academic neuromuscular centers, the prevalence of LOPD was 1% [ 20 ••].

More definitive and specific testing for Pompe disease consists of muscle biopsy, enzyme assays, and genetic testing. Muscle biopsy shows vacuolated fibers filled with glycogen as can be seen on PAS or acid phosphatase staining [ 21 ]. Enzyme assays are able to detect a deficiency of acid alpha-glucosidase, as seen in this condition. This can be done on either muscle tissue or blood spot, leukocytes, or fibroblasts [ 22 •, 23 ]. Some would consider enzyme deficiency confirmed on two different sample types to be diagnostic even without muscle biopsy or genetic testing. Lastly, genetic testing with sequencing of the GAA gene to detect mutations is another definitive diagnostic step [ 23 ]. As mentioned above, over 300 different mutations have been identified in the GAA gene. Specific mutations vary between IOPD and LOPD and across different ethnic groups.

It is common for there to be a 12–13-year delay in diagnosis from onset of symptoms for LOPD due to the rarity of the condition and insidious progression. However, IOPD is diagnosed rapidly with the assistance of newborn screening panels. In 2015, Pompe disease was added to the Recommended Uniform Screening Panel (RUSP), and as of January 2021 there were 23 states screening for Pompe disease. The common method used for newborn screening is to start with a blood spot enzyme assay, followed up by genetic sequencing for confirmation if enzyme levels are reduced. One challenge is that the enzyme assays used cannot reliably differentiate between IOPD and LOPD [ 15 ] . Therefore, confirmatory testing with genetic sequencing or other workup (CK, cardiac evaluation) can help determine if a positive blood spot result indicates already symptomatic IOPD necessitating early treatment, or LOPD which may not manifest until years or decades later. If the clinical picture fits IOPD and the assay shows deficiency, treatment will often begin prior to genetic confirmation, which can take weeks to result.

Diagnostic challenges

A challenging situation arises when LOPD is diagnosed genetically at birth with newborn screening panels before any symptoms are present. This occurs often because LOPD is much more common than IOPD and LOPD accounts for 75% of all cases of Pompe disease diagnosed through NBS. At this time, there is no clear consensus on how to manage these patients and the guidelines, developed primarily by a group of metabolic geneticists without much neurology input [ 24 ], are not uniformly enforced. Many of these kids will not manifest any symptoms until their teenage years or much later. It is not known if early treatment can have any prophylactic effect to delay or prevent symptoms, or if we should wait until symptom onset or laboratory abnormalities arise to initiate treatment. Further, insurance companies generally do not reimburse for asymptomatic checks or care, so it is not clear who is supposed to pay for these routine surveillance visits. There is a desperate need for sensitive biomarkers. In addition to serum CK levels and urinary excretion of tetrasaccharides (Hex4), an interesting potential biomarker is MR spectroscopy that can assess glycogen levels in tissue, and has been demonstrated to be useful in quantifying hepatic and muscle glycogen in glycogen storage diseases and other metabolic conditions [ 25 , 26 , 27 ]. This or other advanced imaging techniques could serve as non-invasive methods of early disease detection in these asymptomatic LOPD cases to determine when to initiate treatment.

The knowledge of the diagnosis, in individuals without symptoms or functional loss, may cause anxiety or depression and unnecessary modifications to their lifestyles as well as unnecessary treatments. This is an area of Pompe disease that needs much more study. The optimal time to initiate ERT is not settled and adds to the complexity of managing pre-symptomatic or asymptomatic patients.

Another major challenge relates to diagnosis of Pompe disease is GAA pseudodeficiency. There are haplotypes of the GAA gene that cause GAA pseudodeficiency, which shows up as low enzyme activity on assays but does not have any clinical effects or lead to symptomatic disease. Using enzyme assays in isolation can lead to many false-positives in the initial screening steps. Therefore, it is important to follow up with genetic testing in these cases, to detect the pseudodeficiency haplotypes, which presents often as homozygous for the c.[1726A; 2065A] pseudodeficiency allele [ 28 ]. This genotype appears to be more common than Pompe disease. In Illinois, the birth prevalence of pseudodeficiency was 1/17,546, in Missouri it was 1/8811, in California it was 1/22,658, and in Pennsylvania it was 1/35,409 [ 9 •, 10 , 11 , 12 ]. Other countries have shown even higher rates of pseudodeficiency such as 1/1368 in Taiwan and 1/8747 in Japan [ 13 , 15 ]. The IPANEMA study showed a prevalence of 1% for both LOPD and pseudodeficiency alleles in that population [ 20 ••].

Supportive care/complications

In Pompe disease, in addition to the disease-modifying treatments, overall management of this condition requires symptomatic management and screening for complications, particularly in LOPD, preferably through a multidisciplinary clinic allowing a team of allied health care professionals, including physical therapy, speech therapy, respiratory therapy, dieticians, and genetic counselors, ensuring that all aspects of patient care are being addressed. Additionally, coordination and communication between different medical teams such as neurology, genetics, pulmonology, gastroenterology, and cardiology can be crucial for proper management.

Light exercise or aerobic exercise such as swimming is very beneficial in maintaining mobility and functionality. The goal is to stay active and exercise as able without inducing muscle soreness or prolonged recovery times after activity.

The two most life-threatening complications of LOPD are related to respiratory and cardiac dysfunction. Patients should undergo routine pulmonary function testing to determine their degree of respiratory insufficiency related to diaphragm weakness. When a patient’s forced vital capacity (FVC) approximates 50% predicted, it is advised to initiate non-invasive ventilation (NIV) with a positive airway pressure respiratory assist devices that help support the diaphragm function. Without this supportive treatment, patients continue to have sleep disordered breathing and may begin to retain CO 2 chronically, leading to headaches, daytime sleepiness, and lack of energy. There should be a low threshold to order polysomnographic studies to monitor for it. It has been shown that NIV can improve survival and quality of life [ 29 ]. Cardiac management is crucial in IOPD, but cardiac dysfunction is less common in LOPD [ 30 ]. It is important to screen patients regularly for cardiac hypertrophy or conduction abnormalities.

An understudied area in the management of LOPD is in regard to vascular malformations, which appear to be quite common in this disease, with 60% of LOPD patients showing intracranial arterial abnormalities, such as vertebrobasilar dolichoectasia and unruptured aneurysms [ 31 , 32 ]. These types of malformations could place patients at risk for strokes, compression, or hemorrhage in severe cases. However, there are no guidelines regarding monitoring for these complications, as well as other complications, in Pompe disease [ 33 ].

Disease-modifying therapies

The treatment of Pompe disease has mainly been targeted at correction of the underlying GAA deficiency. This has included trying to supplement the enzyme in various ways, and gene therapy allowing endogenous production of the GAA enzyme.

Currently available treatments

Enzyme replacement therapy (ERT) is given as human recombinant GAA (rhGAA) has been used in Pompe disease as early as the 1970s primarily studied initially for IOPD [ 34 , 35 ]. A randomized controlled trial in 2006 for IOPD ultimately led to FDA approval of rhGAA [ 36 ] for all forms of Pompe disease. The study in 2006 was done in IOPD and showed that ERT improved overall survival and ventilator-free survival in patients [ 37 ], and suggested earlier intervention provided greater benefit. Significant reduction in left ventricular hypertrophy was seen in all surviving patients in this study as well. Despite these clear benefits seen in early life, long-term follow up of IOPD patients still shows significant morbidity and mortality and requires further study [ 38 ]. While ERT has allowed these patients to survive cardiac and respiratory effects into childhood and often achieve independent walking, many of them start to experience decline in skeletal muscle strength years later and develop cardiac arrhythmias even when cardiac hypertrophy has been avoided or reduced with ERT. Additionally, these IOPD that survive into childhood with ERT go on to develop other problems including hearing loss, speech dysfunction, cognitive impairment, and GI as well as respiratory dysfunction [ 39 ]. There is an unmet need for management of these patients.

With the publication of the LOTS data in 2010, enzyme replacement therapy with alglucosidase alfa in LOPD was shown to improve or at least slow the decline of ambulation, arm and leg function, and respiratory function [ 39 ]. However, the effectiveness seems to wear off after 2–3 years and patients return to their slow decline [ 40 •, 41 ]. Because of this lack of a sustained response to alglucosidase alfa, more recently two new forms of enzyme replacement therapy were developed and tested in clinical trials to meet the unmet need in Pompe Disease. These new iterations of ERT, avalglucosidase alfa and cipaglucosidase alfa plus miglustat, were compared to alglucosidase alfa (the standard of care) in the COMET and PROPEL trials, both published in December 2021 [ 42 ••, 43 ••]. Avalglucosidase alfa (COMET trial) is a form of rhGAA that is designed with enhanced targeting of mannose-6-phosphate receptors, through chemical conjugation of synthetic linkers, to increase the uptake of rhGAA into cells on the target tissues [ 42 ••]. The PROPEL trial examined a two-component therapy that included cipaglucosidase alfa, an rhGAA with enhanced glycosylation for improved cellular uptake, through clonal selection of rhGAA with CHO-cell derived M6P and bis-M6P moieties, and miglustat, a stabilizer of the cipaglucosidase alfa molecule, which prolongs half-life and increases distribution [ 43 ••]. Both new forms of ERT were shown to be non-inferior to alglucosidase alfa and did not meet the pre-specified criteria for superiority compared to alglucosidase alfa [ 42 ••, 43 ••]. At this point, we do not have the long term data on these new agents to see how they will fare after 2–3 years of treatment (Table  1 ).

Treatments under investigation

Newer treatments under development or under investigation are depicted in Table  2 and shown graphically in Fig.  1 .

figure 1

A schematic for the mechanism of action within the cell (liver or skeletal muscle) for the current and upcoming therapies in Pompe Disease. (1) Enzyme replacement treatments with enhancement in the enzyme through modifications that allow better delivery into muscle either through the mannose-6-phosphate receptors (MPR), IGF-II receptor or binding through a monoclonal antibody to CD63 conjugated with the enzyme; (2) delivery of full GAA gene through gene delivery using a viral (AAV or Lentiviral) vector, with either liver or muscle targeting; (3) enzyme stabilization to allow more of the enzyme to remain intact, and the catalytic activity protected from degradation; and (4) substrate reduction strategy, primarily targeted to glycogen synthetase using either small molecule or genetic manipulation.

