Pyruvate dehydrogenase complex (PDHC) is an intramitochondrial multienzyme complex essential for the aerobic oxidation of
glucose. The majority of patients with
PDHC deficiency have abnormalities in the major catalytic and regulatory subunit, E1 alpha, which is encoded on the X chromosome. 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. All had dysmorphic features,
microcephaly with profound global developmental delay, and
hypotonia. Systemic
acidosis was absent, although serum
lactate and
pyruvate were abnormally elevated. Magnetic resonance imaging revealed hypoplasia of the corpus callosum in all patients.
Proton magnetic resonance spectroscopy of brain revealed large increases in relative signal intensities for
lactic acid and decreases in the relative signal intensities of
N-acetylaspartate, a marker of neuronal damage or less.
Phosphorus MRS of muscle revealed abnormally low phosphorylation potentials for all these patients, although the degree of abnormality was variable and not directly correlated with the amount of brain
lactate. It is proposed that cerebral dysgenesis and cerebral lactic acidemia as shown by magnetic resonance imaging and
proton magnetic resonance spectroscopy are useful diagnostic clues to
PDHC deficiency, particularly in females in whom variable patterns of X-inactivation reduce sensitivity of laboratory diagnosis based on the biochemical studies of peripheral tissues. In addition, muscle bioenergetic abnormalities in conjunction with CNS dysfunction may contribute to profound
hypotonia in this disorder.