KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation

Abstract

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5–37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden’s Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

Pallidal Deep Brain Stimulation for Monogenic Dystonia: The Effect of Gene on Outcome

“…Heterozygous variants in the KMT2B gene are emerging as one of the commonest causes of early onset dystonia, with a caudocranial pattern evolving into generalized dystonia ( 109 – 111 ). There may be additional features, such as a characteristic facies, microcephaly, short stature, developmental delay, mild psychomotor impairment, and superimposed choreoathetosis or myoclonus ( 111 , 112 ). Furthermore, MRI findings show characteristic changes including bilateral pallidal hypointensity that may serve as a clue to this disorder ( 110 , 113 ).…”

“…A very recent study described the largest sample of KMT2B-related dystonia to date, including 18 individuals with medication-refractory dystonia ( 111 ). Significant improvement of motor function and disability [BFMDRS movement (BFMDRS-M) and BFMDRS disability (BFMDRS-D)] was evident at 6 months, 1 year and last follow-up (up to 22 years).…”

“…Therefore, one of the characteristic features of dystonia due to KMT2B mutations is a response to DBS, which may be the preferred option in severely affected patients ( 116 ). The effect of DBS is seen in all anatomical regions, apart from perhaps a less beneficial effect upon laryngeal dystonia ( 111 , 114 ).…”

The importance of genetic testing for dystonia patients and translational research

“…Patients affected due to the c.907_909delGAG TOR1A variant respond well to DBS and more predictably so than the carriers of various THAP1 pathogenic changes (Brüggemann et al 2015 ). In addition, a very recent investigation of DBS effects in 18 KMT2B variant carriers reports significant initial improvement (Cif et al 2020 ). When considering combined dystonia forms, particularly promising outcomes can be expected in XDP patients (Brüggemann et al 2019 ; Abejero et al 2019 ) and myoclonus dystonia patients with SGCE variants (Kosutzka et al 2019 ), but not for ATP1A3 -related dystonia (DYT/PARK- ATP1A3 ) (Brücke et al 2015 ; Albanese et al 2017 ; Tisch and Kumar 2021 ).…”

Deep Brain Stimulation in KMT2B-Related Dystonia: Case Report and Review of the Literature With Special Emphasis on Dysarthria and Speech

“…With the advancement of next-generation sequencing techniques, several genetic causes of isolated and combined dystonia have been identified (4). Since 2016, several mutations in the KMT2B gene have been identified as a new etiology of early-onset dystonia (5)(6)(7)(8)(9). KMT2Brelated dystonia is a progressive childhood-onset disorder, commonly evolving from a focal, mainly lower-limb dystonia into generalized dystonia with cranio-cervical involvement.…”