293 Progressive Myoclonus Epilepsies Reetta Kälviäinen, MD, PhD1,2 1 Kuopio Epilepsy Center/Neurocenter, Kuopio University Hospital, Address for correspondence Reetta Kälviäinen, MD, PhD, Department Kuopio, Finland of Clinical Epileptology, Kuopio Epilepsy Center/Neurocenter, Kuopio 2 Faculty of Health Sciences, School of Medicine, Institute of Clinical University Hospital, POB 100, Kuopio 70029 KYS, Finland Medicine, University of Eastern Finland, Kuopio, Finland (e-mail: reetta.kalviainen@kuh.fi). Semin Neurol 2015;35:293–299. Abstract The progressive myoclonus epilepsies (PMEs) comprise a group of rare and heteroge- neous disorders defined by the combination of action myoclonus, epileptic seizures, and Keywords progressive neurologic deterioration. Neurologic deterioration may include progressive ► progressive cognitive decline, ataxia, neuropathy, and myopathy. The gene defects for the most myoclonus epilepsy common forms of PME (Unverricht–Lundborg disease, Lafora disease, several forms of ► EPM1 neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers [MERRF], and ► EPM2 type 1 and 2 sialidoses) have been identified. The prognosis of a PME depends on the ► Unverricht–Lundborg specific disease. Lafora disease, the neuronal ceroid lipofuscinoses, and the neuro- disease nopathic form of Gaucher disease have an invariably fatal course. In contrast, Un- ► Lafora disease verricht–Lundborg disease has a much slower progression, and with adequate care ► neuronal ceroid many patients have a normal life span. The specificdiseasesthatcausePMEare lipofuscinoses diagnosed by recognition of their age of onset, the associated clinical symptoms, the sialidosis clinical course, the pattern of inheritance, and by special investigations such as enzyme ► Gaucher disease measurement, skin/muscle biopsy, or gene testing. Progressive myoclonus epilepsies (PMEs) are neurodegener- Unverricht–Lundborg Disease (EPM1) ative diseases and are among the most disabling forms of epilepsy. They are clinically and genetically heterogeneous, Progressive myoclonus epilepsy type 1 (EPM1) of the Un- characterized by the core features of action myoclonus, verricht–Lundborg type is an autosomal recessive neurode- epileptic seizures, and progressive neurologic decline.1 Typi- generative disorder that has the highest incidence among the cally, the myoclonus shows a focal or segmental distribution, progressive myoclonus epilepsies worldwide.1 Progressive and is characterized by an arrhythmic, asynchronous, and myoclonus epilepsy type 1 is characterized by stimulus- asymmetric occurrence. Generalized tonic–clonic seizures sensitive myoclonus and tonic–clonic epileptic seizures. As predominate, although there may also be other types of EPM1 progresses, patients develop additional neurologic seizures such as absence, tonic, and focal seizures. Most symptoms including ataxia, dysarthria, intention tremor, This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. molecularly characterized PMEs are inherited in an autoso- and decreased coordination.4 Progressive myoclonus epilep- mal recessive manner, but rare cases show autosomal domi- sy type 1 is caused by 14 known mutations in the cystatin B – nant or mitochondrial inheritance.2,3 The diagnosis of specific (CSTB) gene.5 7 forms of PME is challenging because of genetic heterogeneity, At disease onset (6–16 years), EPM1 patients present phenotypic similarities, and an overlap of symptoms with primarily with myoclonic and/or generalized tonic–clonic other epileptic and neurodegenerative diseases (►Table 1). seizures. Most patients show involuntary action-activated Consequently, a substantial proportion of PME cases still or stimulus-sensitive myoclonus (i.e., triggered by light, remain without a molecular diagnosis.2,3 physical activity, noise, cognitive stimulus, and/or stress).4 Issue Theme Etiology of Epilepsy; Guest Copyright © 2015 by Thieme Medical DOI http://dx.doi.org/ Editors: Philip Smith, MD, FRCP, Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0035-1552620. FAcadMEd, and Rhys Thomas, BSc, MRCP, New York, NY 10001, USA. ISSN 0271-8235. MSc, PhD Tel: +1(212) 584-4662. 