{Reference Type}: Journal Article
{Title}: Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study.
{Author}: Carecchio M;Invernizzi F;Gonzàlez-Latapi P;Panteghini C;Zorzi G;Romito L;Leuzzi V;Galosi S;Reale C;Zibordi F;Joseph AP;Topf M;Piano C;Bentivoglio AR;Girotti F;Morana P;Morana B;Kurian MA;Garavaglia B;Mencacci NE;Lubbe SJ;Nardocci N;
{Journal}: Mov Disord
{Volume}: 34
{Issue}: 10
{Year}: 10 2019
{Factor}: 9.698
{DOI}: 10.1002/mds.27771
{Abstract}: Childhood-onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood-onset dystonia.
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.
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.
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.
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.