Lippincott, Williams & Wilkins, Neurology Genetics, 2(9), p. e200058, 2023
DOI: 10.1212/nxg.0000000000200058
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Background and ObjectivesCoenzyme Q10(CoQ10)–deficient cerebellar ataxia can be due to pathogenic variants in genes encoding for CoQ10biosynthetic proteins or associated with defects in protein unrelated to its biosynthesis. Diagnosis is crucial because patients may respond favorably to CoQ10supplementation. The aim of this study was to identify through whole-exome sequencing (WES) the pathogenic variants, and assess CoQ10levels, in fibroblasts from patients with undiagnosed cerebellar ataxia referred to investigate CoQ10deficiency.MethodsWES was performed on genomic DNA extracted from 16 patients. Sequencing data were filtered using a virtual panel of genes associated with CoQ10deficiency and/or cerebellar ataxia. CoQ10levels were measured by high-performance liquid chromatography in 14 patient-derived fibroblasts.ResultsA definite genetic etiology was identified in 8 samples of 16 (diagnostic yield = 50%). The identified genetic causes were pathogenic variants of the genesCOQ8A(ADCK3) (n = 3 samples),ATP1A3(n = 2),PLA2G6(n = 1),SPG7(n = 1), andMFSD8(n = 1). Five novel mutations were found (COQ8An = 3,PLA2G6n = 1, andMFSD8n = 1). CoQ10levels were significantly decreased in 3/14 fibroblast samples (21.4%), 1 carrying compound heterozygousCOQ8Apathogenic variants, 1 harboring a homozygous pathogenicSPG7variant, and 1 with an unknown molecular defect.DiscussionThis work confirms the importance ofCOQ8Agene mutations as a frequent genetic cause of cerebellar ataxia and CoQ10deficiency and suggestsSPG7mutations as a novel cause of secondary CoQ10deficiency.