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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. The diagnosis of GSDI is based on clinical presentation, abnormal blood/plasma concentrations of glucose, lactate, uric acid, triglycerides, and lipids, and molecular genetic testing. Mutations in G6PC (GSDIa) are responsible for 80% of GSD1 and mutations in SLC37A4 (GSDIb) are responsible for 20% of GSD1. Molecular testing is clinically available for both genes.
Management. Treatment of manifestations: medical nutrition therapy to maintain normal glucose concentrations, 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 when lipid levels are elevated 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; surgery or other interventions such as percutaneous ethanol injections and radiofrequency ablation for hepatic adenomas; liver transplantation for patients refractory to medical treatment or with hepatocellular carcinoma; and treatment with human granulocyte colony-stimulating factor (G-CSF) for recurrent infections in GSDIb. Prevention of secondary complications: improve hyperuricemia and hyperlipidemia and maintain normal renal function to prevent development of renal disease. Surveillance: annual ultrasound examination of the kidneys and liver after the first decade of life; liver ultrasound examinations every three to six months if hepatic adenoma is detected. Agents/circumstances to avoid: Diet should be low in fructose and sucrose; galactose and lactose intake should be limited to one serving per day. Testing of relatives at risk: Molecular genetic testing (if the family-specific mutations are known) and/or evaluation by a metabolic physician soon after birth (if the family-specific mutations are not known) allows for early diagnosis and treatment of sibs at risk for GSDI.
Genetic counseling. GSD1 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. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible by molecular genetic testing if both disease-causing alleles of an affected family member have been identified.
There are two major subtypes of glycogen storage disease type I (GSDI) [Chen 2001, Matern et al 2002, Chen 2004, Chen & Bali 2004]:
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 translocase (transporter)
The diagnosis of GSDI is based on the following [Chen 2001, Rake et al 2002a, Rake et al 2002b, Chen 2004, Chen & Bali 2004]:
Clinical presentation
Abnormal blood/plasma concentrations of glucose, lactate, uric acid, triglycerides, and lipid
Molecular genetic testing [Veiga-da-Cunha et al 1998, Chou et al 2002, Matern et al 2002, Rake et al 2002a, Ekstein et al 2004]
Liver biopsy to measure G6Pase enzyme activity
Glucagon or epinephrine administration causes little or no increase in blood glucose concentration, but both increase serum lactate concentrations significantly.
The lack of either G6Pase catalytic activity or glucose-6-phosphate translocase activity in the liver leads to inadequate conversion of glucose-6-phosphate into glucose through normal glycogenolysis and gluconeogenesis, resulting in the following:
Hypoglycemia. Fasting blood glucose concentration lower than 60 mg/dL (reference range: 70-120 mg/dL)
Lactic acidosis. Blood lactate higher than 2.5 mmol/L (reference range: 0.5-2.2 mmol/L)
Hyperuricemia. Blood uric acid higher than 5.0 mg/dL (reference range: 2.0-5.0 mg/dL)
Hyperlipidemia
Triglycerides higher than 250 mg/dL (reference range: 150-200 mg/dL). Hypertriglyceridemia causes the plasma to appear "milky."
Cholesterol higher than 200 mg/dL (reference range: 100-200 mg/dL)
Hepatic enzyme activity. 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 lower than 10% of normal.
In rare individuals with higher residual enzyme activity and milder clinical manifestations, the G6Pase enzyme activity could be higher (>1.0 µmol/min/g tissue).
Glucose-6-phosphate translocase (transporter) activity. G6P translocase activity in vitro 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.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genes. The two genes known to be associated with GSDI are G6PC (GSDIa) and SLC37A4 (GSDIb) [Veiga-da-Cunha et al 1999, Janecke et al 2001]:
Mutations in G6PC account for approximately 80% of GSDI.
Mutations in SLC37A4 account for approximately 20% of GSDI.
