progressive myoclonic epilepsies


Summary: A heterogeneous group of primarily familial EPILEPSY disorders characterized by myoclonic seizures, tonic-clonic seizures, ataxia, progressive intellectual deterioration, and neuronal degeneration. These include LAFORA DISEASE; MERRF SYNDROME; NEURONAL CEROID-LIPOFUSCINOSIS; sialidosis (see MUCOLIPIDOSES), and UNVERRICHT-LUNDBORG SYNDROME.

Top Publications

  1. Shahwan A, Farrell M, Delanty N. Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects. Lancet Neurol. 2005;4:239-48 pubmed
    The progressive myoclonic epilepsies (PMEs) are a group of symptomatic generalised epilepsies caused by rare disorders, most of which have a genetic component, a debilitating course, and a poor outcome...
  2. Yamada M, Wood J, Shimohata T, Hayashi S, Tsuji S, Ross C, et al. Widespread occurrence of intranuclear atrophin-1 accumulation in the central nervous system neurons of patients with dentatorubral-pallidoluysian atrophy. Ann Neurol. 2001;49:14-23 pubmed
  3. Yu J, Ying M, Zhuang Y, Xu T, Han M, Wu X, et al. C-terminal deletion of the atrophin-1 protein results in growth retardation but not neurodegeneration in mice. Dev Dyn. 2009;238:2471-8 pubmed publisher
    ..These results support the model that poly-Q expanded Atrophin-1 proteins cause DRPLA in a manner independent of any functional interaction with wild-type Atrophin-1 proteins. ..
  4. Fukushima Y. [Pediatric neurological disorders and genetic counseling]. No To Hattatsu. 2003;35:285-91 pubmed
    ..Pediatric neurologists should know the special issues of genetic information and contact with clinical geneticists in selected cases. ..
  5. Kin T, Hirano M, Taoka T, Furiya Y, Kataoka H, Kichikawa K, et al. Global and region-specific analyses of apparent diffusion coefficient in dentatorubral-pallidoluysian atrophy. AJNR Am J Neuroradiol. 2006;27:1463-6 pubmed
    ..Thus, histogram and ROI analyses complement each other and may permit the sensitive, quantitative evaluation of neurodegeneration in DRPLA, especially that involving the globus pallidus showing normal T2 signals. ..
  6. Uozumi T, Tamagawa A, Hashimoto T, Tsuji S. High-frequency oscillations in the human motor system. Suppl Clin Neurophysiol. 2006;59:143-7 pubmed
  7. Faruq M, Scaria V, Singh I, Tyagi S, Srivastava A, Mukerji M. SCA-LSVD: a repeat-oriented locus-specific variation database for genotype to phenotype correlations in spinocerebellar ataxias. Hum Mutat. 2009;30:1037-42 pubmed publisher
    ..This would be a very useful starting point for understanding the molecular correlates of phenotypes in ataxia-a multilocus disease in which related molecular mechanisms converge to overlapping phenotypes. ..
  8. Lalioti M, Antonarakis S, Scott H. The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion. Cytogenet Genome Res. 2003;100:213-23 pubmed
    ..Loss of CSTB function due to mutations is consistent with the observed neurodegenerative pathology and phenotype, but the functional link to the epileptic phenotype of EPM1 remains largely unknown. ..
  9. Evert B, Wullner U, Klockgether T. Cell death in polyglutamine diseases. Cell Tissue Res. 2000;301:189-204 pubmed

More Information


  1. Cipollini E, Riccio M, Di Giaimo R, Dal Piaz F, Pulice G, Catania S, et al. Cystatin B and its EPM1 mutants are polymeric and aggregate prone in vivo. Biochim Biophys Acta. 2008;1783:312-22 pubmed
    ..This work describes a protein with a physiological role characterized by highly stable polymers prone to aggregate formation in vivo. ..
  2. Yamada M, Sato T, Shimohata T, Hayashi S, Igarashi S, Tsuji S, et al. Interaction between neuronal intranuclear inclusions and promyelocytic leukemia protein nuclear and coiled bodies in CAG repeat diseases. Am J Pathol. 2001;159:1785-95 pubmed
    ..The results suggest that the interaction between NIIs and nuclear bodies may play a role in the pathogenesis of CAG repeat diseases. ..
