A defect in pyruvate decarboxylase in a child with an intermittent movement disorder

Area of Science:

• Biochemistry
• Genetics
• Neurology

Background:

• A 9-year-old boy presented with recurrent episodes of cerebellar and choreoathetoid movement disorder since infancy.
• Clinical findings included elevated blood pyruvic acid and urinary alanine, with milder increases in blood alanine and lactate.

Purpose of the Study:

• To investigate the underlying metabolic defect in a patient with an inherited movement disorder.
• To characterize the activity of pyruvate decarboxylase in the patient and his family members.

Main Methods:

• Developed methods to assay pyruvate decarboxylase activity in white blood cells, cultured skin fibroblasts, and cell-free sonicates.
• Measured the oxidation of labeled pyruvate (pyruvic acid-1-(14)C and pyruvic acid-2-(14)C) by patient and control cells.
• Assessed the activity of pyruvate decarboxylase in sonicated fibroblasts from the patient and his parents.

Main Results:

• Patient's cells exhibited less than 20% of control pyruvate oxidation and pyruvate decarboxylase activity.
• Oxidation of other substrates (glutamic acid, acetate, palmitate) and alanine incorporation into protein were normal.
• Father's cell pyruvate oxidation and enzyme activity were intermediate, while the mother's were at or below control lower limits.

Conclusions:

• The patient has an inherited defect in pyruvate decarboxylase, explaining his movement disorder.
• Family studies suggest possible multiple forms of pyruvate decarboxylase, with carrier states identified in the father and potentially the mother.
• Further research is needed to elucidate the precise mechanisms linking this enzymatic defect to the observed clinical symptoms.