Clinical testing
G6PC (GSDIa). The following are some ethnic-specific common mutations that account for approximately 90% of known disease alleles [Veiga-da-Cunha et al 1998, Chou et al 2002, Matern et al 2002]. These mutations can be used for up to 100% of genetic testing depending on the specific ethnic group:
p.Arg83Cys (Caucasian 32%, Jewish 93%-100%) [Stroppiano et al 1999, Janecke et al 2001, Ekstein et al 2004]
p.Arg83His (Chinese 38%)
c.378_379dupTA (Hispanic 50%) [Rake et al 1999, Matern et al 2002]
c.648G>T (Japanese 88%, Chinese 36%) [Kajihara et al 1995, Lam et al 1998]
c.79delC, p.Gly188Arg, and p.Gln347X (Caucasian 21%) [Seydewitz & Matern 2000, Chou et al 2002]
G6PC (GSDIa). Sequence analysis of G6PC detects mutations in up to 100% of affected individuals in some homogeneous populations [Seydewitz & Matern 2000], but in mixed populations (e.g., in the US) detection rate is approximately 94% because both mutations could not be detected in some individuals with clinically and enzymatically confirmed GSDIa.
SLC37A4 (GSDIb). Full gene sequence analysis of SLC37A4 is clinically available now through some specialized testing laboratories. Sequencing detects mutations in up to 100% of affected individuals in some homogeneous populations [Kure et al 1998, Veiga-da-Cunha et al 1999, Chou et al 2002, Matern et al 2002, Kojima et al 2004], but in mixed populations (e.g., in the US) detection frequency could be lower because both mutations may not be detected in some individuals even though there is clinical suspicion of GSDIb.
| Gene Symbol | Proportion of GSDI Attributed to Mutations in This Gene | Test Method | Mutations Detected | Mutation Detection Frequency by Gene, Test Method, and Population Group | Test Availability | |
|---|---|---|---|---|---|---|
| Ashkenazi Jewish | Non-Ashkenazi Jewish | |||||
| G6PC | 88% | Targeted mutation analysis | p.Arg83Cys | 93% 1 - 100% 2 | ~30% 3 | Clinical
 |
| p.Gln347X | 0%2 | 15% | ||||
| Mutation panel 4 | 100% | ~70%1 | ||||
| Sequence analysis | Sequence variants | 100% 1,3 | ||||
| SLC37A4 | 95% | Sequence analysis | Sequence variants | 95% | Clinical
| |
| Targeted mutation analysis | p.Trp118Arg | Japanese: 50% 5 | ||||
| c.1042_1043delCT and p.Gly339Cys | Caucasians: 50% 6 | |||||
3. Seydewitz & Matern [2000] (in 40 affected individuals)
4. Panel may include: c.79delC, p.Arg83Cys, p.Arg83His, c.378_379dupTA, p.Gly188Arg, p.Gly270Val, c.648G>T, p.Gln242X, p.Gln347X, p.Phe327del
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To confirm the diagnosis in a proband
If snap-frozen liver biopsy is available, it can be analyzed for G6Pase enzymatic activity. Deficient enzyme activity confirms the diagnosis.
If liver biopsy is not possible, complete G6PC sequencing is the next step, followed by complete SLC37A4 sequencing if no G6PC mutations are identified and there is a strong clinical indication of GSDIb.
Carrier testing for at-risk relatives requires prior identification of the two disease-causing mutations in the family.
Note: (1) Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. (2) No enzyme-based carrier testing is available.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of both disease-causing mutations in the family.
No other phenotypes are known to be associated with mutations in G6PC and SLC37A4.
The clinical manifestations of 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 [Chen 2001, Chou et al 2002, Chen & Bali 2004].
Although some neonates present with severe hypoglycemia, more commonly untreated infants present at age three to four months with hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, and/or hypoglycemic seizures. Hypoglycemia and lactic acidosis can develop after a short fast.
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 couple of 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 [Weinstein et al 2001, Rake et al 2002a]:
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].
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.
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) [Simoes et al 2001, Weinstein & Wolfsdorf 2002, Iida et al 2003].
