%0 Journal Article
%T Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study.
%A Carecchio M
%A Invernizzi F
%A Gonzàlez-Latapi P
%A Panteghini C
%A Zorzi G
%A Romito L
%A Leuzzi V
%A Galosi S
%A Reale C
%A Zibordi F
%A Joseph AP
%A Topf M
%A Piano C
%A Bentivoglio AR
%A Girotti F
%A Morana P
%A Morana B
%A Kurian MA
%A Garavaglia B
%A Mencacci NE
%A Lubbe SJ
%A Nardocci N
%J Mov Disord
%V 34
%N 10
%D 10 2019
%M 31216378
%F 9.698
%R 10.1002/mds.27771
%X Childhood-onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood-onset dystonia.<BR>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.<BR>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.<BR>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.<BR>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.