Enhancements in enzyme replacement strategies

Alternate enzyme replacement strategies have been tried or being developed. A recent trial of a new glycosylation-independent lysosomal targeting (GILT)-tagged ERT that utilized the IGF-II receptors in skeletal muscles to allow entry of the enzyme into the muscles was undertaken but was terminated early due to development of significant symptomatic hypoglycemia [ 33 ]. Newer approaches include a combination of gene therapy to target the liver and using monoclonal antibody (to CD63 or ITGA7)-conjugates with the enzyme to allow for targeted entry into skeletal muscles [ 44 •]. Another effort to show improvement in ERT delivery through an antibody-enzyme fusion product showed safety and tolerability, but the program was discontinued due to lack of funding [ 45 •].

  • Gene therapy

Gene therapy is a very exciting treatment modality on the horizon for Pompe disease. Through a one-time treatment of the transgene that would then endogenously produce the enzyme, this would obviate the need for chronic ERT therapy biweekly. While majority of the gene therapies use adeno-associated virus vectors (AAV) [ 46 ] for a one-time delivery of a non-integrating vector carrying the transgene, one group is proposing use of lentivirus-driven correction of autologous hematopoietic stems cells and reinfusion of cells. The gene therapy approaches differ as well with trials using a liver-directed approach vs. a muscle-directed approach.

For liver-directed therapy, treatment would consist of a one-time intravenous (IV) infusion of the AAV-packaged transgene, which would be delivered into the nucleus of liver cells and would begin to produce the therapeutic protein; in this case GAA, in a sustainable fashion. This would create liver depot for GAA production and the secretable GAA released into the bloodstream and available for delivery to skeletal and cardiac muscle tissues. This approach takes advantage of the high tropism of AAV vectors for hepatic cells, requiring lower vector dose. Further, proteins produced in the liver appear to be immunologically privileged. This form of gene therapy is currently under investigation in phase 1/2a trials (NCT04093349 and NCT03533673). There have been no major safety signals and preclinical findings have shown promising results of reduced glycogen accumulation in skeletal and cardiac tissue and improvement of muscle function [ 47 , 48 ]. However, with all the AAV approaches, there still remain safety concerns related to capsid-related hepatotoxicity as well as development of neutralizing antibodies to the capsid. Currently, individuals who have pre-existing antibodies to AAV are excluded from participation due to concerns for premature neutralization of the capsid and the transgene.

The muscle approach is another exciting opportunity, either intravenous approach with muscle targeting or direct intramuscular approach. With either path, the GAA transgene would be delivered to muscle cells, and begin to produce a functional GAA enzyme to mitigate lysosomal glycogen accumulation in those cells. An ongoing trial uses a skeletal muscle targeting approach, given as an IV infusion using AAV vector with muscle-specific serotype and promoters (NCT04174105). As only 1% of enzyme produced in the liver actually makes it into the target organs (skeletal and cardiac muscle), muscle-directed AAV therapy resolves this problem. The IV delivery method of muscle-directed therapy would aim to deliver the AAV vector systemically to all muscle tissue, but would require a much higher vector dose, which may increase the likelihood of anti-GAA antibodies developing and interfering with the therapeutic effect as well as hepatotoxicity and cardiomyopathy. Preclinical data for muscle-directed IV therapy has been positive in showing substantial clearance of lysosomal glycogen in skeletal and cardiac muscle tissue in mice [ 49 ]. Another approach consists of direct intramuscular (IM) injection to deliver the vector directly to muscle fibers. One advantage of the IM therapy is that certain muscles that are more affected could be targeted, such as the diaphragm, allowing for more flexibility and specificity of treatment. However, this is also a disadvantage in that the positive effects appear to be quite local at the site of injection, which may suggest the need for multiple injections at different sites and potentially a higher risk for antibody development. Preclinical data for this muscle-directed IM therapy has been encouraging in showing success of intralingual and intradiaphragmatic injection in mice [ 50 , 51 •]. Overall gene therapy treatment options are a very exciting area of on-going research and show great promise for more definitive long-term treatment of Pompe disease.

Another approach being considered is an intrathecal or intraventricular approach to maximize delivery into the CNS, especially for IOPD cases, where the burden of disease, in addition to the cardiac muscles, is maximal in motor neuron cells.

Finally, an antisense approach to improve the IVS splicing in Pompe disease was discussed by the Erasmus group at an international meeting (Nadine van der Beek—personal communication). This offers a promising approach to improve enzyme production through mitigation of the most common genetic abnormality in Caucasian patients with Pompe disease.

Glycogen reduction strategies

Alternative strategy of substrate (glycogen) reduction is being studied with the aim of reducing the amount of glycogen in cells, either through small molecules, currently in phase 1 in healthy individuals (NCT05249621), or through genetic approaches [ 52 , 53 , 54 •], thus delaying the onset of symptoms from Pompe disease. This treatment can be used either alone or as an adjunct to the ERT. This approach would also be applicable for other glycogen storage disorders, and may be particularly attractive for delaying disease in at-risk asymptomatic individuals.

Unmet needs

Unmet needs in clinical care as well as in research are described in Table  1 . In addition to the need to improve diagnostic times and diagnosing these patients earlier, before the burden of disease becomes large, and the muscles accrue irreversible damage, there are research unmet needs related to inadequacies of the current available treatments. Additionally, the current outcome measures used in quantifying disease burden, monitoring disease progression, and to quantify treatment-related outcomes are woefully inadequately. Six-minute walk test, traditionally used in this disease unfortunately, is not sensitive enough especially in younger individuals and subject to training effects. Forced vital capacity does not change till much later in the disease and is not a direct measure of diaphragmatic strength. There is a desperate need to develop newer and more sensitive outcome measures and biomarkers in this disease. There has been considerable work that is being done to validate magnetic resonance imaging (MRI) as an outcome measure. There are new strategies to develop MR-spectroscopy as an outcome measure, since it has the potential to assess glycogen burden in muscles non-invasively.

Pompe disease is a heterogeneous disorder with bimodal presentation. Enzyme replacement therapy is currently the mainstay of treatment for all forms of Pompe disease but the current therapies have significant unmet needs. ERT improves overall survival, ventilator free survival, and cardiac function in infantile cases, and stabilizes mobility and skeletal and respiratory muscle strengths in adult. However, after 2–3 years, ERT begins to lose effectiveness and patients continue to decline. Two new ERT treatments were showed to be non-inferior to the existing standard of care but could not establish superiority, and it is not clear if these treatments would lose effectiveness in a few years. There are significant unmet needs in terms of lack of guidance on management of LOPD patients diagnosed at birth, potentially long before the disease will manifest any symptoms. Similarly optimal outcome measures to measure clinical phenotype, progress, and treatment outcomes need to be defined. Newer promising treatments with liver-directed and muscle-directed gene therapies are in clinical trials, and these if they are effective, would result provide long-lasting therapy with only a single necessary treatment, creating endogenous production of the GAA enzyme to correct the underlying deficiency and cardiac and skeletal muscle pathology. Additional development include newer enhanced forms of ERT as well as substrate (glycogen) reduction strategies, which are about to enter clinical trials for LOPD. In addition to the current and upcoming therapies, there remains a need for a multidisciplinary approach and more wholistic approach to care of patients with Pompe disease.

References and Recommended Readings

Papers of particular interest, published recently, have been highlighted as: • of importance •• of major importance.

van der Ploeg AT, Reuser AJ. Pompe’s disease. Lancet. 2008;372(9646):1342–53.

Article   PubMed   CAS   Google Scholar  

Engel AG. Acid maltase deficiency of adult life. Trans Am Neurol Assoc. 1969;94(250–2).

Engel AG. Acid maltase deficiency in adults: studies in four cases of a syndrome which may mimic muscular dystrophy or other myopathies. Brain. 1970;93(3):599–616.

Nigro V, Aurino S, Piluso G. Limb girdle muscular dystrophies: update on genetic diagnosis and therapeutic approaches. Curr Opin Neurol. 2011;24(5):429–36.

• Straub V, Murphy A and Udd B. 229th ENMC international workshop: Limb girdle muscular dystrophies - Nomenclature and reformed classification Naarden, the Netherlands, 17–19 March 2017. Neuromuscul Disord. 2018;28(8):702–10. An importance paper that redefines the classification of limb-girdle muscular dystrophies. A number of previously classified limb-girdle muscular dystrophies (LGMD) were removed from the classification because the muscle biopsies were not dystrophic or there were only small number of families defined previously. Pompe disease, that was previously classified as LGMD was removed.

Lim JA, Li L, Raben N. Pompe disease: from pathophysiology to therapy and back again. Front Aging Neurosci. 2014;6:177.

Article   PubMed   PubMed Central   CAS   Google Scholar  

Ausems MG, Verbiest J, Hermans MP, Kroos MA, Beemer FA, Wokke JH, et al. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet. 1999;7(6):713–6.

Martiniuk F, Chen A, Mack A, Arvanitopoulos E, Chen Y, Rom WN, et al. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Genet. 1998;79(1):69–72.

• Tang H, Feuchtbaum L, Sciortino S, Matteson J, Mathur D, Bishop T, et al. The first year experience of newborn screening for Pompe disease in California. Int J Neonatal Screen. 2020;6(1):9. The experience from California, the largest state in the United States, about newborn screening for Pompe disease, with appreciably higher incidence of Pompe disease and pseudodeficiency.

Burton BK, Charrow J, Hoganson GE, Fleischer J, Grange DK, Braddock SR, et al. Newborn screening for Pompe disease in Illinois: experience with 684,290 infants. Int J Neonatal Screen. 2020;6(1):4.

Article   PubMed   PubMed Central   Google Scholar  

Ficicioglu C, Ahrens-Nicklas RC, Barch J, Cuddapah SR, DiBoscio BS, DiPerna JC, et al. Newborn screening for Pompe disease: Pennsylvania experience. Int J Neonatal Screen. 2020;6(4):89.

Article   PubMed Central   Google Scholar  

Klug TL, Swartz LB, Washburn J, Brannen C, Kiesling JL. Lessons learned from Pompe disease newborn screening and follow-up. Int J Neonatal Screen. 2020;6(1):11.

Sawada T, Kido J, Sugawara K, Momosaki K, Yoshida S, Kojima-Ishii K, et al. Current status of newborn screening for Pompe disease in Japan. Orphanet J Rare Dis. 2021;16(1):516.

