Tremor, Hereditary Essential, 5

A number sign (#) is used with this entry because of evidence that hereditary essential tremor-5 (ETM5) is caused by heterozygous mutation in the TENM4 gene (610084) on chromosome 11q14.

Description

Hereditary essential tremor-5 is an autosomal dominant neurologic disorder characterized by kinetic, intention, and/or postural tremor mainly affecting the upper limbs. The age at onset and severity are highly variable, even within families (summary by Hor et al., 2015).

For a general phenotypic description and a discussion of genetic heterogeneity of hereditary essential tremor, see ETM1 (190300).

Clinical Features

Hor et al. (2015) reported 3 unrelated families of Spanish descent in which multiple individuals had essential tremor. Affected individuals had kinetic, postural, and/or intention tremor mainly affecting the upper limbs, but sometimes affecting the lower limbs and tongue. There was a wide range in the age at onset in all families, from adolescence to late adulthood, and the severity was variable.

Inheritance

The transmission pattern of ETM5 in the families reported by Hor et al. (2015) was consistent with autosomal dominant inheritance. There was some evidence of age-dependent and/or incomplete penetrance.

Molecular Genetics

In affected members of 3 unrelated families of Spanish descent with ETM5, Hor et al. (2015) identified 3 different heterozygous missense mutations in the TENM4 gene (610084.0001-610084.0003). The mutation in the first family was found by whole-exome sequencing and confirmed by Sanger sequencing; mutations in the subsequent 2 families were found by targeted resequencing of TENM4 in 299 Spanish probands with essential tremor. Transfection of the mutations into an oligodendrocyte cell line showed that the mutant proteins clustered at the membrane, whereas the wildtype proteins localized homogeneously at the membrane. Injection of the mutations into zebrafish embryos resulted in a defect in axonal guidance similar to that observed with morpholino knockdown of the tenm4 gene and consistent with a dominant-negative effect.

Animal Model

Suzuki et al. (2012) found that the homozygous mouse mutant, 'furue' (fur), characterized by tremors and hypomyelination in the central nervous system, resulted from a homozygous insertion mutation in the Tenm4 gene. Myelination, particularly of small diameter axons in the spinal cord, was dramatically reduced in mutant mice, and there was a defect in the differentiation of oligodendrocytes. These findings suggest that Tenm4 is a regulator of oligodendrocyte differentiation and that it plays a critical role in the myelination of small diameter axons in the central nervous system.

Hor et al. (2015) found that morpholino knockdown of the tenm4 gene in zebrafish embryos resulted in a modest reduction of myelin in the brain and an increase in the number of small-diameter neuronal axons with aberrant branching along the notochord. These defects could be rescued by wildtype human TENM4.