1. A mother brings her infant son to your pediatric clinic, complaining that he

Question

1. A mother brings her infant son to your pediatric clinic, complaining that he is acting lethargic. You examine the child and find that he is severely underweight for his age and that he has a distended abdomen. You find that the child is hypoglycemic, despite feeding just three hours earlier. You perform more tests, in which you find:

I. The child's muscles are quite weak, suggesting myopathy.

II. The distended abdomen is due to an unusually large liver (hepatomegaly).

III. A liver biopsy shows fibrosis with glycogen filled liver cells.

You suspect that the child may have Cori's disease (a defect in glycogen debranching enzyme). Why does the child have a) hypoglycemia (low blood sugar) and b) glycogen filled liver cells?

Explanation / Answer

In general Glycogen storage disease (GSD) results from the absence of enzymes that ultimately convert glycogen compounds to glucose. Enzyme deficiency results in glycogen accumulation in tissues specially liver and muscles . In many cases, the defect has systemic consequences, but, in some cases, the defect is limited to specific tissues. Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly.

Cori's disease or Forbes - cori disease or Type III GSD associated with a defect in glycogen debranching enzyme rather more specifically mutation in AGL gene for that enzyme,  inherited as an autosomal recessive manner.

Due to lack of the debranching enzyme (alpha-1,6-glucosidase) the stored glycogen can not be utilised fully. Carl and Gerty Cori found that in this patients, the structure of liver and muscle glycogen is abnormal and the amount is markedly increased. Most striking, the outer branches of the glycogen are very short. only the outermost branches of glycogen can be effectively utilized and then the process stops essentially due to lack of debranching enzyme.

The debranching enzyme has two catalytic sites in a single polypeptide chain. One is a glucan transferase that transfers a trisaccharide unit from one branch to the other, exposing the 1 6 branch point. The other is a
1,6-glycosidase that catalyzes hydrolysis of the 1 6 glycoside bond to liberate free glucose. Further phosphorylase action can then proceed.

The liver cells are studed with the abnormal structures of glycogen with very short outer branch as the process of glycogenolysis stops due to lack of that enzyme.

And glycogen ( mainly liver glycogen ) functions as a reserve to maintain the blood glucose concentration in the fasting state, aided by the process glycogenolysis. So without or in reduced rate of that process there would be shortage in supply of glucose in blood. Thus in Cori's disease, without proper utilization of glycogen. there is low blood sugar, presented as hypoglycaemia at the same time accumulation of abnormal structured glycogen in liver presenting as hepatomegali.

Thanks for asking.

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