Correction: Sciacca, F. L., et al. Microduplication of 15q13.3 and Microdeletion of 18q21.32 in a Patient with Moyamoya Syndrome. Int. J. Mol. Sci. 2018, 19, 3675.

The authors wish to make the corrections to this paper [...].

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease-study protocol and preliminary results.

BACKGROUND: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results. METHODS: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies. RESULTS: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed. CONCLUSION: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.

Microduplication of 15q13.3 and Microdeletion of 18q21.32 in a Patient with Moyamoya Syndrome.

Moyamoya angiopathy (MA) is a cerebrovascular disease determining a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and their proximal branches and the compensatory development of abnormal "moyamoya" vessels. MA occurs as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes) including several heritable conditions such as Down syndrome, neurofibromatosis type 1 and other genomic defects. Although the mechanism that links MA to these genetic syndromes is still unclear, it is believed that the involved genes may contribute to the disease susceptibility. Herein, we describe the case of a 43 years old woman with bilateral MA and peculiar facial characteristics, having a 484-kb microduplication of the chromosomal region 15q13.3 and a previously unreported 786 kb microdeletion in 18q21.32. This patient may have a newly-recognized genetic syndrome associated with MA. Although the relationship between these genetic variants and MA is unclear, our report would contribute to widening the genetic scenario of MA, in which not only genic mutation, but also genome unbalances are possible candidate susceptibility factors.

Pediatric NMDAR encephalitis: A single center observation study with a closer look at movement disorders.

Anti-N-Methyl-d-aspartate-receptor (NMDAR) encephalitis is the most frequent autoimmune encephalitis in pediatric age. This retrospective observational study was aimed at describing the clinical characteristics of the disease in a cohort of children and teenagers. Eighteen patients (10 females and 8 males), with a median age of 12.4 years at symptom onset were enrolled. The clinical presentation of the disease was marked by neurological manifestations in 13 patients and by severe psychiatric and behavioral symptoms in 5. The symptoms at onset varied according to the age: all the children presented with prominent neurological symptoms, whereas psychiatric symptoms were prominent in teenagers. Regardless the age, movement disorders (MDs) were distinctive symptoms during the acute stage of the disease. Several MDs might coexist in a given patient, and persist during sleep. The complexity, and the oddness of MDs often challenged their definition and the differential diagnosis with psychiatric manifestations and epileptic seizures. Stereotyped motor phenomena were the most typical MDs, and were recorded in all patients. Among them, perseveration, reproduction of acquired complex motor activities, and orofacial dyskinesia were the most distinctive features. In children, hyperkinetic MDs dominate; in teenagers, by contrast, a constellation of symptoms consistent with catatonia was the most frequent syndrome observed. The management of the several symptoms requires their accurate recognition, definition and assessment, and the knowledge of the potential side effects of antiepileptic and psychotropic drugs which could either mimic or worsen symptoms of encephalitis.

The clinical phenotype of autosomal dominant lateral temporal lobe epilepsy related to reelin mutations.

OBJECTIVE: To describe the clinical phenotype of 7 families with Autosomal Dominant Lateral Temporal Lobe Epilepsy (ADLTE) related to Reelin (RELN) mutations comparing the data with those observed in 12 LGI1-mutated pedigrees belonging to our series. METHODS: Out of 40 Italian families with ADLTE, collected by epileptologists participating in a collaborative study of the Commission for Genetics of the Italian League against Epilepsy encompassing a 14-year period (2000-2014), 7 (17.5%) were found to harbor heterozygous RELN mutations. The whole series also included 12 (30%) LGI1 mutated families and 21 (52.5%) non-mutated pedigrees. The clinical, neurophysiological, and neuroradiological findings of RELN and LGI1 mutated families were analyzed. RESULTS: Out of 28 affected individuals belonging to 7 RELN mutated families, 24 had sufficient clinical data available for the study. In these patients, the epilepsy onset occurred at a mean age of 20years, with focal seizures characterized by auditory auras in about 71% of the cases, associated in one-third of patients with aphasia, visual disturbances or other less common symptoms (vertigo or déjà-vu). Tonic-clonic seizures were reported by almost all patients (88%), preceded by typical aura in 67% of cases. Seizures were precipitated by environmental noises in 8% of patients and were completely or almost completely controlled by antiepileptic treatment in the vast majority of cases (96%). The interictal EEG recordings showed epileptiform abnormalities or focal slow waves in 80% of patients, localized over the temporal regions, with marked left predominance and conventional 1,5T MRI scans were not contributory. By comparing these findings with those observed in families with LGI1 mutations, we did not observe significant differences except for a higher rate of left-sided EEG abnormalities in the RELN group. SIGNIFICANCE: Heterozygous RELN mutations cause a typical ADLTE syndrome, indistinguishable from that associated with LGI1 mutations.

