JIMD Reports, Volume 42

Jessie C. Jacobsen, Whitney Whitford, Brendan Swan, Juliet Taylor, Donald R. Love, Rosamund Hill, Sarah Molyneux, Peter M. George, Richard Mackay, Stephen P. Robertson, Russell G. Snell, Klaus Lehnert, Jacobsen, Jessie C., Whitford, Whitney, Swan, Brendan, Taylor, Juliet, Love, Donald R., Hill, Rosamund, Molyneux, Sarah, George, Peter M., Mackay, Richard, Robertson, Stephen P., Snell, Russell G., Lehnert, Klaus

Autosomal recessive ataxias are characterised by a fundamental loss in coordination of gait with associated atrophy of the cerebellum. There is significant clinical and genetic heterogeneity amongst inherited ataxias; however, an early molecular diagnosis is essential with low-risk treatments available for some of these conditions. We describe two female siblings who presented early in life with unsteady gait and cerebellar atrophy. Whole exome sequencing revealed compound heterozygous inheritance of two pathogenic mutations (p.Leu277Pro, c.1506+1G>A) in the coenzyme Q8A gene (COQ8A), a gene central to biosynthesis of coenzyme Q (CoQ). The paternally derived p.Leu277Pro mutation is predicted to disrupt a conserved motif in the substrate-binding pocket of the protein, resulting in inhibition of CoQ10 production. The maternal c.1506+1G>A mutation destroys a canonical splice donor site in exon 12 affecting transcript processing and subsequent protein translation. Mutations in this gene can result in primary coenzyme Q10 deficiency type 4, which is characterized by childhood onset of cerebellar ataxia and exercise intolerance, both of which were observed in this sib-pair. Muscle biopsies revealed unequivocally low levels of CoQ10, and the siblings were subsequently established on a therapeutic dose of CoQ10 with distinct clinical evidence of improvement after 1 year of treatment. This case emphasises the importance of an early and accurate molecular diagnosis for suspected inherited ataxias, particularly given the availability of approved treatments for some subtypes.