Ans. c. Glucose 6-phosphatase (Ref: Harrison 19/e p433e-1, 433e-2t, 433e-5f, 436e-5, 18/e p3200, 3201; Harper's 27/e p166)Diagnosis of a child with hypoglycemia is not able to utilize glucose from glycogenolvsis or gluconeogenesis is Von Gierk's disease. Von Gierk's disease is due to the deficiency of glucose-6 phosphatase.Von Gierk's disease (AR)Inherited as autosomal recessiveQCaused by glucose-6-phosphatase deficiency in liver, kidney, and intestinal mucosa.Skeletal muscle is deficient in glucose-6 phosphatase, so muscles are not affectedQ.Structure of glycogen is normalQ but not available metabolically.Two subtypes of GSD IType IaType Ib* Defective enzyme: Glucose-6- phosphatase* Defective enzyme: TranslocaseThe defects in both subtypes lead to inadequate conversion in the liver of glucose-6-phosphate to glucose and thus make affected individuals susceptible to fasting hypoglycemia.Clinical Features:Clinical features are hypoglycemia, lactic academia, ketosis, hyperlipidemia, increased uric acid and hepato- splenomegalyQ.Liver cells and renal tubule cells loaded with glycogenQ.Organs affected are liver, intestine and kidneyQLong-Term ComplicationsGout, polycystic ovaries, hepatic adenomasIncreased risk of pancreatitis, cardiovascular disease.Frequent fractures (osteopenia/osteoporosis)Renal disease (proteinuria, hypertension, kidney stones, nephrocalcinosis, and altered creatinine clearance)Pulmonary hypertension (rare)Diagnosis:Clinical presentation and abnormal plasma lactate and lipid values suggest that a patient may have GSD IGene-based mutation analysis provides a noninvasive means of reaching a definitive diagnosis for most patients of GSD IDefinitive diagnosis required a liver biopsy to demonstrate a deficiency.Treatment of Type I GSD:Maintenance of normal blood glucose levels through continuous infusion of glucose via feeding tube or oral administration of uncooked cornstarch (slow-release form of glucose)Fructose and galactose cannot be converted to free glucose, their dietary intake should be restricted.Dietary supplements of multivitamins, calcium and Vitamin DAllopurinolUse of medium chain triglycerides, fish oil and lipid-lowering drugs such as statins and fibric acids.ACE inhibitors, Citrate supplementationOrthotropic liver transplantation: Reserved for GSD I patients with liver malignancy, multiple liver adenomas, metabolic derangements refractory to medical management, and/or liver failure.A child was brought to the hospital was found to have hypoglycemia, hepatomegaly and accumulation of highly branched glycogen called limit dextrins. He is likely to be suffering from Cori's disease.Type IIIa Glycogen Storage Disease or Cori's Disease or Forbes Disease:Caused by a deficiency of glycogen debranching enzyme.Childhood: Hepatomegaly, growth retardation, muscle weakness, fasting hypoglycemia,Accumulation of characteristic branched polysaccharide (limit dextrins)Type IlIa Glycogen Storage Disease or Cori's Disease or Forbes DiseaseCaused by a deficiency of glycogen debranching enzymeQ.Debranching & phosphorytase enzyme are responsible for complete degradation of glycogen.When the debranching enzyme is defective, glycogen breakdown is incompleteQ.Abnormal glycogen accumulates with short outer chains and resembles dextrin.Clinical and Laboratory Findings:Deficiency of glycogen debranching enzyme causes hepatomegaly, hypoglycemia, short stature, variable skeletal myopathy, and cardiomyopathy. The disorder usually involves both liver and muscle and is termed type IlIa glycogen storage diseaseHypoglycemia, hyperlipidemia, and elevated liver transaminases occur in childrenQ.Diagnosis:Deficient debranching enzyme activity can be demonstrated in fiver, skeletal muscle, and heart * DNA-based analyses now provide a noninvasive way of subtyping these disorders in most patients.Treatment:Frequent high-carbohydrate meals with cornstarch supplements or nocturnal gastric drip feedings are usually effective in treating hypoglycemiaQA high-protein diet is recommended as gluconeogenesis is intact, providing a source for glucose.Fig. 8: Metabolic pathways related to glycogen storage diseases and galactose and fructose disorders (GSa, active glycogen synthase: GSb, inactive glycogen synthase: Pa. active phosphorylase; Pb, inactive phosphorylase; PaP. phosphorylase a phosphatase; PbKa, active phosphorylase b kinase; PbKb: inactive phosphorylase b kinase; G, glycogenin. the primer prolein for glycogen synthesis)Features of Glycogen Storage Diseases (Disorders with hepatomegaly and hypoglycemia)Type/ Common NameBasic DefectClinical FeaturesCommentsla/ von GierkeGlucose-6-phosphataseGrowth retardation, enlarged liver and kidney, hypoglycemia, elevated blood lactate, cholesterol, triglycerides, and uric acidQCommon, severe hypoglycemia Complications in adulthood include hepatic adenomas, hepatic carcinoma, renal failureQIbGlucose-6-phosphate trans- locaseAs for la. with additional findings of neutropenia and neutrophil dysfunction10% of type IIIIa/ Cori's or Forbes DiseaseLiver & muscle debranching enzymeChildhood: Hepatomegaly, growth retardation, muscle weakness, fasting hypoglycemia, accumulation of characteristic branched polysaccharide (limit dex- trins), elevated liver transaminases; liver symptoms improve with ageQ Adulthood: muscle atrophy and weakness; onset: third to fourth decades; variable cardiomyopathyCommon, intermediateseverity of hypoglycemia; hepatic adenomas, liver cirrhosis, and hepatic carcinoma can occurQIIIbLiver debranching enzyme(normal muscle debrancher activity)Liver symptoms same as in type Illa; no muscle symptoms15% of type IIIVI/ HersLiver phosphorylaseHepatomegaly, variable hypoglycemia, hyperlipidemia and ketosis; symptoms may improve with ageRare, often a "benign"- glycogenosis. severe cases being recognizedIX/ phosphorylase kinase deficiencyLiver phosphorylase kinase a subunitAs for VICommon, X-linked, typically less severe than autosomal forms; clinical variability within and between subtypes; severe cases being recognized0/ glycogen synthase deficiencyGlycogen synthaseFasting hypoglycemia and ketosis, elevated lactic acid & hyperglycemia after glucose loadDecreased glycogen storesXI/ Fanconi-BickelGlucose transporter-2 Failure to thrive, rickets, hepatomegaly, proximal renal tubular dysfunction,impaired glucose & galactose utilizationRare, consanguinity in 70%