Pyruvate dehydrogenase deficiency: Novel PDHA1 mutation in a child with progressive encephalopathy

Abstract

Pyruvate dehydrogenase complex (PDHc) deficiency is an inborn error of carbohydrate metabolism that is heterogeneous in its presentation and clinical course. Most cases of PDHc deficiency are attributable to mutations in the X-chromosomal PDHA1 gene which encodes the E1α subunit. We report the case of a girl with first symptoms at age 4 months including muscular hypotonia, lactic acidosis and microcephaly. Brain MRI revealed an incomplete corpus callosum and a pronounced generalized cortical atrophy. Muscle biopsy performed for clinically suspected mitochondriopathy revealed normal respiratory chain enzymes. Functional investigation of intact mitochondria from unfrozen muscle tissue showed a deficiency of pyruvate oxidation. Sequencing of PDHA1 gene revealed a heterogeneous mutation c.523G>A resulting in a predicted alanine to threonine substitution at amino acid 175. To the best of our knowledge, this mutation has not yet been reported. However, another mutation in the same codon has been described in a girl with PDHc-deficiency resulting in an amino acid substitution of alanine to proline. The fact that alanine 175 is highly conserved suggests that this substitution is the causative mutation.