PROGRESSIVE MYOCLONUS-ATAXIA SYNDROMES: DIAGNOSTIC CHALLENGES AND PRACTICAL APPROACHES
Abstract
Background: Progressive myoclonus-ataxia syndromes (PMAs) are a heterogeneous group of rare neurological conditions characterized by the coexistence of myoclonus and cerebellar ataxia, frequently associated with epilepsy and cognitive decline. Their rarity, phenotypic overlap, and genetic variability create major diagnostic difficulties.
Aim: This article provides a narrative review of the principal PMA syndromes, emphasizing clinical features, diagnostic strategies, and management options.
Methods: A narrative review of PubMed and Embase publications (2013–2023), supplemented with earlier landmark studies, was conducted. The review highlights diagnostic algorithms and therapeutic approaches across the PMA spectrum.
Results: Classic syndromes include Unverricht–Lundborg disease, Lafora disease, sialidosis, neuronal ceroid lipofuscinoses, North Sea progressive myoclonus epilepsy (GOSR2), and mitochondrial disorders (MERRF, MELAS). Key diagnostic clues involve age of onset, epilepsy phenotype, ophthalmologic findings, and neuroimaging. Next-generation sequencing has revolutionized diagnostic precision, although accessibility remains a challenge.
Conclusion: Early recognition of PMAs improves patient management and avoids harmful therapies. A structured diagnostic approach is essential, and recent developments in molecular genetics and enzyme replacement provide hope for future targeted interventions.
References
Rossi, M., Anheim, M., Durr, A., Espay, A. J., Wirth, T., Klein, C., Cortese, A., Ganos, C., Fung, V. S. C., & Bhatia, K. P. (2020). Myoclonus-ataxia syndromes: A diagnostic approach. Movement Disorders Clinical Practice, 8(1), 9–24. https://doi.org/10.1002/mdc3.13106
van der Veen S, Delgado-Escueta AV, Sisodiya SM. Progressive myoclonus epilepsies: recent advances and future challenges. Prog Neurobiol. 2018;160:13–25. https://doi.org/10.1016/j.pneurobio.2017.10.004.
Franceschetti S, Canafoglia L, Savoiardo M. Progressive myoclonus epilepsies: clinical and neurophysiological aspects. Neurology. 2014;82(13):1081–1090. https://doi.org/10.1212/WNL.0000000000000265.
Crespel A, Rogemond V, Beurrier C. Progressive myoclonus epilepsies. Orphanet J RareDis. 2016;11(1):1–12. https://doi.org/10.1186/s13023-016-0431-3.
Joensuu T, Lehesjoki AE, Kopra O. Mutations in cystatin B cause progressive myoclonus epilepsy. Hum Mol Genet. 2008;17(23):3662–3671. https://doi.org/10.1093/hmg/ddn261.
Rossi M, Franceschetti S, Genton P. The natural history of Unverricht-Lundborg disease: a 30-year cohort study. Epilepsy Behav. 2018;80:13–20. https://doi.org/10.1016/j.yebeh.2018.01.016.
Vanni N, Franceschetti S, Nardocci N. Clinical variability of Unverricht-Lundborg disease. Epilepsia. 2014;55(9):1388–1397. https://doi.org/10.1111/epi.12692.
Muona M, et al. Diagnosis of Unverricht-Lundborg disease requires targeted genetic assays. Genet Med. 2015;17(9):759–764. https://doi.org/10.1038/gim.2014.190.
Kälviäinen R, et al. Antiepileptic drug treatment in Unverricht-Lundborg disease. Epileptic Disord. 2008;10 Suppl 1:27–31. https://doi.org/10.1684/epd.2008.0164.
Nitschke F, et al. Lafora disease—clinical perspectives. Lancet Neurol. 2018;17(10):989–1000. https://doi.org/10.1016/S1474-4422(18)30248-7.
Carlson A, Dienel S, Colbran R. Clinical progression in Lafora disease. Brain. 2018;141(12):3445–3456. https://doi.org/10.1093/brain/awy292.
Araya K, Hernández-Echeagaray E, et al. Lafora disease and diagnostic strategies. Epilepsia. 2018;59(6):1188–1197. https://doi.org/10.1111/epi.14178.
Cohen S, et al. Treatment outcomes in Lafora disease. Epilepsia. 2017;58(4):545–553. https://doi.org/10.1111/epi.13702.
Lukong KE, et al. Mutations in the NEU1 gene cause sialidosis. Am J Hum Genet. 2000;66(3):797–807. https://doi.org/10.1086/302816.
