MEDizzy - A 6-month-old Caucasian girl is hospitalized for evaluation

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Carbohydrate Metabolism

A 6-month-old Caucasian girl is hospitalized for evaluation of short stature, enlarged liver, and intermittent lethargy/irritability that, on a recent emergency room visit, was accompanied by low blood glucose (hypoglycemia). In the same ward is a 6-year-old African American boy who is being evaluated for severe muscle cramping that raised suspicions for sickle cell disease. The family history is unremarkable for these children; each has a normal sibling and normal parents. Both children are given diagnoses of glycogen storage disease with the infant girl having type I (MIM*232200) affecting liver and the older boy type V (McArdle disease, MIM*232600) affecting mainly muscle. Which of the following conversions explains the difference in these presentations?

ExplanationGlycolysis in muscle produces lactate, which must be converted to glucose by liver or kidney via the Cori cycle. Defects in liver glycogen metabolism therefore impair glucose 6-phosphate production or gluconeogenesis (alanine is also a substrate for gluconeogenesis) with resulting hypoglycemia and liver glycogen storage with or without toxicity (cirrhosis). Defects in muscle glycogen metabolism impair contraction (cramps, fatigue) with decreased serum lactate production during exercise and muscle glycogen accumulation (progressive weakness and atrophy). Glucose 1-phosphate is the first intermediate in the conversion of glycogen to glucose. The enzyme glycogen phosphorylase catalyzes this first step. The second intermediate, glucose 6-phosphate, is subsequently converted to glucose by the enzyme glucose-6-phosphatase. This enzyme is found only in the liver and kidney; thus, these are the only tissues able to break down glycogen for use by other tissues. In tissues such as muscle, glycogen can be broken down to glucose 6-phosphate but can only be used in the cell in which it was produced.