Cerebellar ataxia and severe muscle CoQ₁₀ deficiency in a patient with a novel mutation in ADCK3

Abstract

Inherited ataxias are a group of heterogeneous disorders in children or adults but their genetic definition remains still undetermined in almost half of the patients. However, CoQ10 deficiency is a rare cause of cerebellar ataxia and ADCK3 is the most frequent gene associated with this defect. We herein report a 48 year old man, who presented with dysarthria and walking difficulties. Brain magnetic resonance imaging showed a marked cerebellar atrophy. Serum lactate was elevated. Tissues obtained by muscle and skin biopsies were studied for biochemical and genetic characterization. Skeletal muscle biochemistry revealed decreased activities of complexes I+III and II+III and a severe reduction of CoQ10, while skin fibroblasts showed normal CoQ10 levels. A mild loss of maximal respiration capacity was also found by high-resolution respirometry. Molecular studies identified a novel homozygous deletion (c.504del_CT) in ADCK3, causing a premature stop codon. Western blot analysis revealed marked reduction of ADCK3 protein levels. Treatment with CoQ10 was started and, after 1 year follow-up, patient neurological condition slightly improved. This report suggests the importance of investigating mitochondrial function and, in particular, muscle CoQ10 levels, in patients with adult-onset cerebellar ataxia. Moreover, clinical stabilization by CoQ10 supplementation emphasizes the importance of an early diagnosis.

Pathogenicity of two COQ7 mutations and responses to 2,4‐dihydroxybenzoate bypass treatment

“…Compared with the patient reported previously , the patient described in this study exhibits fewer and milder symptoms. We speculate that this is most likely because of lesser severity of the patient's UQ deficiency, based on the comparison of quinone levels in skin fibroblasts derived from the patients as well as in vitro assessment of the functional impact of the patients' mutations (Figs A, B, and A).…”

“…Fibroblasts of the previously reported COQ7 patient (V141E) were shown to exhibit severe UQ deficiency . However, the previous study did not report DMQ levels, which is a more sensitive and a more direct indication of reduced COQ7 enzymatic activity.…”

“…Mutations in eight of the 10 genes currently known to be necessary for UQ biosynthesis have been reported . Recently, Freyer et al .…”

“…The main symptoms of the patient we report here are spasticity and hearing loss. Using patient fibroblast cell lines and a heterologous expression system, we first show that both COQ7 mutations (the mutation first described here as well as the mutation from the only previously identified patient ) lead to a drastic decrease of protein stability and consequently a reduction in ubiquinone levels. We also demonstrate different degrees of severity for the two mutations and how the severity of the novel mutation (L111P) depends on another polymorphism in the COQ7 gene but not on the presence of the 1555A>G mtDNA mutation.…”

Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity

“…Here, in contrast, we demonstrated that lack of COQ8A in mice results in a mild phenotype with progressive cerebellar ataxia, mild exercise intolerance, and moderate CoQ deficiency (Figure 6B), recapitulating the more frequent features of ARCA2 (Aure et al, 2004; Barca et al, 2016; Gerards et al, 2010; Horvath et al, 2012; Lagier-Tourenne et al, 2008; Mignot et al, 2013; Mollet et al, 2008). Thus, this work establishes Coq8a −/− mice as a valid model system for studying ARCA2 and testing potential treatments.…”