  3. Suzuki T, Tomiyasu H, Motokawa M, Sugito K, Suzuki T. [A sporadic case of dentatorubral-pallidoluysian atrophy diagnosed by MRI findings]. No To Shinkei. 2002;54:170-1 pubmed
  4. Licht D, Lynch D. Juvenile dentatorubral-pallidoluysian atrophy: new clinical features. Pediatr Neurol. 2002;26:51-4 pubmed
  5. Alakurtti K, Weber E, Rinne R, Theil G, de Haan G, Lindhout D, et al. Loss of lysosomal association of cystatin B proteins representing progressive myoclonus epilepsy, EPM1, mutations. Eur J Hum Genet. 2005;13:208-15 pubmed
    ..Gln71Pro, fail to associate with lysosomes. These data imply an important lysosome-associated physiological function for CSTB and suggest that loss of this association contributes to the molecular pathogenesis of EPM1. ..
  6. Brown P. Action myoclonus-renal failure syndrome: the definitive clinico-pathological description. Brain. 2004;127:2151-2 pubmed
  7. González De la Rosa M, Alva Moncayo E. [Lafora disease presentation, two cases in a Mexican family]. Rev Med Inst Mex Seguro Soc. 2017;55:252-256 pubmed
    ..El artículo reporta los casos de dos hermanas, en quienes se confirmó en forma definitiva su diagnóstico que permitió orientarse sobre la detección temprana del otro caso. ..
  8. Vinton A, Fahey M, O Brien T, Shaw J, Storey E, Gardner R, et al. Dentatorubral-pallidoluysian atrophy in three generations, with clinical courses from nearly asymptomatic elderly to severe juvenile, in an Australian family of Macedonian descent. Am J Med Genet A. 2005;136:201-4 pubmed
  9. Shimohata T, Onodera O, Honma Y, Hirota K, Nunomura Y, Kimura T, et al. [Gene diagnosis of patients with chorea]. Rinsho Shinkeigaku. 2004;44:149-53 pubmed
    ..Therefore, further genetic heterogeneity is expected in the cases of chorea in Japan. ..
  10. Tsuji S. [Molecular mechanisms of neurodegeneration in polyglutamine diseases]. Nihon Ronen Igakkai Zasshi. 2007;44:154-7 pubmed
  11. Hashi R, Nakamura A, Sugimoto T, Kaneko K. [Electroencephalographic changes in sisters with infantile-onset dentatorubral-pallidoluysian atrophy (DRPLA)]. No To Hattatsu. 2007;39:445-9 pubmed
    ..Myoclonic seizures developed at 4 years and 7 months, but have been well controlled using sodium valproate. EEG showed diffuse 3-4 Hz spike-and-wave complexes that were rather different from the findings in her elder sister. ..
  12. Hirasawa M, Ikebe S, Komatsuzaki Y, Takanashi M, Mori H, Urabe T, et al. [A 52-year-old woman with dyskinesia, epilepsy and gait disturbance]. No To Shinkei. 2002;54:919-27 pubmed
    ..The cerebral white matters were unremarkable. Other areas were unremarkable. The pathological diagnosis was dentatorubral-pallidoluysian atrophy. The pathologic lesion which might explain her dementia was not apparent. ..
  13. Wardle M, Majounie E, Williams N, Rosser A, Morris H, Robertson N. Dentatorubral pallidoluysian atrophy in South Wales. J Neurol Neurosurg Psychiatry. 2008;79:804-7 pubmed
    ..The prevalence of high-normal length alleles may account for the relatively high prevalence of DRPLA in Wales. ..
  14. de Haan G, Halley D, Deelen W, Lindhout D. [From gene to disease; progressive myoclonus epilepsy of Unverricht-Lundborg and mutations in the cystatin B gene]. Ned Tijdschr Geneeskd. 2002;146:846-8 pubmed
    ..An early diagnosis is important to optimise treatment and to provide an adequate prognosis and prediction of recurrence. ..
  15. Kecmanovic M, Ristic A, Sokic D, Keckarevic Markovic M, Vojvodic N, Ercegovac M, et al. Coexistence of Unverricht-Lundborg disease and congenital deafness: molecular resolution of a complex comorbidity. Epilepsia. 2009;50:1612-5 pubmed publisher
    ..To the best of our knowledge this is the first genetic confirmation of the coexistence of these two mutations. ..
