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 nephromegaly. Severely affected infants present in the neonatal period with severe hypoglycemia due to fasting intolerance. More commonly, untreated infants present at age three to four months with hepatomegaly, severe hypoglycemia with or without seizures, lactic acidosis, hyperuricemia, and hypertriglyceridemia. Affected children typically have doll-like faces with full cheeks, relatively thin extremities, short stature, and a protuberant abdomen. Xanthoma and diarrhea may be present. Impaired platelet function and development of reduced or dysfunctional von Willebrand factor can lead to a bleeding tendency with frequent epistaxis and menorrhagia in females. Individuals with untreated GSDIb are more likely to develop impaired neutrophil and monocyte function as well as chronic neutropenia resulting in recurrent bacterial infections, gingivitis, periodontitis, and genital and intestinal ulcers. Long-term complications of untreated GSDI include short stature, osteoporosis, delayed puberty, renal disease (including proximal and distal renal tubular acidosis, renal stones, and renal failure), gout, systemic hypertension, pulmonary hypertension, hepatic adenomas with potential for malignancy, pancreatitis, and polycystic ovaries. Seizures and cognitive impairment may occur in individuals with prolonged periods of hypoglycemia. Normal growth and puberty are 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 (GSDIa) or SLC37A4 (GSDIb). If molecular genetic testing is inconclusive, hepatic enzyme activity analysis is only available for glucose-6-phosphatase catalytic activity (GSDIa).
Management: Treatment of manifestations: Uncooked cornstarch alternating with frequent meals and snacks high in complex carbohydrates as directed by a metabolic specialist and metabolic dietitian to maintain normal blood glucose levels, prevent hypoglycemia, and provide optimal nutrition for growth and development. Nutritional supplements to avoid deficiencies. Surgery or other interventions such as percutaneous ethanol injections and radiofrequency ablation for hepatic adenomas; liver transplantation for individuals refractory to medical treatment. Other treatments include lipid-lowering medications for hyperlipidemia, angiotensin-converting enzyme inhibitors to treat microalbuminuria, allopurinol to prevent and/or treat gout, citrate supplementation to prevent urinary calculi or ameliorate nephrocalcinosis, kidney transplantation for end-stage renal disease, and combined renal and liver transplant when needed. Management of hypertension with avoidance of beta blockers; standard treatment of pancreatitis; developmental support and treatment of seizures as needed, antifibrinolytics and deamino-8-d-arginine vasopressin as needed for bleeding diathesis. Human granulocyte colony-stimulating factor (G-CSF) for neutropenia, recurrent infections, enterocolitis and bowel ulcers. Management of polycystic ovaries and/or irregular menstrual cycles per gynecologist. Thyroid supplementation for hypothyroidism. Social worker or counselor for discussion and coping with chronic disease and possible body image considerations.
Surveillance: Home blood glucose monitoring using a glucometer or continuous glucose monitoring; liver ultrasound every 12 to 24 months until age 16 years; liver CT, ultrasound, or MRI with contrast every six to 12 months in individuals beginning at age 16 years or earlier in individuals with hepatic adenomas; growth and nutritional assessment at each visit; surveillance labs to assess liver function, nutrition, and renal function including blood glucose, lactate, lipid panel, serum uric acid, comprehensive metabolic panel (including BUN, creatinine, AST, ALT, bilirubin, albumin, and electrolytes) every six to 12 months; PT/INR and aPTT every six months. Assess for anemia including CBC, iron, TIBC, and ferritin every six to 12 months; CBC with differential count (including WBC with ANC) every three months for those on G-CSF; serum CRP, ESR, TSH, and free T4 levels annually. Bone density every one to two years and serum 25(OH)-vitamin D annually; renal ultrasound annually beginning at age ten years; blood pressure at each visit; developmental assessment as indicated; evaluation by a gastroenterologist when indicated; colonoscopy when indicated.
Agents/circumstances to avoid: Avoid sucrose, galactose, fructose, high fructose corn syrup, honey, maple syrup, molasses, agave nectar, and sorbitol. Combined oral contraception (including high-dose estrogen) should be avoided in women, particularly those with adenomas. Metformin, amoxicillin/clavulanic acid, and lactate-containing infusions such as Ringer’s lactate should be avoided. Glucagon should not be used to treat hypoglycemia.
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. If both parents are known to be heterozygous for a GSDI-causing pathogenic variant, each sib of an affected individual has at conception 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.
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