• Chien YH, Lee NC, Huang HJ, Thurberg BL, Tsai FJ and Hwu WL. Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. J Pediatr. 2011;158(6):1023–27.e1. This paper details the efforts made by investigators in Taiwan to introduce NBS for a number of lysosomal disorders, including Pompe Disease. Taiwan was the first country in the world to introduce NBS for Pompe Disease and had to contend with issues with false positives from pseudodeficiency, that has a much higher prevalence in South East Asian populations.

Yang CF, Liu HC, Hsu TR, Tsai FC, Chiang SF, Chiang CC, et al. A large-scale nationwide newborn screening program for Pompe disease in Taiwan: towards effective diagnosis and treatment. Am J Med Genet A. 2014;164a(1):54–61.

Deenen JC, Horlings CG, Verschuuren JJ, Verbeek AL, van Engelen BG. The epidemiology of neuromuscular disorders: a comprehensive overview of the literature. J Neuromuscul Dis. 2015;2(1):73–85.

Article   PubMed   Google Scholar  

Johnson NE. Myotonic Muscular Dystrophies. Continuum (Minneap Minn). 2019;25(6):1682–95.

Google Scholar  

Hagemans ML, Winkel LP, Van Doorn PA, Hop WJ, Loonen MC, Reuser AJ, et al. Clinical manifestation and natural course of late-onset Pompe’s disease in 54 Dutch patients. Brain. 2005;128(Pt 3):671–7.

Herzog A, Hartung R, Reuser AJ, Hermanns P, Runz H, Karabul N, et al. A cross-sectional single-centre study on the spectrum of Pompe disease, German patients: molecular analysis of the GAA gene, manifestation and genotype-phenotype correlations. Orphanet J Rare Dis. 2012;7:35.

•• Wencel M, Shaibani A, Goyal NA, Dimachkie MM, Trivedi J, Johnson NE, et al. Investigating Pompe Prevalence in Neuromuscular Medicine Academic Practices (The IPaNeMA Study) Neurology: Genetics. 2021;7:e623. A well-designed investigator-initiated study that assessed the prevalence of Pompe Disease in a consortium of academic/tertiary neuromuscular neurology practices. It found the prevalence of LOPD to be 1% but another 1% of patients were found to have pseudodeficiency.

Werneck LC, Lorenzoni PJ, Kay CS, Scola RH. Muscle biopsy in Pompe disease. Arq Neuropsiquiatr. 2013;71(5):284–9.

• Niño MY, Wijgerde M, de Faria DOS, Hoogeveen-Westerveld M, Bergsma AJ, Broeders M, et al. Enzymatic diagnosis of Pompe disease: lessons from 28 years of experience. Eur J Hum Genet. 2021;29(3):434–46. A nice paper describing the collective experiences from diagnosis of Pompe disease using enzymatic assays.

Ausems MG, Lochman P, van Diggelen OP, Ploos van Amstel HK, Reuser AJ and Wokke JH. A diagnostic protocol for adult-onset glycogen storage disease type II. Neurology. 1999;52(4):851–3.

Kronn DF, Day-Salvatore D, Hwu WL, Jones SA, Nakamura K, Okuyama T, et al. Management of confirmed newborn-screened patients with Pompe disease across the disease spectrum. Pediatrics. 2017;140(Suppl 1):S24–45.

Buehler T, Bally L, Dokumaci AS, Stettler C, Boesch C. Methodological and physiological test-retest reliability of (13) C-MRS glycogen measurements in liver and in skeletal muscle of patients with type 1 diabetes and matched healthy controls. NMR Biomed. 2016;29(6):796–805.

Heinicke K, Dimitrov IE, Romain N, Cheshkov S, Ren J, Malloy CR, et al. Reproducibility and absolute quantification of muscle glycogen in patients with glycogen storage disease by 13C NMR spectroscopy at 7 Tesla. PLoS ONE. 2014;9(10): e108706.

Wary C, Laforêt P, Eymard B, Fardeau M, Leroy-Willig A, Bassez G, et al. Evaluation of muscle glycogen content by 13C NMR spectroscopy in adult-onset acid maltase deficiency. Neuromuscul Disord. 2003;13(7–8):545–53.

Labrousse P, Chien YH, Pomponio RJ, Keutzer J, Lee NC, Akmaev VR, et al. Genetic heterozygosity and pseudodeficiency in the Pompe disease newborn screening pilot program. Mol Genet Metab. 2010;99(4):379–83.

Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol. 2006;5(2):140–7.

Forsha D, Li JS, Smith PB, van der Ploeg AT, Kishnani P, Pasquali SK. Cardiovascular abnormalities in late-onset Pompe disease and response to enzyme replacement therapy. Genet Med. 2011;13(7):625–31.

Montagnese F, Granata F, Musumeci O, Rodolico C, Mondello S, Barca E, et al. Intracranial arterial abnormalities in patients with late onset Pompe disease (LOPD). J Inherit Metab Dis. 2016;39(3):391–8.

Pichiecchio A, Sacco S, De Filippi P, Caverzasi E, Ravaglia S, Bastianello S, et al. Late-onset Pompe disease: a genetic-radiological correlation on cerebral vascular anomalies. J Neurol. 2017;264(10):2110–8.

Chan J, Desai AK, Kazi ZB, Corey K, Austin S, Hobson-Webb LD, et al. The emerging phenotype of late-onset Pompe disease: a systematic literature review. Mol Genet Metab. 2017;120(3):163–72.

Amalfitano A, Bengur AR, Morse RP, Majure JM, Case LE, Veerling DL, et al. Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial. Genet Med. 2001;3(2):132–8.

PubMed   CAS   Google Scholar  

Van den Hout H, Reuser AJ, Vulto AG, Loonen MC, Cromme-Dijkhuis A, Van der Ploeg AT. Recombinant human alpha-glucosidase from rabbit milk in Pompe patients. Lancet. 2000;356(9227):397–8.

Kishnani PS, Nicolino M, Voit T, Rogers RC, Tsai AC, Waterson J, et al. Chinese hamster ovary cell-derived recombinant human acid alpha-glucosidase in infantile-onset Pompe disease. J Pediatr. 2006;149(1):89–97.

Kishnani PS, Corzo D, Nicolino M, Byrne B, Mandel H, Hwu WL, et al. Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology. 2007;68(2):99–109.

Hahn A, Schänzer A. Long-term outcome and unmet needs in infantile-onset Pompe disease. Ann Transl Med. 2019;7(13):283.

Kishnani PS, Steiner RD, Bali D, Berger K, Byrne BJ, Case LE, et al. Pompe disease diagnosis and management guideline. Genet Med. 2006;8(5):267–88.

• Harlaar L, Hogrel JY, Perniconi B, Kruijshaar ME, Rizopoulos D, Taouagh N, et al. Large variation in effects during 10 years of enzyme therapy in adults with Pompe disease. Neurology. 2019;93(19):e1756-e1767. This paper critically analyzes the long term experience with enzyme replacement therapy and how the treatment loses its benefit over a period of years, often starting at 36 months. The loss of benefits was across the board in all functional elements.

Papadimas GK, Anagnostopoulos C, Xirou S, Michelakakis H, Terzis G, Mavridou I, et al. Effect of long term enzyme replacement therapy in late onset Pompe disease: a single-centre experience. Neuromuscul Disord. 2021;31(2):91–100.

•• Diaz-Manera J, Kishnani PS, Kushlaf H, Ladha S, Mozaffar T, Straub V, et al. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial. Lancet Neurol. 2021;20(12):1012–26. This paper reports the results of the Phase 3 randomized controlled trial of avalglucosidase alfa vs. alglucosidase alfa in treatment naive patients with LOPD. This was a true head-to-head comparison of avalglucosidase alfa, a newly designed ERT, with more M6P moeities, to alglucosidase alfa, the standard of care in LOPD since 2010. The results show that avalglucosidase alfa was non-inferior to alglucosidase alfa, but there were trends in some outcome measures that showed avalglucosidase alfa to be significantly better than alglucosidase alfa. This resulted in FDA approval of avalglucosidase alfa for treatment of all forms of Pompe Disease in 2021.

•• Schoser B, Roberts M, Byrne BJ, Sitaraman S, Jiang H, Laforêt P, et al. Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial. Lancet Neurol. 2021;20(12):1027–37. This paper reports the results of the Phase 3 randomized controlled trial of cipaglucosidase alfa in combination with miglustat, a stabilizer of the enzyme, vs. alglucosidase alfa and a placebo in treatment naive patients with LOPD. This was comparison of cipaglucosidase alfa, a newly designed ERT with through clonal selection of rhGAA with CHO-cell derived M6P and bis-M6P moieties, to alglucosidase alfa, the standard of care in LOPD since 2010. The results show that avalglucosidase alfa was non-inferior to alglucosidase alfa, but there were trends in some outcome measures that showed cipaglucosidase alfa to be significantly better than alglucosidase alfa. This new drug will go up for FDA review in Fall 2022.

• Baik AD, Calafati P, Zhang X, Aaron NA, Mehra A, Moller-Tank S, et al. Cell type-selective targeted delivery of a recombinant lysosomal enzyme for enzyme therapies. Mol Ther. 2021;29(12):3512–24. A very interesting paper that describes a two-step process being developed by Regeneron for treatment of Pompe Disease. They also use a gene therapy approach to create a liver-depot to create endogenous supply of these ERT that are conjugated with monoclonal antibodies to CD63 and ITGA7 to ensure maximal delivery to muscle and cardiac tissue.

• Zhou Z, Austin GL, Shaffer R, Armstrong DD, Gentry MS. Antibody-mediated enzyme therapeutics and applications in glycogen storage diseases. Trends Mol Med. 2019;25(12):1094–109. A good review of new efforts to develop enzyme replacement therapies conjugated with monoclonal antibodies to allow better delivery to skeletal muscle and cardiac tissue.

Ronzitti G, Collaud F, Laforet P, Mingozzi F. Progress and challenges of gene therapy for Pompe disease. Ann Transl Med. 2019;7(13):287.

Ding E, Hu H, Hodges BL, Migone F, Serra D, Xu F, et al. Efficacy of gene therapy for a prototypical lysosomal storage disease (GSD-II) is critically dependent on vector dose, transgene promoter, and the tissues targeted for vector transduction. Mol Ther. 2002;5(4):436–46.

Kishnani PS, Koeberl DD. Liver depot gene therapy for Pompe disease. Ann Transl Med. 2019;7(13):288.

