Short communicationEvaluation of SCN8A as a candidate gene for autosomal dominant essential tremor
Introduction
Essential tremor (ET) is one of the most common neurological disorders of adults, affecting 0.4–3.9% of the population [1]. ET is characterized by bilateral, predominantly symmetrical, postural and/or kinetic tremor involving mostly the upper extremities, including head and voice tremor [1]. ET is clinically heterogeneous, and additional movement abnormalities such as dystonia may be associated with postural or kinetic tremor [1]. Patients with advanced ET also develop predominantly midline ataxia. Most reported pathologic changes are localized in the cerebellum, supporting the emerging view that that ET is primarily a cerebellar disorder [2].
ET appears to be inherited in a significant proportion of cases. A positive family history is present in 30–70% of ET cases, suggesting a strong genetic component [3]. Childhood onset is observed in ∼5% of ET patients, and among these early onset patients, approximately 80% belong to families with autosomal dominant inheritance [4]. There is considerable variation in age of onset within families, suggesting that childhood onset ET is unlikely to be a separate condition [5]. Genetic loci responsible for ET in individual families have been mapped to chromosome 3q13, 2p24.1, 6p23, and 5q31.1–q33.1, but disease causing genes have not been conclusively identified. The Ser9Gly variant in the dopamine receptor gene DRD3 may increase susceptibility to the disease [2], but this finding was not replicated in a large cohort of patients [6]. A SNP in the HS1-BP3 gene, which is located within the ET locus on chromosome 2p is also likely to be a benign polymorphism [2].
Since the genetics of ET is fraught with difficulties, animal models with similar clinical phenotypes may be useful in identifying genes with a role in pathogenesis. Several mouse mutants of the voltage gated sodium channel gene Scn8a exhibit postural and kinetic tremor of the extremities, in combination with ataxia and dystonia [7]. For example, mice with the medjolting mutant that alters the voltage dependence of the channel display a wide unsteady gait and a rhythmic tremor in the head and neck.
Voltage gated sodium channel α subunits are large transmembrane proteins composed of four homologous domains with voltage sensor and pore regions. Voltage gated sodium channels are responsible for the initiation and propagation of neuronal action potentials. The nine orthologous mammalian sodium channels differ in biophysical properties, subcellular localization and tissue specificity. Mutations in different neuronal sodium channel genes are responsible for inherited forms of epilepsy, migraine, and pain disorders [8].
SCN8A encodes the voltage gated sodium channel Nav1.6, one of the most abundant channels in the central and peripheral nervous system. Nav1.6 is localized at axonal initial segments, dendrites, and nodes of Ranvier in myelinated axons. Expression of Nav1.6 is required for repetitive firing of neuronal populations implicated in tremorogenesis, including cerebellar Purkinje neurons, cortical pyramidal neurons, and subthalamic nucleus neurons [7]. Heterozygotes for a null mutation of human SCN8A exhibit ataxia and cognitive defects [9]. Because tremor is a common feature of mice with mutations in Scn8a, we explored the role of the human gene as a candidate gene for autosomal dominant (AD) form of ET.
Section snippets
Subjects
Every patient was diagnosed by a movement disorder neurologist (PH) and signed an informed consent, approved by the Institutional Review Board at Vanderbilt University. The cohort of unrelated Caucasian patients of a northern European ancestry was diagnosed with definite ET based on the following criteria: the presence of bilateral postural and kinetic arm tremor without prominent asymmetry lasting at least for more than five years, the absence of additional neurologic abnormalities, no history
Results
We included 95 ET patients (42 men, 53 women, average current age 53 ± 22 years) with mean WHIGET score 16.3 ± 3.7 (range = 6–25). The subgroup of early onset ET patients had average age of disease onset at 11 ± 7 years (23 men, 25 women, average current age 44 ± 13 years). The subgroup of adult onset ET had average age of onset of 49 ± 12 years (19 men, 28 women, average current age 62 ± 9 years). Disease severity did not differ between the early onset patients (mean WHIGET score 13.8 ± 4.7, range = 6–22) and
Discussion
Animal models with spontaneous tremor provide an opportunity for identification of causative ET genes. The postural and action extremities tremor in Scn8a mutant mice are associated with neurologic abnormalities such as dystonia and ataxia that are commonly present in ET patients. In spite of the phenotypic similarities, our results indicate that mutations in the SCN8A gene are not a common cause of autosomal dominant familial ET. We studied Caucasian individuals only and cannot exclude the
Acknowledgements
Supported by NIH R01 NS34509 (MHM) and the Center for Genetics in Heath and Disease, University of Michigan (LMS). PH is supported by NIH K08 NS42743.
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