Pulmonary hypertension. Overt pulmonary hypertension as a long-term complication of GSDI has been reported [Humbert et al 2002]
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].
Polcystic ovaries. Virtually all females have ultrasound findings consistent with polycystic ovaries; however, it remains to be seen whether ovulation and fertility are affected.
Pancreatitis. 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].
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 many 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.
No strong genotype-phenotype correlations have been identified for GSDI.
SLC37A4. No clear phenotype-genotype correlations have been found in GSDIb.
G6Pase is a multicomponent enzyme complex often referred to as the G6Pase system. Most authors today prefer 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 mutations in SLC37A4 [Veiga-da-Cunha et al 1998, Veiga-da-Cunha et al 1999, Veiga-da-Cunha et al 2000]. Hence, the classification of GSDI into four subtypes no longer exists. Historically, GSD-I is also referred to as Von Gierke disease after Dr. Von Gierke, who first described the disease in 1929.
Overall incidence of GSDI is one in 100,000.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Glycogen storage disease type III (Cori or Forbes disease; also known as limit dextrinosis) is clinically similar to GSD type I (GSDI) in infancy. However, with age, the 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 (CK) 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 (GSD-IIIa only)
Absence of renomegaly
Other conditions that can present clinically like GSDI include GSD type VI, GSD type IX, diabetes mellitus, and Niemann-Pick type B (see Acid Sphingomyelinase Deficiency).
To establish the extent of disease 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, lipids including cholesterol and triglycerides
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
Bleeding time to evaluate platelet function
Measurement of bone density (after the first decade)
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 also 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
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).
Night-time 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 bed so as not to interfere with appetite at meal time.
Note: Recommendations for 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.
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 [Rake et al 2002a, Rake et al 2002b]. 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 [Rake et al 2002a, Rake et al 2002b]. One serving per day for an older child usually entails 1.5 ounces 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 biological 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.
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 development of urinary calculi [Weinstein 2001, Wolfsdorf & Weinstein 2003].
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 [Weinstein et al 2001].
Hepatic adenomas can be treated with surgery or other interventions including percutaneous ethanol injections and radiofrequency ablation [Yoshikawa et al 2001].
Liver transplantation can be considered when other interventions have failed [Faivre et al 1999].
Treatment with human granulocyte colony-stimulating factor (G-CSF) for recurrent infections in GSDIb may:
Increase the number and improve the function of circulating neutrophils;
Improve the symptoms of Crohn's-like inflammatory bowel disease in individuals with GSDIb [Myrup et al 1998, Visser et al 2000, Calderwood et al 2001, Steinmetz et al 2001, Visser et al 2002c].
Improve hyperuricemia and hyperlipidemia and maintain normal renal function to prevent the development of renal disease.
Annual ultrasound examination of the kidneys for nephrocalcinosis should be initiated after the first decade of life.
Annual ultrasound examination of the liver to monitor for hepatic adenoma formation [Franco et al 2005] is appropriate after the first decade of life.
When hepatic adenoma is detected, ultrasound examination of the liver every three to six months (or more frequently as indicated) is appropriate. Liver imaging studies (MRI/CT scan) for liver size, adenomas, evidence of portal hypertension, or liver carcinoma (nodules, heterogeneous echogenic shadows) should be considered [Faivre et al 1999, Franco et al 2005].
Diet should be low in fructose and sucrose.
Limit galactose and lactose intake to one serving per day.
If the family-specific mutations are known, molecular genetic testing of sibs at risk for GSD type I allows for early diagnosis and treatment with much-improved outcome.
If the family-specific mutations are not known or if molecular genetic testing is not available, sibs at risk for GSDI should be evaluated by a metabolic physician soon after birth for symptoms pertaining to GSDI.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
A new physically modified cornstarch is under clinical investigation [Bhattacharya et al 2007].
Gene therapy is in early stages of research in animals [Yiu et al 2007, Koeberl et al 2008].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Glycogen storage disease type I (GSDI) is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
Heterozygotes (carriers) are asymptomatic.