Eggers M, Vannoy CH, Huang J, Purushothaman P, Brassard J, Fonck C, et al. Muscle-directed gene therapy corrects Pompe disease and uncovers species-specific GAA immunogenicity. EMBO Mol Med. 2022;14(1): e13968.

Salabarria SM, Nair J, Clement N, Smith BK, Raben N, Fuller DD, et al. Advancements in AAV-mediated gene therapy for Pompe disease. J Neuromuscul Dis. 2020;7(1):15–31.

• Smith BK, Collins SW, Conlon TJ, Mah CS, Lawson LA, Martin AD, et al. Phase I/II trial of adeno-associated virus-mediated alpha-glucosidase gene therapy to the diaphragm for chronic respiratory failure in Pompe disease: initial safety and ventilatory outcomes. Hum Gene Ther. 2013;24(6):630–40 This seminal paper details the development of gene therapy that could be delivered intramuscularly to different skeletal muscles in infantile and late-onset Pompe Disease, including laparoscopic injections into the diaphragm. The paper also discusses the initial experiences with this construct.

Clayton NP, Nelson CA, Weeden T, Taylor KM, Moreland RJ, Scheule RK, et al. Antisense oligonucleotide-mediated suppression of muscle glycogen synthase 1 synthesis as an approach for substrate reduction therapy of Pompe disease. Mol Ther Nucleic Acids. 2014;3(10): e206.

Douillard-Guilloux G, Raben N, Takikita S, Ferry A, Vignaud A, Guillet-Deniau I, et al. Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease. Hum Mol Genet. 2010;19(4):684–96.

• Tang B, Frasinyuk MS, Chikwana VM, Mahalingan KK, Morgan CA, Segvich DM, et al. Discovery and development of small-molecule inhibitors of glycogen synthase. J Med Chem. 2020;63(7):3538–51. This paper focuses on the development of new strategy of substrate reduction in Lysosomal Disorders, especially Pompe Disease. This paper mainly covers development of small-molecules that can inhibit Glycogen Synthetase. The implications are huge, as these treatments may be used not only as adjunctive therapy to existing enzyme replacement therapies in Lysosomal Disorders, but may potentially be used in at-risk asymptomatic individuals who carry mutations in genes responsible for Glycogen Storage disorders.

Download references


The authors acknowledge Nita Chen, MD for her help with creating the illustration used as Fig.  1 .

Author information

Authors and affiliations.

Departments of Neurology, 200 S. Manchester Avenue, Ste. 206, Orange, CA, 92868, USA

David Stevens MD, Shadi Milani-Nejad DO & Tahseen Mozaffar MD

Pathology & Laboratory Medicine, School of Medicine, University of California, Irvine, USA

Tahseen Mozaffar MD

The Institute for Immunology, School of Medicine, University of California, Irvine, USA

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Tahseen Mozaffar MD .

Ethics declarations

Conflict of interest.

Drs. Stevens and Milani declare that they have no financial interests. Dr. Mozaffar discloses an advisory role for and/or receiving research funds from Alexion, Amicus, Argenx, Arvinas, Audentes, AvroBio, Horizon Therapeutics, Immunovant, Maze Therapeutics, Momenta (now Janssen), Sanofi-Genzyme, Sarepta, Spark Therapeutics, UCB, and Modis/Zogenix. Dr. Mozaffar also serves on the data safety monitoring board for Acceleron, Avexis, and Sarepta.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Neuromuscular Disorders

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and Permissions

About this article

Stevens, D., Milani-Nejad, S. & Mozaffar, T. Pompe Disease: a Clinical, Diagnostic, and Therapeutic Overview. Curr Treat Options Neurol 24 , 573–588 (2022). https://doi.org/10.1007/s11940-022-00736-1

Download citation

Accepted : 21 July 2022

Published : 04 August 2022

Issue Date : November 2022

DOI : https://doi.org/10.1007/s11940-022-00736-1

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

  • Pompe disease
  • Glycogen storage disease II (GSDII)
  • Acid maltase deficiency
  • Alpha-glucosidase deficiency
  • Enzyme replacement therapy


  • Find a journal
  • Publish with us

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • View all journals
  • My Account Login
  • Explore content
  • About the journal
  • Publish with us
  • Sign up for alerts
  • Open access
  • Published: 29 March 2021

Clinical and genetic spectrum of glycogen storage disease in Iranian population using targeted gene sequencing

  • Zahra Beyzaei 1 ,
  • Fatih Ezgu 2 ,
  • Bita Geramizadeh 1 , 3 ,
  • Mohammad Hadi Imanieh 4 ,
  • Mahmood Haghighat 4 ,
  • Seyed Mohsen Dehghani 4 ,
  • Naser Honar 4 ,
  • Mojgan Zahmatkeshan 4 , 5 ,
  • Amirreza Jassbi 6 ,
  • Marjan Mahboubifar 6 &
  • Alireza Alborzi 7  

Scientific Reports volume  11 , Article number:  7040 ( 2021 ) Cite this article

2930 Accesses

8 Citations

Metrics details

  • Medical research
  • Molecular medicine

An Author Correction to this article was published on 26 July 2021

This article has been updated

Glycogen storage diseases (GSDs) are known as complex disorders with overlapping manifestations. These features also preclude a specific clinical diagnosis, requiring more accurate paraclinical tests. To evaluate the patients with particular diagnosis features characterizing GSD, an observational retrospective case study was designed by performing a targeted gene sequencing (TGS) for accurate subtyping. A total of the 14 pediatric patients were admitted to our hospital and referred for molecular genetic testing using TGS. Seven genes namely SLC37A4 , AGL , GBE1 , PYGL , PHKB , PGAM2 , and PRKAG2 were detected to be responsible for the onset of the clinical symptoms. A total number of 15 variants were identified i.e. mostly loss-of-function (LoF) variants, of which 10 variants were novel. Finally, diagnosis of GSD types Ib, III, IV, VI, IXb, IXc, X, and GSD of the heart, lethal congenital was made in 13 out of the 14 patients. Notably, GSD-IX and GSD of the heart-lethal congenital (i.e. PRKAG2 deficiency) patients have been reported in Iran for the first time which shown the development of liver cirrhosis with novel variants. These results showed that TGS, in combination with clinical, biochemical, and pathological hallmarks, could provide accurate and high-throughput results for diagnosing and sub-typing GSD and related diseases.


Glycogen storage diseases (GSDs) are known as a group of disorders characterized by genetic errors leading to accumulation of glycogen in various tissues 1 . All the main types of GSD that are currently recognized primarily affect the liver and/or muscles as the main organs of involvement 2 . However, accurate identification of the sub-types of GSDs, especially hepatic forms, is not an easy task for clinicians and pathologists because of their similar and overlapping features as well as wide phenotypic variations 3 .

It is known that early diagnosis is important for proper treatment of patients to decrease organ damage and to increase life expectancy 4 . The diagnosis of GSDs mostly depends on paraclinical, clinical and biochemical assays 5 . Molecular analysis, based on DNA testing, similarly permits accurate diagnosis when enzymological and pathological results are equivocal or unavailable 6 . Identification of GSD patients’ genetic background along with mutation screening can provide the best approach to diagnosis and classification 7 .

NGS has been applied in clinical diagnostics for a diversity of symptoms to characterize the inherent genetic cause of diseases 8 . Although single-gene testing and gene panels for specific disorders are still being used, NGS is progressively being utilized in diagnostic evaluation, especially for disorders that are genetically heterogeneous, such as GSDs 9 , 10 . Currently, targeted gene sequencing (TGS) panels have gained popularity for heterogeneous genetic anomalies in monogenic disorders (MDs) because of their time- and cost-effectiveness as well as their ability in simultaneous detection of common and rare genetic variations 11 . According to the aforementioned background, the present study aimed to identify the genetic background of GSDs in a small sample of Iranian patients by using targeted gene sequencing (TGS) to search for molecular etiology. To the best of our knowledge, this is the first study from Iran.

Demographic characteristics of the patients

A total number of 14 pediatric patients were recruited in this retrospective observational case study. There were particular diagnosis features leading to their selection as GSD patients. Among them, six cases (42.8%) were male and eight (57.2%) were female. Parents of 13 patients (86.7%) were consanguineous, five of them with a family history of liver diseases from early infancy. The mean age of the disease onset was 14.1 months (range: 1–35) and average delay to establish an accurate diagnosis was 33.4 months (range: 14–51). Short stature (< 3%) was also observed in eight patients. High triglyceride (TG), total cholesterol (TChol), and lactate dehydrogenase (LDH) were observed in nine (64%), nine (64%), and eight patients (57%), respectively. High creatine phosphokinase (CPK) and platelet count was detected in five patients (36%) and low uric acid was observed in one patient (7%). High blood urea nitrogen (BUN)/creatinine ratio (BCR) was additionally detected in eight patients (57%). Elevated liver enzymes, i.e., aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hepatomegaly, were observed in all patients except one. All clinical manifestations are summarized in Table 1 .

Targeted gene sequencing (TGS) data

In order to identify the molecular etiology, TGS was performed using the patients’ peripheral blood. A total of 450 genes of inherited metabolic diseases were included in this panel. All coding regions for the 450 genes were enriched in an unbiased fashion, with sufficient coverage. The analysis was successful with 100% reads on target, 100 × coverage of 99.99% and 20 × coverage of 99.99%. Mean coverage of the targeted regions was 144 × per sample, (ranged: 116 × to 178 ×). Each patient showed an average 1200 sequence variants. All the variants were identified by TGS, confirmed by Sanger sequencing for each patient (Supplementary Table 1 ). Both the sensitivity and the specificity for base calls were 100% for the comparison with the results of Sanger sequencing of the same set of samples. Finally, the results showed to be concordant in terms of zygosity.