  16. Hatano T, Okuma Y, Iijima M, Fujishima K, Goto K, Mizuno Y. Cervical dystonia in dentatorubral-pallidoluysian atrophy. Acta Neurol Scand. 2003;108:287-9 pubmed
    ..Cranial magnetic resonance imaging showed a mild atrophy of the brainstem and the cerebellum in both of these patients. DRPLA should be considered in the differential diagnosis of patients presenting with cervical dystonia. ..
  17. Cil B, Akpinar E, Karcaaltincaba M, Akinci D. Case 76: May-Thurner syndrome. Radiology. 2004;233:361-5 pubmed
  18. Pataskar S, Dash D, Brahmachari S. Intramolecular i-motif structure at acidic pH for progressive myoclonus epilepsy (EPM1) repeat d(CCCCGCCCCGCG)n. J Biomol Struct Dyn. 2001;19:307-13 pubmed
    ..The stability of the structure increases with the increase in the length of the repeat. Transient formation of stable, folded back structure like i-motif could play an important role in the mechanism of expansion of this repeat. ..
  19. Teoh H, Solyom A, Schuchman E, Mowat D, Roscioli T, Farrar M, et al. Polyarticular Arthritis and Spinal Muscular Atrophy in Acid Ceramidase Deficiency. Pediatrics. 2016;138: pubmed
    ..Acid ceramidase deficiency is an important consideration in patients presenting with polyarticular arthritis and motor neuron disease. ..
  20. O Brien A, Marshall C, Blaser S, Ray P, Yoon G. Severe neurodegeneration, progressive cerebral volume loss and diffuse hypomyelination associated with a homozygous frameshift mutation in CSTB. Eur J Hum Genet. 2017;25:775-778 pubmed publisher
    ..The neuroimaging features of our patients are consistent with those observed in Cstb-knockout mice, which supports the hypothesis that disease severity is inversely correlated with the amount of residual functional cystatin B protein. ..
  21. Tsuji S. Dentatorubral-pallidoluysian atrophy: clinical aspects and molecular genetics. Adv Neurol. 2002;89:231-9 pubmed
  22. Blanz J, Groth J, Zachos C, Wehling C, Saftig P, Schwake M. Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand beta-glucocerebrosidase. Hum Mol Genet. 2010;19:563-72 pubmed publisher
  23. Gabellini D, Tupler R, Green M. Transcriptional derepression as a cause of genetic diseases. Curr Opin Genet Dev. 2003;13:239-45 pubmed
    ..The putative target genes, whose inappropriate expression is thought to cause disease, have remained elusive but are being searched for intensively. ..
  24. Terashima T, Kawai H, Fujitani M, Maeda K, Yasuda H. SUMO-1 co-localized with mutant atrophin-1 with expanded polyglutamines accelerates intranuclear aggregation and cell death. Neuroreport. 2002;13:2359-64 pubmed
    ..These results suggest that SUMO-1 is implicated in the pathogenesis of DRPLA and accelerates aggregate formation and cell death. ..
  25. Takano T, Okuno K, Maruo Y, Takeuchi Y. A pediatric patient with sporadic dentatorubral pallidoluysian atrophy. Pediatr Neurol. 2003;28:72-3 pubmed
    ..Gene analysis of the patient's parents was not performed. The molecular mechanisms of the occurrence of sporadic cases have not been clarified. ..
  26. Chan E, Andrade D, Franceschetti S, Minassian B. Progressive myoclonus epilepsies: EPM1, EPM2A, EPM2B. Adv Neurol. 2005;95:47-57 pubmed
  27. Takeuchi Y, Matsushita H, Sakai H, Kawano H, Ochi M. Developmental changes in cerebrospinal fluid concentrations of monoamine-related substances in patients with dentatorubral-pallidoluysian atrophy. J Child Neurol. 2001;16:79-82 pubmed
    ..These abnormal developmental changes in monoamine-related substances may be implicated in age-related differences in clinical symptoms of dentatorubral-pallidoluysian atrophy. ..
  28. Costello D, Chiappa K, Siao P. Progressive myoclonus epilepsy with demyelinating peripheral neuropathy and preserved intellect: a novel syndrome. Arch Neurol. 2009;66:898-901 pubmed publisher
    The progressive myoclonic epilepsies (PMEs) are a disparate group of syndromes whose common features include disabling myoclonus, progressive cognitive decline, and seizures, typically with a relentless deterioration over time...
