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.
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Glucose-6-phosphatase deficiency.Orphanet J Rare Dis. 2011 May 20;6:27. doi: 10.1186/1750-1172-6-27. Orphanet J Rare Dis. 2011. PMID: 21599942 Free PMC article. Review.
Phosphorylase Kinase Deficiency.2011 May 31 [updated 2018 Nov 1]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020. GeneReviews®. 1993–2020. PMID: 21634085 Free Books & Documents. Review.