Kojovic M, Cordivari C, Bhatia K. Movement disorders in sialidosis. MovDisord. 2011;26(3):527–529. https://doi.org/10.1002/mds.23431.
D’Azzo, A., Machado, E. and Annunziata, I. (2015) ‘Pathogenesis, emerging therapeutic targets and treatment in sialidosis’, Expert Opinion on Orphan Drugs, 3(5), pp. 491–504.Availableat: https://doi.org/10.1517/21678707.2015.1025746.
Wang, D., Maegawa, G. H., Noda, Y., Zhao, H., Suzuki, Y., &Oshima, A. (2005). Short-term, high dose enzyme replacement therapy in sialidosis mice. Molecular Genetics and Metabolism, 85(3), 181–189. https://doi.org/10.1016/j.ymgme.2005.03.007
Orlin, A., Bielschowsky, K., Kim, H. J., van Diggelen, O. P., & Mole, S. E. (2013). Spectrum of ocular manifestations in CLN2-associated Batten (Jansky-Bielschowsky) disease correlate with advancing age and deteriorating neurological function. PLoS ONE, 8(8), e73128. https://doi.org/10.1371/journal.pone.0073128
Lourenço, C. M., de Oliveira, D. L., de Souza, C. F., & Sampaio, L. P. (2021). Revealing the clinical phenotype of atypical neuronal ceroid lipofuscinosis type 2 disease: Insights from the largest cohort in the world. Journal of Paediatrics and Child Health, 57(4), 519–525. https://doi.org/10.1111/jpc.15250
Schulz A, Strunk U, Kalkanoglu-Sivrikaya S, et al. Study of intraventricular cerliponase alfa for CLN2 disease. N Engl J Med. 2018;378(20):1898–1907. https://doi.org/10.1056/NEJMoa1712649.
de Brito Sampaio, L. P., Pereira, A. C., Rodrigues, D. C., & da Silva, L. A. (2023). Clinical management and diagnosis of CLN2 disease: Consensus of the Brazilian experts group. Arquivos de Neuro-Psiquiatria, 81(3), 284. https://doi.org/10.1055/s-0043-1761434
Ostergaard, J. R., Nelvagal, H. R., & Cooper, J. D. (2022). Top-down and bottom-up propagation of disease in the neuronal ceroid lipofuscinoses. Frontiers in Neurology, 13, 1061363. https://doi.org/10.3389/fneur.2022.1061363
Mole, S. E., Williams, R. E., & Goebel, H. H. (2019). Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis. The Lancet Neurology, 18(1), 107–116. https://doi.org/10.1016/S1474-4422(18)30368-5
Polet, S. S., van Egmond, M., Boissé Lomax, L., Praschberger, R., & Corbett, M. A. (2020). A detailed description of the phenotypic spectrum of North Sea Progressive Myoclonus Epilepsy in a large cohort of seventeen patients. Parkinsonism&RelatedDisorders, 72, 44–48. https://doi.org/10.1016/j.parkreldis.2020.02.005
Finsterer J, Zarrouk-Mahjoub S, Shoffner JM. Clinical features of mitochondrial epilepsies. Genet Med. 2017;19(6):619–626. https://doi.org/10.1038/gim.2016.152.
Hameed T, Tadi P. MERRF syndrome. StatPearls. 2023. https://www.ncbi.nlm.nih.gov/books/NBK538175/.
Ikeda T, et al. MELAS syndrome and stroke-like episodes. Brain. 2018;141(2):e10. https://doi.org/10.1093/brain/awx363.
Agier, V., Auré, K., &Lombès, A. (2009). MELAS syndrome. Drugs of the Future, 34(3), 237–241. https://doi.org/10.1358/dof.2009.034.03.1340065
Acquaah, J., Ferdinand, P., &Roffe, C. (2024). Adult-onset mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): A diagnostic challenge. BMJ Case Reports, 17(2), e256306. https://doi.org/10.1136/bcr-2023-256306
Li, J., Zhang, W., Wang, Z., Zhang, Y., Liu, Y., & Liu, X. (2021). Epilepsy associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Frontiers in Neurology, 12, 675816. https://doi.org/10.3389/fneur.2021.675816
Views:
29
Downloads:
13
Copyright (c) 2025 Karolina Wojdat-Krupa, Karol Sikora, Paulina Lewaśkiewicz, Filip Lachowski, Martyna Wasyluk, Paweł Jan Babiński, Anita Jalali
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
