Unraveling the Molecular Landscape of Progressive Myoclonus Epilepsy: A Case Series of 4 Adolescent Males

Background and Aims: Progressive myoclonus epilepsy (PME) represents a heterogeneous group of rare neurodegenerative disorders characterized by myoclonus, seizures, and progressive neurological decline. With expanding genetic insights, disorders such as Lafora disease and sialidosis are increasingly recognized. We aim to describe the clinical, electrophysiological, and genetic spectrum of four PME cases, highlighting diagnostic challenges and genotype–phenotype correlations. Materials and Methods: We retrospectively reviewed four unrelated male patients (ages 18–26 years) presenting with progressive myoclonus, generalized tonic–clonic seizures, and cognitive decline between 2021 and 2024. All underwent clinical evaluation, electroencephalography (EEG), magnetic resonance imaging (MRI), and blood-based clinical exome sequencing or whole exome sequencing. Variants were classified per the American College of Medical Genetics (ACMG) guidelines. Results: All patients presented in adolescence or early adulthood with myoclonus and generalized tonic–clonic seizures. Cognitive decline and ataxia were variably present. Neuroimaging was normal in most cases. EEG showed generalized or multifocal epileptiform discharges. Genetic analysis revealed variants in the EPM2A gene consistent with Lafora disease in three patients and a NEU1 gene variant suggestive of sialidosis type I in one patient. All variants were homozygous, with consanguinity noted in two cases. Skin biopsy confirming polyglucosan bodies supported Lafora disease in one patient. Most variants were classified as variants of uncertain significance, underscoring interpretative challenges. Discussion: This series highlights the clinical and genetic heterogeneity of PME, with Lafora disease (EPM2A mutations) being the most common subtype, consistent with existing literature. Sialidosis, though rarer, remains an important differential. The presence of normal MRI, early cognitive decline, and refractory myoclonus should prompt genetic evaluation. The frequent identification of variants of uncertain significance emphasizes the need for genotype–phenotype correlation, segregation studies, and functional validation. Conclusion: PME remains a diagnostic challenge requiring a high index of suspicion and multidisciplinary evaluation. Genetic testing plays a pivotal role but is limited by variant interpretation. Early diagnosis aids prognostication, genetic counseling, and avoidance of inappropriate therapies. Publication History Article published online: 15 July 2026 © 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Medical and Scientific Publishers Private Limited A-13A, Graphix Tower 1, 6th floor, Sector 62, Noida 201309, Uttar Pradesh, India