👤 Peter Hedera

Blepharospasm (BSP) is a type of focal dystonia characterized by involuntary orbicularis oculi spasms that are usually bilateral, synchronous, and symmetrical. Despite strong evidence for genetic contributions to BSP, progress in the field has been constrained by small cohorts, incomplete penetrance, and late age of onset. Although several genetic etiologies for dystonia have been identified through whole-exome sequencing (WES), none of these are characteristically associated with BSP as a singular or predominant manifestation. We performed WES on 31 subjects from 21 independent pedigrees with BSP. The strongest candidate sequence variants derived from in silico analyses were confirmed with bidirectional Sanger sequencing and subjected to cosegregation analysis. Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM₀₀₁₁₂₇₂₂₂.1: c.7261₇₂₆₂delinsGT, p.Pro2421Val), REEP4 (NM₀₂₅₂₃₂.3: c.109C>T, p.Arg37Trp), TOR2A (NM₁₃₀₄₅₉.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM₀₀₅₁₇₃.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM₀₂₂₄₆₀.3: c.94C>A, p.Gly32Cys) and GNA14 (NM₀₀₄₂₉₇.3: c.989₉₉₀del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17, TRPV4, CAPN11, VPS13C, UNC13B, SPTBN4, MYOD1, and MRPL15 were found in two or more independent pedigrees. To our knowledge, none of these genes have previously been associated with isolated BSP, although other CACNA1A mutations have been associated with both positive and negative motor disorders including ataxia, episodic ataxia, hemiplegic migraine, and dystonia. Our WES datasets provide a platform for future studies of BSP genetics which will demand careful consideration of incomplete penetrance, pleiotropy, population stratification, and oligogenic inheritance patterns. Show less

Currently available therapies for essential tremor (ET) provide sufficient control only for less than a half of patients and many unmet needs exist. This is in part due to the empiric nature of existing treatment options and persisting uncertainties about the pathogenesis of ET. The emerging concept of ET as a possible neurodegenerative disorder, better understanding of associated biochemical changes, including alterations in the γ-aminobutyric acid (GABA)-ergic system and gap junctions, and the identification of the role of the leucine-rich repeat and immunoglobulin-like domain-containing 1 (LINGO-1) gene in ET pathogenesis suggest new avenues for more targeted therapies. Here we review the most promising new approaches to treating ET, including allosteric modulation of GABA receptors and modifications of the LINGO-1 pathway. Medically refractory tremor can be successfully treated by high-frequency deep brain stimulation (DBS) of the ventral intermediate nucleus, but surgical therapies are also fraught with limitations due to adverse effects of stimulation and the loss of therapeutic response. The selection of additional thalamic and extrathalamic targets for electrode placements and the development of a closed-loop DBS system enabling automatic adjustment of stimulation parameters in response to changes in electrophysiologic brain activity are also reviewed. Tremor cancellation methods using exoskeleton and external hand-held devices are also briefly discussed. Show less