Clinico‐Genetic, Imaging and Molecular Delineation of COQ8A‐Ataxia: A Multicenter Study of 59 Patients

Abstract

Objective To foster trial‐readiness of coenzyme Q8A (COQ8A)‐ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A‐ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). Methods Cross‐modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype–phenotype correlations, 3D‐protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. Results Fifty‐nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A‐ataxia presented as variable multisystemic, early‐onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss‐of‐function variants (82–93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross‐sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild‐to‐moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: −0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. Interpretation This study provides a deeper understanding of the disease, and paves the way toward large‐scale natural history studies and treatment trials in COQ8A‐ataxia. ANN NEUROL 2020;88:251–263

Microarray and qPCR Analysis of Mitochondrial Metabolism Activation during Prenatal and Early Postnatal Development in Rats and Humans with Emphasis on CoQ10 Biosynthesis

“…More than 70 patients suffering from primary CoQ 10 deficiency were described in the literature, and novel cases appear every year [ 66 , 67 , 68 ]. However, up to 123,789 patients were predicted according to the prevalence of homozygous and compound heterozygous afflicted individuals worldwide (27,321 patients carrying a mutation in COQ8A ) [ 69 ].…”

Primary coenzyme Q10 deficiency due to COQ8A gene mutations

“…While the worldwide frequency of primary Coenzyme Q deficiencies has been estimated as 1/50,000 (Alcazar‐Fabra et al, 2018), it is very rare in China; only 11 patients with primary coenzyme Q deficiency‐7 (COQ10D7; with a founder mutation COQ4 : c.370G>A, p.(Gly124Ser) have been reported from southern China (Yu et al, 2019). The clinical manifestations of COQ10D4 are also highly heterogeneous, age of onset can range from infant to late adult onset (Galosi et al, 2019; Horvath et al, 2012; Mignot et al, 2013; Traschütz et al, 2020). The usual clinical phenotypes are progressive gait ataxia and movement disorders (dystonia, tremor, chorea, jerk myoclonus) (Liu et al, 2014; Mignot et al, 2013; Traschütz et al, 2020), similar to our patient.…”

“…The clinical manifestations of COQ10D4 are also highly heterogeneous, age of onset can range from infant to late adult onset (Galosi et al, 2019; Horvath et al, 2012; Mignot et al, 2013; Traschütz et al, 2020). The usual clinical phenotypes are progressive gait ataxia and movement disorders (dystonia, tremor, chorea, jerk myoclonus) (Liu et al, 2014; Mignot et al, 2013; Traschütz et al, 2020), similar to our patient. Other neurological abnormalities include adolescence onset exercise intolerance due to fatigability, seizures, stroke‐like episodes, intellectual disability, spasticity, ophthalmic involvement, decreased visual acuity, sensorineural hearing loss, depression, and pes cavus have been reported (Alcazar‐Fabra et al, 2018; Aure et al, 2004; Blumkin et al, 2014; Horvath et al, 2012; Lagier‐Tourenne et al, 2008; Mollet et al, 2008; Traschütz et al, 2020).…”

The ARCA Registry: A Collaborative Global Platform for Advancing Trial Readiness in Autosomal Recessive Cerebellar Ataxias

“…For example, for RFC1-ataxia, it has helped to reveal multisystemic phenotypes mimicking cerebellar type multiple system atrophy and progressive supranuclear palsy, and hyperkinetic movement disorders such as chorea and dystonia, and provided first sample size calculations based on longitudinal SARA assessments (24). For COQ8A/ADCK3-ataxia, the ARCA Registry facilitated the delineation of clinico-genetic associations, and the longitudinal analysis of SARA scores has provided the first systematic, groupbased evidence for a possible treatment effect of coenzyme Q10 (25). Similarly, the ARCA Registry has enabled the natural history of POLG-related ataxia to be documented through longitudinal SARA and INAS assessments (26).…”