Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause an autosomal recessive fatal disorder called Lafora's disease (LD) classically described as an adolescent-onset stimulus-sensitive myoclonus, epilepsy and neurologic deterioration. Here we related mutations in EPM2A with phenotypes of 22 patients (14 families) and identified two subsyndromes: (i) classical LD with adolescent-onset stimulus-sensitive grand mal, absence and myoclonic seizures followed by dementia and neurologic deterioration, and associated mainly with mutations in exon 4 (P = 0.0007); (ii) atypical LD with childhood-onset dyslexia and learning disorder followed by epilepsy and neurologic deterioration, and associated mainly with mutations in exon 1 (P = 0.0015). To understand the two subsyndromes better, we investigated the effect of five missense mutations in the carbohydrate-binding domain (CBD-4; coded by exon 1) and three missense mutations in the dual phosphatase domain (DSPD; coded by exons 3 and 4) on laforin's intracellular localization in HeLa cells. Expression of three mutant proteins (T194I, G279S and Y294N) in DSPD formed ubiquitin-positive cytoplasmic aggregates, suggesting that they were folding mutants set for degradation. In contrast, none of the three CBD-4 mutants showed cytoplasmic clumping. However, CBD-4 mutants W32G and R108C targeted both cytoplasm and nucleus, suggesting that laforin had diminished its usual affinity for polysomes. Our data, thus, represent the first report of a novel childhood syndrome for LD. Our results also provide clues for distinct roles for the CBD-4 and DSP domains of laforin in the etiology of two subsyndromes of LD.
Diplopia, blurred vision and colour disturbances are well-known side effects associated with anti-epileptic drugs (AEDs). Farnsworth-Munsell 100-hue colour test (F-100) is an accepted and sensitive tool to detect changes in colour perception. To determine the impact of AEDs upon colour vision, we evaluated 37 consecutive patients with complex partial seizures exposed to monotherapy with phenytoin (PHT, carbamazepine (CBZ) or valproic acid (VPA). All had normal IQ and no congenital disturbances in colour vision or ocular diseases. Twenty normal controls were used for statistical analysis. Thirteen patients were exposed to PHT, 12 to CBZ and 12 to VPA. Visual colour perception was impaired in 30/37 (82%) of the study group. The most significant abnormality was detected in the blue-yellow axis in 10/13 patients exposed to PHT (p < 0.02) and in 8/12 treated with CBZ (p < 0.009). In 8/12 patients taking VPA, no significant abnormality was observed (p < 0.06). None of the studied patients complained of colour vision disturbances. Our findings strongly support the negative effect of AEDs upon colour vision discrimination, most likely due to changes at the retinal processing level. F-100 proved to be very useful to assess early toxicity due to AEDs.
Aim. Psychiatric disorders are relatively frequent comorbidities in epilepsy and they have an impact on morbidity, mortality, and quality of life. This is a report from the Task Force on Education of the ILAE Commission on Neuropsychiatry based on a survey about educational needs of epileptologists regarding management of the psychiatric comorbidities of epilepsy. Methods. The Task Force designed a quantitative questionnaire to survey the self‐perceived confidence of child and adult epileptologists and psychiatrists in managing major psychiatric comorbidities of epilepsy to identify: (1) critical areas of improvement from a list of skills that are usually considered necessary for effective management of these conditions, and (2) the preferred educational format for improving these skills. Results. A total of 211 respondents from 36 different countries participated in the survey. Confidence and usefulness scores suggest that responders would most value education and training in the management of specific clinical scenarios. Child neurologists identified major Axis I disorders, such as mood and anxiety disorders, while adult neurologists identified attention deficit hyperactivity disorder, intellectual disabilities, and autistic spectrum disorder as key areas. Both adult and child neurologists identified screening skills as the priority. Psychiatrists mainly valued specific training in the management of psychiatric complications of epilepsy surgery or psychiatric adverse events of antiepileptic drugs. Sessions during congresses and face‐to‐face meetings represent the preferred educational format, while e‐learning modules and review papers were chosen by a minority of respondents. Conclusions. Results of this survey identify key areas for improvement in managing the psychiatric comorbidities of epilepsy and suggest specific strategies to develop better training for clinicians involved in epilepsy care.
SUMMARYObjectives: To validate and translate the English version of the Neurologic Depression Disorders Inventory in Epilepsy (NDDI-E) into Spanish as a screening instrument for major depressive episodes (MDE) for patients with epilepsy from Argentina and Uruguay. Methods: One hundred fifty-five consecutive outpatients with epilepsy participated in this study. The module of MDE of the MINI International Neuropsychiatric Instrument (MINI Plus version) was used as the gold standard against which the translated version of the NDDI-E was validated. Results: Among the 155 patients, 25 (16%) met Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) criteria for MDE according to the MINI. With a total score of >15, The NDDI-E identified MDE with an 80% sensitivity, 90% specificity, 60% positive predictive value, and 95.5% negative predictive value. Significance: These data indicate that the Spanish version of the NDDI-E can reliably identify MDE in patients with epilepsy from Argentina and Uruguay.
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