Dystonia 28, Childhood-Onset

A number sign (#) is used with this entry because of evidence that childhood-onset dystonia-28 (DYT28) is caused by heterozygous mutation in the KMT2B gene (606834) on chromosome 19p13.

Description

Dystonia-28 is an autosomal dominant neurologic disorder characterized by onset of progressive dystonia in the first decade of life. Dystonia typically begins focally in the lower limbs, resulting in gait difficulties, with later progression to other body regions, including the upper limbs, neck, and orofacial region. The severity is variable, and some patients may become wheelchair-bound. Many patients also have an elongated face with bulbous nose, and some have abnormal eye movements. About half of patients show delayed motor and/or cognitive development with mild intellectual disability (summary by Zech et al., 2016 and Meyer et al., 2017).

Clinical Features

Zech et al. (2016) reported 4 unrelated probands of Austrian or German descent, with onset of lower-limb dystonia between ages 3 and 11 years. The dystonia was progressive and eventually became generalized with involvement of the upper limbs, hands, neck, face, tongue, and trunk. Three patients had mild microcephaly, including 2 with overall poor growth and short stature. One patient had isolated, mildly delayed motor milestones, and 2 others had global developmental delay with mild cognitive impairment and speech delay. Two had astigmatism. There were no additional motor neurologic features, and brain imaging was normal in all 4 probands. The oldest proband (family F1), aged 31 years, underwent deep brain stimulation of the globus pallidus with improvement of her condition. Another proband (family F4) had an affected father and paternal grandfather. The dystonia in these 2 relatives remained focal, with clumsiness and action-induced hand dystonia since childhood. Both also had dysarthria and mild cognitive impairment; one also had microcephaly, short stature, and astigmatism.

Meyer et al. (2017) reported 17 probands, ranging in age from 6 to 40 years, with childhood-onset dystonia. All patients had onset of symptoms in the first decade, except for a 46-year-old affected mother who reportedly had onset at age 23 years; her son had onset at age 8 years. Most patients had involvement of the lower limbs at disease onset, resulting in foot posturing, toe walking, and gait disturbance. This was followed by abnormal posturing or dystonic tremor in the upper limbs, resulting in decreased dexterity and handwriting difficulties. All patients developed cervical symptoms, including torticollis and retrocollis, as well as severe cranial involvement, including facial dystonia and oromandibular dysfunction resulting in dysarthria, difficulties chewing and swallowing, and laryngeal involvement with dysphonia. The disorder was progressive, and most patients developed generalized dystonia; however, none had compromise of the airways. Less common motor features included dystonic tremor, spasticity, and myoclonus. About half of patients had developmental delay and intellectual disability, and some had additional features, such as eye movement abnormalities. There was a characteristic facial appearance with elongated face and bulbous nasal tip. Brain imaging showed lesions in the globus pallidus in most patients. Several patients who underwent deep brain stimulation showed clinical benefit, which was dramatic in some.

Inheritance

The transmission pattern of DYT28 in 1 of the families reported by Zech et al. (2016) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 4 unrelated probands with DYT28, Zech et al. (2016) identified 4 different heterozygous loss-of-function mutations in the KMT2B gene (606834.0001-606834.0004). The mutations, which were found by whole-exome sequencing, were confirmed by Sanger sequencing. Three of the mutations occurred de novo, and 1 was inherited (family F4). Analysis of cells from 2 unrelated patients showed that the mutations resulted in nonsense-mediated mRNA decay and haploinsufficiency. The 4 probands were part of a cohort of 31 patients with dystonia who underwent genetic studies. Zech et al. (2016) noted that some patients with heterozygous deletion of chromosome 19p13 (613026) that includes the KMT2B gene have dystonia, supporting haploinsufficiency of this gene and defects in histone modification in the pathogenesis of this disorder.

In 17 probands with DYT28, Meyer et al. (2017) identified heterozygous mutations in the KMT2B gene (see, e.g., 606834.0005-606834.0008). There were 7 frameshift mutations, 2 nonsense mutations, 1 splice site mutation, and 7 missense mutations. The mutations were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing. Most of the mutations occurred de novo, but the mutation was maternally inherited in 3 cases, and 2 of these mothers were asymptomatic, suggesting incomplete penetrance. Functional studies of the variants were not performed, but studies of some patient cells showed decreased expression of KMT2B, suggesting haploinsufficiency. However, patient cells did not show differences in histone H3K4 methylation compared to controls. Fibroblasts derived from 3 patients showed reduced transcript levels of THAP1 (609520) and TOR1A (605204) compared to controls, and immunoblot studies showed decreased THAP1 protein expression in these cells, but only 1 patient had decreased TOR1A protein expression. These findings suggested that the KMT2B mutations may affect the expression profiles of specific genes involved in dystonia.