Heterozygous Mutations in the ADCK3 Gene in Siblings with Cerebellar Atrophy and Extreme Phenotypic Variability

Abstract

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.

ADCK3‐related Coenzyme Q10 Deficiency: A Potentially Treatable Genetic Disease

“…From a total of 38 cases, we reviewed twenty‐three, including our three new cases, where a response to CoQ 10 was described. Patient characteristics are shown in Table …”

“…The AarF domain containing kinase 3 gene (ADCK3) is involved in CoQ 10 biosynthesis and regulation, and mutations in this gene lead to CoQ 10 deficiency through loss of function, resulting in mitochondrial dysfunction. Owing to advances in molecular genetic tests (i.e., whole‐exome sequencing [WES] or targeted gene panels using next‐generation sequencing [NGS]), variable phenotypic manifestations have been reported . Here we present two patients with a striking response to CoQ 10 replacement, and a third who failed to benefit from inconsistent therapy.…”

Molecular diagnosis of coenzyme Q10deficiency

“…Likewise, for the ADCK3 gene, four patients from two families have been reported as autosomal recessive cerebellar ataxias [39,40]. Strikingly, two siblings sharing the same compound heterozygosity mutations in ADCK3 display extreme phenotypic variability [40]. The most recent discovery is the characterization of six patients with autosomal recessive COQ4 pathogenic mutations [41], supporting the previous observations that CoQ deficiency may also be caused by haploinsufficiency of this and likely other COQ genes [42].…”

“…Interestingly, after a WGS approach, the presence of mutations in COQ2 has been consistently associated with familial and sporadic multiple system atrophy [38]. Likewise, for the ADCK3 gene, four patients from two families have been reported as autosomal recessive cerebellar ataxias [39,40]. Strikingly, two siblings sharing the same compound heterozygosity mutations in ADCK3 display extreme phenotypic variability [40].…”

Biochemical Assessment of Coenzyme Q10 Deficiency

“…The clinical phenotypes of primary CoQ 10 -deficient patients are broader than initially reported in 1989 [33], including (i) a multisystem disorder with steroid-resistant nephrotic syndrome as the main clinical manifestation ( COQ1-PDSS2) [34], ( COQ2 ) [35], ( COQ6) [36] and ( ADCK4 ) [37]; (ii) a multisystem disorder without nephrotic syndrome ( COQ1 - PDSS1) [38], ( COQ9 ) [39] and (COQ7) [40]; (iii) cerebellar ataxia ( COQ8 - ADCK3) [41,42,43,44,45,46,47]; and (iv) myopathy and encephalopathy ( COQ4 ) [48,49,50]. …”