Horga, A, Woodward, CE, Mills, A, Pareés, I, Hargreaves, IP, Brown, RM, Bugiardini, E, Brooks, T, Manole, A, Remzova, E, Rahman, S, Reilly, MM, Houlden, H, Sweeney, MG, Brown, GK, Polke, JM, Gago, F, Parton, MJ, Pitceathly, RDS and Hanna, MG (2019) Differential phenotypic expression of a novel PDHA1 mutation in a female monozygotic twin pair. Human Genetics, 138 (11-12). pp. 1313-1322. ISSN 0340-6717

Preview

Text Differential phenotypic expression of a novel PDHA1 mutation.pdf - Published Version Available under License Creative Commons Attribution. Download (833kB) | Preview

Abstract

Pyruvate dehydrogenase complex (PDC) deficiency caused by mutations in the X-linked PDHA1 gene has a broad clinical presentation, and the pattern of X-chromosome inactivation has been proposed as a major factor contributing to its variable expressivity in heterozygous females. Here, we report the first set of monozygotic twin females with PDC deficiency, caused by a novel, de novo heterozygous missense mutation in exon 11 of PDHA1 (NM_000284.3: c.1100A>T). Both twins presented in infancy with a similar clinical phenotype including developmental delay, episodes of hypotonia or encephalopathy, epilepsy, and slowly progressive motor impairment due to pyramidal, extrapyramidal, and cerebellar involvement. However, they exhibited clear differences in disease severity that correlated well with residual PDC activities (approximately 60% and 20% of mean control values, respectively) and levels of immunoreactive E1α subunit in cultured skin fibroblasts. To address whether the observed clinical and biochemical differences could be explained by the pattern of X-chromosome inactivation, we undertook an androgen receptor assay in peripheral blood. In the less severely affected twin, a significant bias in the relative activity of the two X chromosomes with a ratio of approximately 75:25 was detected, while the ratio was close to 50:50 in the other twin. Although it may be difficult to extrapolate these results to other tissues, our observation provides further support to the hypothesis that the pattern of X-chromosome inactivation may influence the phenotypic expression of the same mutation in heterozygous females and broadens the clinical and genetic spectrum of PDC deficiency.

Item Type:	Article
Uncontrolled Keywords:	0604 Genetics, 1104 Complementary and Alternative Medicine, 1114 Paediatrics and Reproductive Medicine
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics
Divisions:	Pharmacy & Biomolecular Sciences
Publisher:	Springer
Related URLs:	Author
Date Deposited:	26 Feb 2020 10:49
Last Modified:	04 Sep 2021 07:50
DOI or ID number:	10.1007/s00439-019-02075-9
URI:	https://researchonline.ljmu.ac.uk/id/eprint/12317

View Item