  29. Michlewski G, Krzyzosiak W. Molecular architecture of CAG repeats in human disease related transcripts. J Mol Biol. 2004;340:665-79 pubmed
  30. Garvey M, Toro C, Goldstein S, Altarescu G, Wiggs E, Hallett M, et al. Somatosensory evoked potentials as a marker of disease burden in type 3 Gaucher disease. Neurology. 2001;56:391-4 pubmed
    ..The authors conclude that abnormal cortical inhibition is a unifying feature of GD3 patients and correlates with the degree of cognitive deficit. ..
  31. Vossler D, Conry J, Murphy J. Zonisamide for the treatment of myoclonic seizures in progressive myoclonic epilepsy: an open-label study. Epileptic Disord. 2008;10:31-4 pubmed publisher
    ..These results suggest that zonisamide may be useful in the treatment of patients with PME. However, due to the size and open-label character of this study, further research is required. ..
  32. Kanazawa I. Dentatorubral-pallidoluysian atrophy or Naito-Oyanagi disease. Neurogenetics. 1998;2:1-17 pubmed
    ..The impact of gene analysis of DRPLA on the clinical genetics and neurology are discussed. Moreover, possible mechanism(s) underlying the neuronal cell death in DRPLA are discussed in terms of the molecular pathology. ..
  33. Wardle M, Morris H, Robertson N. Clinical and genetic characteristics of non-Asian dentatorubral-pallidoluysian atrophy: A systematic review. Mov Disord. 2009;24:1636-40 pubmed publisher
    ..Non-Asian DRPLA clinico-genetic phenomenology are similar to Asian series and our study confirms marked genetic anticipation together with a clear association between repeat length and clinical phenotype and disease severity...
  34. Munhoz R, Bergeron C, Lang A. Sporadic case of dentatorubral pallidoluysian atrophy with no CAG repeat expansion and no intranuclear inclusions. Mov Disord. 2004;19:580-3 pubmed
    ..Family history and genetic testing were unrevealing. Neuropathological findings were identical to genetic dentatorubral pallidoluysian (DRPLA) except for the lack of intranuclear inclusions. ..
  35. Jung D, Lee J, Lee J, Park H, You H, Lee J. Corneal endothelial changes as a clinical diagnostic indicator of dentatorubropallidoluysian atrophy. Cornea. 2004;23:210-4 pubmed
  36. El Shanti H, Daoud A, Sadoon A, Leal S, Chen S, Lee K, et al. A distinct autosomal recessive ataxia maps to chromosome 12 in an inbred family from Jordan. Brain Dev. 2006;28:353-7 pubmed
    ..A recently described autosomal recessive variant of Unverricht-Lundborg disease also maps to the same region. We discuss the similarities and differences between our family and the family with the Unverricht-Lundborg disease variant. ..
  37. Lefaucheur J. Myoclonus and transcranial magnetic stimulation. Neurophysiol Clin. 2006;36:293-7 pubmed
    ..Therapeutic-like perspectives are opened for rTMS in these forms of myoclonus that are related to motor cortical hyperexcitability secondary to the loss of ICI. ..
  38. Gourfinkel An I, Duyckaerts C, Camuzat A, Meyrignac C, Sonderegger P, Baulac M, et al. Clinical and neuropathologic study of a French family with a mutation in the neuroserpin gene. Neurology. 2007;69:79-83 pubmed
    ..The typical cerebral inclusions (Collins bodies) were abundant in the frontal cortex and in the head of the caudate nucleus but spared the cerebellum. ..
  39. Tsuji S. [Dentatorubral-pallidoluysian atrophy (DRPLA)]. Rinsho Shinkeigaku. 2007;47:932-3 pubmed
  40. Ying M, Xu R, Wu X, Zhu H, Zhuang Y, Han M, et al. Sodium butyrate ameliorates histone hypoacetylation and neurodegenerative phenotypes in a mouse model for DRPLA. J Biol Chem. 2006;281:12580-6 pubmed
  41. Yamada M, Tan C, Inenaga C, Tsuji S, Takahashi H. Sharing of polyglutamine localization by the neuronal nucleus and cytoplasm in CAG-repeat diseases. Neuropathol Appl Neurobiol. 2004;30:665-75 pubmed
  42. Butler R, Bates G. Histone deacetylase inhibitors as therapeutics for polyglutamine disorders. Nat Rev Neurosci. 2006;7:784-96 pubmed
    ..Here, we discuss the potential therapeutic pathways through which histone deacetylase inhibitors might act to correct the aberrant transcription observed in Huntington's disease and other polyglutamine repeat diseases. ..
