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A Novel Exon 1 Mutation in a Patient with Atypical Lafora Progressive Myoclonus Epilepsy Seen as Childhood-onset Cognitive Deficit

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A Novel Exon 1 Mutation in a Patient with Atypical Lafora Progressive Myoclonus Epilepsy Seen as Childhood-onset Cognitive Deficit
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   Epilepsia,  45 (3):294–295, 2004Blackwell Publishing, Inc. C   2004 International League Against Epilepsy A Novel Exon 1 Mutation in a Patient with Atypical LaforaProgressive Myoclonus Epilepsy Seen as Childhood-onsetCognitive Deficit ∗ Grazia Annesi,  † Vito Sofia, ∗ § Antonio Gambardella, ∗ Innocenza C. Cir`o Candiano, ∗ Patrizia Spadafora, ∗ Ferdinanda Annesi,  † Nunzio Cutuli, ∗ Elvira V. De Marco, ∗ Donatella Civitelli, ∗ Sara Carrideo, ∗ Patrizia Tarantino,  ‡ Rita Barone, ∗ § Mario Zappia, and ∗ § Aldo Quattrone ∗  Institute of Neurological Sciences, National Research Council, Cosenza; Institute of †Neurologyand ‡Pediatrics, University of Catania; and §Institute of Neurology, University Magna Græcia, Catanzaro, Italy Lafora progressive myoclonus epilepsy (LD; OMIM254780) is an autosomal-recessive disorder caused in ∼ 80%ofpatientsbymutationsinthe  EMP2A gene,whichis located on chromosome 6q24 (1–3). The  EPM2A  geneis composed of four exons that encode a dual-specificityphosphatase (laforin) (2,3). Recently, mutations in thegene  NHLRC1  (also called  EPM2B ), which is a putativeE3 ubiquitin ligase encoding malin, also have been shownto be responsible for LD (4).LDclassicallystartsduringearlyadolescenceinanoth-erwiseneurologicallynormalindividualasmyoclonicandoccipital lobe seizures followed by rapidly progressiveneurologic deterioration that leads to death between ages17 and 24 years (1). A recent study (5), however, gave ev-idence of a genotype–phenotype relation in LD with twomainsubsyndromes:(a)classicLDassociatedmainlywithmutations in exon 4, and (b) atypical LD with childhood-onset learning disorder followed by epilepsy and neuro-logic deterioration, associated mainly with mutations inexon 1.We report on a 17-year-old right-handed boy with LDfrom southern Italy, who had a normal birth and earlydevelopment milestones. His father and mother were un-related and healthy. Around the age of 5 years, he was no-ticedtobelessbrightthanhisolderbrothers.Hehadlearn-ingproblemsandeducationaldifficulties,asevidencedbypoor school performance, poor memory and calculatingabilities, with repetition of school years. In the ensuingyears, an insidious progressing intellectual deterioration Accepted October 7, 2003.Address correspondence and reprint requests to Professor AntonioGambardella at Cattedra ed U.O. di Neurologia, Universit`a MagnaGræcia, Catanzaro, Policlinico Mater Domini, Via Tommaso Cam-panella, 88100 Catanzaro, Italy. E-mail: a.gambardella@isn.cnr.it becameevident,anditwasassociatedwithbehavioraldif-ficulties and emotional lability.At age 11 years, versive and staring seizures devel-oped. His interictal EEG showed normal backgroundactivity and bilateral occipital and generalized spike–wave discharges associated with a photoparoxysmal re-sponse. Brain computed tomography and magnetic res-onance imaging study were normal. Treatment with vi-gabatrin (VGB; 2,000 mg/day) was started, and a goodcontrol of seizures was achieved. After 3 years, at age14 years, partial visual seizures and staring episodes de-veloped, associated with jerks of both arms and legs. Hisinterictal EEG showed a slow background activity anddiffusespike–andpolyspike–wavedischarges.Moreover,axilla skin biopsy revealed pathognomonic polyglucosaninclusions (6).In the last 3 years, the patient has had a significant de-crease in intelligence quotient with apraxia, and severepsychiatric problems with periods of agitation and maniahavedeveloped.Despitepolytherapywithvalproate,clon-azepam, zonisamide, and topiramate in association witha ketogenic diet, his seizures and myoclonus have wors-ened, and he also has had daily falls.Genomic DNA was extracted from peripheral blood of thepatientbystandardprocedures,afterinformedconsentwas obtained from his parents. Mutation screening identi-fied a novel homozygous point mutation G272C in exon 1ofthe  EPM2A genethatresultedinaArg91Proamino-acidsubstitution. This Arg91Pro missense mutation is locatedin a highly conserved region of tryptophan residues of thecarbohydrate-binding domain (CBD), which is possiblyinvolved in hydrophobic interaction with polyglucosans,through laforin binding with glycogen (5). This mutationwas not detected in 50 unrelated controls matched forethnicity. 294   NOVEL EXON 1 MUTATION ASSOCIATED WITH ATYPICAL LD 295 Our findings expand the spectrum of mutations knownin the  EPM2A  gene and are consistent with the belief thatmutations in exon 1 are associated with atypical LD (5).It is very unlikely that the early-onset cognitive deficitwas a coincidental finding not associated with LD, con-sidering both its progressive nature and the lack of anyprevious stressful pathologic event, as well as the normalneuroimaging study. So, because LD has long been con-sidered a clinically homogeneous disorder that starts asepilepsy during adolescence in an otherwise neurologi-cally normal individual, such a diagnosis of LD shouldbe considered in patients with childhood-onset learningdifficulties in whom epileptic seizures develop. An ex-planation of this peculiar genotype–phenotype relation inLD is that mutations that disrupt the CBD may be moredeleterious for the expression of laforin itself because theCBD is essential to target laforin to intracellular glycogenparticles where it is likely to function. REFERENCES 1. Serratosa JM, Delgado-Escueta AV, Posada I, et al. The gene of pro-gressivemyoclonusepilepsyoftheLaforatypemapstochromosome6q.  Hum Mol Genet   1995;4:1657–63.2. MinassianBA,LeeJR,HerbrickJA,etal.Mutationsinageneencod-inganovelproteintyrosinephosphatasecauseprogressivemyoclonusepilepsy.  Nat Genet   1998;20:171–4.3. Serratosa JM, Gomez-Garre P, Gallardo ME, et al. A novel pro-tein tyrosine phosphatase gene is mutated in progressive myoclonusepilepsy of the Lafora type (EPM2).  Hum Mol Genet   1999;8:345–52.4. Chan EM, Young EJ, Ianzano L, et al. Mutations in  NHLRC1 cause progressive myoclonus epilepsy.  Nat Genet   2003 35:125–7.5. Ganesh S, Delgrado-Escueta AV, Suzuki T, et al. Genotype-phenotype correlations for  EPM2A  mutations in Lafora’s progres-sive myoclonus epilepsy: exon 1 mutations associate with an early-onsetcognitivedeficitsubphenotype.  HumMolGenet  2002;11:1263–71.6. Busard HL, Gabreels-Festen AAWM, Renier WO, et al. Axilla skinbiopsy:areliabletestforthediagnosisofLafora’sdisease.  AnnNeurol 1987;21:599–601.  Epilepsia, Vol. 45, No. 3, 2004
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