Genomic diagnostic results

Diagnoses and zygosity of the 14 patients are illustrated in Table 2 . Pathogenic or novel variants in different GSD associated genes were detected in 13 out of 14 patients (93%). Accordingly, one patient (6.7%) had GSD-I, four (26.6%) were affected with GSD-III, one (6.7%) had GSD-IV, two cases (13.3%) were suffering from GSD-VI, three patients (20%) had GSD-IX, one case was affected with (6.7%) GSD-X, and one patient (6.7%) was suffering from GSD of heart—lethal congenital disorder. Overall, 15 mutations were detected in the GSD-associated genes in 13 patients, 10 of whom had not been previously reported. These novel mutations included one frameshift variant in AGL (c.1351_1355delAAAGC), one nonsense change in SLC37A4 (c.24T > G), and one splicing mutation (c.1127-2A > G) in PHKB . Moreover, there were seven missense variants, i.e. one in PGAM2 (c.130C > T), one in PYGL (c.1964A > G), two in PHKB (c.134T > A; c.2840A > G), one in PRKAG2 (c.592A > T), one in SLC37A4 (c.337C > T), and one in GBE1 (c.292G > C) (Table 2 ). Two patients were also detected to have bi-allelic mutations; patient no. 6 had mutations in GBE1 gene, and patient no. 11 had mutations in two different genes, i.e., SLC37A4 and PHKB (Table 2 ). The most common defects were found in AGL (GSD-III) and PHKB (GSD-IX). Allele frequency of all variants were searched in Iranome database (public Iranian data set). Only 13.3% of novel variants were observed in this database (which is rare with an allele frequency less than 0.001), as presented in Table 2 . Finally, the diagnostic rate for TGS in patients suspected with GSD was 93% (13/14).

Comprehensive analysis for detection of variants in GSD patients

Patient no. 1 was a 1-year-old girl who presented with hypoglycemia, hepatomegaly, elevated TG, acidic urine, platelet count, and low white blood cells (WBCs) from a consanguineous marriage, suggestive of GSD-I (Table 1 ). Pathological results also indicated GSD-I with severe bridging fibrosis, diagnosed as cirrhosis. A novel homozygous nonsense variant, i.e., c.24T > G (p.Tyr8Ter), was also detected in the SLC37A4 gene (GSD type-Ib) by TGS (Table 2 ). No other deleterious variant was found in other GSD genes in the panel.

Patients no. 2–3 had clinicopathological and histochemical findings, strongly suggestive of GSD-I or III. Both patients were presented with hypoglycemia (patient no. 2 also had experienced seizures at the age of 2), hepatomegaly, short stature, elevated TG, TChol, LDH, albumin (Alb), AST, and ALT enzymes (Table 1 ). Histopathological findings were suggestive of type I or III GSD, with mild portal fibrosis. The variants in the glycogen debranching enzyme gene, AGL, were also observed by TGS. A homozygous deleterious frameshift mutation, i.e. c.753_756delCAGA (p.Asp251fs*23), was further detected in the AGL gene in both patients, which had been previously reported in patients affected with GSD-IIIa 12 .

Patient no. 4 was a 4-year-old girl with hypoglycemia, hepatomegaly, short stature, elevated LDH, CPK, platelet count, AST, and ALT, whose parents were first cousins. The liver biopsy from this case suggested GSD-I or III along with severe fibrosis. A novel pathogenic homozygote variant, c.1351_1355delAAAGC (p.Lys451LeufsTer14), was also detected in the AGL gene. This variant had not been listed in Iranome and gnomAD databases or described in the related literature.

Another example of GSD-III was patient 5 , a 3-year-old boy, who presented with hepatomegaly, elevated TG, TChol, LDH, BCR, AST, and ALT. The liver biopsy diagnosis in this case was GSD-I or III with cirrhosis. The targeted NGS also detected a homozygote variant, c.3980G > A (p.Trp1327Ter), which had been previously reported 13 , 14 .

Patient no. 6 was a 4.5-year-old boy with clinical and paraclinical findings such as hepatosplenomegaly, as well as elevated BCR, AST, and ALT (Table 1 ). In addition, the liver biopsy showed cirrhosis and suggested GSD-IV. He had also successfully received a partial liver transplant at the age of 2. Moreover, the targeted NGS panel revealed two variants in GBE1 gene. A homozygous deleterious variant, namely c.998A > T (p.Glu333Val) 15 , and another novel homozygous variant c.292G > C (p.Val98Leu), were additionally detected in the GBE1 gene. The new variant was not listed in Iranome and gnomAD databases or described in the related literature, so it could be interpreted as a variant of uncertain significance (VUS).

Patient no. 7 was a 4-year-old girl, presented with hepatomegaly, short stature, high TG, LDH, BCR, Alb, AST, ALT, and acidosis (Table 1 ). Her liver biopsy also suggested unclassified GSD with marked fibrosis. Using TGS, a novel homozygous missense variant, c.1964A > G (p.Glu655Gly), was detected in PYGL gene, indicating GSD-VI (Table 2 ).

Patient no. 8 was a 1.5-year-old boy, referred with hepatomegaly, abdominal protrusion, and malaise (Table 1 ). Para-clinical results also showed increased TG, TChol, BCR, AST, and ALT (Table 1 ). Histopathological studies of his liver biopsy also suggested GSD-I or III with mild fibrosis. However, a homozygous pathogenic deletion variant, c.229-231delGAC (p.Asp77del), was detected in the liver isoform glycogen phosphorylase, the PYGL gene (Table 2 ) 16 .

Patient no. 9 was a 2-year-old girl from a non-consanguineous marriage with episodes of hypoglycemia starting from six months of age during nighttime, hepatomegaly, short stature, elevated AST, and ALT (Table 1 ). Her liver biopsy also showed unclassified GSD with fibrosis. A homozygous pathogenic variant, c.130C > T (p.Arg44Ter), was additionally detected in a PHKG2 gene by TGS. This missense mutation had been previously reported in patients with GSD-IXc 17 , 18 , 19 .

Patient no. 10 was a 3-year-old boy, who presented with hepatomegaly, short stature, and muscular hypotonia as well as elevated TG, LDH, TChol, AST, and ALT since the age of six months (Table 1 ). The results of liver histopathological studies also showed unclassified GSD with bridging fibrosis. Using TGS analysis additionally revealed a novel heterozygous variant, c.134T > A (p.Leu45His), in the glycogen phosphorylase kinase regulatory sub-unit beta gene, PHKB (GSD-IXb). No other pathogenic variants were detected in other GSD genes in the panel.

Patient no. 11 was an asymptomatic girl whose parents were first cousins. She was referred because of poor feeding at the age of 3. Laboratory investigations also showed elevated TG, TChol, LDH, Alb, AST, and ALT, as well as leukopenia and acidosis (Table 1 ). The liver biopsy revealed unclassified GSD, and moderate periportal fibrosis. She harbored three novel variants, namely one heterozygote variant c.337C > T (p.Leu113Phe) in the SLC37A4 gene and two homozygote variants c.1127-2A > G (p.?) and c.2840A > G (p.Gln947Arg) in the PHKB gene. The pathogenic novel variant, c.1127-2A > G (p.?), was possibly damaging the splice site located within intron. As a result, she was most probably suffering from IXb, whose symptoms tended to appear with increasing age. Moreover, targeted NGS successfully identified these three mutations with 100 × coverage.

Patient no. 12 was a 2.5-year-old boy with mild hepatomegaly, high TG, TChol, LDH, BCR, AST, and ALT enzyme and very low creatinine (Table 1 ). Histopathological studies of his liver biopsy also suggested unclassified GSD, with cirrhosis. Using TGS, a novel heterozygous variant, c.14G > A (p.Arg5His), was detected in phosphoglycerate mutase gene, the PGAM2 (GSD-X). To note, GSD-X is an autosomal recessive disorder and the detection of a single heterozygous variant did not confirm the diagnosis. Nevertheless, lack of a second pathogenic allele or any identified pseudo-deficiency variant had left the molecular diagnosis of this patient in question. The signs may be caused by pathogenic variants in other genes including disorders of fatty acid oxidation and/or mitochondrial respiratory chain disorders.

Patient no. 13 was a 2.5-year-old girl who presented with short stature and normal biochemical analysis of a non-consanguineous marriage (Table 1 ). Pulmonary hypertension, moderate mitral regurgitation, and mild tricuspid regurgitation were also observed. Moreover, the liver biopsy results revealed cirrhosis, which was suggestive of unclassified GSD. A novel heterozygous variant, c.592A > T (p.Met198Leu), was further detected in the PRKAG2 gene by TGS and implied PRKAG2 deficiency (i.e. GSD of heart—lethal congenital). Since the PRKAG2 deficiency is an autosomal dominant inheritance with full penetrance, single heterozygote variants could confirm all of her clinical, molecular, and biochemical results.

The diagnosis of none of the GSD and non-GSD-associated genes was confirmed in patient no. 14 . She was a 2-year-old girl, who presented with hepatomegaly, clubbed fingers, failure to thrive, diarrhea, vomiting, as well as high platelet count, AST, ALT and low uric acid (Table 1 ). Her liver biopsy was suggestive of GSD or lipid storage disease with mild fibrosis. No deleterious mutations were also detected in any of the related GSD genes analyzed. There was, therefore, no definite diagnosis for this patient.

Histological findings and association with genetic sequencing

In five patients, the features of liver histopathology were suggestive of unclassified GSD, molecular genetic investigations of these patients which confirmed the diagnosis of GSD-VI in one patient (no. 7), GSD-IXb in two cases (no. 10 and 11), diagnosis of GSD-IXc (no. 9), and diagnosis of GSD of heart—lethal congenital disorder—in one patient (no. 3). In one case, not only the features of liver histopathology were shown ambiguous results, but also no deleterious mutations were detected in any of the GSD genes analyzed (no. 14).

Among the nine calculated pathogenic variants identified in our cohort, we identified eight cases (88%) to have severe fibrosis/ cirrhosis. On the other hand, one case (12%) of VUS showed severe fibrosis/ cirrhosis in liver biopsy. Therefore, there was a significant association between the pathogenicity of the variants and the features of liver histopathology in the patients, as presented in Table 3 ( P  = 0.049).

Classification and sub-typing of GSD patients are important steps towards personalized patient management, which can help clinicians practice the best and the most correct therapy with the fewest adverse events for patients 20 . Here, the first and largest cohort is reported about GSD sub-typing from the Middle East and Asia. It is also the first study, addressing clinical characteristics and genomics in sub-typing of patients with GSDs from Iranian population. In this cohort of 14 pediatric patients, 10 novel pathogenic variants in the SLC37A , AGL , GBE1 , PHKB , PGAM2 and PRKAG2 genes were found. In our patient cohort, the most common subtype was GSD III (27%). Notably, GSD-IX was detected in three patients, which had not been reported from Iran, so far. Concerning GSD-IX patients, the estimated prevalence is 1:100,000 and they account for 25–30% of all GSD cases 21 , 22 . It means that it has been overlooked in our population because of subtle patient presentations and self-limited outcomes as well as lack of molecular diagnosis analyses. Therefore, it has been classified as other types of GSD, such as GSD-III or VI.

Chronic liver diseases, such as cirrhosis and fibrosis, have been also rarely reported in some types of GSDs e.g. GSD-VI and IX 21 . However, in the present study, 40% of the patients had liver cirrhosis and 60% had different degrees of liver fibrosis. In addition, asymptomatic heart problems with liver involvement were identified in a GSD of the heart-lethal congenital disorder (i.e. PRKAG2 deficiency) in one patient in our study cohort. To the best of our knowledge, we report for the first time liver cirrhosis in GSD-X and GSD of the heart-lethal congenital (i.e. PRKAG2 deficiency). In this pathological report, 13 patients were suggestive to have one type of GSD without exact sub-typing, so molecular genetic analysis (namely, targeted genome sequencing based on NGS) was performed, confirming the exact type of GSD. According to these results, molecular genetic testing, especially NGS-based GSD or inborn inherited metabolic panel exome sequencing, was recommended for definite diagnosis of GSD sub-types prior to invasive liver biopsy. Liver histopathology may also be a powerful and effective method for monitoring long-term liver complications and evaluating the status of the liver in these patients, but not for confirming diagnosis and accurate sub-typing.

NGS-based targeted exome sequencing is thus reported as the best future routine method of molecular diagnosis. This is especially useful for complex disorders with less specific clinical findings 23 . Nevertheless, in defining the syndromes or diseases like GSD, clinical features or biochemical phenotypes can effectively address a particular pathway or a group of genes responsible for the disease. In such cases, a custom-targeted gene-sequencing panel has been confirmed to be an efficient as well as time- and cost-effective technique with high diagnostic yields 24 . Analytical workflows for the diagnosis of GSD diseases are not fully standardized; however, a useful and practical approach based on clinical and biochemical evaluations followed by targeted molecular analysis was reported later, as shown in Fig.  1 24 . Moreover, using custom-target sequencing vs. exome sequencing would become a routine technique due to the focus on a limited number of suspected diseases and appropriate balance between the cost, time, throughput, and deep coverage, especially for low-income countries such as Iran 25 . To note, utilizing TGS panel is suitable to detect mutations, especially in communities with high numbers of consanguineous marriages such as Iran. In this country, the prevalence rate of consanguineous marriage is approximately seen in 38.6% of the population with a mean inbreeding coefficient (alpha) of 0.018, probably resulting in a higher incidence of autosomal recessive diseases such as GSDs 26 . Moreover, the samples from patients without a definite diagnosis would be recommended to be analyzed by genome sequencing or exome sequencing.

figure 1

Integration of clinical and laboratory workflows to optimize hepatic glycogen storage disease diagnosis 24 .

The present work revealed unexpected findings for two patients. Patient no.13 carried mutations associated with PRKAG2 gene, which also developed liver failure. However, in previous studies, reported manifestations had been less severe and essentially heart-specific, non-lysosomal glycogenosis, and mild-to-severe cardiac hypertrophy, enhancing the risk of sudden cardiac death in midlife without liver involvement 27 , 28 . This was the first patient with PRKAG2 gene mutation reported to have liver cirrhosis; however, a functionality of the novel variant remains underdiagnosed. Another patient (no. 14) showed liver problem and all similar clinical features to GSD; nevertheless, it was not possible to match it with any variant in the custom panel of inborn errors of metabolism. These two patients had atypical clinicopathological features, precluding accurate classification and diagnosis with clinicopathological features and in need of more specific genetic testing for definite diagnosis.

Despite genetic homogeneity, we found evidence of unusual features with novel variants. A possible reason for the high rate of novel variations we saw might be the lack of molecular genetic analysis before. It is known that mutations can have a specific race as well as restricted geographical or ethnical distribution, while was never analyzed such patients in our country. In addition, the results of this study will help improve gene variant spectrum, diagnostic panels, clinical diagnosis, and patient management not only in this country but also in the region. A deeper knowledge of genomic variants also leads to better findings of determinants associated with the genotype–phenotype match in GSDs 29 .

In conclusion, the study indicated the benefits of TGS method in diagnosing GSD, especially when the clinical findings were equivocal. Given the cost- and time-efficiency of these methods, they can prevent the patients from receiving long-term improper treatments. The diagnosis of the patients reported here has helped expand the genetic and phenotypic spectrum of the GSDs disorders.

Materials and methods


From March 2017 to December 2019, a total number of 14 pediatric patients suspected to GSDs who presented with hepatomegaly, hypoglycemia, growth and development delay during childhood were selected at Shiraz Transplant Research Center (STRC) and Namazi Hospital (Shiraz, Iran). None of these 14 cases had molecular diagnoses. All the patients had already have liver biopsies with histopathological features, which suggested hepatic GSDs by the pathologist (Liver biopsy was performed to determine the details of the liver pathology especially stage of fibrosis). Two independent research team members reviewed electronic and paper charts for clinical features, biochemical investigations, histopathological results, and diagnostic imaging. Whole blood samples were collected from all study subjects and sent to the Pediatric Metabolic Diseases Laboratory, Gazi Hospital (Ankara, Turkey) for targeted NGS-based panel analysis. To this end, the subjects’ parents/guardians signed written informed consents. The Ethics Committee of Shiraz University of Medical Sciences also approved this study (Approval #: IR.SUMS.REC.1396.S805), which was in accordance with the Declaration of Helsinki.

Gene panel sequencing

In brief, genomic DNA from 2 ml peripheral blood was extracted using AutoMate Express Nucleic Acid Extraction System (Life Technologies, Guilford, CT, South San Francisco, CA, US). They were also hybridized and enriched for TGS. Then, Ion Torrent S5 platform was employed for DNA sequencing analysis. A custom-targeted Ion AmpliSeq panel that included 7219 amplicons covering 450 genes associated with Inborn Metabolic Diseases was used. Among 450 genes, the GSD genes were also present in this panel which included the genes for Glycogen Storage Disorders with hepatic involvement such as G6PC (Type Ia), SLC37A4 (Type Ib), AGL (Type III), GBE1 (Type IV), PYGL (Type VI), PHKA2 (Type IXa), PHKB (Type IXb), PHKG2 (Type IXc) and GLUT2 (Type XI). The other genes for gluconeogenesis, namely PC (Pyruvate Carboxylase deficiency), PCK2 (Phosphoenolpyruvate carboxykinase deficiency) and FBP1 (Fructose-1,6-bisphosphatase), were also present in this panel.

The panel similarly covered 3′ untranslated regions (UTRs) of the genes and extended 5 bp on either side of each exon (Life Technologies, Guilford, CT, South San Francisco, CA, US). Analyses were done using an Ion Torrent 540 chip (Life Technologies, Guilford, CT, South San Francisco, CA).

The results were analyzed with Ion Reporter Software (Life Technologies, Guilford, CT, South San Francisco, CA, US) as well as Integrated Genomic Viewer 30 . The human genome 19 was also used as the reference. Polymorphism Phenotyping v2 (PolyPhen2), Scale-Invariant Feature Transform (SIFT), and MutationTaster were further employed for in silico analysis. Genomic Evolutionary Rate Profiling (GERP) and the Phastcons scores were also utilized to evaluate the conservation of the variants. The population frequency of each variation was correspondingly estimated using the data from the Genome Aggregation Database (gnomAD) and Iranome database 31 . The American College of Medical Genetics and Genomics (ACMG) guidelines were additionally used for variant interpretations 32 . The sequence variants were also described according to the Human Genome Variation Society Nomenclature 33 . Accession number of the relevant reference sequence(s) of GSD genes are presented in Supplementary File 1 .

Validation of candidate genes

Direct Sanger sequencing was performed in all subjects for validation of the causal mutations in candidate genes. Primers were designed using OLIGO primers design v.7 (Molecular Biology Insights, Inc., DBA Oligo, Inc.) which were sequenced by standard Sanger’s sequencing technique using BigDyeTerminator (Invitrogen, ABI, Foster City, CA).

Liver biopsy

All patients had undergone ultrasound-guided liver biopsy using the standard Tru-Cut biopsy needles. Histopathology slides were prepared and stained routinely by Hematoxylin and Eosin (H&E), Periodic acid-Schiff (PAS), PAS with diastase (PAS + D), Trichrome, Reticulin, and Iron staining. All the slides were reviewed by an expert hepatopathologist (B.G.).

Statistical analysis

Data were analyzed using SPSS 16.0 for Windows (SPSS Inc., Chicago, IL, USA). Continuous data were presented as the mean and standard deviation (SD) or median and range. The Fisher’s exact test was used to compare the relationship between the liver pathogenesis and pathogenic variant presence. A two-tailed value for P  < 0.05 was considered statistically significant.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Bioethics Committee of the Medical University of Shiraz, Iran (No. IR.SUMS.REC.1396.S805).

Consent for publication

Informed consent was obtained from legal guardians.

Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.

Change history

26 july 2021.

A Correction to this paper has been published: https://doi.org/10.1038/s41598-021-94296-0


Glycogen storage disease

Massively parallel sequencing

Next-generation sequencing

Targeted genome sequencing

Variant of unknown significance

Hicks, J., Wartchow, E. & Mierau, G. Glycogen storage diseases: a brief review and update on clinical features, genetic abnormalities, pathologic features, and treatment. Ultrastruct. Pathol. 35 , 183–196 (2011).

Article   PubMed   Google Scholar  

Burda, P. & Hochuli, M. Hepatic glycogen storage disorders: what have we learned in recent years?. Curr. Opin. Clin. Nutr. Metab. Care 18 , 15–421 (2015).

Article   Google Scholar  

Vega, C. M. et al. Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing. Genet. Med. 18 , 1037–1043 (2016).

Article   CAS   PubMed   Google Scholar  

Wang, J. et al. Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin. Genet. Med. 15 , 106–114 (2013).

Chen, Y. T., Kishnani, P. S. & Koeberl, D. Glycogen Storage Diseases (McGraw-Hill, 2009).

Google Scholar  

Beyzaei, Z. & Geramizadeh, B. Molecular diagnosis of glycogen storage disease type I: a review. EXCLI J. 18 , 30–46 (2019).

PubMed   PubMed Central   Google Scholar  

Ng, S. B. et al. Exome sequencing identifies the cause of a mendelian disorder. Nat. Genet. 42 , 30–35 (2010).

Boycott, M. R. V., Bulman, D. E. & MacKenzie, A. E. Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat. Rev. Genet. 14 , 681–691 (2013).

Nicastro, E. & D’Antiga, L. Next generation sequencing in pediatric hepatology and liver transplantation. Liver Transpl. 24 , 282–293 (2018).

Wang, J. et al. Capture-based high-coverage NGS: a powerful tool to uncover a wide spectrum of mutation types. Genet. Med. 18 , 513–521 (2016).

Ng, S. B. et al. Targeted capture and massively parallel sequencing of twelve human exomes. Nature 461 , 272–276 (2009).

Article   CAS   ADS   PubMed   PubMed Central   Google Scholar  

Sentner, C. P. et al. Mutation analysis in glycogen storage disease type III patients in the Netherlands: novel genotype-phenotype relationships and five novel mutations in the AGL gene. JIMD Rep. 7 , 19–26 (2013).

Lucchiari, S. et al. Molecular characterisation of GSD III subjects and identification of six novel mutations in AGL. Hum. Mutat. 20 , 480–488 (2002).

Crushell, E., Treacy, E. P., Dawe, J., Durkie, M. & Beauchamp, N. J. Glycogen storage disease type III in the Irish population. JIMD 33 , S215-218 (2010).

PubMed   Google Scholar  

Magoulas, P. L. Diffuse reticuloendothelial system involvement in type IV glycogen storage disease with a novel GBE1 mutation: a case report and review. Hum. Pathol. 43 , 943–951 (2012).

Brown, L., Corrado, M. M. & Derks, T. G. J. Evaluation of glycogen storage disease as a cause of ketotic hypoglycemia in children. JIMD 38 , 489–493 (2014).

Li, C. et al. PHKG2 mutation spectrum in glycogen storage disease type IXc: a case report and review of the literature. J. Pediatr. Endocrinol. Metab. 31 , 331–338 (2018).

Burwinkel, B., Shiomi, S., Al Zaben, A. & Kilimann, M. W. Liver glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene structure and mutations associated with cirrhosis. Hum. Mol. Genet. 7 , 149–154 (1998).

Bali, D. S., Goldstein, J. L. & Fredrickson, K. Variability of disease spectrum in children with liver phosphorylase kinase deficiency caused by mutations in the PHKG2 gene. Mol. Genet. Metab. 111 , 309–313 (2014).

Retterer, K., Juusola, J., Cho, M. T. & Vitazka, P. Clinical application of whole-exome sequencing across clinical indications. Genet. Med. 18 , 696–704 (2016).

Roscher, A. et al. The natural history of glycogen storage disease types VI and IX: long-term outcome from the largest metabolic center in Canada. Mol. Genet. Metab. 113 , 171–176 (2014).

Rodríguez-Jiméneza, C., Santos-Simarroac, F., Campos-Barrosac, A. & Camarenab, C. A new variant in PHKA2 is associated with glycogen storage disease type IXa. Mol. Genet. Metab. Rep. 10 , 52–55 (2017).

Jones, M. A., Bhide, S. & Chin, E. Targeted polymerase chain reaction-based enrichment and next generation sequencing for diagnostic testing of congenital disorders of glycosylation. Genet. Med. 13 , 921–932 (2011).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Beyzaei, Z., Geramizadeh, B. & Karimzadeh, S. Diagnosis of hepatic glycogen storage disease patients with overlapping clinical symptoms by massively parallel sequencing: a systematic review of literature. Orphanet J. Rare Dis. 15 , 286–299 (2020).

Article   PubMed   PubMed Central   Google Scholar  

Smith, H. S. et al. Clinical application of genome and exome sequencing as a diagnostic tool for pediatric patients: a scoping review of the literature. Genet. Med. 21 , 3–16 (2019).

Saadat, M., Ansari-Lari, M. & Farhud, D. D. Consanguineous marriage in Iran. Ann. Hum. Biol. 31 , 263–269 (2004).

Burwinkel, B., Scott, J. W., Buhrer, C. & van Landeghem, F. K. H. Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the g2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. Am. J. Hum. Genet. 76 , 1034–1049 (2005).

Gilbert-Barness, E. Metabolic cardiomyopathy and conduction system defects in children. Ann. Clin. Lab. Sci. 34 , 15–34 (2004).

CAS   PubMed   Google Scholar  

Richter, S., Gieldon, L. & Pang, Y. Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma clinical genetics. Genet. Med. 21 , 705–717 (2019).

Robinson, J. T. et al. Integrative genomics viewer. Nat. Biotechnol. 29 , 24–26 (2011).

Fattahi, Z. et al. Iranome: a catalog of genomic variations in the Iranian population. Hum. Mutat. 40 (11), 1968–1984 (2019).

Richards, S., Aziz, N., Bale, S. & Bick, D. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17 , 405–423 (2015).

Den Dunnen, J. T. & Antonarakis, S. E. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum. Mutat. 15 , 7–12 (2000).

Download references


The authors hereby extend their gratitude to the patients for their participation in the present study. Also, we would like to appreciate Mr. Kazemi from Namazi Laboratory at Namazi Hospital for his assistance.

This study was financially supported by the Shiraz Transplant Research Center (STRC), affiliated with Shiraz University of Medical Sciences, Shiraz, Iran (Grant No.1396-01-106-15748); and National Institute for Medical Research Development (NIMAD), Tehran, Iran (Grant No. 976961).

Author information

Authors and affiliations.

Shiraz Transplant Research Center (STRC), Shiraz University of Medical Sciences, Shiraz, Iran

Zahra Beyzaei & Bita Geramizadeh

Department of Pediatric Metabolism and Genetic, Gazi University Faculty of Medicine, Ankara, Turkey

Department of Pathology, Shiraz University of Medical Sciences, Khalili St., Research Tower, Seventh Floor, Shiraz Transplant Research Center (STRC), Shiraz, Iran

  • Bita Geramizadeh

Gastroenterology and Hepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Mohammad Hadi Imanieh, Mahmood Haghighat, Seyed Mohsen Dehghani, Naser Honar & Mojgan Zahmatkeshan

Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, Iran

Mojgan Zahmatkeshan

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Amirreza Jassbi & Marjan Mahboubifar

Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran

Alireza Alborzi

You can also search for this author in PubMed   Google Scholar


Z.B. and B.G. developed the conception of the study, coordinated the clinical study to collect the clinical data, and assessed the obtained clinical findings. Patients were clinically evaluated and recruited with informed consent by B.G., M.H.I., M.H., S.M.D., N.H., M.Z., A.J., M.M., and A.A., Z.B. and F.E. performed the molecular genetic studies, sequence alignments, and annotations of identified sequence alterations. Z.B. and B.G. drafted the manuscript. All authors discussed, read and approved the final manuscript.

Corresponding author

Correspondence to Bita Geramizadeh .

Ethics declarations

Competing interests.

The authors declare no competing interests.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this Article was revised: The original version of this Article contained an error in the Abstract. It now reads: “A total of the 14 pediatric patients were admitted to our hospital and referred for molecular genetic testing using TGS. Seven genes namely  SLC37A4,  AGL,  GBE1,  PYGL,  PHKB,  PGAM2, and  PRKAG2  were detected to be responsible for the onset of the clinical symptoms.”

Supplementary Information

Supplementary information., rights and permissions.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and Permissions

About this article

Cite this article.

Beyzaei, Z., Ezgu, F., Geramizadeh, B. et al. Clinical and genetic spectrum of glycogen storage disease in Iranian population using targeted gene sequencing. Sci Rep 11 , 7040 (2021). https://doi.org/10.1038/s41598-021-86338-4

Download citation

Received : 21 October 2020

Accepted : 15 March 2021

Published : 29 March 2021

DOI : https://doi.org/10.1038/s41598-021-86338-4

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Liver transplantation in glycogen storage disease: a single-center experience.

  • Zahra Beyzaei
  • Alireza Shamsaeefar

Orphanet Journal of Rare Diseases (2022)

Novel mutations in the PHKB gene in an iranian girl with severe liver involvement and glycogen storage disease type IX: a case report and review of literature

  • Alireza Shojazadeh

BMC Pediatrics (2021)

By submitting a comment you agree to abide by our Terms and Community Guidelines . If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Quick links

  • Explore articles by subject
  • Guide to authors
  • Editorial policies

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

glycogen storage disease research paper

Academia.edu no longer supports Internet Explorer.

To browse Academia.edu and the wider internet faster and more securely, please take a few seconds to  upgrade your browser .

Enter the email address you signed up with and we'll email you a reset link.

  • We're Hiring!
  • Help Center

paper cover thumbnail

Glycogen storage disease

Profile image of Paul Gissen

2011, Paediatrics and Child Health

Related Papers

Ultrastructural Pathology

glycogen storage disease research paper

Sarar Mohamed

Archives of medical science : AMS

Elżbieta Ciara


Bibiana Mello de Oliveira , Carolina de Souza

Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disease caused by variants in the GBE1 gene, which encodes the glycogen branching enzyme (GBE). GSD IV accounts for approximately 3% of all GSD. The phenotype of GSD IV ranges from neonatal death to mild adult-onset disease with variable hepatic, muscular, neurologic, dermatologic, and cardiac involvement. There is a paucity of literature and clinical and dietary management in GSD IV, and liver transplantation (LT) is described to correct the primary hepatic enzyme defect. Objectives: We herein describe five cases of patients with GSD IV with different ages of onset and outcomes as well as a novel GBE1 variant. Methods: This is a descriptive case series of patients receiving care for GSD IV at Reference Centers for Rare Diseases in Brazil and in the United States of America. Patients were selected based on confirmatory GBE1 genotypes performed after strong clinical suspicion. Results: Pt #1 is a Latin mal...

Annals of Translational Medicine

Areeg el-gharbawy

European Journal of Pediatrics

Gepke Visser

Corrado I Angelini , Corrado Angelini

Glycogen storage disease type II (GSDII) is an autosomal recessive lysosomal disorder caused by mutations in the gene encoding alpha-glucosidase (GAA). The disease can be clinically classified into three types: a severe infantile form, a juvenile and an adult-onset form. Cases with juvenile or adult onset GSDII mimic limb-girdle muscular dystrophy or polymyositis and are often characterized by respiratory involvement. GSDII patients are diagnosed by biochemical assay and by molecular characterization of the GAA gene. Ascertaining a natural history of patients with heterogeneous late-onset GSDII is useful for evaluating their progressive functional disability. A significant decline is observed over the years in skeletal and respiratory muscle function. Enzyme replacement therapy (ERT) has provided encouraging results in the infantile form. It is not yet known if ERT is effective in late-onset GSDII. We examined a series of 11 patients before and after ERT evaluating muscle strength by MRC, timed and graded functional tests, 6-minute walk test (6MWT), respiratory function by spirometric parameters and quality of life. We observed a partial improvement during a prolonged follow-up from 3 to 18 months. The use of different clinical parameters in the proposed protocol seems crucial to determine the efficacy of ERT, since not all late-onset patients respond similarly to ERT.

Indian pediatrics

Masaomi Nangaku

The Egyptian Journal of Hospital Medicine

marium iqbal

Advances in Therapy

Cesare Danesino


Gerard Smit

Khadiga Ali

Jornal de Pediatria

Matias Epifanio

Genetics in Medicine

Journal of Clinical Lipidology

Joseph Wolfsdorf

Molecular Genetics and Metabolism

Andreas Schulze , Annette Feigenbaum

Pediatrics International

Gülden Gökçay

Genetics Research


Archives of Medical Science

Wojciech Czarny

Heather Saavedra

Rossella Parini , Alessandra Brambilla

Journal of Inherited Metabolic Disease

Dev Desai , Pamela Arn


Benedikt Schoser

Biochemical and Biophysical Research Communications

Willem de Boode

American Journal of Medical Genetics Part A

Robert J Hopkin

Proceedings of the Nutrition Society

francis de sa

Pediatrics & Neonatology

Yin-hsiu Chien

Nature Reviews Neurology

Journal of Human Genetics

Khalifa Limem , wafa cherif

Journal of pediatric endocrinology & metabolism : JPEM

Saliha Senel

New England Journal of Medicine

Ingegerd Östman-Smith

Hajer Mansouri


  •   We're Hiring!
  •   Help Center
  • Find new research papers in:
  • Health Sciences
  • Earth Sciences
  • Cognitive Science
  • Mathematics
  • Computer Science
  • Academia ©2023


  1. (PDF) The Glycogen Storage Disorders

    glycogen storage disease research paper

  2. The glycogen storage diseases

    glycogen storage disease research paper

  3. (PDF) Glycogen storage disease type VI with a novel mutation in PYGL gene

    glycogen storage disease research paper

  4. (PDF) Dietary dilemmas in the management of glycogen storage disease type I

    glycogen storage disease research paper

  5. (PDF) Molecular diagnosis of glycogen storage disease type I: A review

    glycogen storage disease research paper

  6. Glycogen Storage Disease Case Study

    glycogen storage disease research paper


  1. Glycogen Storage disease type 3a Interview

  2. 10 Glycogen Storage Diseases

  3. Day 5 glycolysis version 2

  4. Glycogen storage Diseases

  5. Biochemistry|Glycogen Metabolism Pathways and Glycogen Storage Diseases (GSD)|AKTU Digital Education

  6. Glycogen storage disease شرح عربي وانجليزي


  1. Glycogen Storage Disease

    Objectives: Identify the etiology of various glycogen storage diseases. Explain the typical patient history associated with glycogen storage diseases. Outline the diagnostic evaluation of patients suspected to have a glycogen storage disease.

  2. Glycogen Storage Disease Type I

    Glycogen storage disease type I (GSD I), also known as Von Gierke disease, is an inherited disorder caused by deficiencies of specific enzymes in the glycogen metabolism pathway. It was first described by Von Gierke in 1929 who reported excessive hepatic and renal glycogen in the autopsy reports of 2 children.

  3. Hepatic glycogen storage diseases: pathogenesis, clinical symptoms and

    Due to the fairly wide access of the authors to unpublished materials and research, as well as direct contact with the GSD patients, the article addresses the problem of actual diagnostic procedures for patients with the suspected diseases. ... Glycogen storage disease (GSD) ... This division can also be found in all sorts of general papers on ...

  4. Dietary Management of the Glycogen Storage Diseases: Evolution of

    The hepatic glycogen storage diseases (GSDs) are a group of inborn errors of metabolism caused by abnormalities of the enzymes that catalyze the synthesis or degradation of glycogen. The first GSD was described by Edgar von Gierke in 1929 ( 1. ) and there are now at least 16 recognized types ( Table 1 ).

  5. Glycogen storage diseases

    Glycogen storage diseases (GSDs) are a group of rare, monogenic disorders that share a defect in the synthesis or breakdown of glycogen. This Primer describes the multi-organ clinical features of hepatic GSDs and muscle GSDs, in addition to their epidemiology, biochemistry and mechanisms of disease, …

  6. Glycogen Storage Disease Type Ia: Current Management Options, Burden

    Introduction Glycogen storage diseases (GSD) are a collection of inherited metabolic disorders caused by pathogenic variants in the genes that encode proteins involved in glycogen synthesis, glycogenolysis and/or gluconeogenesis.

  7. Glycogen Storage Disease

    Glycogen storage diseases (GSDs) are inherited inborn errors of carbohydrate metabolism. Disorders of carbohydrate metabolism that result in abnormal storage of glycogen are classified as GSDs. They are classified numerically in the order of recognition and identification of the enzyme defect causing the disorder. Clinical onset can range from ...

  8. Glycogen storage diseases: a brief review and update on clinical

    Glycogen storage diseases (GSD) affect primarily the liver, skeletal muscle, heart, and sometimes the central nervous system and the kidneys. ... whereas other glycogen storage diseases are relatively asymptomatic or may cause only exercise intolerance. The paper provides a brief review and update of glycogen storage diseases, with respect to ...

  9. Biomarkers in Glycogen Storage Diseases: An Update

    Glycogen storage diseases (GSDs) are a group of 19 hereditary diseases caused by a lack of one or more enzymes involved in the synthesis or degradation of glycogen and are characterized by deposits or abnormal types of glycogen in tissues. Their frequency is very low and they are considered rare diseases.

  10. Glycogen storage diseases

    Glycogen storage diseases (GSDs) are a group of rare, monogenic disorders that share a defect in the synthesis or breakdown of glycogen. This Primer describes the multi-organ clinical features of ...

  11. Glycogen storage diseases: New perspectives

    PMID: 17552001 Glycogen storage diseases: New perspectives Hasan Özen Author information Article notes Copyright and License information PMC Disclaimer Go to: Abstract Glycogen storage diseases (GSD) are inherited metabolic disorders of glycogen metabolism.

  12. A case study of glycogen storage disease type Ia presenting with

    Introduction. Glycogen storage disease type Ia (GSD Ia) is an extremely rare autosomal recessive inherited disorder affecting glycometabolism, with a prevalence of 1 in 100,000 ().Deficiency of the enzyme glucose 6-phophatase (G6Pase) leads to abnormal glycogen metabolism, which then causes abnormal deposits of glycogen in the endoplasmic reticulum cavity.

  13. Efficacy and safety of empagliflozin in glycogen storage disease type

    Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire ... 24 Division of Metabolism and Children`s Research Center, University Children's Hospital ... This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals ...

  14. Diagnosis and management of glycogen storage diseases type VI ...

    Glycogen storage disease (GSD) types VI and IX are rare diseases of variable clinical severity affecting primarily the liver. GSD VI is caused by deficient activity of hepatic glycogen ...

  15. Gene therapy for glycogen storage diseases

    The focus of this review is the development of gene therapy for glycogen storage diseases (GSDs). GSD results from the deficiency of specific enzymes involved in the storage and retrieval of glucose in the body. Broadly, GSDs can be divided into types that affect liver or muscle or both tissues. For example, glucose-6-phosphatase (G6Pase ...

  16. Impact of glycogen storage disease type I on adult daily life: a survey

    Published: 03 September 2021 Impact of glycogen storage disease type I on adult daily life: a survey Sven F. Garbade, Viviane Ederer, Peter Burgard, Udo Wendel, Ute Spiekerkoetter, Dorothea Haas & Sarah C. Grünert Orphanet Journal of Rare Diseases 16, Article number: 371 ( 2021 ) Cite this article 4755 Accesses 11 Citations 1 Altmetric Metrics

  17. Pompe Disease: a Clinical, Diagnostic, and Therapeutic Overview

    Pompe disease, also known as glycogen storage disease type II (GSD II) or acid maltase deficiency (AMD), is a genetic disorder caused by a deficiency of the acid alpha-glucosidase (GAA) enzyme, due to recessive mutations in the GAA gene, which leads to accumulation of lysosomal glycogen [], diffusely but primarily affecting the skeletal and cardiac muscle tissue.

  18. Clinical and genetic spectrum of glycogen storage disease in Iranian

    Glycogen storage diseases (GSDs) are known as a group of disorders characterized by genetic errors leading to accumulation of glycogen in various tissues 1. All the main types of GSD that...

  19. Mutational spectrum and identification of five novel mutations in

    Introduction. Glycogen Storage Disease type 1a (GSD-1a; MIM # 232200), an autosomal recessive inherited metabolic disorder caused by mutations in G6PC1 gene leading to deficiency of glucose-6-phosphatase catalytic unit (G6Pase-α) enzyme that catalyzes hydrolysis of glucose-6-phosphate (G6P) in to glucose and phosphate in the terminal step of gluconeogenesis and glycogenolysis to maintain the ...

  20. (PDF) Glycogen storage disease

    ... Introduction GSD-I (GSD-Ia: OMIM #232200; GSD-Ib: OMIM #232220) is an autosomal recessive disorder first described by von Gierke in 1929 [23], caused by glucose-6-phosphatase enzyme (G6Pase)...

  21. Glycogen Storage Disease

    Glycogen storage disease (GSD) is a rare condition that changes the way the body uses and stores glycogen, a form of sugar or glucose. Glycogen is a main source of energy for the body. Glycogen is stored in the liver. When the body needs more energy, certain proteins called enzymes break down glycogen into glucose.

  22. Glycogen Storage Disease (GSD)

    Glycogen storage diseases (GSDs) are a group of rare conditions in which your body can't use or store glycogen properly. They're types of inherited (passed from parent to child) metabolic disorders. Glycogen is the stored form of glucose (sugar). Glucose is your body's main source of energy.

  23. (PDF) Glycogen storage disease

    Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disease caused by variants in the GBE1 gene, which encodes the glycogen branching enzyme (GBE). GSD IV accounts for approximately 3% of all GSD.