Heterozygous mutations in the ADCK3 gene in siblings with cerebellar atrophy and extreme phenotypic variability

We describe a highly variable clinical presentation of cerebellar ataxia in two sisters. The younger sister demonstrates early onset rapidly progressive cerebellar ataxia accompanied by motor and nonmotor cerebellar features, as well as cognitive decline and psychiatric problems. Mitochondrial respiratory chain enzyme analysis in muscle showed a decrease in complex I + III. Progressive cerebellar atrophy was demonstrated on serial brain MR imaging. Coenzyme Q10 (CoQ10) supplementation, started at the age of 5 years, led to a significant improvement in motor and cognitive abilities with partial amelioration of the cerebellar signs. Discontinuation of this treatment resulted in worsening of the ataxia, cognitive decline, and severe depression. The older sister, who is 32 years old, has nonprogressive dysarthria and clumsiness from the age of 10 years and MRI reveals cerebellar atrophy. Exome sequencing identified compound heterozygosity for a known (p. Thr584delACC (c.1750_1752delACC)) and a novel (p.P502R) mutation in the ACDK3 gene. Conclusions: Patients with primary CoQ10 deficiency due to ADCK3 mutations can demonstrate a wide spectrum of clinical presentations even in the same family. It is difficult to diagnose CoQ10 deficiency based solely on the clinical presentation. Exome sequencing can provide the molecular diagnosis but since it is expensive and not readily available, we recommend a trial of CoQ10 treatment in patients with ataxia and cerebellar atrophy even before confirmation of the molecular diagnosis.