Dr Ira Shah
M.D, DNB, DCH(Gold Medalist), FCPS

A 5 month old male child born of non-consanguineous marriage presented with gradually increasing abdominal distension and generalized tonic convulsion. There were no fever or loose motions.

He had multifocal multiple convulsion on Day 2 of life for which he was admitted for 7 days and diagnosed as hypoglycemic convulsions. At that time his RBS was 19 mg%, CRP was negative with WBC count of 5,600/cumm. He was treated with Phenytoin and Phenobarbitone at that time.

On examination, he had hepatomegaly with liver span of 12 cms and splenomegaly of 4 cms. There was no evidence of cataracts or rickets. In view of the above findings a differential diagnosis of GLYCOGEN STORAGE DISORDER (GSD) Type I or III or galactosemia was considered.

His RBS on admission was 75 mg% which on fasting for 4 hours was 10 mg% Urine showed trace amount of reducing substances but urine sugar chromatography showed only trace amounts of galactose & lactose ruling out galactosemia. His WBC was 5,900/cumm with absolute neutrophil count of 360/cumm suggestive of neutropenia. His serum electrolytes, BUN, creatinine were normal. His lives enzymes were elevated (SGOT = 635 IU/dl, SGPT = 210 IU/dl). His VBG did not show acidosis. His S.LDH was elevated (1764 mg/dl) and so was uric acid [7.6 mg/dl – (Normal – 2.2 – 7.0 mg/dl)] and S.lactate was 75.7 mg/dl (Normal = 5.7-22 mg/dl). An ultrasound of the abdomen showed hepatosplenomegaly with no evidence of portal hypertension.

Thus, a diagnosis of either GSD Type I or Type III was considered, though presence of neutropenia, lactic academia and hyperuricemia was suggestive of Type I b GSD. A glucagon challenge test was done which showed no improvement in the hypoglycemia. However there was presence of metabolic acidosis post glucagons challenge. (S. Lactic acid levels could not be done).

	RBS	pH	HCO3
Pre glucagon	10 mg/dl	7.35	21.8 mmol/L
Past glucagon	8 mg/dl	7.30	10.3 mmol/L

Thus glucagon test was suggestive of GSD I. A liver biopsy was done that showed diffuse fatty change with few dispersed vacuolated cells suggestive of diffused marked steatosis with glycogen storage disorder. This a diagnosis of GSD Type I b was made and the child was advised frequent 2 hourly feeds and uncooked cornstarch supplementation.

Glycogen Storage Disorder: Glycogen storage disorders are inherited disorders of carbohydrate metabolism that affect the glycogen metabolism. The glycogen found in these disorders is abnormal in either quantity or quality. Virtually all enzymes involved in synthesis or degradation of glycogen cause some type of GSD

More than 12 forms of GSD are known at present of which Glucose-6-Phosphatase deficiency (Type I), Pompe’s disease (Type II), debrancher deficiency (Type III) and liver phosphorylase kinase deficiency are the most common forms in children and (Type V) Myophosphorylase deficiency is common in adults.

Type 1-GSD (Von Gierke’s disease) – Type 1 GSD is due to absence or deficiency of Glucose-6-Phosphatase activity in liver, kidney and intestinal mucosa with excessive accumulation of glycogen in these organs. It is an autosomal recessive disorder. Patients with Type 1 GSD present in neonatal period with hygoglycemic seizures and lactic acidosis. They may present at 3-4 mo with hepatomegaly and hypoglycemic seizures with doll like facies due to accumulation of fat on cheeks and growth retardation. Laboratory parameters show hypoglycemia and lactic acidosis on short fast, hyperuricemia and normal or slightly elevated liver enzymes with hyperlipidemia. Liver histology shows not only glycogen but also presence of fat in the hepatocytes with little associated fibrosis. Long-term complications include gout, hepatic adenomas, osteoporosis, renal disease and short stature with most patients surviving to mid adulthood. Diagnosis is suspected on clinical presentation and abnormal lactate & lipid levels. Administration of glucagons or epinephrine results in little or no rise in blood glucose. A definite diagnosis is determination of enzyme activity on liver biopsy or identification of mutations for G-6-P or translocase gene. Treatment is designed to maintain normal blood glucose levels and is achieved by continuous nasogastric infusion or oral administration of uncooked cornstarch. Allopurinol may be given to lower uric acid levels.

A variant, Type I b may have associated findings of neutropenia and impaired neutrophil function resulting in recurrent bacterial infections and oral and intestinal mucosal ulceration.

Type III GSD (Debrancher deficiency, Limit Dextrinosis): It is caused by deficiency of glycogen debranching enzyme activity as a result of which glycogen breakdown is incomplete and an abnormal glycogen with short outer branch chains accumulates. It is an autosomal recessive disorder with genetic defect on chromosome 1p21. The disorder usually affects liver and muscle, however in 15% of patients only liver is involved. Patients present in childhood with hepatomegaly, hypoglycemia, hyperlipidemia and growth retardation and may be indistinguishable from type I disease. In Type III, however blood lactate and uric acid levels are normal and liver enzymes are elevated. The liver symptoms improve with age and disappear after puberty. In patients with muscle involvement, the muscle weakness becomes predominant in adulthood leading to distal muscle wasting and ventricular hypertrophy. Liver histology is characterized by distension of hepatocytes by glycogen and presence of fibrous septa with paucity of fat. Glucagon administered 2 hours after a carbohydrate meal provokes a normal rise of blood glucose but no change after overnight fast. Definitive diagnosis requires enzyme assay in liver or muscle or both. Mutation analysis can also be done. Treatment is symptomatic with frequent feeds and uncooked cornstarch supplementation.

Type IV GSD (Branching enzyme deficiency/Andersen’s disease): Presents with failure to thrive, hypotonia, hepatosplenomegaly progressive cirrhosis and death by 5th year. Liver transplant is effective treatment.

Type VI GSD is caused by deficiency of liver phosphorylase and is a benign condition causing hepatomegaly, mild hypoglycemia, hyperlipidemia and ketosis. There is no hyperlactic acidema or hyperuricemia. Treatment is high carbohydrate diet and frequent feedings.

Type IX GSD – It is due to phosphorylase kinase deficiency and clinical picture depends on organs involved. X-linked liver phosphorylase results in growth retardation and incidentally detected hepatomegaly. Hypoglycemia is mild if present. Symptoms improve with age.

Type V GSD (McArdle’s disease) – is caused by deficiency of muscle phosphorylase and presents in adulthood with exercise intolerance, muscle cramps and attacks of myoglobinuria.

Type VII GSD is caused by deficiency of muscle phosphofructokinase with clinical features similar to GSD V but also associated with hemolytic anemia.

Type II GSD (Pompe’s disease) – It is due to acid maltase deficiency and is an autosomal recessive disorder. Infantile variety presents at 0-6 months with cardiomegaly, hypotonia and hepatomegaly with death by 2 years. Juvenile form presents as myopathy, cardiomyopathy in childhood and death by 2nd decade due to respiratory failure. Adult form presents as slow progressive myopathy without cardiac involvement between 2nd & 7th decade with progressive respiratory failure.