Abstract
Background
Childhood‐onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood‐onset dystonia.
Objective
To define the frequency of KMT2B mutations in a cohort of dystonic patients aged <18 years at onset, the associated clinical and radiological phenotype, and the natural history of disease.
Methods
Whole‐exome sequencing or customized gene panels were used to screen a cohort of 65 patients who had previously tested negative for all other known dystonia‐associated genes.
Results
We identified 14 patients (21.5%) carrying KMT2B variants, of which 1 was classified as a variant of unknown significance. We also identified 2 additional patients carrying pathogenic mutations in GNAO1 and ATM. Overall, we established a definitive genetic diagnosis in 23% of cases. We observed a spectrum of clinical manifestations in KMT2B variant carriers, ranging from generalized dystonia to short stature or intellectual disability alone, even within the same family. In 78.5% of cases, dystonia involved the lower limbs at onset, with later caudocranial generalization. Eight patients underwent pallidal DBS with a median decrease of Burke‐Fahn‐Marsden Dystonia Rating Scale‐Motor score of 38.5% in the long term. We also report on 4 asymptomatic carriers, suggesting that some KMT2B mutations may be associated with incomplete disease penetrance.
Conclusions
KMT2B mutations are frequent in childhood‐onset dystonia and cause a complex neurodevelopmental syndrome, often featuring growth retardation and intellectual disability as additional phenotypic features. A dramatic and long‐lasting response to DBS is characteristic of DYT‐KMT2B dystonia. © 2019 International Parkinson and Movement Disorder Society
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