Movement-activated cortical myoclonus in Dravet syndrome.

PURPOSE: we characterized multifocal myoclonus in Dravet syndrome (DS) that was never systematically typified before. METHODS: we studied EEG-EMG recordings of 19 consecutive patients, aged 2-29 years, with DS associated with SCN1A gene mutations to detect and evaluate myoclonus based on the spectrum of EMG activity on antagonist muscle pairs and cortico-muscular coherence (CMC). RESULTS: multifocal action myoclonus was detected in all patients corresponding to brief EMG bursts, which occurred synchronously on antagonist muscles at a frequency peaking in beta band. There was significant CMC in beta band, and a cortico-muscular transfer time consistent with a cortical origin of the jerks. The somatosensory evoked potentials (SSEPs) were giant in only one patient who also showed exaggerated long-loop reflexes (LLRs). The nine patients who had experienced myoclonic seizures showed greater CMC. CONCLUSIONS: The cortical myoclonus consistently observed in patients with DS shows features that are similar to those characterizing progressive myoclonus epilepsy, but differs because it does not have a severely worsening course and is not commonly associated with increased SSEPs or enhanced LLRs. This kind of myoclonus is an intrinsic feature of DS associated with SCN1A mutations, and may be a cause of disability. SIGNIFICANCE: We hypothesize that myoclonus is generated in cortical motor areas by hyper-synchronous oscillations, which are possibly due to sodium channel dysfunction.

PARADISE 24 instrument: An observational study on psychosocial difficulties, quality of life, and disability levels in patients with epilepsy.

AIM: The aim of this observational study was to test the effectiveness of the PARADISE 24 instrument in describing the psychosocial difficulties (PSDs) reported by people with epilepsy, their relation with disability, and quality-of-life (QoL) levels and, overall, to explore a horizontal epidemiology methodology applied to a sample of patients with epilepsy. METHODS: A convenience sample of 80 adult patients with epilepsy was included in this cross-sectional study. Patients were interviewed using a structured protocol composed of demographic, clinical, and patient-reported outcome measures to collect PSDs associated with epilepsy. RESULTS: There were 80 patients, 40 females; mean age was 41.2years; mean disease duration was 18.7years; and mean number of AED was 2.09. Moderate severity rating according to clinicians' rating scale, low impact of comorbidities (mean: 2.36, SD: 2.97), high levels of QoL (mean: 30.00, SD: 4.4), medium levels of resilience (mean: 13.56, SD: 2.66), high levels of perceived empathy (mean: 15.05, SD: 4.74), poor or moderate perceived social support, and low levels of disability (mean: 10.85, SD: 10.05) were observed. The most frequently reported PSDs were related to tiredness (80%), emotional problems (73.75%), anxiety (68.75%), depressive mood (66.25%), and driving problems (61.25%). The EUROHIS-QOL (p=.003) had a negative significant relationship with PARADISE 24 while WHODAS-12 (p=.000) and CRS (p=.027) had a positive significant relationship with PARADISE 24. CONCLUSIONS: The PARADISE 24 permits data comparison and the creation of a complete description of a person's functioning and of all of his/her PSDs and allows better and more tailored interventions.

Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations.

OBJECTIVES: To describe the clinical and neurophysiologic patterns of patients with neuronal ceroid lipofuscinoses associated with CLN6 mutations. METHODS: We reviewed the features of 11 patients with different ages at onset. RESULTS: Clinical disease onset occurred within the first decade of life in 8 patients and in the second and third decades in 3. All children presented with progressive cognitive regression associated with ataxia and pyramidal and extrapyramidal signs. Recurrent seizures, visual loss, and myoclonus were mostly reported after a delay from onset; 7 children were chairbound and had severe dementia less than 4 years from onset. One child, with onset at 8 years, had a milder course. Three patients with a teenage/adult onset presented with a classic progressive myoclonic epilepsy phenotype that was preceded by learning disability in one. The EEG background was slow close to disease onset in 7 children, and later showed severe attenuation; a photoparoxysmal response (PPR) was present in all. The 3 teenage/adult patients had normal EEG background and an intense PPR. Early attenuation of the electroretinogram was seen only in children with onset younger than 5.5 years. Somatosensory evoked potentials were extremely enlarged in all patients. CONCLUSIONS: In all patients, multifocal myoclonic jerks and seizures were a key feature, but myoclonic seizures were an early and prominent sign in the teenage/adult form only. Conversely, the childhood-onset form was characterized by initial and severe cognitive impairment coupled with electroretinogram and EEG attenuation. