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

• Published in: Clinical genetics Vol. 90; no. 2; pp. 156 - 160
• Main Authors: Barca, E., Musumeci, O., Montagnese, F., Marino, S., Granata, F., Nunnari, D., Peverelli, L., DiMauro, S., Quinzii, C.M., Toscano, A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-08-2016
• Subjects: ADCK3; Ataxia; Ataxia - complications; Ataxia - diagnosis; Ataxia - genetics; Ataxia - physiopathology; cerebellar ataxia; Cerebellar Ataxia - complications; Cerebellar Ataxia - diagnosis; Cerebellar Ataxia - genetics; Cerebellar Ataxia - physiopathology; Codon, Nonsense; CoQ10; Delayed Diagnosis; Electron Transport Chain Complex Proteins - deficiency; Electron Transport Chain Complex Proteins - genetics; Fibroblasts - metabolism; Gene Expression; Homozygote; Humans; Lactic Acid - blood; Magnetic Resonance Imaging; Male; Middle Aged; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Diseases - complications; Mitochondrial Diseases - diagnosis; Mitochondrial Diseases - genetics; Mitochondrial Diseases - physiopathology; mitochondrial disorders; Mitochondrial Proteins - deficiency; Mitochondrial Proteins - genetics; Muscle Weakness - complications; Muscle Weakness - diagnosis; Muscle Weakness - genetics; Muscle Weakness - physiopathology; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiopathology; Mutation; neurodegenerative diseases; Skin - metabolism; Ubiquinone - analogs & derivatives; Ubiquinone - deficiency; Ubiquinone - genetics; neurodegenerative diseases; cerebellar ataxia; ADCK3; mitochondrial disorders; CoQ10
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.12742

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.