Essential Tremor
Genetics
ET may occur sporadically or be hereditary. Although sporadic and familial ET are widely considered to be phenotypically similar, this premise remains unsubstantiated. According to some reports, familial ET appears to have an earlier age at onset, indicating the increased influence genetic susceptibility may have in hereditary cases. However, increased awareness may be a factor in these kindreds.
Positive family history
It is widely reported that 50% or more of ET patients will demonstrate a positive family history. However, more accurately stated, the estimated range varies from as low as 17% to as high as 100%. Because many epidemiologic studies have not included control subjects, it remains unclear the degree to which the observed aggregation of cases within families exceeds that beyond chance. In addition, most studies have assessed genetic effect based solely on positive family history. However, the likelihood of a positive familial history may be proportional to the size of the family, the age of relatives, and the genetic relationships among the family group. In other words, a positive history is more often recognized in larger families with aging members who are closely related to the patient. Ascertainment bias may also result from other factors. For example, as mentioned previously, in retrospective epidemiologic studies based on clinic and hospital records, it has been demonstrated that patients with affected relatives are more likely to seek medical attention.
Mode of transmission and gene penetrance
Familial ET has been shown to have autosomal dominant inheritance. Gene penetrance is high but variable by the age of 65 to 70 years. For example, in a detailed investigation of familial ET in multigenerational kindreds, segregation analysis demonstrated autosomal dominant inheritance with nearly complete penetrance by age 65. In addition, it has often been observed that large kindreds may have unaffected parents, suggesting the possibility of autosomal dominant inheritance with age-dependent or reduced penetrance; mild, unrecognized expression in the parents; or other modes of transmission, such as autosomal recessive or multigenic inheritance.
Linkage
During a genome scan for familial ET in 16 Icelandic kindreds with 75 affected members, investigators identified linkage to chromosome 3q13.1 with a LOD score of 3.71. The gene was designated as FET1. A second study evaluated a large American kindred of Czech descent in whom ET affected 18 of 67 family members. In this kindred, a gene for ET (ETM2) was mapped to chromosome 2p22-p25 with a maximum LOD score of 5.92. Although genetic anticipation was suggested in this kindred, other studies have not supported anticipation in familial ET. Rather that a true biologic effect, apparent anticipation may result from increased awareness or ascertainment bias.
The chromosome 2p gene has been proposed to be HS1-BP3 (hematopoietic-specific protein 1 binding protein 3). Genotyping carried out on 73 individuals with dominantly inherited ET from 73 families showed that 12 of 73 ET individuals (16.4%) were heterozygous for the HS1-BP3 828C=>G variant, versus none of 304 unaffected controls. ET patients with the variant had no atypical features and were classified as definite ET by clinical criteria. Age at onset was significantly younger for those with the variant compared to those without (26 years vs. 44 years).
While the mechanism linking this gene variant to clinical features of ET remains unknown, the authors note that the protein is involved in signaling pathways in the cerebellum and motor neurons, and that abnormal regulation of these pathways "may disturb regional catecholamine or serotonin synthesis." They also note the possibility that this gene may not be causal for ET, but instead may be tightly linked to an undiscovered mutation in a nearby gene.
JJ Higgins, RQ Lombardi, J Pucilowska, J Jankovic, LI Golbe, L Verhagen. HS1-BP3 gene variant is common in familial essential tremor. Movement Disorders 2006;21:306-309