294 Progressive Myoclonus Epilepsies Kälviäinen Table 1 Diagnostic investigations in different progressive myoclonus epilepsies (PMEs) 1. Unverricht–Lundborg disease (EPM1) Gene test: EPM1 (CSTB) mutation analysis 2. Lafora body disease (EPM2) Skin biopsy: Lafora bodies Gene tests: EPM2A or EPMP2B(NHLRC1) mutation analysis 3. Neuronal ceroid lipofuscinoses (NCL) Skin biopsy: Granular osmophilic deposit Leukocyte enzyme analyses: PPT1,TPP1, CTSD Gene tests: CLN1/PPT1,CLN2/TPP1,CLN3,CLN4/DNAJC5, CLN5, CLN6, CLN7/MFSD8, CLN8, CLN10/CTSD, CLN11/GRN, CLN12/ATP13A2, CLN13/CTSF, CLN14/KCTD7 mutation analysis 4. Sialidosis Urine: Sialo-oligosaccharides Leukocyte enzyme analysis: Neuraminidase Gene test: NEU1 mutation analysis 5. Myoclonus epilepsy and ragged-red fibers (MERFF) Plasma lactate and pyruvate Muscle biopsy: Ragged-red fibers Gene test: MT-TK mutation analysis 6. Type 3 neuronopathic Gaucher disease Leukocyte enzyme analysis (β-glucocerebrosidase) Gene test: GBA mutation analysis 7. Dentatorubral-pallidoluysian atrophy Gene test: DRPLA mutation analysis 8. Action myoclonus-renal failure syndrome (AMRF; EPM4) Gene test: SCARB2/LIMP2 mutation analysis 9. PME-ataxia syndrome (EPM5) Gene test: PRICKLE1 mutation analysis 10. North Sea PME (EPM6) Gene test: GOSR2 mutation analysis This asynchronized myoclonus occurs primarily in the proxi- At disease onset, brain magnetic resonance imaging (MRI) mal muscles of the extremities; it may be focal or multifocal, is typically normal. However, voxel-based morphometry may and it may generalize to myoclonic seizures or status show cortical and thalamic atrophy and thinned cortical myoclonicus. thickness in the sensorimotor areas.9,10 Abnormalities in Approximately one-third of the patients become wheel- the EEG (background slowing, spike-wave discharges, poly- chair bound due to progressive myoclonus and ataxia. An spike discharges during REM sleep and photosensitivity) are earlier age at onset for EPM1 and longer disease duration are more pronounced at initial diagnosis, when disease onset associated with more severe action myoclonus and also lower may be accompanied by generalized tonic–clonic seizures. performance IQ.8 Patients with more severe myoclonus re- Some patients at presentation have focal epileptiform dis- port more marked disability and more difficulties in everyday charges, primarily in the occipital region. In general, EEG activities. Patients with EPM1 may experience emotional abnormalities diminish as the disease stabilizes.4 Navigated lability, depression, and a mild intellectual decline over transcranial magnetic stimulation also shows significant time, but overall their cognitive functions, such as verbal neurophysiological changes in cortical excitability.11 abilities and memory, are less impaired than their motor The clinical diagnosis should be complemented with ge- functions. netic testing, which is commercially available. The gene The diagnosis should be considered in any previously responsible for Unverricht–Lundborg disease was initially This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. healthy child who, between the ages of 6 to 16 years, presents mapped to the long arm of chromosome 21, band q22.3. with at least one of the following four symptoms: (1) invol- The CSTB gene is approximately 2.5 kb in length and contains untary, stimulus, and/or action-activated myoclonic jerks; (2) three small exons. The most common mutation (90%) con- generalized tonic–clonic seizures; (3) mild neurologic signs in sists of the expansion of a dodecamer repeat in the promoter motor function or coordination; (4) photosensitivity, with region of the CSTB gene. The general consensus has been that generalized spike-and-wave and polyspike-and-wave parox- Finnish patients display a more severe clinical phenotype ysms, and background slowing on the electroencephalogram than patients from the Mediterranean region.12 Earlier it was (EEG), with concurrent deterioration of neurologic symp- reported that although the expanded alleles in Finnish pa- toms, such as myoclonus and ataxia.4 The clinical examina- tients were longer, the actual length did not correlate with the tion should include funduscopy, and an evaluation of walking, clinical disease severity or with the age of the EPM1 onset.13 coordination, handwriting, school performance, and emo- Recently, with more detailed phenotyping of the patients, it tional state. An examination of the myoclonus should entail has been shown that the actual size of the longer CSTB an evaluation of the myoclonus at rest, with action, and in expansion mutation allele is likely to have a modulating effect response to stimuli including light, noise, and/or stress.4 on the age at disease onset, myoclonus severity, and cortical Seminars in Neurology Vol. 35 No. 3/2015 Progressive Myoclonus Epilepsies Kälviäinen 295 neurophysiology.8 Only a minority of EPM1 alleles (14%) presence of a slow background rhythm, drug-resistant seiz- harbor mutations within the transcriptional unit of CSTB. ures and neurologic deterioration in a patient diagnosed with Most of the compound heterozygous EPM1 patients exhibit a juvenile myoclonic epilepsy or absence epilepsy should raise more severe phenotype.6,14 Cystatin B is a small, 98 amino suspicion and lead to more investigation. acid