ANO10 mutations cause ataxia and coenzyme Q10 deficiency

Abstract

Inherited ataxias are heterogeneous disorders affecting both children and adults, with over 40 different causative genes, making molecular genetic diagnosis challenging. Although recent advances in next-generation sequencing have significantly improved mutation detection, few treatments exist for patients with inherited ataxia. In two patients with adult-onset cerebellar ataxia and coenzyme Q10 (CoQ10) deficiency in muscle, whole exome sequencing revealed mutations in ANO10, which encodes anoctamin 10, a member of a family of putative calcium-activated chloride channels, and the causative gene for autosomal recessive spinocerebellar ataxia-10 (SCAR10). Both patients presented with slowly progressive ataxia and dysarthria leading to severe disability in the sixth decade. Epilepsy and learning difficulties were also present in one patient, while retinal degeneration and cataract were present in the other. The detection of mutations in ANO10 in our patients indicate that ANO10 defects cause secondary low CoQ10 and SCAR10 patients may benefit from CoQ10 supplementation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-014-7476-7) contains supplementary material, which is available to authorized users.

Executive and Attentional Disorders, Epilepsy and Porencephalic Cyst in Autosomal Recessive Cerebellar Ataxia Type 3 Due to <b><i>ANO10</i></b> Mutation

“…The coenzyme Q10 deficit observed in case report 1 confirmed that ANO10 mutations can induce this phenotype with metabolic disorder [4] . However, supplementation did not improve ARCA3 symptoms in our patient.…”

“…Seven ARCA3 patients presented cognitive decline (27%) [3,6] and between 2 and 4 presented epilepsy (7-15%) [4,5] out of the 26 cases reported. In addition to the previous 2 epileptic ANO10 patients (one confirmed [4] and one suspected [5] ) in the literature, we reported 2 new epileptic ARCA3 patients. No epileptogenic origin other than ARCA3 was found in case report 1.…”

“…One patient presented with generalized epilepsy [4] . One had presented loss of consciousness and was treated with sodium valproate [5] .…”

“…Mental retardation was reported in 3 patients [1,4] and cognitive decline in 5 patients [3,6] . Reports of neuropsychological performances of 3 Roma/Gypsies patients with childhood-onset ARCA3 due to a truncating ANO10 defect showed mental retardation following ataxia onset [6] .…”

Exposure of phosphatidylserine on the cell surface

“…and Savarese et al 130 for TMEM16E, from Suzuki et al 40 and Castoldi et al 93 for TMEM16F, and Vermeer et al 131 and Balreira et al 132 for TMEM16K Figure 3 The molecular mechanism for PtdSer exposure in cells with high Ca 2+ -concentration. The flippase comprised of P4-ATPase (ATP11A or ATP11C) and CDC50A, and a Ca 2+ -dependent scramblase (TMEM16F) are schematically shown.…”