  43. Yamada M, Piao Y, Toyoshima Y, Tsuji S, Takahashi H. Ubiquitinated filamentous inclusions in cerebellar dentate nucleus neurons in dentatorubral-pallidoluysian atrophy contain expanded polyglutamine stretches. Acta Neuropathol. 2000;99:615-8 pubmed
  44. Tsuji S. [Molecular mechanisms of neurodegeneration in dentatorubral-pallidoluysian atrophy (DRPLA)]. Rinsho Shinkeigaku. 2001;41:1064-6 pubmed
    ..Taken together, these findings suggest that the interference of CREB-dependent transcription by expanded polyglutamine stretches is involved in the neuronal dysfunction in polyglutamine diseases. ..
  45. Manganotti P, Tamburin S, Zanette G, Fiaschi A. Hyperexcitable cortical responses in progressive myoclonic epilepsy: a TMS study. Neurology. 2001;57:1793-9 pubmed
    ..These findings suggest cortical and subcortical components of abnormal sensorimotor integration in addition to hyperexcitability of the sensory and motor cortex in our myoclonic patients. ..
  46. Ono S, Kaneda K, Suzuki M, Tagawa A, Shimizu N. Dentatorubropallidoluysian atrophy with chronic renal failure in a Japanese family. Eur Neurol. 2002;47:222-3 pubmed
    ..Thus, we suggest a possible unifying hypothesis that the coexistence of DRPLA and chronic renal failure may be caused by the same etiology. ..
  47. Le Ber I, Camuzat A, Castelnovo G, Azulay J, Genton P, Gastaut J, et al. Prevalence of dentatorubral-pallidoluysian atrophy in a large series of white patients with cerebellar ataxia. Arch Neurol. 2003;60:1097-9 pubmed
    ..In both familial and sporadic cases, molecular testing for DRPLA could be restricted to patients with ataxia with one of the following features: chorea, dementia, or myoclonic epilepsy. ..
  48. Ohta M, Okuyama R, Ogawa E, Kisu K, Sato H, Aoki M, et al. Cutaneous accumulation of abnormal polyglutamine proteins of patients with dentatorubral-pallidoluysian atrophy. Eur J Neurol. 2009;16:1246-9 pubmed publisher
    ..The skin is accessible by biopsy, making it important in the diagnosis. Furthermore, the polyglutamine staining in the skin may be useful for evaluation of therapeutic modalities for DRPLA and other polyglutamine diseases. ..
  49. Berkovic S, Dibbens L, Oshlack A, Silver J, Katerelos M, Vears D, et al. Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. Am J Hum Genet. 2008;82:673-84 pubmed publisher
    ..The heterogeneous pathology in the kidney and brain suggests that SCARB2/Limp2 has pleiotropic effects that may be relevant to understanding the pathogenesis of other forms of glomerulosclerosis or collapse and myoclonic epilepsies. ..
  50. CoÅŸkun T, Kiziltan M, Gündüz A, Delil Å, Yeni N, Özkara Ã. Blink reflex in progressive myoclonic epilepsies. Seizure. 2015;29:169-73 pubmed publisher
    b>Progressive myoclonic epilepsies (PME) include a heterogeneous group of disorders. The brainstem is involved in these disorders, as demonstrated by neuroimaging and autopsy studies...
  51. Kinrions P, Ibrahim N, Murphy K, Lehesjoki A, Jarvela I, Delanty N. Efficacy of levetiracetam in a patient with Unverricht-Lundborg progressive myoclonic epilepsy. Neurology. 2003;60:1394-5 pubmed
  52. Chan E, Young E, Ianzano L, Munteanu I, Zhao X, Christopoulos C, et al. Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat Genet. 2003;35:125-7 pubmed
    ..Laforin and malin colocalize to the ER, suggesting they operate in a related pathway protecting against polyglucosan accumulation and epilepsy. ..
  53. Muñoz E, Campdelacreu J, Ferrer I, Rey M, Cardozo A, Gomez B, et al. Severe cerebral white matter involvement in a case of dentatorubropallidoluysian atrophy studied at autopsy. Arch Neurol. 2004;61:946-9 pubmed
    ..In our case, the disproportion between the severity of white matter damage and vascular changes does not support a cardinal role for ischemic mechanisms in leukoencephalopathy. ..