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.

Mutation in the KMT2B gene can also cause autosomal dominant intellectual developmental disorder-68 (MRD68; 619934).

Dystonia-28 (DYT28) 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).

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.

Cif et al. (2020) described the clinical features of 44 DYT28 patients ascertained through international collaborative efforts after genetic analysis identified heterozygous mutations in the KMT2B gene. The patients, who ranged in age from 3 to 44 years, had a median age at symptom onset of 5.0 years (range, 1.5-29 years). Twenty-nine of the 44 patients presented with lower limb symptoms with a subsequent caudocranial progression leading to laryngeal, oromandibular, and cervical involvement. Status dystonicus occurred in 5 patients. Additional features were present in all 44 patients, including short stature (71.1%), microcephaly (68.6%), and nonspecific dysmorphic features, such as bulbous nose, long face, and clinodactyly (52.4%). Fourteen children (34.1%) showed developmental delay before the onset of dystonia. Subsequent cognitive difficulties, ranging from mild to severe intellectual disability, were seen in 47.6%. Several (14.3%) had autism spectrum disorder, and 18 (42.9%) had psychiatric features, such as ADHD, anxiety, and depression. Endocrine abnormalities, including hypothyroidism and precocious puberty, were seen in 10 patients (23.3%). Ophthalmologic features, including refractive errors, nystagmus, and slow saccades, were observed in 42.9% of patients. MRI showed bilateral symmetrical hypointensities of the globus pallidus in 17 of 21 patients tested. Less common features included pyramidal signs and gastroesophageal reflux.

The heterozygous mutations in 3 of the families with DYT28 reported by Zech et al. (2016) occurred de novo; in 1 family, the mutation was inherited.

Most of the heterozygous mutations in the KMT2B gene that were identified in patients with DYT28 by Cif et al. (2020) occurred de novo. Some mutations were inherited from affected or unaffected parents, consistent with autosomal dominant inheritance with incomplete penetrance, particularly for missense variants (85.3% penetrance).

Mirza-Schreiber et al. (2022) used an epigenome-wide association study in peripheral blood DNA to identify 113 CpG sites that were hypermethylated in 12 individuals with pathogenic or likely pathogenic variants in the KMT2B gene. This episignature was shown to have high specificity and sensitivity for DYT28. The normalized mean of methylation levels detected in peripheral blood DNA also correlated to the age of onset of dystonia, being lower in samples with later onset or incomplete penetrance.

Cif et al. (2020) reported clinical outcomes in 18 patients with DYT28 who were treated with deep brain stimulation (DBS) to the globus pallidus. After 1 year, 8 of 15 treated patients had significant improvement when assessed with the Burke-Fahn-Marsden Dystonia Rating Scale movement subscale (BFMDRS-D) and 7 of 15 had significant improvement on the BFMDRS disability subscale.

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.

Cif et al. (2020) reported heterozygous mutations in the KMT2B gene in 44 patients (patients 1-44) with DYT28 and in 9 patients (patients 45-53) with MRD68 (619934). The mutations in patients with DYT28, which were identified by a combination of microarray and gene panel, whole-exome, whole-genome, or Sanger sequencing, included truncating, missense, splicing, and chromosome microdeletions. Twenty-nine patients had de novo mutations; a few inherited the mutation from a symptomatic parent, and the inheritance pattern was unknown in the other patients. Missense variants showed slightly reduced penetrance compared to protein-truncating variants. The protein-truncating mutations occurred throughout the gene, whereas missense variants clustered in putative functional domains. Functional studies of the variants were not performed, and the authors noted that missense variants should be interpreted with caution. It was postulated that haploinsufficiency or dysfunction of KMT2B affects the downstream expression of key genes regulating neurodevelopment and motor control. There were several instances of discordant phenotypes associated with a particular mutation that resulted in both DYT28 and MRD68: 2 sibs (patients 18 and 47) carried a frameshift mutation (606834.0011), and 2 unrelated patients (patients 25 and 50) shared an R1597W mutation (606834.0010). Moreover, P17, who had DYT28, inherited a KMT2B frameshift mutation from his 57-year-old mother (P46), who did not have dystonia but was noted to have intellectual disability and short stature, consistent with MRD68. The finding of the same mutation in individuals with discordant phenotypes illustrated the phenotypic spectrum that can result from KMT2B mutations. The authors suggested that disease manifestations may be influenced by other genetic, epigenetic, or environmental factors.

Cif et al. (2020) evaluated molecular and clinical features in 133 patients with DYT28 and found that onset of dystonia was slightly earlier in patients with protein-truncating mutations and microdeletions in the KMT2B gene compared to patients with missense mutations. The median age of dystonia onset in those with truncating mutations was 5.0 (+/- 3.8) years compared to those with missense mutations who had onset at 6.0 (+/- 4.0) years (p = 0.02).