Lactate dehydrogenase M-subunit deficiencies: clinical features, metabolic background, and genetic heterogeneities

Lactate dehydrogenase M-subunit deficiency was first reported 1980 as an exertional myoglobinuria. Since then, 6 Japanese and 3 Caucasian families have been reported. Also, typical skin lesions were observed in 1 Japanese patient. Since then, 2 families, one Japanese and one Caucasian, have been found with this typical skin eruption. The metabolic background of exertional myoglobinuria was demonstrated as a result of the impaired reoxidation of NADH produced by glyceraldehyde-3-phosphate-dehydrogenase (G3PD) action. The excess NADH was partly reoxidized by the action of alpha-glycerophosphate dehydrogenase abundant in cytosolic fraction of skeletal muscle. This enzyme reoxidizes excess NADH simultaneously draining out triose phosphate from the glycolytic pathway. Abortive glycolysis results in impaired ATP production followed by rhabdomyolysis. Genomic analysis revealed the heterogeneities of the mutations of this disease.