Clinical characteristics.

KMT2B-related dystonia (DYT-KMT2B) is a complex childhood-onset (mean age 7 years) movement disorder described to date in 39 individuals. It is characterized by a progressive disease course evolving commonly from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement. Communication difficulties, secondary to articulation difficulties and low speech volume, are common. Bulbar dysfunction leads to impaired swallowing. Intellectual disability (ID) / developmental delay (DD) are commonly reported.

Additional findings can include eye movement abnormalities, skin changes, psychiatric comorbidities (attention-deficit/hyperactivity disorder, anxiety, depression, and obsessive-compulsive disorder), myoclonus, seizures, spasticity, and sensorineural hearing loss. Many affected individuals follow a similar disease course, though milder and atypical findings have been described.

Diagnosis/testing.

The diagnosis of DYT-KMT2B is established in a proband with either a heterozygous pathogenic variant in KMT2B or a heterozygous interstitial deletion of 19q13.12 that includes a KMTB2 whole-gene deletion.

Management.

Treatment of manifestations:

• Dystonia: Although pharmacologic treatment with levodopa and other commonly used anti-dystonic agents generally does not result in long-term benefit for the majority of patients, a trial of these agents is considered reasonable. One group observed a significant improvement of motor manifestations with an antimuscarinic (anticholinergic) agent. Bilateral globus pallidus interna deep brain stimulation results in substantial clinical improvement, particularly in younger patients.
• Other: Early initiation of physiotherapy and a tailored exercise program is advised as well as use of adaptive aids (e.g., ankle-foot orthoses, walkers) as necessary to support and maintain ambulation. Speech and language therapy is crucial to assist in feeding skills and communication. Nutrition specialists / dieticians are needed to assess calorie needs and reduce the risk of malnutrition. Address DD/ID issues through appropriate specialists/agencies.

Surveillance: Regular monitoring of weight and height in children, nutritional status, swallowing function, speech and language, adaptive functioning (ability to perform activities of daily living), orthopedic complications (hip dislocation and kyphoscoliosis), hearing, eye movements, skin, and psychiatric status.

Genetic counseling.

DYT-KMT2B is inherited in an autosomal dominant manner. To date, ~84% of individuals have the disorder as the result of a de novo KMT2B pathogenic variant and ~16% have inherited the KMT2B variant (10% from an affected parent; 6% from a clinically asymptomatic parent). Each child of an individual with DYT-KMT2B has a 50% chance of inheriting the KMT2B pathogenic variant; reduced penetrance and intrafamilial clinical variability have been reported. Once the KMT2B pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

DYT-KMT2B should be suspected in individuals with the following findings.

Neuroimaging

Brain MRI abnormalities frequently reported in younger affected individuals (age range: 3-18 years) include subtle and symmetric hypointense lateral streaks in the external globus pallidus (Figure 1) on T₂-weighted, T₂*-weighted, susceptibility-weighted, and echo-planar b0-diffusion imaging data sets [Meyer et al 2017].

Figure 1.

Radiologic MRI features of patients with KMT2B variants a-l. T₂*-weighted (a, d) and T₂-weighted (b, c) images; echo-planar technique diffusion imaging data set images with b value of zero (e-h); susceptibility-weighted sequences (i-l)

Note: This pattern may represent an age-dependent phenomenon as these features were often not evident in adults and may become less prominent over time. Indeed, in one individual such MR changes were less evident on MRI performed at age 17 years compared to neuroimaging performed at age 13 years.

DaTSCAN and FDG-PET-CT scan were normal in the three individuals evaluated with these methods.

Establishing the Diagnosis

The diagnosis of DYT-KMT2B is established in a proband with one of the following [Zech et al 2016, Lange et al 2017, Meyer et al 2017, Zech et al 2017a, Zech et al 2017b] (see Table 1):

• A heterozygous pathogenic variant in KMT2B (26/36 probands reported to date)
• A heterozygous interstitial deletion of 19q13.12 that encompasses the entirety of KMTB2 (10/36 probands reported to date)

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, genomic sequencing, exome array) depending on the phenotype.

Persons with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom a specific diagnosis has been elusive are more likely to be diagnosed using comprehensive genomic testing (see Option 2).

Clinical Description

KMT2B-related dystonia (DYT-KMT2B) is a complex childhood-onset movement disorder. It typically presents with a progressive disease course evolving commonly from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement. Additional neurologic, psychiatric, and systemic features are commonly reported. Many affected individuals follow a similar disease course, though milder and atypical cases have been described.

DYT-KMT2B has been recently described in 36 probands. Of these, one proband had an affected mother and another had a similarly affected father and grandfather (total 39 individuals reported).

