CEREBRAL DYSGENESIS AND LACTIC ACIDEMIA - AN MRI MRS PHENOTYPE ASSOCIATED WITH PYRUVATE-DEHYDROGENASE DEFICIENCY/

Pyruvate dehydrogenase complex (PDHC) is an intramitochondrial multien zyme complex essential for the aerobic oxidation of glucose. The major ity of patients with PDHC deficiency have abnormalities in the major c atalytic and regulatory subunit, E1 alpha, which is encoded on the X c hromosome. The clinical spectrum of PDHC deficiency is heterogeneous, particularly in heterozygous females, and diagnosis may be difficult. Three affected infant girls with PDHC deficiency were investigated. Al l had dysmorphic features, microcephaly with profound global developme ntal delay, and hypotonia. Systemic acidosis was absent, although seru m lactate and pyruvate were abnormally elevated. Magnetic resonance im aging revealed hypoplasia of the corpus callosum in all patients. Prot on magnetic resonance spectroscopy of brain revealed large increases i n relative signal intensities for lactic acid and decreases in the rel ative signal intensities of N-acetylaspartate, a marker of neuronal da mage or loss. Phosphorus MRS of muscle revealed abnormally low phospho rylation potentials for all these patients, although the degree of abn ormality was variable and not directly correlated with the amount of b rain lactate. It is proposed that cerebral dysgenesis and cerebral lac tic acidemia as shown by magnetic resonance imaging and proton magneti c resonance spectroscopy are useful diagnostic clues to PDHC deficienc y, particularly in females in whom variable patterns of X-inactivation reduce sensitivity of laboratory diagnosis based on the biochemical s tudies of peripheral: tissues. In addition, muscle bioenergetic abnorm alities in conjunction with CNS dysfunction may contribute to profound hypotonia in this disorder.