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.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. The offspring of an individual with GSDI are obligate heterozygotes (carriers) for a disease-causing mutation.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing using molecular genetic testing for at-risk family members is available if the family-specific mutations are known.
Enzymatic testing is unreliable for use in carrier detection.
See Management, Testing 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. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Biochemical testing. Prenatal testing based on assay of G6Pase enzymatic activity or G6Ptranslocase 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 a normal individual or a carrier from an affected pregnancy [Chen et al 2002].
Requests for prenatal testing for conditions such as GSDI that do not affect intellect and have some treatment available are not common. 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 with genetic counselors or a geneticist is appropriate.
Preimplantation genetic diagnosis (PGD). Preimplantation genetic diagnosis may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | HGMD |
|---|---|---|---|
| G6PC | 17q21 | Glucose-6-phosphatase | G6PC |
| SLC37A4 | 11q23 | Glucose-6-phosphate translocase | SLC37A4 |
| 232200 | GLYCOGEN STORAGE DISEASE I |
| 232220 | GLYCOGEN STORAGE DISEASE Ib |
| 602671 | SOLUTE CARRIER FAMILY 37 (GLUCOSE-6-PHOSPHATE TRANSPORTER), MEMBER 4; SLC37A4 |
G6PC
Normal allelic variants. G6PC spans approximately 12.5 kb and consists of five coding exons.
| DNA Nucleotide Change (Alias 1) | Protein Amino Acid Change (Alias 1) | Reference Sequence | |
|---|---|---|---|
| c.79delC (158delC) | p.Gln27ArgfsX9 | NM_000151.2NP_000142.1 | |
| c.247C>T | p.Arg83Cys | ||
| c.248G>A | p.Arg83His | ||
| c.378_379dupTA (459insTA) | p.Tyr128ThrfsX3 | ||
| c.562G>C (641G>C) | p.Gly188Arg | ||
| c.809G>T | p.Gly270Val | ||
| c.648G>T (G727T) | Silent amino acid change (Leu216Leu) that creates new splice site resulting in premature termination at p.Tyr202X 2 | ||
| c.724C>T | p.Gln242X | ||
| c.979_981del | p.Phe327del | ||
| c.1039C>T (1118C>T) | p.Gln347X | ||
| c.379_380dupTA (459insTA) | p.Tyr128ThrfsX3 | ||
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://www.hgvs.org).
1. Variant designation that does not conform to current naming conventions
Normal gene product. G6Pase is a multicomponent 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 disease-causing mutations 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
Normal allelic variants. SLC37A4 spans approximately 5.3 kb and contains nine exons [Veiga-da-Cunha et al 1998, Veiga-da-Cunha et al 2000, Chou et al 2002, Matern et al 2002].
Some ethnic-specific common mutations:
p.Gly339Cys (Caucasian 15%, German 29%) and c.1042_1043delCT (Caucasian 31%, German 32%) [Veiga-da-Cunha et al 1999, Santer et al 2000, Chou et al 2002]
p.Trp118Arg (50% Japanese) [Kure et al 1998, Nakamura et al 1999, Matern et al 2002, Kojima et al 2004]
| DNA Nucleotide Change (Alias 1) | Protein Amino Acid Change | Reference Sequence |
|---|---|---|
| c.352T>C (521T>C) | p.Trp118Arg | NM_001467.4NP_001458.1 |
| c.1015G>T (1184G>T) | p.Gly339Cys | |
| c.1042_1043delCT (1211delCT) | p.Leu348ValfsX53 | |
| c.1099G>A | p.Ala367Thr |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://www.hgvs.org).
1. Variant designation that does not conform to current naming conventions
Normal gene product. Glucose-6-phosphate translocase (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 tissue like 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.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
We acknowledge the AGSD association, patients with GSD, physicians treating patients with GSD, and laboratory personnel for their untiring work and cooperation.
2 September 2008 (me) Comprehensive update posted live
19 April 2006 (me) Review posted to live Web site
30 March 2005 (ytc) Original submission
