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.

Carecchio, M., Invernizzi, F., Gonzalez-latapi, P., Panteghini, C., Zorzi, G., Romito, L., Leuzzi, V., Galosi, S., Reale, C., Zibordi, F., Joseph, A. P., Topf, M., Piano, C., Bentivoglio, A. R., Girotti, F., Morana, P., Morana, B., Kurian, M. A., Garavaglia, B., Mencacci, N. E., Lubbe, S. J., Nardocci, N., Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study, <<MOVEMENT DISORDERS>>, 2019; 34 (10): 1516-1527. [doi:10.1002/mds.27771] [http://hdl.handle.net/10807/142042]

Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study

Zorzi, Gianni;Romito L.;Zibordi F.;Piano C.;Bentivoglio A. R.;
2019

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.
Inglese
http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1531-8257
Carecchio, M., Invernizzi, F., Gonzalez-latapi, P., Panteghini, C., Zorzi, G., Romito, L., Leuzzi, V., Galosi, S., Reale, C., Zibordi, F., Joseph, A. P., Topf, M., Piano, C., Bentivoglio, A. R., Girotti, F., Morana, P., Morana, B., Kurian, M. A., Garavaglia, B., Mencacci, N. E., Lubbe, S. J., Nardocci, N., Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study, <>, 2019; 34 (10): 1516-1527. [doi:10.1002/mds.27771] [http://hdl.handle.net/10807/142042]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10807/142042
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