doi:10.1684/epd.2012.0489 , 1 1 Epileptic Disord, Vol. 14, No. 1, March 2012 , Meral Kızıltan 2 ˘ ai¸ University gazic¸i , S Naz Yeni Case report In October 1998, a 35-year-oldpatient male was referred to our epilepsy centre for thegeneralised evaluation of tonic-clonic three (without aura) and seizures cognitive decline within five years. Examination offamily his history revealed firstconsanguinity degree between his parents. The patient had six siblings.his One older brothers of died as aan result epileptic of disorder which wasclassified not with regard to syndromes. The onset ofthe epilepsy age occurred of at 11presented years with and myoclonic jerks the and a patient progressive course to a bedridden level and finallyyears. The death patient and within the observers reported five that there was noor absence myoclonus in his past history. 3 gene. To our knowledge, this is the first ˘ glayan ¸a EMP2B et al., 2005; , Hande C 1 , Cem Leblebici 1 ˘ gac¸ late onset dementia, extrapyramidal signs, epilepsy, disabling – Lafora disease is a rare, fatal, autosomal recessive progressive et al., 2002). This case report Epileptic Disord 2012; 14 (1): 94-8 Clinical commentary Division of Neurology, Istanbul University Medical Cerrahpas¸a Division Faculty of Genetics and MolecularDivision Biology, Bo of Pathology, Samatya Educational and Research Hospital, Istanbul, Turkey Lafora diseaselogically (LD) belongs phenomeno- toof the progressive spectrum myoclonic(PME) and epilepsy generally presents a more or less homogeneouscharacterised by seizures phenotype, preceding visual auras, myoclonus, dementia, and ataxia (Minassian, 2002).recent Some studieshave reported and variability of the clini- casecal characteristics reports withthe respect age to (Minassian, at 2002; Baykan onsetGanesh and prognosis describes a male patientof at 30 the age presentinglised with rare tonic-clonic genera- at jerks, the dementia extrapyramidal age signs, ofabling but 30, myoclonus or no and ataxia. Axillary skin dis- late-onset biopsyconfirmed and the diagnosis of genetic LD. analysis Naci Karaa Received May 17, 2011; Accepted January 25, 2012 description of a patientmyoclonus suffering and from ataxia a but Laforadementia. rather disease without rare disabling seizures, extrapyramidalKey signs, words: and myoclonus Presentation of an unusual patient with Lafora disease Selim Gökdemir 1 2 3 ABSTRACT myoclonic epilepsy. The condition is characterisedand by dementia. seizures, myoclonus In thislised tonic-clonic case seizures report, at a thethe age patient patient of who 30 did is presented not discussed.controlled with have Until seizures. He genera- the myoclonic developed age jerks dementia of andAxillary or 48, late skin extrapyramidal ataxia biopsy signs. revealed clinically, typical but Laforasis inclusion had showed bodies. a well Genetic mutation analy- in the 94 Correspondence: Selim Gökdemir Istanbul University, MedicalCerrahpas¸a Faculty Neurology Department, IstanbulCerrahpas¸a, 34220, Turkey An unusual case of Lafora disease

