Glycogen Storage Disease Type I

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 G6PC1 (formerly 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, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if both pathogenic variants have been identified in an affected family member.

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:

• Biallelic pathogenic variants in G6PC1 (formerly G6PC) (GSDIa) or SLC37A4 (GSDIb) on molecular genetic testing
• Deficient hepatic enzyme activity

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 liver and kidneys (resulting 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].

G6PC1 (formerly 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 multicomponent 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].

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 G6PC1 (formerly 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
• Consultation with a metabolic specialist
• 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.

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 six to 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 – including progressive renal failure and development of hepatic adenomas that progress to hepatocellular carcinoma (HCC) – 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 G6PC1 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].

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