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Deficiency of pyruvate dehydrogenase caused by novel and known mutations in the E 1 α subunit
Author(s) -
Cameron Jessie M.,
Levandovskiy Valeriy,
MacKay Neviana,
Tein Ingrid,
Robinson Brian H.
Publication year - 2004
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.30287
Subject(s) - missense mutation , pyruvate dehydrogenase complex , phenotype , mutation , biology , genetics , frameshift mutation , gene , lactic acidosis , protein subunit , ataxia , endocrinology , enzyme , biochemistry , neuroscience
Pyruvate dehydrogenase (PDH)‐complex deficiency (OMIM 312170) is a clinically heterogeneous disorder, with phenotypes ranging from fatal lactic acidosis (LA) in the newborn to chronic neurological dysfunction. To date, over 80 different mutations have been identified in the PDHA1 gene in patients with PDH complex deficiency, which are thus thought to contribute to the PDH deficient phenotype. We have identified 14 additional patients with total PDH complex deficiency, all of whom were found to contain mutations within the PDHA1 gene (E 1 α subunit). The mutations include both missense mutations and duplications. Eight of these patients had novel mutations, and the remaining had mutations that have been identified previously in PDH complex deficient patients, with residual fibroblast activity ranging from 2.4 to 69% of control values. The nature of these mutations illustrates the variability in phenotype for a given gene defect, with intermittent ataxia being the mildest presentation, Leigh syndrome being the most common and severe neonatal LA the most severe. © 2004 Wiley‐Liss, Inc.