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

Abstract

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

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features

“…Further examples are some symptomatic treatments that have produced a dramatic and unexpected therapeutic response in specific disorders, suggesting an interference with the disease mechanisms, namely carbamazepine in PRRT2 gene mutations, 87 acetazolamide in CACNA1A, 88 tetrabenazine in GNAO1 (Video S9), 89 and neuromodulation in DYT1 and KMT2B. 90,91 The personal observation of a dramatic and sustained response to levodopa in a patient with isolated cervical dystonia and reduced CSF dopamine levels, subsequently diagnosed as KMT2B dystonia (Video S10 and patient 10 in ref. 91,91 could be considered a further example.…”

“…90,91 The personal observation of a dramatic and sustained response to levodopa in a patient with isolated cervical dystonia and reduced CSF dopamine levels, subsequently diagnosed as KMT2B dystonia (Video S10 and patient 10 in ref. 91,91 could be considered a further example.…”

“…This patient has been recently published as part of a single-center cohort by Carecchio and colleagues. 91…”

Treatable Movement Disorders of Infancy and Early Childhood

“…Age of onset can be a differentiator, as DYT6 dystonia typically emerges in adolescence while DYT28 can emerge much earlier in childhood. 31,32 In more severe cases, DYT28-associated symptoms can include seizures, spasticity, sensorineural hearing loss, and psychiatric disturbances. However, DYT28 can also present as an isolated dystonia.…”

Bi-allelic variants inTSPOAP1, encoding the active zone protein RIMBP1, cause autosomal recessive dystonia

“…Whole-exome sequencing. Whole-exome sequencing (WES) was performed in all three affected children and both parents for family A, in the proband only for family B and in the proband and her unaffected sibling for family C. WES and bioinformatic analysis were performed as previously described (56)(57)(58). Given the reported history of parental consanguinity in family A and the result of homozygosity mapping suggesting cryptic parental relatedness in family B and C, the analysis focused on homozygous coding and essential splice-site variants.…”