Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR ¼ 3.9, p value ¼ 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.

Objective Eyelid myoclonia with absences (EMA) is a syndrome characterized by eyelid myoclonia with or without absences, eye closure‐induced generalized electroencephalographic (EEG) paroxysms and photosensitivity. Few data are available about the prognostic factors of this syndrome. The main objectives of our study were to describe the clinical and EEG features of a group of patients with EMA and to evaluate the presence of prognostic factors. Methods We retrospectively selected a cohort of patients with diagnosis of EMA evaluated in the epilepsy service of the Neurological Clinic of Catania, in the Neurology and Clinical Neurophysiopathology Unit of Oasi Research Institute, Troina and in the Regional Epilepsy Centre of Bianchi‐Melacrino‐Morelli Hospital of Reggio Calabria. We considered the features of the patients during the first year of disease, and at the last follow‐up visit. We stratified the patients into two groups: “seizure‐free”, defined as the absence of seizures for at least 2 years, and “not seizure‐free” and we evaluated the evolution of their characteristics and the presence of factors associated with outcome. Results We enrolled 51 patients (40 women (78%); mean age: 30.8 years ± 15.5 [range 10‐79]). The mean follow‐up time was 8.7 ± 5.8 years. Eleven patients (21.6%) achieved the condition of seizure‐free. Family history of epilepsy was associated with the condition of seizure‐free (P = 0.05). At the last follow‐up visit, EEG photosensitivity and eye closure sensitivity were significantly associated with the condition of “not seizure‐free”. Significance The results of our study revealed that a positive family history of epilepsy might be associated with a better outcome in EMA. Furthermore, the persistence of photosensitivity and eye closure sensitivity might indicate persistence of seizures, offering an aid in therapeutic management.

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IntroductionEpilepsy is one of the most common neurological diseases in Latin American Countries (LAC) and epilepsy associated with convulsive seizures is the most frequent type. Therefore, the detection of convulsive seizures is a priority, but a validated Spanish-language screening tool to detect convulsive seizures is not available. We performed a field validation to evaluate the accuracy of a Spanish-language questionnaire to detect convulsive seizures in rural Bolivia using a three-stage design. The questionnaire was also administered face-to-face, using a two-stage design, to evaluate the difference in accuracy.MethodsThe study was carried out in the rural communities of the Gran Chaco region. The questionnaire consists of a single screening question directed toward the householders and a confirmatory section administered face-to-face to the index case. Positive subjects underwent a neurological examination to detect false positive and true positive subjects. To estimate the proportion of false negative, a random sample of about 20% of the screened negative underwent a neurological evaluation.Results792 householders have been interviewed representing a population of 3,562 subjects (52.2% men; mean age 24.5 ± 19.7 years). We found a sensitivity of 76.3% (95% CI 59.8–88.6) with a specificity of 99.6% (95% CI 99.4–99.8). The two-stage design showed only a slightly higher sensitivity respect to the three-stage design.ConclusionOur screening tool shows a good accuracy and can be easily used by trained health workers to quickly screen the population of the rural communities of LAC through the householders using a three-stage design.