His neurological examination at admission revealed amplitude C reflex during the stimulation of median only mild to moderate cognitive dysfunction and nerve below motor threshold was also recorded apathia. EEG revealed brief generalised epileptiform (figure 5). All EEGs during follow-up were similar to activities on a slow background and no increase the initial EEG. in photosensitivity (figure 1). Retinal examination Mutational scanning of the EPM2A and EPM2B genes and routine biochemistry including lactate levels by PCR amplification and subsequent DNA sequence were unremarkable. Cranial MRI and somatosenso- analysis revealed a c.436 G>A homozygous substitu- rial evoked potential recordings were normal. Sodium tion in exon 1 of the EPM2B gene which results in the valproate treatment was started. He had a neuropsy- recurrent missense mutation (Asp146Asn) in the malin chological assessment when he was 37 which revealed protein (http://projects.tcag.ca/lafora). severe impairment of memory and frontal lobe func- tions. Seizures remitted and cognitive dysfunction deteriorated which led to his retirement at the age of Discussion 40 years. Mini-mental test score was 10/30. An axillary skin biopsy revealed Lafora inclusion bodies (figures Lafora disease is an autosomal recessive PME. Onset is 2 and 3). When he was 46, he presented with mild between ages nine and 18 years (Minassian, 2002). The bradykinesia and resting tremor of the left upper limb. typical features are myoclonic jerks, generalised tonic- In his recent neurological examination (48 years clonic seizures with visual auras, ataxia, and dementia. old), he had behavioural problems, dementia and Generalised or segmental, spontaneous and action right-sided resting tremor, bilateral asymmetric myocloni associated with EEG paroxysms are promi- rigidity, bilateral bradykinesia, hypomimia, mild ante- nent features and the presence of negative myoclonus flexion posture, mild Parkinsonian gait, sphinctary associated with polyspike-wave discharges is typical dyscontrol and sebaceous skin. He had no seizure and common (Reutens et al., 1993). Photo-convulsive recurrences during the follow-up. Valproate treat- response on EEG is a hallmark. High-amplitude corti- ment was replaced with levetiracetam which did not cal SEPs (giant SEPs) are also typical (Shibasaki, 2002). resolve Parkinsonian symptoms within six months. Diagnosis depends on axillary skin biopsy and genetic Electrophysiological tremor analysis revealed a analysis (Minassian, 2002; Ganesh et al., 2002; Lesca 5.5-Hz alternating resting tremor and 6-6.5-Hz pos- et al., 2010). tural tremor. With the arms outstretched, occasional In this case description, an atypical LD patient is pre- negative and positive myoclonic activity, which was sented. The severity and onset age of LD are variable; not clinically apparent (figure 4), was recorded. High- however, to our knowledge, there is no similar case

12:02:08[00:04:00] [SENS *7 HF *70 TC *0.1 CAL *50] DATE: 14.05.2009 ID: 000216816 SENS Patt. IIB ACFilt. *ON Refer. OFF 70 V x1

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Scale 84 %

Figure 1. EEG revealed brief generalised epileptiform activities on a slow background.

Epileptic Disord, Vol. 14, No. 1, March 2012 95 S. Gökdemir, et al.

Figure 2. Lafora bodies in axillary biopsy, examined by haematoxylin/eosin staining.

Figure 3. Lafora bodies in axillary biopsy, examined by PAS staining. description in the literature with rare well-controlled bling PME and since his parents were consanguineous, seizures, dementia, and late extrapyramidal signs with- he was examined in the context of PMEs. Extrapyra- out disabling myoclonic jerks. This patient presented midal signs may be the result of chronic valproate with a late onset of disease and never experienced dis- use. However, this well-known rare side effect of val- abling myoclonus. Prominent features were dementia, proate is reversible and may not exceed six months well controlled seizures, and late-onset extrapyramidal after withdrawal, according to case descriptions in the signs. As one of his brothers died from a disease resem- literature (Onofrj et al., 1998; Ristic´ et al., 2006).

96 Epileptic Disord, Vol. 14, No. 1, March 2012 An unusual case of Lafora disease

B []Stop 18, AUG’ 10 10:40:22

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Figure 4. Alternating 5.5-Hz resting tremor resembling Parkinson’s disease. Channels: left deltoid, biceps brachii, flexors of forearm, extensors of forearm, and abductor pollicis brevis.

HB []Review wave 18, AUG’ 10 11 : 58 : 03

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Figure 5. High-amplitude C reflex from biceps and deltoid muscles, elicited with the excitation of median nerve with 8 mA, at the same side. Channels: right abductor pollicis brevis, left deltoid, biceps brachii, flexors of forearm, extensors of forearm, and left abductor pollicis brevis.

