Somatic mosaicism for a novel PDHA1 mutation in a male with severe pyruvate dehydrogenase complex deficiency

Abstract

Pyruvate dehydrogenase complex (PDC) deficiencies are mostly due to mutations in the X-linked PDHA1 gene. Males with hemizygous PDHA1 mutations are clinically more severely affected, while those with mosaic PDHA1 mutations may manifest milder phenotypes. We report a patient harboring a novel, mosaic missense PDHA1 mutation, c.523G > A (p.A175T), with a severe clinical presentation of congenital microcephaly, significant brain abnormalities, persistent seizures, profound developmental delay, and failure to thrive. We review published cases of PDHA1 mosaicism.

Keywords: Mosaicism; Mutation analysis; PDHA1 gene; PDHc Deficiency.

Figures

Fig. 1

MRI showing brain anomalies, sequence analysis and protein structure prediction of PDHA1 with c.523G > A (p.A175T) mutation in our patient. A. Brain MRI with and without contrast of our patient at 27 months of age: T2 sagittal image showing severely hypoplastic corpus callosum (arrowhead) (A-i); T2 and T1 axial images, respectively, showing marked ventriculomegaly (arrowhead) and marked loss of volume of the brain parenchyma with marked prominence of the cortical sulci (arrow) (A-ii and iii); and T1 axial image showing a component of cerebellar vermian hypoplasia (arrowhead), consistent with Dandy-Walker variant (A-iv). No abnormalities noted in the basal ganglia and there was absence of the cavum septum pellucidum (not shown here). B. Sequence chromatograms of PDHA1 showing a normal sequence in the proband's mother's blood (B-i); mosaicism for c.523G > A (p.A175T) in the proband's cultured SFs (B-ii); the proband's blood (B-iii); and the proband's buccal cells (B-iv). Note the difference in mosaic ratio among samples; the peak heights vary in forward and reverse sequences and are not quantitative. C.In silico prediction of altered protein structure of PDHA1 c.523G > A (p.A175T) mutation (red) based on Protein Data Bank entry 3EXE (Swiss-pdbViewer 4.1.0, http://spdbv.vital-it.ch). Side-chains and polypeptide backbone of E1α and E1β are depicted in yellow and blue, respectively. Hydrogen bonds are shown in green.