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

Lookup NU author(s): Professor Robert Taylor


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© 2022 Wiley Periodicals LLC. 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.

Publication metadata

Author(s): Lok A, Fernandez-Garcia MA, Taylor RW, French C, MacFarland R, Bodi I, Champion M, Josifova D, Raymond FL, Iuso A, Jungbluth H, Milan A, Singh RR

Publication type: Article

Publication status: Published

Journal: American Journal of Medical Genetics, Part A

Year: 2022

Pages: Epub ahead of print

Online publication date: 26/05/2022

Acceptance date: 26/03/2022

ISSN (print): 1552-4825

ISSN (electronic): 1552-4833

Publisher: John Wiley and Sons Inc


DOI: 10.1002/ajmg.a.62848


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