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Glycogen Storage Disease Type I

, PhD, , MD, PhD, , MS, MA, CGC, and , PhD, MS, CGC.

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Initial Posting: ; Last Update: August 25, 2016.

Summary

Clinical characteristics.

Glycogen storage disease type I (GSDI) is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly. The two subtypes (GSDIa and GSDIb) are clinically indistinguishable. Some untreated neonates present with severe hypoglycemia; more commonly, however, untreated infants present at age three to four months with hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, hypertriglyceridemia, and/or hypoglycemic seizures. Affected children typically have doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen. Xanthoma and diarrhea may be present. Impaired platelet function can lead to a bleeding tendency with frequent epistaxis. Untreated GSDIb is associated with impaired neutrophil and monocyte function as well as chronic neutropenia after the first few years of life, all of which result in recurrent bacterial infections and oral and intestinal mucosal ulcers. Long-term complications of untreated GSDI include growth retardation resulting in short stature, osteoporosis, delayed puberty, gout, renal disease, pulmonary hypertension, hepatic adenomas with potential for malignant transformation, polycystic ovaries, pancreatitis, and changes in brain function. Normal growth and puberty is expected in treated children. Most affected individuals live into adulthood.

Diagnosis/testing.

The diagnosis of GSDI is established in a proband by identification of biallelic pathogenic variants in either G6PC or SLC37A4. Deficient hepatic enzyme activity (glucose-6-phosphatase catalytic activity or glucose-6-phosphate exchanger SLC37A4 activity) from a liver biopsy specimen establishes the diagnosis if molecular genetic testing is inconclusive.

Management.

Treatment of manifestations: Medical nutritional therapy to maintain normal blood glucose levels, prevent hypoglycemia, and provide optimal nutrition for growth and development; allopurinol to prevent gout when dietary therapy fails to completely normalize blood uric acid concentration; lipid-lowering medications for elevated lipid levels despite good metabolic control; citrate supplementation to help prevent development of urinary calculi or ameliorate nephrocalcinosis; angiotensin-converting enzyme (ACE) inhibitors to treat microalbuminuria; kidney transplantation for end-stage renal disease (ESRD); surgery or other interventions such as percutaneous ethanol injections and radiofrequency ablation for hepatic adenomas; liver transplantation for those individuals refractory to medical treatment; and treatment with human granulocyte colony-stimulating factor (G-CSF) for recurrent infections.

Prevention of secondary complications: Improve hyperuricemia and hyperlipidemia and maintain normal renal function to prevent development of renal disease; maintain lipid levels within the normal range to prevent atherosclerosis and pancreatitis.

Surveillance: Annual ultrasound examination of the kidneys after the first decade of life; liver ultrasound every 12 to 24 months until age 16 years; in individuals age 16 years and older, liver CT or MRI with contrast every six to 12 months to monitor for hepatic adenomas; liver ultrasound or MRI examinations (depending on age) every three to six months if hepatic adenoma is detected; hepatic profile (AST, ALT, albumin, bilirubin, PT/INR, aPTT) and serum creatinine every six to 12 months; complete blood count every three months for those on G-CSF; imaging with measurement of the spleen for those on G-CSF; systemic blood pressure at every clinic visit beginning in infancy; echocardiography every three years beginning at age ten years (or earlier if symptoms are present) to screen for pulmonary hypertension; routine monitoring of vitamin D levels.

Agents/circumstances to avoid: Diet should be low in fructose and sucrose; galactose and lactose intake should be limited to one serving per day; combined oral contraception should be avoided in women, particularly those with adenomas.

Evaluation of relatives at risk: Molecular genetic testing (if the family-specific pathogenic variants are known) and/or evaluation by a metabolic physician soon after birth (if the family-specific pathogenic variants are not known) allows for early diagnosis and treatment of sibs at risk for GSDI.

Genetic counseling.

GSDI is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic variants have been identified in an affected family member.

Diagnosis

The two major subtypes of glycogen storage disease type I (GSDI) are:

  • GSD type Ia, caused by the deficiency of glucose-6-phosphatase (G6Pase) catalytic activity;
  • GSD type Ib, caused by a defect in glucose-6-phosphate exchanger SLC37A4 (transporter).

The lack of either G6Pase catalytic activity or glucose-6-phosphate exchanger SLC37A4 (transporter) activity in the liver leads to inadequate conversion of glucose-6-phosphate into glucose through normal glycogenolysis and gluconeogenesis pathways, resulting in severe hypoglycemia and many other signs and symptoms of the GSDI disorders.

Guidelines for diagnosis and management have been published by the American College of Medical Genetics and Genomics [Kishnani et al 2014] (full text).

Suggestive Findings

GSDI should be suspected in individuals with the following clinical, laboratory, and histopathologic features.

Clinical findings. Signs of hypoglycemia, hepatomegaly, and growth failure

Laboratory findings

  • Hypoglycemia. Fasting blood glucose concentration <60 mg/dL (reference range: 70-120 mg/dL)
  • Lactic acidosis. Blood lactate >2.5 mmol/L (reference range: 0.5-2.2 mmol/L)
  • Hyperuricemia. Blood uric acid >5.0 mg/dL (reference range: 2.0-5.0 mg/dL)
  • Hyperlipidemia
    • Triglycerides >250 mg/dL (reference range: 150-200 mg/dL); hypertriglyceridemia causes the plasma to appear “milky.”
    • Cholesterol >200 mg/dL (reference range: 100-200 mg/dL)
  • Glucagon or epinephrine challenge test. Administration of glucagon or epinephrine causes little or no increase in blood glucose concentration, but both increase serum lactate concentrations significantly.

Histopathologic liver findings. Distention of the liver cells by glycogen and fat; PAS positive and diastase sensitive glycogen that is uniformly distributed within the cytoplasm; normal or only modestly increased glycogen as compared with that seen in other liver GSDs (especially GSDIII and GSDIX); and large and numerous lipid vacuoles. Fibrosis and cirrhosis do not occur in GSDI.

Note: As liver biopsy is invasive, it should only be done when a diagnosis cannot be made using molecular genetic testing (see Establishing the Diagnosis). Liver tissue may be obtained at the same time as another surgery (e.g., G-tube placement) as a snap-frozen liver sample and diagnosis can be made by measuring G6Pase enzyme activity; however, G6Pase enzyme activity on a piece of snap-frozen liver biopsy tissue will not detect GSDIb.

Establishing the Diagnosis

The diagnosis of GSDI is established in a proband by identification of EITHER of the following:

Molecular Genetic Testing

Molecular testing approaches can include serial single-gene testing, targeted analysis for pathogenic variants, use of a multi-gene panel, and more comprehensive genomic testing:

Enzyme Activity Assay

A sample of 15-20 mg of snap-frozen liver obtained by percutaneous or open biopsy should be shipped on dry ice via overnight delivery to the clinical diagnostic laboratory.

  • Glucose-6-phosphatase (G6Pase) catalytic activity. The normal G6Pase enzyme activity level in liver is 3.50±0.8 µmol/min/g tissue:
    • In most individuals with GSDIa, the G6Pase enzyme activity is <10% of normal.
    • In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (>1.0 µmol/min/g tissue and <2.0 µmol/min/g tissue).
  • Glucose-6-phosphate exchanger SLC37A4 (transporter) activity. G6P exchanger SLC37A4 activity using an in vitro assay is difficult to measure in frozen liver; therefore, fresh (unfrozen) liver is often needed to assay enzyme activity accurately. As a result, most clinical diagnostic laboratories refrain from offering this enzyme activity assay.

Note: Because of its relatively high sensitivity, molecular genetic testing is increasingly the preferred confirmatory test when weighed against the need for liver biopsy to determine the level of enzyme activity. However liver biopsy can additionally be used to obtain histology and electronic micrographic information, which along with enzyme analysis can be used to further investigate pathology associated with variants of uncertain significance (VOUS) found on genetic testing.

Table 1.

Molecular Genetic Testing Used in Glycogen Storage Disease Type I

Gene 1Proportion of GSDI Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detected by Test Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
G6PC80%~95% 52 individuals 6
SLC37A420%~95%Unknown 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.
6.

Although the frequency of (multi)exon deletions is unknown, very few have been reported in either of these genes [Janecke et al 2000, Wang et al 2012].

7.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

The clinical manifestations of glycogen storage disease type I (GSDI) are growth retardation leading to short stature and accumulation of glycogen and fat in the liver and kidneys, which result in hepatomegaly and renomegaly, respectively [Kishnani et al 2014].

Although some neonates present with severe hypoglycemia, more commonly untreated infants present at age three to four months with hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, hypertriglyceridemia, and/or hypoglycemic seizures. Hypoglycemia and lactic acidosis can develop after a short fast (2-4 hours).

Untreated children typically have doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen caused by massive hepatomegaly. The spleen is of normal size. Xanthoma and diarrhea may be present. Impaired platelet function can lead to a bleeding tendency, making epistaxis a frequent problem.

In addition to the above findings, untreated GSDIb is associated with chronic neutropenia and impaired neutrophil and monocyte function. Neutropenia is noted typically after the first few years of life, resulting in recurrent bacterial infections and oral and intestinal mucosal ulcers [Visser et al 1998, Visser et al 2002a]. Oral manifestations such as ulcers, gingivitis, periodontal disease, bleeding diathesis, dental caries, and delayed dental maturation and eruption have been reported in a few affected individuals [Mortellaro et al 2005].

Long-term complications of untreated GSDI include the following:

  • Short stature. Children with GSDI have poor growth and short stature in adulthood; however, with strict dietary regimens and control, growth and final adult stature have improved [Weinstein & Wolfsdorf 2002, Mundy et al 2003, Kishnani et al 2014].
  • Osteoporosis. Frequent fractures and radiographic evidence of osteopenia are common. Bone mineral content can be significantly reduced even in prepubertal children [Schwahn et al 2002, Visser et al 2002b, Wolfsdorf 2002, Rake et al 2003, Cabrera-Abreu et al 2004].
  • Delayed puberty. Untreated affected individuals historically showed delayed onset of puberty; however, with adherence to a strict dietary regimen, age of onset of puberty can be normal [Sechi et al 2013].
  • Gout. Although hyperuricemia is present in young affected children, gout rarely develops in untreated children before puberty [Matern et al 2002].
  • Renal disease. Proteinuria, hypertension, renal stones, nephrocalcinosis, and altered creatinine clearance may occur in younger affected individuals. With disease progression, interstitial fibrosis becomes evident. Some individuals progress to end-stage renal disease (ESRD) and may require a renal transplant [Simöes et al 2001, Weinstein & Wolfsdorf 2002, Iida et al 2003].
  • Systemic hypertension does not usually develop until the second decade or later and is often found in those individuals with GSDI who also have renal disease [Rake et al 2002].
  • Pulmonary hypertension. Overt pulmonary hypertension as a long-term complication of GSDI has been reported [Kishnani et al 1996, Humbert et al 2002]. Those at highest risk typically have a coexisting condition that also predisposes them to developing pulmonary hypertension [Pizzo 1980, Furukawa et al 1990, Hamaoka et al 1990, Bolz et al 1996, Kishnani et al 2014].
  • Hepatic adenomas with potential for malignant transformation. By the second or third decade of life, most affected individuals exhibit hepatic adenomas, a complication of which is intrahepatic hemorrhage. In some, the adenomas may undergo malignant transformation into hepatocellular carcinoma (HCC) [Kelly & Poon 2001, Kudo 2001, Weinstein & Wolfsdorf 2002, Franco et al 2005]. Evidence for a relationship between poor metabolic control and the development of adenomas is conflicting [Di Rocco et al 2007, Wang et al 2011, Kishnani et al 2014, Beegle et al 2015]. While it has been reported, the pathogenesis is likely to be multifactorial [Wang et al 2011].
  • Pancreatitis, a secondary complication of hypertriglyceridemia, is seen in some affected individuals, particularly those in poor dietary compliance.
  • Neurocognitive effects. Changes in IQ, MRI findings, and EEG were found to correlate with the frequency of hypoglycemic episodes, particularly in those in poor dietary compliance [Melis et al 2004].
  • Anemia is a common problem in individuals with GSDI [Rake et al 2002], although the pathophysiology appears to differ in individuals with GSDIa and those with GSDIb [Wang et al 2012]: those with GSDIa and severe anemia are likely to have hepatic adenomas, while those with GSDIb and severe anemia may have enterocolitis [Wang et al 2012].
  • Vitamin D deficiency. In one study, 16/26 affected individuals had suboptimal levels of vitamin D suggesting that 25(OH)-vitamin D levels should be measured on a routine basis [Banugaria et al 2010].
  • Polycystic ovaries. Virtually all affected females have ultrasound findings consistent with polycystic ovaries. While this may affect ovulation and fertility in some females, in general fertility does not appear to be reduced [Sechi et al 2013].
  • Irregular menstrual cycles. About half of women with GSDI were found to have irregular menstrual cycles [Sechi et al 2013].
  • Bleeding diathesis. Some individuals have features suggestive of a von Willebrand disease-like defect with reduced von Willebrand factor antigen and/or dysfunctional von Willebrand factor. Manifestations include epistaxis, easy bruising, menorrhagia, and bleeding during surgical procedures. Menorrhagia appears to be a problem for reproductive-age females with GSDI [Austin et al 2013]. This issue should be addressed when reviewing the clinical history of reproductive-age females with GSDI. Referral to a gynecologist for management should be made when appropriate.

In addition, individuals with GSDIb may develop the following:

  • Neutropenia and impaired neutrophil function. Neutropenia and recurrent infections are common in individuals with GSDIb and can also occur in a small subset of individuals with GSDIa [Weston et al 2000]. Evidence suggests that the neutropenia in those with GSDIb may be caused by increased apoptosis and migration of the neutrophils to inflamed tissues rather than by impairment in maturation [Visser et al 2012, Kishnani et al 2014].
  • Inflammatory bowel disease/enterocolitis is common in individuals with GSDIb [Visser et al 2002b].
  • Thyroid autoimmunity. The prevalence of thyroid autoimmunity and hypothyroidism has been found to be increased in individuals with GSDIb [Melis et al 2007].

In the past, many individuals with GSDI who were untreated died at a young age and the prognosis was guarded in survivors. However, early diagnosis and treatment have improved prognosis. Normal growth and puberty may be expected in treated children, and most affected individuals live into adulthood. However, it is not known if all long-term secondary complications can be avoided by good metabolic control. Some individuals treated early develop hepatic adenoma and proteinuria in adulthood.

Genotype-Phenotype Correlations

No strong genotype-phenotype correlations have been identified for GSDI [Matern et al 2002, Chou & Mansfield 2008, Eminoglu et al 2013, Kishnani et al 2014].

G6PC. Two case reports suggested that individuals with GSDIa who are homozygous for the c.648G>T pathogenic splicing variant may be at increased risk of developing hepatocellular carcinoma (HCC) [Nakamura et al 1999, Matern et al 2002]. This pathogenic variant is the most common cause of GSDIa in individuals of Japanese descent. Of 19 Japanese adults who were homozygous for c.648G>T, three had HCC, one had cholangiocellular carcinoma, and seven had hepatic adenoma [Nakamura et al 2001]. A study of 40 individuals who were homozygous for this pathogenic variant found that c.648G>T is associated with a milder phenotype with respect to hypoglycemia [Akanuma et al 2000, Chou & Mansfield 2008].

Individuals with GSDIa who are homozygous for the pathogenic variant c.562G>C were reported to have a GSDIb-like phenotype with mild neutropenia [Weston et al 2000, Chou & Mansfield 2008]. This phenotype was not observed in an individual who was compound heterozygous for this pathogenic variant [Eminoglu et al 2013].

SLC37A4. No clear phenotype-genotype correlations have been found in GSDIb [Melis et al 2005].

Nomenclature

G6Pase is a multi-component enzyme complex often referred to as the G6Pase system. Some authors preferred to classify GSD type I into 'type Ia' and 'type I non-a' phenotypes because most individuals previously classified as having GSDIc and Id have now been shown to have pathogenic variants in SLC37A4 [Veiga-da-Cunha et al 1998, Veiga-da-Cunha et al 1999, Veiga-da-Cunha et al 2000]. However, all newer publications prefer to classify the GSDI subtypes as GSDIa and GSDIb. Hence, the classification of GSDI into four subtypes no longer exists.

Historically, GSDI is also referred to as von Gierke disease after Dr. Edgar von Gierke, who first described the disease in 1929.

Prevalence

The overall incidence of GSDI is one in 100,000.

GSDIa is the most common GSD subtype in individuals of European descent.

In Ashkenazi Jews the estimated carrier frequency of the most common pathogenic variant (p.Arg83Cys) is 1.4% and disease prevalence is one in 20,000.

The increased frequency of some pathogenic variants in different ethnic groups (e.g., c.648G>T in 88% of affected individuals of Japanese ancestry, c.379_380dupTA in 50% of affected Hispanic Americans) may reflect population-specific differences in disease prevalence [Janecke et al 2001, Chou et al 2002, Ekstein et al 2004].

Differential Diagnosis

Glycogen storage disease type III (GSDIII) (debranching enzyme deficiency) is clinically similar to GSDI in infancy. With age, however, clinical findings and biochemical work up can differentiate between the two disorders. Major manifestations of GSDIII include the following:

  • Hypoglycemia that improves with age
  • Hepatomegaly caused by abnormal glycogen accumulation
  • Hyperlipidemia
  • Skeletal myopathy and increased serum creatine kinase concentration (in GSDIIIa only)

In contrast to GSDI, GSDIII is characterized by the following:

  • Normal glucagon response two hours after a carbohydrate meal
  • Elevated liver transaminases
  • Myopathy/cardiomyopathy (GSDIIIa only)
  • Absence of renomegaly

Other conditions that can present clinically like GSDI include GSD type VI, GSD type IX (phosphorylase kinase deficiency), fructose-1,6-bisphosphatase deficiency (OMIM), diabetes mellitus, and Niemann-Pick type B (see Acid Sphingomyelinase Deficiency).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type I (GSDI), the following evaluations are recommended:

  • Serum/plasma concentration of glucose, lactic acid, uric acid, 25(OH)-vitamin D, and lipids including cholesterol and triglycerides
  • Complete blood count to evaluate for neutropenia in individuals with GSDIb and those with GSDIa due to homozygosity for the p.Gly188Arg pathogenic variant in G6PC
  • Measurement of length or height and weight and calculation of body mass index
  • Evaluation of nutritional status
  • Liver imaging to evaluate for hepatomegaly
  • Liver function tests
  • Kidney imaging to evaluate for renomegaly
  • Kidney function tests
  • Platelet function assay to evaluate platelet function
  • Measurement of bone density (after the first decade)
  • Screening to detect systemic and pulmonary hypertension
  • Metabolic specialist consultation
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Guidelines for management have been published by the American College of Medical Genetics [Kishnani et al 2014] (full text).

Treatment includes care by a metabolic team familiar with the medical issues associated with long-term management of persons with GSD. At a minimum, such a team should include the following:

  • Metabolic specialist familiar with the multisystem nature of GSDI. This individual should monitor current medical issues while providing anticipatory guidance and feedback regarding potential future medical issues (e.g., malignant transformation of liver adenomas, kidney stone management).
  • Metabolic nutritionist who monitors nutritional adequacy, weight management, food choices, and timing of cornstarch and food intake, and who works with the individual and/or family to assure understanding of the parameters of compliance at different life stages
  • Health care provider (nurse, genetic counselor, physician assistant) familiar with the inheritance of GSDI who can address questions related to implications of this diagnosis for other family members and future childbearing of the affected person. Such an individual may focus on health care compliance by assisting affected children to transition to independent understanding and management of their GSDI-related health care issues.

Care teams often establish relationships with additional health care workers including:

  • Medical social worker to assist with formula acquisition and access to community-based services (e.g., access to regular exercise and physical activity plans) and provide early intervention for long-term health management and wellness;
  • Psychologist with experience in helping affected individuals cope with eating disorders and chronic illness.

Medical Nutrition Therapy Goals

Maintain normal glucose levels and prevent hypoglycemia:

  • Frequent daytime feedings. Small frequent meals and snacks high in complex carbohydrates with additional feedings between meals and before bedtime are recommended (monitoring of blood glucose concentration may help adjust feeding schedules to meet individual needs).
  • Nighttime intragastric continuous glucose infusion through a nasogastric tube or a gastrostomy tube. An optimal infusion should provide 8-10 mg/kg/min glucose in an infant and 6-8 mg/kg/min glucose in an older child.
  • Uncooked cornstarch orally can be started during infancy [Wolfsdorf & Crigler 1999, Weinstein & Wolfsdorf 2002]. Cornstarch should be given between meals or before bedtime so as not to interfere with appetite at meal time.
    • Argo® is the preferred brand in the United States in terms of both taste and sustainability. Other brands should be used with caution, and randomly switching between brands is not recommended. A modified cornstarch, waxy maize extended-release cornstarch, Glycosade®, is available in Europe and the United States for overnight treatment [Ross et al 2016].
    • There is no consensus on the age at which cornstarch therapy should be initiated but a trial is often introduced between ages six months and one year. Amylase is required to digest cornstarch and may not be present until age two years.
    • The severity and recurrence of hypoglycemic episodes determines the timing of cornstarch therapy initiation via nasogastric tube or gastrostomy tube in infancy and childhood and oral ingestion in teenagers and adults.
    • Note: Recommendations for uncooked cornstarch dosing are: 1.6 g/kg body weight every four hours for infants, 1.7-2.5 g/kg body weight every six hours for young children through puberty, and 1.7-2.5 g/kg body weight given before bed time for adults. Dosing for modified cornstarch should be decided under the guidance of a metabolic treatment team using frequent glucose monitoring.

Provide optimal nutrition for growth and development:

  • Complex carbohydrates (60%-70% of recommended total energy intake) including cornstarch and starches from whole-grain bread, rice, and potatoes for children and adolescents and rice cereals for infants
    Note: (1) Intake of sucrose and fructose should be restricted for infants and older children. Avoid sugar, fruits, fruit juice, high-fructose corn syrup, sorbitol, cane juice, and other foods that cannot be broken down into glucose. (2) Intake of lactose and galactose should be limited. One serving per day for an older child usually entails 1.5 ounces of cheese OR 1 cup of yogurt OR 1 cup of skim milk. (3) Blood glucose monitoring for hypoglycemia is important so that overtreatment with cornstarch may be avoided. If excess weight gain occurs, consider decreasing the amount of cornstarch gradually over time and mixing cornstarch in water instead of Prosobee® or Tolerex®.
  • Protein (10%-15% of recommended total energy intake) of high quality, high biologic value (e.g., protein low in fat). Soy formula (Prosobee®) and soy milk (lactose/galactose free) can be used both in infancy and childhood for carbohydrate and protein needs.
    Note: (1) Avoid soy milks that are sweetened with sucrose; the ones with rice syrup or brown rice syrup can be taken. (2) Soy milk mixed with cane sugar should be avoided.
  • Fat (10%-15% of recommended total energy intake) as part of a low-fat diet that includes heart-healthy fats such as canola oil and olive oil. Note: Families need explicit guidelines on fat intake as part of monitoring total energy intake and avoiding excessive weight gain.
  • Calcium and vitamin D supplements to support bone growth and mineralization. If the individual is not on calcium-fortified soy milk, calcium citrate or calcium carbonate with vitamin D is recommended to meet RDA for age needs and to prevent nutritional deficiencies.
  • Iron supplements in complete multivitamins with minerals (100% RDA iron and zinc) to avoid anemia and iron deficiency

Treatment of Other Manifestations

Allopurinol, a xanthine oxidase inhibitor, is used to prevent gout when dietary therapy fails to completely normalize blood uric acid concentration, especially after puberty.

Lipid-lowering medications, such as HMG-CoA reductase inhibitors and fibrate (e.g., Lipitor®, gemfibrozil), are used when lipid levels remain elevated despite good metabolic control, especially after puberty.

Citrate supplementation may help prevent or ameliorate nephrocalcinosis and the development of urinary calculi.

  • In young children, an initial dose of 1 mEq/kg/day in liquid form divided into three doses should be instituted. The dose should be increased based on urinary citrate excretion.
  • In older children and adults, potassium citrate tablets can be started at a dose of 10 mEq/3x/day. Citrate use should be monitored as it can cause hypertension and life-threatening hyperkalemia in affected individuals with renal impairment. Sodium levels should also be monitored.

Angiotensin-converting enzyme (ACE) inhibitors such as captopril are used to treat microalbuminuria, an early indicator of renal dysfunction.

Kidney transplantation can be performed for ESRD.

Hepatic adenomas can be treated with surgery or other interventions including percutaneous ethanol injections and radiofrequency ablation.

Liver transplantation can be considered when other interventions have failed.

Human granulocyte colony-stimulating factor (G-CSF) can be used to treat recurrent infections:

  • G-CSF may increase the number and improve the function of circulating neutrophils.
  • G-CSF may improve the symptoms of Crohn's-like inflammatory bowel disease in individuals with GSDIb.
  • G-CSF should be administered subcutaneously starting at 1.0 μg/kg given daily or every other day. The G-CSF dose should be increased stepwise at approximately two-week intervals until the target absolute neutrophil count (ANC) of greater than 500 to up to 1.0 x 109/L is reached.

Standard management of individuals with platelet dysfunction/von Willebrand disease include antifibrinolytics and deamino-8-d-arginine vasopressin (DDAVP), which acts by stimulating factor VIII from endothelial cells and improving von Willebrand factor activity and the platelet release reaction. However, DDAVP should be used with caution due to the risk for fluid overload and hyponatremia.

Prevention of Primary Manifestations

See Treatment of Manifestations.

Prevention of Secondary Complications

Improve hyperuricemia and hyperlipidemia and maintain normal renal function to prevent the development of renal disease.

Maintain lipid levels within the normal range to prevent atherosclerosis and pancreatitis.

Surveillance

Follow GSDI guidelines published recently through a group of experts in the field [Kishnani et al 2014].

Annual ultrasound examination of the kidneys for nephrocalcinosis should be initiated after the first decade of life.

Surveillance of the liver may include the following:

  • In younger children (age <16 years), liver ultrasound performed at diagnosis and thereafter every 12 to 24 months. In affected individuals who are 16 years and older, liver computed tomography (CT) or magnetic resonance imaging (MRI) scanning using intravenous contrast should be done every six to 12 months to monitor for hepatic adenoma formation [Franco et al 2005].
  • Hepatic profile: serum AST, ALT, albumin, bilirubin, PT/INR, and aPTT, and creatinine every six to 12 months to monitor for liver damage
  • When hepatic adenoma is detected. Abdominal CT/MRI with contrast should be performed in older individuals or individuals within the pediatric age group once adenomas are detected on ultrasound. Imaging should be repeated every 6-12 months or more often depending on laboratory and clinical findings. Liver imaging studies (MRI/CT scan) should evaluate liver size, adenomas, evidence of portal hypertension, or features suggestive of liver carcinoma (nodules, heterogeneous echogenic shadows) [Franco et al 2005].
    Note: Serum AFP and CEA levels are not reliable markers of hepatocellular carcinoma [Shieh et al 2012].

For those individuals treated with G-CSF serial blood counts should be performed approximately every three months to assess response to treatment and, although the risk of acute myeloid leukemia (AML) is low, to evaluate for the presence of myeloblasts in the blood. Any imaging performed for liver surveillance (e.g., ultrasound, CT, or MRI) should include measurements of the spleen to identify and monitor splenomegaly.

Cardiovascular surveillance

  • Systemic blood pressure measurements should be obtained at all clinic visits beginning in infancy.
  • Screening for pulmonary hypertension by echocardiography every three years beginning at age ten years (or earlier if symptoms are present) is appropriate.

25(OH)-vitamin D levels should be monitored routinely and treated as needed.

Agents/Circumstances to Avoid

Maintain a low-sucrose, low-fructose diet.

Limit galactose and lactose intake to one serving per day.

Due to potential negative effects of sex hormones on hepatic adenomas, combined oral contraception must be avoided in women with GSDI, especially those with adenomas [Sechi et al 2013, Austin et al 2013].

Evaluation of Relatives at Risk

Evaluation of sibs of a proband as early as possible allows for prompt diagnosis and treatment with much-improved outcome. Evaluations include:

  • Molecular genetic testing if the pathogenic variants in the family are known;
  • Evaluation by a metabolic physician soon after birth for symptoms pertaining to GSDI if the family-specific pathogenic variants are not known or if molecular genetic testing is not available.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although successful pregnancies have been reported in women with GSDI, certain precautions should be taken:

  • Pre-pregnancy counseling regarding diet to avoid low blood glucose and to stress the importance of blood glucose monitoring prior to and during pregnancy
  • Baseline ultrasound of liver and kidneys prior to pregnancy
  • Consideration of referral to high-risk obstetrician
  • Review of medications prior to conception to weigh risks and benefits:
    • Exposure to ACE inhibitors in the second and third trimesters of pregnancy can cause fetal damage and death.
    • No data on the use of allopurinol during pregnancy in humans exist; however, high doses have been shown to interfere with embryo development in animal models.
    • Lipid-lowering drugs may also lead to adverse fetal effects and should be avoided during pregnancy.

Metabolic control should be followed closely throughout the pregnancy. Because carbohydrate requirements may increase with pregnancy, glucose levels should be monitored closely and treated accordingly [Martens et al 2008, Dagli et al 2010, Yamamoto et al 2010, Ferrecchia et al 2014].

Abdominal ultrasound should be performed every six to 12 weeks. Sechi et al [2013] reported an increase in the size of pre-existent adenomas and the development of new adenomas during pregnancy and recommended monitoring by imaging before, during, and after pregnancy. Resection of large (≥5 cm) or growing adenomas before pregnancy has been recommended [Terkivatan et al 2000].

Renal function should be followed closely, as this may worsen during pregnancy [Martens et al 2008, Dagli et al 2010, Yamamoto et al 2010]. Development of renal calculi has been reported in pregnant women with GSDIb [Dagli et al 2010].

Glucose infusion during labor has been used [Martens et al 2008, Dagli et al 2010, Ferrecchia et al 2014].

Platelet count, hemoglobin, and clotting studies should be performed because of the potential for increased bleeding at delivery [Lewis et al 2005].

Therapies Under Investigation

Current dietary treatment prevents hypoglycemia and greatly improves the life expectancy of individuals with GSDI. However, long-term complications, such as development of hepatic adenomas that progress to hepatocellular carcinoma (HCC), and progressive renal failure, still occur. The development of new therapies for GSDI has focused on correcting the primary cause of these disorders and avoiding long-term complications. Pilot studies of hepatocyte transplantation have shown that donor cells persist. However, further studies are needed to investigate the long-term efficacy of this approach [Lee et al 2007, Ribes-Koninckx et al 2012]. Gene therapy strategies for GSDIa and GSDIb have focused, most recently, on recombinant adeno-associated virus (rAAV) vectors. These studies have shown promising results in animal models [Chou & Mansfield 2011, Chou et al 2015]. Increased hepatic G6Pase and G6PT activity and improvement of metabolic parameters has been observed using rAAV-mediated G6PC gene transfer in animal models. However, transgene expression decreased over time, indicating that repeated administration may be necessary for long-term treatment in humans. Strategies to integrate the G6Pase transgene into the genome are being investigated, with promising results [Landau et al 2016]. Of note, a relatively low level (3% of normal) of hepatic G6Pase activity is needed for survival and to prevent formation of hepatocellular adenomas [Lee at al 2015]. Correction of renal G6Pase deficiency by gene therapy has been less well studied, and the most efficient methods for transducing kidney cells continue to be investigated [Chou et al 2015]. Identification of AAV serotypes that effectively transduce all affected tissue types (including liver, kidney, and hematopoietic stem cells) would be beneficial [Chou et al 2015].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Glycogen storage disease type I (GSDI) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one G6PC or SLC37A4 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with GSDI are obligate heterozygotes (carriers) for a pathogenic variant in G6PC or SLC37A4.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier in G6PC or SLC37A4.

Carrier (Heterozygote) Detection

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the G6PC or SLC37A4 pathogenic variants in the family.

Biochemical genetic testing. Enzymatic testing is unreliable and not available for use in carrier detection.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the G6PC or SLC37A4 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Biochemical testing. Prenatal testing based on assay of G6Pase enzymatic activity or G6P translocase enzymatic activity is not available because of the low accuracy rate and risk associated with fetal liver biopsy. The G6Pase enzyme assay in vitro may not differentiate a carrier from either a normal or an affected pregnancy [Chen et al 2002] and thus is not recommended.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association for Glycogen Storage Disease (AGSD)
    PO Box 896
    Durant IA 52747
    Phone: 563-514-4022
    Email: maryc@agsdus.org
  • My46 Trait Profile
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    United Kingdom
    Phone: 0800-652-3181
    Email: info.svcs@climb.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Glycogen Storage Disease Type I: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Glycogen Storage Disease Type I (View All in OMIM)

232200GLYCOGEN STORAGE DISEASE Ia; GSD1A
232220GLYCOGEN STORAGE DISEASE Ib; GSD1B
602671SOLUTE CARRIER FAMILY 37 (GLUCOSE-6-PHOSPHATE TRANSPORTER), MEMBER 4; SLC37A4
613742GLUCOSE-6-PHOSPHATASE, CATALYTIC; G6PC

G6PC

Gene structure. G6PC spans approximately 12.5 kb and consists of five exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. More than 100 pathogenic variants that are scattered throughout the gene have been reported (see Table A). These pathogenic variants include missense and nonsense variants, small deletions and insertions, splice site variants (see Table 2), and other rare large gene rearrangements (See Table 1).

The following are some ethnic-specific common pathogenic variants that account for approximately 90% of known disease alleles [Veiga-da-Cunha et al 1998, Chou et al 2002, Matern et al 2002, Chou & Mansfield 2008].

Table 2.

G6PC Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.79delC
(158delC)
p.Gln27ArgfsTer9NM_000151​.3
NP_000142​.1
c.247C>Tp.Arg83Cys
c.248G>Ap.Arg83His
c.562G>C
(641G>C)
p.Gly188Arg
c.648G>T
(G727T)
p.Tyr202Ter 2
c.1039C>T
(1118C>T)
p.Gln347Ter 3
c.379_380dupTA
(459insTA)
p.Tyr128ThrfsTer3

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

Silent amino acid change (Leu216Leu) that creates a new splice site resulting in premature termination at p.Tyr202Ter [Lam et al 1998]

3.

Normal gene product. G6Pase is a multi-component enzyme system localized in the endoplasmic reticulum membrane. It helps catalyze the terminal reaction of both glucogenolysis and gluconeogenesis, hydrolyzing G6P to glucose and inorganic phosphate in hepatocytes and renal cells.

Abnormal gene product. The pathogenic variants in the G6Pase system cause deficiency of the catalytic activity of the enzyme, thus preventing release of free glucose in the affected tissues (liver, kidney, intestinal mucosa).

SLC37A4

Gene structure. SLC37A4 spans approximately 5.3 kb and comprises nine exons [Veiga-da-Cunha et al 1998, Veiga-da-Cunha et al 2000, Chou et al 2002, Matern et al 2002]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. More than 100 pathogenic variants are known (see Table A). Most are nucleotide substitutions resulting in pathogenic missense or nonsense variants. Some small deletions, splicing variants, and one large deletion have also been found [Janecke et al 2000, Qiu et al 2011] (see Table 3).

Some ethnic-specific common pathogenic variants:

Table 3.

SLC37A4 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.352T>C
(521T>C)
p.Trp118ArgNM_001467​.5
NP_001458​.1
c.1015G>T
(1184G>T)
p.Gly339Cys
c.1042_1043delCT
(1211delCT)
p.Leu348ValfsTer53

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. Glucose-6-phosphate exchanger SLC37A4 (transporter) produces a transport protein that helps transport G6P into the lumen of the endoplasmic reticulum from the cytoplasm and endoplasmic reticulum membrane compartment. G6P transporter is expressed ubiquitously in tissues such as liver, kidney, large intestine, small intestine, skeletal muscle, and (to a lesser extent) the brain and heart, unlike G6Pase.

Abnormal gene product. Deficiency of G6P transporter prevents G6P from crossing the microsomal membrane for hydrolysis and production of glucose.

References

Literature Cited

  1. Akanuma J, Nishigaki T, Fujii K, Matsubara Y, Inui K, Takahashi K, Kure S, Suzuki Y, Ohura T, Miyabayashi S, Ogawa E, Iinuma K, Okada S, Narisawa K. Glycogen storage disease type Ia: molecular diagnosis of 51 Japanese patients and characterization of splicing mutations by analysis of ectopically transcribed mRNA from lymphoblastoid cells. Am J Med Genet. 2000;91:107–12. [PubMed: 10748407]
  2. Austin SL, El-Gharbawy AH, Kasturi VG, James A, Kishnani PS. Menorrhagia in patients with type I glycogen storage disease. Obstet Gynecol. 2013;122:1246–54. [PubMed: 24201678]
  3. Banugaria SG, Austin SL, Boney A, Weber TJ, Kishnani PS. Hypovitaminosis D in glycogen storage disease type I. Mol Genet Metab. 2010;99:434–7. [PubMed: 20060350]
  4. Beegle RD, Brown LM, Weinstein DA. Regression of hepatocellular adenomas with strict dietary therapy in patients with glycogen storage disease type I. JIMD Rep. 2015;18:23–32. [PMC free article: PMC4361930] [PubMed: 25308557]
  5. Bolz D, Stocker F, Zimmermann A. Pulmonary vascular disease in a child with atrial septal defect of the secundum type and type I glycogen storage disease. Pediatr Cardiol. 1996;17:265–7. [PubMed: 8662053]
  6. Cabrera-Abreu J, Crabtree NJ, Elias E, Fraser W, Cramb R, Alger S. Bone mineral density and markers of bone turnover in patients with glycogen storage disease types I, III and IX. J Inherit Metab Dis. 2004;27:1–9. [PubMed: 14970741]
  7. Chen YT, Bali D, Sullivan J. Prenatal diagnosis in glycogen storage diseases. Prenat Diagn. 2002;22:357–9. [PubMed: 12001186]
  8. Chou JY, Jun HS, Mansfield BC. Type I glycogen storage diseases: disorders of the glucose-6-phosphatase/glucose-6-phosphate transporter complexes. J Inherit Metab Dis. 2015;38:511–9. [PubMed: 25288127]
  9. Chou JY, Matern D, Mansfield BC, Chen YT. Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex. Curr Mol Med. 2002;2:121–43. [PubMed: 11949931]
  10. Chou JY, Mansfield BC. Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease. Hum Mutat. 2008;29:921–30. [PMC free article: PMC2475600] [PubMed: 18449899]
  11. Chou JY, Mansfield BC. Recombinant AAV-directed gene therapy for type I glycogen storage diseases. Expert Opin Biol Ther. 2011;11:1011–24. [PMC free article: PMC3126888] [PubMed: 21504389]
  12. Dagli AI, Lee PJ, Correia CE, Rodriguez C, Bhattacharya K, Steinkrauss L, Stanley CA, Weinstein DA. Pregnancy in glycogen storage disease type Ib: gestational care and report of first successful deliveries. J Inherit Metab Dis. 2010;33 Suppl 3:S151–7. [PMC free article: PMC3800278] [PubMed: 20386986]
  13. Di Rocco M, Buzzi D, Tarò M. Glycogen storage disease type II: clinical overview. Acta Myol. 2007;26:42–4. [PMC free article: PMC2949314] [PubMed: 17915568]
  14. Ekstein J, Rubin BY, Anderson SL, Weinstein DA, Bach G, Abeliovich D, Webb M, Risch N. Mutation frequencies for glycogen storage disease Ia in the Ashkenazi Jewish population. Am J Med Genet A. 2004;129A:162–4. [PubMed: 15316959]
  15. Eminoglu TF, Ezgu FS, Hasanoglu A, Tumer L. Rapid screening of 12 common mutations in Turkish GSD 1a patients using electronic DNA microarray. Gene. 2013;518:346–50. [PubMed: 23352793]
  16. Ferrecchia IA, Guenette G, Potocik EA, Weinstein DA. Pregnancy in women with glycogen storage disease Ia and Ib. J Perinat Neonatal Nurs. 2014;28:26–31. [PubMed: 24476649]
  17. Franco LM, Krishnamurthy V, Bali D, Weinstein DA, Arn P, Clary B, Boney A, Sullivan J, Frush DP, Chen YT, Kishnani PS. Hepatocellular carcinoma in glycogen storage disease type Ia: a case series. J Inherit Metab Dis. 2005;28:153–62. [PubMed: 15877204]
  18. Furukawa N, Kinugasa A, Inoue F, Imashuku S, Takamatsu T, Sawada T. Type I glycogen storage disease with vasoconstrictive pulmonary hypertension. J Inherit Metab Dis. 1990;13:102–7. [PubMed: 2109144]
  19. Hamaoka K, Nakagawa M, Furukawa N, Sawada T. Pulmonary hypertension in type I glycogen storage disease. Pediatr Cardiol. 1990;11:54–6. [PubMed: 2304882]
  20. Humbert M, Labrune P, Simonneau G. Severe pulmonary arterial hypertension in type 1 glycogen storage disease. Eur J Pediatr. 2002;161 Suppl 1:S93–6. [PubMed: 12373580]
  21. Iida S, Matsuoka K, Inoue M, Tomiyasu K, Noda S. Calcium nephrolithiasis and distal tubular acidosis in type 1 glycogen storage disease. Int J Urol. 2003;10:56–8. [PubMed: 12534929]
  22. Janecke AR, Lindner M, Erdel M, Mayatepek E, Möslinger D, Podskarbi T, Fresser F, Stöckler-Ipsiroglu S, Hoffmann GF, Utermann G. Mutation analysis in glycogen storage disease type 1 non-a. Hum Genet. 2000;107:285–9. [PubMed: 11071391]
  23. Janecke AR, Mayatepek E, Utermann G. Molecular genetics of type 1 glycogen storage disease. Mol Genet Metab. 2001;73:117–25. [PubMed: 11386847]
  24. Kajihara S, Matsuhashi S, Yamamoto K, Kido K, Tsuji K, Tanae A, Fujiyama S, Itoh T, Tanigawa K, Uchida M, Setoguchi Y, Motomura M, Mizuta T, Sakai T. Exon redefinition by a point mutation within exon 5 of the glucose-6-phosphatase gene is the major cause of glycogen storage disease type 1a in Japan. Am J Hum Genet. 1995;57:549–55. [PMC free article: PMC1801279] [PubMed: 7668282]
  25. Kelly PM, Poon FW. Hepatic tumours in glycogen storage disease type 1 (von Gierke's disease). Clin Radiol. 2001;56:505–8. [PubMed: 11428803]
  26. Kishnani PS, Austin SL, Abdenur JE, Arn P, Bali DS, Boney A, Chung WK, Dagli AI, Dale D, Koeberl D, Somers MJ, Wechsler SB, Weinstein DA, Wolfsdorf JI, Watson MS. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med. 2014;16:e1. [PubMed: 25356975]
  27. Kishnani P, Bengur AR, Chen YT. Pulmonary hypertension in glycogen storage disease type I. J Inherit Metab Dis. 1996;19:213–6. [PubMed: 8739968]
  28. Kojima K, Kure S, Kamada F, Hao K, Ichinohe A, Sato K, Aoki Y, Yoichi S, Kubota M, Horikawa R, Utsumi A, Miura M, Ogawa S, Kanazawa M, Kohno Y, Inokuchi M, Hasegawa T, Narisawa K, Matsubara Y. Genetic testing of glycogen storage disease type Ib in Japan: five novel G6PT1 mutations and a rapid detection method for a prevalent mutation W118R. Mol Genet Metab. 2004;81:343–6. [PubMed: 15059622]
  29. Kudo M. Hepatocellular adenoma in type Ia glycogen storage disease. J Gastroenterol. 2001;36:65–6. [PubMed: 11211215]
  30. Kure S, Suzuki Y, Matsubara Y, Sakamoto O, Shintaku H, Isshiki G, Hoshida C, Izumi I, Sakura N, Narisawa K. Molecular analysis of glycogen storage disease type Ib: identification of a prevalent mutation among Japanese patients and assignment of a putative glucose-6-phosphate translocase gene to chromosome 11. Biochem Biophys Res Commun. 1998;248:426–31. [PubMed: 9675154]
  31. Lam CW, But WM, Shek CC, Tong SF, Chan YS, Choy KW, Tse WY, Pang CP, Hjelm NM. Glucose-6-phosphatase gene (727G-->T) splicing mutation is prevalent in Hong Kong Chinese patients with glycogen storage disease type 1a. Clin Genet. 1998;53:184–90. [PubMed: 9630072]
  32. Landau DJ, Brooks ED, Perez-Pinera P, Amarasekara H, Mefferd A, Li S, Bird A, Gersbach CA, Koeberl DD. In Vivo Zinc Finger Nuclease-mediated Targeted Integration of a Glucose-6-phosphatase Transgene Promotes Survival in Mice With Glycogen Storage Disease Type IA. Mol Ther. 2016;24:697–706. [PMC free article: PMC4886939] [PubMed: 26865405]
  33. Lee YM, Kim GY, Pan CJ, Mansfield BC, Chou JY. Minimal hepatic glucose-6-phosphatase-α activity required to sustain survival and prevent hepatocellular adenoma formation in murine glycogen storage disease type Ia. Mol Genet Metab Rep. 2015;3:28–32. [PMC free article: PMC4750588] [PubMed: 26937391]
  34. Lee KW, Lee JH, Shin SW, Kim SJ, Joh JW, Lee DH, Kim JW, Park HY, Lee SY, Lee HH, Park JW, Kim SY, Yoon HH, Jung DH, Choe YH, Lee SK. Hepatocyte transplantation for glycogen storage disease type Ib. Cell Transplant. 2007;16:629–37. [PubMed: 17912954]
  35. Lewis R, Scrutton M, Lee P, Standen GR, Murphy DJ. Antenatal and Intrapartum care of a pregnant woman with glycogen storage disease type 1a. Eur J Obstet Gynecol Reprod Biol. 2005;118:111–2. [PubMed: 15596284]
  36. Martens DH, Rake JP, Schwarz M, Ullrich K, Weinstein DA, Merkel M, Sauer PJ, Smit GP. Pregnancies in glycogen storage disease type Ia. Am J Obstet Gynecol. 2008;198:646.e1–7. [PMC free article: PMC3812528] [PubMed: 18241814]
  37. Matern D, Seydewitz HH, Bali D, Lang C, Chen YT. Glycogen storage disease type I: diagnosis and phenotype/genotype correlation. Eur J Pediatr. 2002;161 Suppl 1:S10–9. [PubMed: 12373566]
  38. Melis D, Fulceri R, Parenti G, Marcolongo P, Gatti R, Parini R, Riva E, Della Casa R, Zammarchi E, Andria G, Benedetti A. Genotype/phenotype correlation in glycogen storage disease type 1b: a multicentre study and review of the literature. Eur J Pediatr. 2005;164:501–8. [PubMed: 15906092]
  39. Melis D, Parenti G, Della Casa R, Sibilio M, Romano A, Di Salle F, Elefante R, Mansi G, Santoro L, Perretti A, Paludetto R, Sequino L, Andria G. Brain damage in glycogen storage disease type I. J Pediatr. 2004;144:637–42. [PubMed: 15127000]
  40. Melis D, Pivonello R, Parenti G, Della Casa R, Salerno M, Lombardi G, Sebastio G, Colao A, Andria G. Increased prevalence of thyroid autoimmunity and hypothyroidism in patients with glycogen storage disease type I. J Pediatr. 2007;150:300–5. [PubMed: 17307551]
  41. Mortellaro C, Garagiola U, Carbone V, Cerutti F, Marci V, Bonda PL. Unusual oral manifestations and evolution in glycogen storage disease type Ib. J Craniofac Surg. 2005;16:45–52. [PubMed: 15699644]
  42. Mundy HR, Hindmarsh PC, Matthews DR, Leonard JV, Lee PJ. The regulation of growth in glycogen storage disease type 1. Clin Endocrinol (Oxf) 2003;58:332–9. [PubMed: 12608939]
  43. Nakamura T, Ozawa T, Kawasaki T, Nakamura H, Sugimura H. Glucose-6-phosphatase gene mutations in 20 adult Japanese patients with glycogen storage disease type 1a with reference to hepatic tumors. J Gastroenterol Hepatol. 2001;16:1402–8. [PubMed: 11851840]
  44. Nakamura T, Ozawa T, Kawasaki T, Yasumi K, Wang DY, Kitagawa M, Takehira Y, Tamakoshi K, Yamada M, Kida H, Sugie H, Nakamura H, Sugimura H. Case report: Hepatocellular carcinoma in type 1a glycogen storage disease with identification of a glucose-6-phosphatase gene mutation in one family. J Gastroenterol Hepatol. 1999;14:553–8. [PubMed: 10385064]
  45. Pizzo CJ. Type I glycogen storage disease with focal nodular hyperplasia of the liver and vasoconstrictive pulmonary hypertension. Pediatrics. 1980;65:341–3. [PubMed: 6928317]
  46. Qiu ZQ, Lu CX, Wang W, Qiu JJ, Wei M. Mutation in the SLC37A4 gene of glycogen storage disease type Ib in 15 families of the mainland of China. Zhonghua Er Ke Za Zhi. 2011;49:203–8. [PubMed: 21575371]
  47. Rake JP, ten Berge AM, Verlind E, Visser G, Niezen-Koning KE, Buys CH, Smit GP, Scheffer H. Glycogen storage disease type Ia: four novel mutations (175delGG, R170X, G266V and V338F) identified. Mutations in brief no. 220. Online. Hum Mutat. 1999;1999;13:173. [PubMed: 10094563]
  48. Rake JP, ten Berge AM, Visser G, Verlind E, Niezen-Koning KE, Buys CH, Smit GP, Scheffer H. Glycogen storage disease type Ia: recent experience with mutation analysis, a summary of mutations reported in the literature and a newly developed diagnostic flow chart. Eur J Pediatr. 2000;159:322–30. [PubMed: 10834516]
  49. Rake JP, Visser G, Huismans D, Huitema S, van der Veer E, Piers DA, Smit GP. Bone mineral density in children, adolescents and adults with glycogen storage disease type Ia: a cross-sectional and longitudinal study. J Inherit Metab Dis. 2003;26:371–84. [PubMed: 12971425]
  50. Rake JP, Visser G, Labrune P, Leonard JV, Ullrich K, Smit GP. 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. [PubMed: 12373567]
  51. Ribes-Koninckx C, Ibars EP, Calzado Agrasot MÁ, Bonora-Centelles A, Miquel BP, Vila Carbó JJ, Aliaga ED, Pallardó JM, Gómez-Lechón MJ, Castell JV. Clinical outcome of hepatocyte transplantation in four pediatric patients with inherited metabolic diseases. Cell Transplant. 2012;21:2267–82. [PubMed: 23231960]
  52. Ross KM, Brown LM, Corrado MM, Chengsupanimit T, Curry LM, Ferrecchia IA, Porras LY, Mathew JT, Weinstein DA. Safety and Efficacy of Chronic Extended Release Cornstarch Therapy for Glycogen Storage Disease Type I. JIMD Rep. 2016;2016;26:85–90. [PMC free article: PMC4864714] [PubMed: 26303612]
  53. Santer R, Rischewski J, Block G, Kinner M, Wendel U, Schaub J, Schneppenheim R. Molecular analysis in glycogen storage disease 1 non-A: DHPLC detection of the highly prevalent exon 8 mutations of the G6PT1 gene in German patients. Hum Mutat. 2000;16:177. [PubMed: 10923042]
  54. Schwahn B, Rauch F, Wendel U, Schonau E. Low bone mass in glycogen storage disease type 1 is associated with reduced muscle force and poor metabolic control. J Pediatr. 2002;141:350–6. [PubMed: 12219054]
  55. Sechi A, Deroma L, Lapolla A, Paci S, Melis D, Burlina A, Carubbi F, Rigoldi M, Di Rocco M. Fertility and pregnancy in women affected by glycogen storage disease type I, results of a multicenter Italian study. J Inherit Metab Dis. 2013;36:83–9. [PubMed: 22562700]
  56. Seydewitz HH, Matern D. Molecular genetic analysis of 40 patients with glycogen storage disease type Ia: 100% mutation detection rate and 5 novel mutations. Hum Mutat. 2000;15:115–6. [PubMed: 10612834]
  57. Shieh JJ, Lu YH, Huang SW, Huang YH, Sun CH, Chiou HJ, Liu C, Lo MY, Lin CY, Niu DM. Misdiagnosis as steatohepatitis in a family with mild glycogen storage disease type 1a. Gene. 2012;509:154–7. [PubMed: 22909800]
  58. Simöes A, Domingos F, Fortes A, Prata MM. Type 1 glycogen storage disease and recurrent calcium nephrolithiasis. Nephrol Dial Transplant. 2001;16:1277–9. [PubMed: 11390734]
  59. Stroppiano M, Regis S, DiRocco M, Caroli F, Gandullia P, Gatti R. Mutations in the glucose-6-phosphatase gene of 53 Italian patients with glycogen storage disease type Ia. J Inherit Metab Dis. 1999;22:43–9. [PubMed: 10070617]
  60. Terkivatan T, de Wilt JH, de Man RA, Ijzermans JN. Management of hepatocellular adenoma during pregnancy. Liver. 2000;20:186–7. [PubMed: 10847490]
  61. Veiga-da-Cunha M, Gerin I, Chen YT, de Barsy T, de Lonlay P, Dionisi-Vici C, Fenske CD, Lee PJ, Leonard JV, Maire I, McConkie-Rosell A, Schweitzer S, Vikkula M, Van Schaftingen E. A gene on chromosome 11q23 coding for a putative glucose- 6-phosphate translocase is mutated in glycogen-storage disease types Ib and Ic. Am J Hum Genet. 1998;63:976–83. [PMC free article: PMC1377500] [PubMed: 9758626]
  62. Veiga-da-Cunha M, Gerin I, Chen YT, Lee PJ, Leonard JV, Maire I, Wendel U, Vikkula M, Van Schaftingen E. The putative glucose 6-phosphate translocase gene is mutated in essentially all cases of glycogen storage disease type I non-a. Eur J Hum Genet. 1999;7:717–23. [PubMed: 10482962]
  63. Veiga-da-Cunha M, Gerin I, Van Schaftingen E. How many forms of glycogen storage disease type I? Eur J Pediatr. 2000;159:314–8. [PubMed: 10834514]
  64. Visser G, de Jager W, Verhagen LP, Smit GP, Wijburg FA, Prakken BJ, Coffer PJ, Buitenhuis M. Survival, but not maturation, is affected in neutrophil progenitors from GSD-1b patients. J Inherit Metab Dis. 2012;35:287–300. [PubMed: 21863279]
  65. Visser G, Herwig J, Rake JP, Niezen-Koning KE, Verhoeven AJ, Smit GP. Neutropenia and neutrophil dysfunction in glycogen storage disease type 1c. J Inherit Metab Dis. 1998;21:227–31. [PubMed: 9686363]
  66. Visser G, Rake JP, Kokke FT, Nikkels PG, Sauer PJ, Smit GP. Intestinal function in glycogen storage disease type I. J Inherit Metab Dis. 2002a;25:261–7. [PubMed: 12227456]
  67. Visser G, Rake JP, Labrune P, Leonard JV, Moses S, Ullrich K, Wendel U, Groenier KH, Smit GP. Granulocyte colony-stimulating factor in glycogen storage disease type 1b. Results of the European Study on Glycogen Storage Disease Type 1. Eur J Pediatr. 2002b;161 Suppl 1:S83–7. [PubMed: 12373578]
  68. Wang DQ, Carreras CT, Fiske LM, Austin S, Boree D, Kishnani PS, Weinstein DA. Characterization and pathogenesis of anemia in glycogen storage disease type Ia and Ib. Genet Med. 2012;14:795–9. [PMC free article: PMC3808879] [PubMed: 22678084]
  69. Wang DQ, Fiske LM, Carreras CT, Weinstein DA. Natural history of hepatocellular adenoma formation in glycogen storage disease type I. J Pediatr. 2011;159:442–6. [PMC free article: PMC3135733] [PubMed: 21481415]
  70. Weinstein DA, Wolfsdorf JI. Effect of continuous glucose therapy with uncooked cornstarch on the long-term clinical course of type 1a glycogen storage disease. Eur J Pediatr. 2002;161 Suppl 1:S35–9. [PubMed: 12373568]
  71. Weston BW, Lin JL, Muenzer J, Cameron HS, Arnold RR, Seydewitz HH, Mayatepek E, Van Schaftingen E, Veiga-Da-Cunha M, Matern D, Chen YT. Glucose-6-phosphatase mutation G188R confers an atypical glycogen storage disease type Ib phenotype. Pediatr Res. 2000;48:329–34. [PubMed: 10960498]
  72. Wolfsdorf JI. Bones benefit from better biochemical control in type 1 glycogen storage disease. J Pediatr. 2002;141:308–10. [PubMed: 12219049]
  73. Wolfsdorf JI, Crigler JF Jr. Effect of continuous glucose therapy begun in infancy on the long-term clinical course of patients with type I glycogen storage disease. J Pediatr Gastroenterol Nutr. 1999;29:136–43. [PubMed: 10435649]
  74. Yamamoto T, Suzuki Y, Kaneko S, Hattori Y, Obayashi S, Suzumori N, Sugiura M. Glycogen storage disease type Ia (GSD Ia) during pregnancy: report of a case complicated by fetal growth restriction and preeclampsia. J Obstet Gynaecol Res. 2010;36:1125–9. [PubMed: 21058447]

Chapter Notes

Acknowledgments

We acknowledge the Association for Glycogen Storage Disease, individuals with GSD, physicians treating individuals with GSD, and laboratory personnel for their untiring work and cooperation.

Revision History

  • 25 August 2016 (sw) Comprehensive update posted live
  • 19 September 2013 (me) Comprehensive update posted live
  • 23 December 2010 (me) Comprehensive update posted live
  • 2 September 2008 (me) Comprehensive update posted live
  • 19 April 2006 (me) Review posted to live Web site
  • 30 March 2005 (ytc) Original submission
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