Progressive Myoclonus Epilepsy: A Scoping Review of Diagnostic, Phenotypic and Therapeutic Advances

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TL;DR

This scoping review summarizes the past decade of clinical work on progressive myoclonic epilepsies (PMEs), highlighting advances in genetic diagnosis, phenotypic characterization, and emerging therapies. Key findings include the role of neuroinflammation as a common pathophysiologic feature, the utility of next-generation sequencing in increasing diagnostic yield, and promising therapeutic approaches such as perampanel for symptom control, antisense oligonucleotides for Lafora disease, and gene therapy for several PME subtypes. The review underscores the need for early intervention and the potential for cross-disease translation of diagnostic and therapeutic strategies.

Full summary

3,892 CHARS

**Background:** Progressive myoclonus epilepsies (PMEs) are a heterogeneous group of genetic disorders characterized by variable-onset myoclonus, epilepsy, cerebellar involvement, and dementia, often leading to disability and early death. This scoping review aims to provide a comprehensive overview of diagnostic, phenotypic, and therapeutic advances in PMEs over the past decade (January 2013 to January 2023).

**Methods:** The review used a scoping review methodology, searching PubMed with the term "progressive myoclonus epilepsy" and limiting to English-language full-text articles published between 1 January 2013 and 11 January 2023. The initial search returned 399 articles; after excluding non-English and non-available texts, 172 articles remained, and manual relevance screening yielded a final 116 articles for review. The review covers common PMEs (Unverricht-Lundborg disease [ULD], Lafora disease [LD], neuronal ceroid lipofuscinoses [NCL], sialidosis, North Sea PME, acid ceramidase deficiencies, MERRF) and rarer genetic PMEs.

**Key Results:** - **Pathophysiology:** Neuroinflammation is a common feature in ULD, LD, and NCL, as evidenced by mouse models showing microglial activation, upregulation of immune-related genes (e.g., complement proteins, MHC-I, GFAP, cytokines), and serum chemokine changes (e.g., Cxcl13 as a potential biomarker for ULD). Enhanced cortical excitability, reflected by giant somatosensory evoked potentials (SSEP) and abnormal blink reflexes, is also observed. - **Diagnostic Advances:** Next-generation sequencing (NGS) significantly improved diagnostic yield. An Italian study of 165 unrelated PME patients found that NGS evaluations of 38 unsolved cases led to new genetic diagnoses in 16 patients, increasing overall yield to 82%. Whole-exome sequencing (WES) in 84 unsolved PME patients identified novel disease-causing variants in 24 of 78 (31%) unrelated individuals, with trio WES outperforming singleton WES. Newly identified genes include NUS1, DHDDS, and ALG10, involved in dolichol-dependent protein glycosylation. - **Therapeutic Progress:** Perampanel, an anti-epileptic drug, reduced myoclonus disability in 9 of 11 PME patients in a case series and in half of 104 patients in a systematic review. For ULD, valproic acid, piracetam, topiramate, levetiracetam, and perampanel improved seizures and myoclonus; brivaracetam showed no effect on action myoclonus in phase 3 trials. For LD, metformin (orphan drug status by EMA and FDA), 4-phenylbutyric acid, trehalose, and dexamethasone showed preclinical benefits; antibody-enzyme fusion (VAL-0417) degraded Lafora bodies in mice; antisense oligonucleotide (Gys1-ASO) targeting glycogen synthase prevented Lafora body formation; and cationic liposomes for gene therapy demonstrated laforin expression in vitro. For NCL, enzyme replacement therapy (cerliponase alfa) was approved for CLN2 disease in 2017. For sialidosis, perampanel improved myoclonus and seizures. For North Sea PME, the modified Atkins diet improved quality of life in one of four patients, and deep brain stimulation reduced seizures in two of three patients. For MERRF, rapamycin, MTO1 overexpression, and CNF1 protein showed preclinical promise.

**Clinical Implications:** The review emphasizes the importance of early genetic diagnosis using NGS/WES to identify treatable or targetable PME subtypes. Neuroinflammation as a common pathway suggests anti-inflammatory therapies may be broadly applicable. Emerging therapies, particularly for LD (e.g., ASO, gene therapy) and MERRF (e.g., epitranscriptomic approaches), offer hope for disease modification, though most remain preclinical. Symptom management with perampanel and other anti-seizure medications remains central. The review highlights the need for early intervention, as many therapies are most effective before significant neurodegeneration occurs.