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

    Carecchio, Miryam and Invernizzi, F. and Gonzàlez-Latapi, P. and Panteghini, C. and Zorzi, G. and Romito, L. and Leuzzi, V. and Galosi, S. and Reale, C. and Zibordi, F. and Joseph, A.P. and Topf, Maya and Piano, C. and Bentivoglio, A.R. and Girotti, F. and Morana, P. and Morana, B. and Kurian, M.A. and Garavaglia, B. and Mencacci, N.E. and Lubbe, S.J. and Nardocci, N. (2019) Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single‐center cohort study. Movement Disorders 34 (10), pp. 1516-1527. ISSN 0885-3185.

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    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 less than 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 sixty-five patients who had previously tested negative for all other known dystonia-associated genes. Results: We identified fourteen patients (21.5%) carrying KMT2B variants, of which one was classified as a Variant of Unknown Significance (VUS). We also identified two 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 caudo-cranial generalization. Eight patients underwent pallidal Deep Brain Stimulation with a median decrease of BFMDRS-M score of 38.5% in the long term. We also report four 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 Deep Brain Stimulation is characteristic of DYT-KMT2B dystonia.


    Item Type: Article
    Additional Information: This is the peer reviewed version of the article, which has been published in final form at the link above. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
    Keyword(s) / Subject(s): childhood, DBS, dystonia, KMT2B, WES
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Depositing User: Maya Topf
    Date Deposited: 10 Sep 2019 15:37
    Last Modified: 02 Aug 2023 17:53


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