Carecchio, M; Invernizzi, F; Gonzàlez-Latapi, P; Panteghini, C; Zorzi, G; Romito, L; Leuzzi, V; ... Nardocci, N; + view all Carecchio, M; Invernizzi, F; Gonzàlez-Latapi, P; Panteghini, C; Zorzi, G; Romito, L; Leuzzi, V; Galosi, S; Reale, C; Zibordi, F; Joseph, AP; Topf, M; Piano, C; Bentivoglio, AR; Girotti, F; Morana, P; Morana, B; Kurian, MA; Garavaglia, B; Mencacci, NE; Lubbe, SJ; Nardocci, N; - view fewer (2019) Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study. Movement Disorders 10.1002/mds.27771. (In press).

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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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