Progressive Myoclonus Epilepsies

Abstract

Background and ObjectivesTo assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort.MethodsOf 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: “Unverricht-Lundborg disease-like PME,” “late-onset PME,” “PME plus developmental delay,” and “PME plus dementia.”ResultsSixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS, CACNA2D2, STUB1, AFG3L2, CLN6, NAXE, and CHD2. Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories.DiscussionThe application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield >80%, PME is one of the best genetically defined epilepsy syndromes.

Genes4Epilepsy: An epilepsy gene resource

“…The success in uncovering the hundreds of monogenic genes associated with this rarer group of epilepsies, in addition to the PMEs and MCDs, stands in stark contrast to that seen for common focal and generalized epilepsies. Although more than 50% of patients with a DEE 17 and up to 80% of patients with a PME 18 are currently genetically “solved” by finding a pathogenic variant in an established monogenic epilepsy gene, the same currently holds true for only a small minority of patients with a common form of epilepsy. Of interest, large case–control burden studies show molecular overlap between the DEEs and GGE, as they find that rare variants in DEE genes are enriched in patients with GGE 19,20 .…”

IRF2BPL: A new genotype for progressive myoclonus epilepsies

“…He was included as PME with unidentified etiology in the Italian PME collection after the exclusion of known genetic variants. 1 Patient 2 had rare seizures throughout life and a less-active EEG, and his condition would be better characterized as on the PME/ progressive myoclonic ataxia continuum. 17,18 Only after years did other symptoms occur in both patients, which included psychiatric symptoms, dystonia, and cognitive decline.…”

“…Progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders characterized by cortical myoclonus, generalized tonic-clonic seizures, and progressive neurological decline, with ataxia and/or cognitive impairment. 1,2 PMEs typically present in late childhood and have numerous genetic etiologies, many of which involve lysosomal or endosomal function. The most common causes in most centers are Unverricht-Lundborg disease (CTSB), Lafora disease (EPM2A, NHLRC1), and neuronal ceroid lipofuscinoses (CLN2, CLN4, CLN5, CLN6), but ~40 genes have now been described as causes of PME.…”

“…1 In only about 20% of cases, the cause remains unknown. 1 Here we use wholeexome sequencing (WES) to study two unsolved patients with PME and identify two different truncating variants in the IRF2BPL gene.…”

Progressive myoclonus epilepsies due to SEMA6B mutations. New variants and appraisal of published phenotypes

“…Based on the discovery of several new genes associated with PME, a novel classification was proposed. 4,14 Specifically, the presence of cognitive delay preceding the PME phenotype identified the nosological group of "PME plus developmental delay," which could include PMEs associated with SEMA6B mutations.…”