SUMMARY Dystonia is a brain disorder causing involuntary, often painful movements. Apart from a role for dopamine deficiency in some forms, the cellular mechanisms underlying most dystonias are currently unknown. Here, we discover a role for deficient eIF2α signaling in DYT1 dystonia, a rare inherited generalized form, through a genome-wide RNAi screen. Subsequent experiments including patient-derived cells and a mouse model support both a pathogenic role and therapeutic potential for eIF2α pathway perturbations. We further find genetic and functional evidence supporting similar pathway impairment in patients with sporadic cervical dystonia, due to rare coding variation in the eIF2α effector ATF4/CREB2. Considering also that another dystonia, DYT16, involves a gene upstream of the eIF2α pathway, these results mechanistically link multiple forms of dystonia and put forth a new overall cellular mechanism for dystonia pathogenesis – impairment of eIF2α signaling, a pathway known for its roles in cellular stress responses and synaptic plasticity.

ObjectiveTo identify the genetic cause of autosomal dominant spinocerebellar ataxia and retinitis pigmentosa in a large extended pedigree.MethodsClinical studies were done at 4 referral centers. Ten individuals in the same extended family participated in at least a portion of the study. Records were obtained from an 11th, deceased, individual. Neurologic and dermatological examinations were performed. Ophthalmologic evaluation including funduscopic examination and in some cases ocular coherence tomography were used to identify the presence of retinal disease. Whole exome sequencing (WES), in conjunction with Sanger sequencing and segregation analysis, was used to identify potential genetic mutation.ResultsAffected individuals reported slowly progressive cerebellar ataxia with age at onset between 38 and 57. Imaging demonstrated cerebellar atrophy (3/3). WES identified a novel heterozygous mutation in the elongation of very long chain fatty acids 4 (ELOVL4) gene (c.512T>C, p.Ile171Thr) that segregated with ataxia in 7 members tested. Four of 8 members who underwent ophthalmologic evaluation were found to have retinitis pigmentosa. No skin findings were identified or reported. Ocular movement abnormalities and pyramidal tract signs were also present with incomplete penetrance.ConclusionsWe report a family with both spinocerebellar ataxia and retinal dystrophy associated with an ELOVL4 mutation. In addition, to supporting prior reports that ELOVL4 mutations can cause spinocerebellar ataxia, our findings further broaden the spectrum of clinical presentations associated with spinocerebellar ataxia 34.