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

TL;DR

This study expands the understanding of KMT2B-related disorders by detailing a large patient cohort, identifying new phenotypes, and demonstrating long-term benefits of deep brain stimulation in treating dystonia.

Contribution

It provides a comprehensive phenotypic spectrum of KMT2B mutations and evaluates the long-term efficacy of deep brain stimulation in a sizable patient cohort.

Findings

New atypical dystonia patterns identified

Deep brain stimulation significantly improves motor function

Systemic co-morbidities are common in KMT2B mutations

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 to 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 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).