Dystonia 26, Myoclonic

A number sign (#) is used with this entry because of evidence that myoclonic dystonia-26 (DYT26) is caused by heterozygous mutation in the KCTD17 gene (616386) on chromosome 22q12.

Description

Myoclonic dystonia-26 is an autosomal dominant neurologic disorder characterized by onset of myoclonic jerks affecting the upper limbs in the first or second decade of life. The disorder is progressive, and patients later develop dystonia with predominant involvement of the craniocervical regions and sometimes the trunk and/or lower limbs. Dystonia dominates the clinical picture (summary by Mencacci et al., 2015).

Clinical Features

Mencacci et al. (2015) reported 2 unrelated families with myoclonic dystonia. The first family was of British origin and consisted of 7 individuals with onset of movement disorder symptoms between 5 and 20 years of age. All affected family members presented with myoclonic jerks or a jerky tremor predominantly affecting the upper limbs. Dystonia of the upper limbs and craniocervical region occurred later. Symptoms included spasmodic dysphonia, facial myoclonus, blepharospasm, torticollis, and dystonic head jerks. At least 1 patient had dystonia of the trunk and feet in late adulthood. Two patients had psychiatric symptoms of anxiety, social phobia, and depression. Older individuals were more severely affected, consistent with the progressive nature of the disorder. None of the patients reported improvement of the symptoms with alcohol. The proband of the second family, which was of German origin, was a 62-year-old man who developed arm jerks and difficulty writing in childhood. Torticollis and a jerky head tremor appeared around age 40 and became progressively debilitating. He underwent surgery with pallidal deep brain stimulation at age 58, resulting in marked improvement. At age 62, he had generalized dystonia with prominent craniocervical involvement and myoclonic jerks of the upper limbs. A brother and deceased father were reportedly similarly affected, but DNA samples from these individuals were not available.

Inheritance

The transmission pattern of DYT26 in the families reported by Mencacci et al. (2015) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of a British family with DYT26, Mencacci et al. (2015) identified a heterozygous missense mutation in exon 4 of the KCTD17 gene (R145H; 616386.0001). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Sequencing the KCTD17 gene in 87 additional probands with familial myoclonic dystonia identified the same R145H mutation in a German proband. No KCTD17 mutations were found by direct screening of exon 4 in 358 patients with sporadic myoclonic dystonia. Studies of patient fibroblasts showed reduced and delayed cytosolic calcium signaling in response to stimulation, reduced calcium stores in the endoplasmic reticulum, and reduced intracellular calcium stores compared to controls.