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Lok, A.* ; Fernandez-Garcia, M.A.* ; Taylor, R.W.* ; French, C.E.* ; MacFarland, R.* ; Bodi, I.* ; Champion, M.* ; Josifova, D.* ; Raymond, F.L.* ; Iuso, A. ; Jungbluth, H.* ; Milan, A.* ; Singh, R.R.*

Novel phosphopantothenoylcysteine synthetase (PPCS) mutations with prominent neuromuscular features: Expanding the phenotypical spectrum of PPCS-related disorders.

Am. J. Med. Genet. A 188, 2783-2789 (2022)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Biallelic pathogenic variants in phosphopantothenoylcysteine synthetase, PPCS, are a rare cause of a severe early-onset dilated cardiomyopathy with high morbidity and mortality. To date, only five individuals with PPCS-mutations have been reported. Here, we report a female infant who presented in the neonatal period with hypotonia, a necrotizing myopathy with intermittent rhabdomyolysis and other extracardiac manifestations before developing a progressive and ultimately fatal dilated cardiomyopathy. Gene agnostic trio genome sequencing revealed two rare variants in the PPCS [MIM: 609853] in trans, a previously reported pathogenic c.320_334del p. (Pro107_Ala111del) variant, and a c.613-3C>G intronic variant of uncertain significance. Functional studies confirmed the likely pathogenicity of this variant. Our case provides clinical and histopathological evidence for an associated neuromuscular phenotype not previously recognized and expands the evolving phenotypic spectrum of PPCS-related disorders. We also performed a literature search of all previously published cases and summarize the common features.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Coenzyme A ; Dilated Cardiomyopathy ; Pantethine, Neonatal Necrotizing Myopathy ; Phosphopantothenoylcysteine Synthetase ; Ppcs Gene ; Rhabdomyolysis
ISSN (print) / ISBN 1552-4825
e-ISSN 1552-4833
Journal American Journal of Medical Genetics, Part A
Quellenangaben Volume: 188, Issue: 9, Pages: 2783-2789 Article Number: , Supplement: ,
Publisher Wiley
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants UK NHS Specialist Commissioners
Lily Foundation
UK NIHR Biomedical Research Centre for Aging and Age-related disease award
Mitochondrial Disease Patient Cohort (UK)
UK Research & Innovation (UKRI) Medical Research Council UK (MRC)
Wellcome Centre for Mitochondrial Research