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Background: Childhood-onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood-onset dystonia. \ud Objective: To define the frequency of KMT2B mutations in a cohort of dystonic patients aged less than 18 years at onset, the associated clinical and radiological phenotype, and the natural history of disease. \ud Methods: Whole-exome sequencing or customized gene panels were used to screen a cohort of sixty-five patients who had previously tested negative for all other known dystonia-associated genes.\ud Results: We identified fourteen patients (21.5%) carrying KMT2B variants, of which one was classified as a Variant of Unknown Significance (VUS). We also identified two 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 caudo-cranial generalization. Eight patients underwent pallidal Deep Brain Stimulation with a median decrease of BFMDRS-M score of 38.5% in the long term. We also report four asymptomatic carriers, suggesting that some KMT2B mutations may be associated with incomplete disease penetrance. \ud 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 Deep Brain Stimulation is characteristic of DYT-KMT2B dystonia.

Objective: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy.\ud \ud Methods: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system.\ud \ud Results: We identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine.\ud \ud Conclusions: Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.

Objective: To characterise the phenotypic spectrum, molecular genetic findings and\ud functional consequences of pathogenic variants in early onset KCNT1-epilepsy.\ud Methods: We identified a cohort of 31 patients with epilepsy of infancy with\ud migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct\ud Sanger sequencing, a multiple gene next generation sequencing panel and whole\ud exome sequencing. Additional patients with non-EIMFS early onset epilepsy in\ud whom we identified KCNT1 variants on local diagnostic multiple gene panel testing\ud were also included. Where possible, we performed homology modelling to predict\ud putative effects of variants on protein structure and function. We undertook\ud electrophysiological assessment of mutant KCNT1 channels in a Xenopus oocyte\ud model system.\ud Results: We identified pathogenic variants in KCNT1 in 12 patients, four of which\ud are novel. Most variants occurred de novo. Ten had a clinical diagnosis of EIMFS\ud and the other two presented with early onset severe nocturnal frontal lobe seizures.\ud Three patients had a trial of quinidine with good clinical response in one.\ud Computational modelling analysis implicates abnormal pore function (F346L) and\ud impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated\ud KCNT1 variants resulted in marked gain-of-function, with significantly increased\ud channel amplitude and variable blockade by quinidine.\ud Conclusions: Gain-of-function KCNT1 pathogenic variants cause a spectrum of\ud severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype\ud correlations are unclear, though clinical outcome is poor for the majority of cases.\ud Further elucidation of disease mechanisms may facilitate the development of\ud targeted treatments, much needed for this pharmacoresistant genetic epilepsy.