Disease onset typically occurs between ages one and 10 years (33/39 individuals); however, onset in the second decade was reported in five individuals for whom data were available. Mean age of onset was 7.05 years in 38 individuals for whom data were available.

Presenting manifestations (documented for 37/39 individuals) include the following:

• Lower-limb dystonia characterized by foot posturing, toe walking, and gait disturbance (in 28 individuals)
• Upper-limb dystonia leading to abnormal hand/arm posturing, dystonic tremor, and difficulties in handwriting and hand dexterity (6)
• Cervical dystonia (1)
• Truncal/axial dystonia (1)
• Dystonic tremor and (action) myoclonus (1)

Over time, the majority of individuals developed progressive cranial, cervical, and laryngeal dystonia with features of retrocollis, torticollis, dysarthria/anarthria, dysphonia, and difficulties in swallowing and chewing.

Affected individuals often have communication difficulties, secondary to articulation difficulties and low speech volume.

Bulbar dysfunction leads to impaired swallowing, which can cause substantial morbidity due to the risk of aspiration pneumonia. A few individuals with DYT-KMT2B have required gastrostomy insertion for feeding difficulties.

Generalized dystonia becomes evident in most individuals (34/39) within two to 11 years of initial presentation. The level of gross motor disability comprises a broad spectrum ranging from minor gait disturbance to wheelchair dependence (GMFCS II-V).

Developmental delay, described in 16 of 39 affected individuals, usually precedes the onset of dystonia and is thought to be non-progressive. Eight presented with neurodevelopmental delay, seven had isolated speech delay, and one had only delay in attainment of fine motor skills.

Mild cognitive impairment was reported in 21 of 39 affected individuals, most of whom developed variable degrees of functional independence in adolescence and adulthood.

Life expectancy is not known, but individuals in the seventh decade of life with DYT-KMT2B have been reported [Zech et al 2016].

Additional clinical features of DYT-KMT2B included the following (note that 9 individuals had >1 additional clinical feature):

• Eye movement abnormalities including strabismus, astigmatism, delay in saccade initiation, hypometric vertical saccades, oculomotor apraxia (in 8 individuals)
• Dermatologic features of ectodermal dysplasia including cutis aplasia, sparse hair, sparse to absent eyelashes or brows, hypertrichosis, and ichthyotic skin with criss-cross pattern under the feet and at the knees (5). Although broad postsurgical scarring and "phimosis" have been reported, it is not currently known if these features are incidental or truly disease related. Future identification of further individuals with molecularly confirmed DYT-KMT2B may better clarify these associations.
• Psychiatric comorbidities including attention-deficit/hyperactivity disorder (ADHD), anxiety, depression, and obsessive-compulsive disorder (3)
• Myoclonus (3)
• Microcephaly (3)
• Seizures (2), including one with absence seizures
• Spasticity (1)
• Sensorineural hearing loss (1)
• Subtle dysmorphic features that may include an elongated face and bulbous nasal tip [Zech et al 2016, Meyer et al 2017, Zech et al 2017a, Zech et al 2017b]

The following atypical DYT-KMT2B disease manifestations [Meyer et al 2017] are rarely reported:

• Paroxysmal cervical dystonia, reported in one individual. Notably, the mother of this proband, who was found to harbor this KMT2B variant, had onset of symptoms in early adulthood. She developed gait abnormalities, a progressive inability to run, and periodic paroxysmal upper-limb and neck dystonia.
• Solely oromandibular features without clinical evidence of limb dystonia

Genotype-Phenotype Correlations

Meyer and colleagues [2017] reported statistically significant earlier disease onset in individuals with DYT-KMT2B with loss-of-function variants (e.g., interstitial deletions; frameshift, splice site, and stop-gain variants) compared to those with missense variants. However, genotype does not appear to influence the rate of disease progression, disease severity, or clinical response to deep brain stimulation.

Early neurodevelopmental delay was reported in 5/10 individuals with a heterozygous 19q13.12 contiguous gene deletion, compared to 11/29 with intragenic KMT2B pathogenic variant. Likewise, the majority of individuals (8/10) with a heterozygous 19q13.12 contiguous gene deletion had mild cognitive impairment, compared to 13/29 with an intragenic KMT2B pathogenic variant. Identification of additional individuals with DYT-KMT2B will determine if this is a true genotype-phenotype correlation.

Penetrance

DYT-KMT2B is postulated to show reduced penetrance as asymptomatic heterozygotes have been identified. Although parental status is not always known, to date two (6%) of 32 reported pathogenic variants have been inherited from a seemingly unaffected parent [Meyer et al 2017].

Gender differences have not been observed to date.

Prevalence

Disease prevalence is not yet established. To date, 39 individuals (from 36 families) with DYT-KMT2B have been described.