Biallelic pathogenic variants in the COASY gene have been associated with two distinct disease phenotypes, that is, COASY-protein associated neurodegeneration (CoPAN) and pontocerebellar hypoplasia type 12 (PCH 12). We present two siblings that independently presented with significant hypotonia and respiratory insufficiency at birth. Comprehensive genetic testing revealed homozygous variants within COASY, however, the progressive clinical and neuroradiologic findings described here are unique and have not been described previously. Magnetic resonance imaging showed progressive diffuse parenchymal loss throughout the bilateral cerebral hemispheres and atrophy of the basal ganglia and brainstem. As such, this article brings forth two additional cases of COASY-related disorder with abnormal newborn screening acylcarnitine profiles resembling carnitine palmitoyl transferase 1a (CPT1a) deficiency in two siblings who presented at birth with contractures, marked hypotonia and absent respiratory drive.
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CoA synthase plays a critical role in neurodevelopment and neurodegeneration.
Front Cell Neurosci
September 2024
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Article Synopsis
- Coenzyme A (CoA) is super important for our cells because it helps make and break down energy sources in our bodies.
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Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY-associated diseases.
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June 2024
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Objective: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders.
Methods: Patients were identified through targeted or exome sequencing.
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Coenzyme A (CoA) is a vital and ubiquitous cofactor required in a vast number of enzymatic reactions and cellular processes. To date, four rare human inborn errors of CoA biosynthesis have been described. These disorders have distinct symptoms, although all stem from variants in genes that encode enzymes involved in the same metabolic process.
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