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

• Published in: Movement disorders Vol. 34; no. 10; pp. 1516 - 1527
• Main Authors: Carecchio, Miryam, Invernizzi, Federica, Gonzàlez‐Latapi, Paulina, Panteghini, Celeste, Zorzi, Giovanna, Romito, Luigi, Leuzzi, Vincenzo, Galosi, Serena, Reale, Chiara, Zibordi, Federica, Joseph, Agnel P., Topf, Maya, Piano, Carla, Bentivoglio, Anna Rita, Girotti, Floriano, Morana, Paolo, Morana, Benedetto, Kurian, Manju A., Garavaglia, Barbara, Mencacci, Niccolò E., Lubbe, Steven J., Nardocci, Nardo
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.10.2019; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Aged; Child; Childhood; Children; Cohort analysis; Cohort Studies; DBS; Deep Brain Stimulation - methods; Dystonia; Dystonic Disorders - genetics; Female; Genetic screening; Growth rate; Histone-Lysine N-Methyltransferase - genetics; Humans; Intellectual disabilities; Intellectual Disability - genetics; KMT2B; Male; Middle Aged; Movement disorders; Mutation; Mutation - genetics; Neurodevelopmental disorders; Phenotype; Phenotypes; WES; Young Adult; DBS; WES; childhood; dystonia; KMT2B
• ISSN: 0885-3185; 1531-8257
• DOI: 10.1002/mds.27771

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