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

Miryam Carecchio, Federica Invernizzi, Paulina Gonzàlez-Latapi, Celeste Panteghini, Giovanna Zorzi, Luigi Romito, Vincenzo Leuzzi, Serena Galosi, Chiara Reale, Federica Zibordi, Agnel P. Joseph, Maya Topf, Carla Piano, Anna Rita Bentivoglio, Floriano Girotti, Paolo Morana, Benedetto Morana, Manju A. Kurian, Barbara Garavaglia, Niccolò E. MencacciSteven J. Lubbe, Nardo Nardocci*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1516-1527
Number of pages12
JournalMovement Disorders
Issue number10
StatePublished - Oct 1 2019


  • DBS
  • KMT2B
  • WES
  • childhood
  • dystonia

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology


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