Varying degrees of Lafora body inclusions are dal signs might not be unexpected, despite a lack of observed in all regions of the central nervous system reports. Patients with LD usually die during adoles- (CNS) including basal ganglia (Minassian, 2001; Striano cence which may explain the absence of additional et al., 2009; Kaufman et al., 1993). Thus, extrapyrami- CNS findings. As a progressive disease, sufficient

Epileptic Disord, Vol. 14, No. 1, March 2012 97 S. Gökdemir, et al.

accumulation of inclusions in basal ganglia to a critical Guerrero RS, Vernia, Sanz R, et al. A PTG variant contributes level may delay overt signs. to a milder phenotype in Lafora disease. PLoS One 2011; 6: In a recent review, it was concluded that more e21294. careful and extensive description of the clinical Kaufman MA, Dwork AJ, Willson NJ, John S, Liu JD. Late- phenotype (follow-up) of patients and their muta- onset Lafora’s disease with typical intraneuronal inclusions. tional genotype could provide better insight into Neurology 1993; 43: 1246-8. the genotype/phenotype correlation and the exis- Lesca G, Boutry-Kryza N, de Toffol B, et al. Novel mutations in tence of possible modifiers for LD. Beyond the clinic, EPM2A and NHLRC1 widen the spectrum of Lafora disease. elucidation of the biological functions of the two Epilepsia 2010; 51: 1691-8. known genes and identification of at least another, Minassian BA. Lafora’s disease: towards a clinical, pathologic, as yet unknown, gene are necessary to better under- and molecular synthesis. Pediatr Neurol 2001; 25: 21-9. stand the disease mechanism (Singh and Ganesh, 2009). Recently, a protein targeting to glycogen (PTG) Minassian BA. Progressive myoclonus epilepsy with polyglu- cosan bodies: Lafora disease. Adv Neurol 2002; 89: 199-210. variant that contributes to a milder phenotype of Lafora disease has also been reported (Guerrero et al., 2011). Onofrj M, Thomas A, Paci C. Reversible parkinsonism In summary, we suggest that any progressive disease induced by prolonged treatment with valproate. J Neurol 1998; 245: 794-6. presenting with epileptic seizures, cognitive decline and late extrapyramidal signs, even without disabling Reutens DC, Puce A, Berkovic SF. Cortical hyperexcitability myoclonic jerks, should be investigated for LD.
in progressive myoclonus epilepsy: a study with transcranial magnetic stimulation. Neurology 1993; 43: 186-92. Disclosures. Ristic´ AJ, Vojvodic´ N, Jankovic´ S, Sindelic´ A, SokicD.The´ None of the authors has any conflict of interest to disclose. frequency of reversible parkinsonism and cognitive decline associated with valproate treatment: a study of 364 patients with different types of epilepsy. Epilepsia 2006; 47: 2183-5. References Shibasaki H. Physiology of negative myoclonus. Adv Neurol 2002; 89: 103-13. Baykan B, Striano P, Gianotti S, et al. Late-onset and slow- progressing Lafora disease in four siblings with EPM2B Singh S, Ganesh S. Lafora progressive myoclonus epilepsy: a mutation. Epilepsia 2005; 46: 1695-7. meta-analysis of reported mutations in the first decade fol- lowing the discovery of the EPM2A and NHLRC1 genes. Hum Ganesh S, Delgado-Escueta AV, Suzuki T, et al. Genotype- Mutat 2009; 30: 715-23. phenotype correlations for EPM2A mutations in Lafora’s progressive myoclonus epilepsy: exon 1 mutations associate Striano P, Ackerley CA, Cervasio M, et al. 22-year-old girl with with an early-onset cognitive deficit subphenotype. Hum Mol status epilepticus and progressive neurological symptoms. Genet 2002; 11: 1263-71. Brain Pathol 2009; 19: 727-30.

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