Somatic mosaicism for a novel PDHA1 mutation in a male with severe pyruvate dehydrogenase complex deficiency
Kristin K Deeb, Jirair K Bedoyan, Raymond Wang, Leighann Sremba, Molly C Schroeder, George J Grahame, Monica Boyer, Shawn E McCandless, Douglas S Kerr, Shulin Zhang, Kristin K Deeb, Jirair K Bedoyan, Raymond Wang, Leighann Sremba, Molly C Schroeder, George J Grahame, Monica Boyer, Shawn E McCandless, Douglas S Kerr, Shulin Zhang
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.
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References
- Kerr D.S., Zinn A.B. Disorders of pyruvate metabolism and the tricarboxylic acid cycle. In: Sarafoglu K., editor. Essentials of Pediatric Endocrinology and Metabolism. McGraw-Hill; New York: 2009.
- DeBrosse S.D., Okajima K., Zhang S., Nakouzi G., Schmotzer C.L., Lusk-Kopp M., Frohnapfel M.B., Grahame G., Kerr D.S. Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype. Mol. Genet. Metab. 2012;107:394–402.
- Patel K.P., O'Brien T.W., Subramony S.H., Shuster J., Stacpoole P.W. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol. Genet. Metab. 2012;105:34–43.
- Imbard A., Boutron A., Vequaud C., Zater M., de Lonlay P., de Baulny H.O., Barnerias C., Mine M., Marsac C., Saudubray J.M., Brivet M. Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency. Structural implications of novel amino acid substitutions in E1 protein. Mol. Genet. Metab. 2011;104:507–516.
- Barnerias C., Saudubray J.M., Touati G., De Lonlay P., Dulac O., Ponsot G., Marsac C., Brivet M., Desguerre I. Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Dev. Med. Child Neurol. 2010;52:e1–e9.
- Lissens W., De Meirleir L., Seneca S., Liebaers I., Brown G.K., Brown R.M., Ito M., Naito E., Kuroda Y., Kerr D.S., Wexler I.D., Patel M.S., Robinson B.H., Seyda A. Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum. Mutat. 2000;15:209–219.
- Quintana E., Gort L., Busquets C., Navarro-Sastre A., Lissens W., Moliner S., Lluch M., Vilaseca M.A., De Meirleir L., Ribes A., Briones P., Group P.D.H.W. Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency. Clin. Genet. 2010;77:474–482.
- Seyda A., Chun K., Packman S., Robinson B.H. A case of PDH-E1 alpha mosaicism in a male patient with severe metabolic lactic acidosis. J. Inherit. Metab. Dis. 2001;24:551–559.
- Boichard A., Venet L., Naas T., Boutron A., Chevret L., de Baulny H.O., De Lonlay P., Legrand A., Nordman P., Brivet M. Two silent substitutions in the PDHA1 gene cause exon 5 skipping by disruption of a putative exonic splicing enhancer. Mol. Genet. Metab. 2008;93:323–330.
- Mine M., Zater M., Ogier H., Feneux D., Legrand A., Brivet M. A puzzling case of mosaicism with mutation leading to nonsense mediated mRNA decay (NMD) in a male patient with pyruvate dehydrogenase (PDH) deficiency. J. Inherit. Metab. Dis. 2004;27(Suppl. 1):123.
- Okajima K., Warman M.L., Byrne L.C., Kerr D.S. Somatic mosaicism in a male with an exon skipping mutation in PDHA1 of the pyruvate dehydrogenase complex results in a milder phenotype. Mol. Genet. Metab. 2006;87:162–168.
- Soares-Fernandes J.P., Teixeira-Gomes R., Cruz R., Ribeiro M., Magalhaes Z., Rocha J.F., Leijser L.M. Neonatal pyruvate dehydrogenase deficiency due to a R302H mutation in the PDHA1 gene: MRI findings. Pediatr. Radiol. 2008;38:559–562.
- Coughlin C.R., II, Krantz I.D., Schmitt E.S., Zhang S., Wong L.J., Kerr D.S., Ganesh J. Somatic mosaicism for PDHA1 mutation in a male with pyruvate dehydrogenase complex deficiency. Mol. Genet. Metab. 2010;100:296–299.
- Ridout C.K., Brown R.M., Walter J.H., Brown G.K. Somatic mosaicism for a PDHA1 mutation in a female with pyruvate dehydrogenase deficiency. Hum. Genet. 2008;124:187–193.
- Johnson M.T., Mahmood S., Hyatt S.L., Yang H.S., Soloway P.D., Hanson R.W., Patel M.S. Inactivation of the murine pyruvate dehydrogenase (Pdha1) gene and its effect on early embryonic development. Mol. Genet. Metab. 2001;74:293–302.
- Takakubo F., Thorburn D.R., Dahl H.H. A novel mutation and a polymorphism in the X chromosome located pyruvate dehydrogenase E1 alpha gene (PDHA1) Hum. Mol. Genet. 1993;2:1961–1962.
- NCBI, National Center for Biotechnology Information ( , and )
- Ciszak E.M., Korotchkina L.G., Dominiak P.M., Sidhu S., Patel M.S. Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase. J. Biol. Chem. 2003;278:21240–21246.
- Marchler-Bauer A., Zheng C., Chitsaz F., Derbyshire M.K., Geer L.Y., Geer R.C., Gonzales N.R., Gwadz M., Hurwitz D.I., Lanczycki C.J., Lu F., Lu S., Marchler G.H., Song J.S., Thanki N., Yamashita R.A., Zhang D., Bryant S.H. CDD: conserved domains and protein three-dimensional structure. Nucleic Acids Res. 2013;41:D348–D352.
Source: PubMed