Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Movement disorders, 2019-10, Vol.34 (10), p.1516-1527

Ort / Verlag

Hoboken, USA: John Wiley & Sons, Inc

Erscheinungsjahr

2019

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• 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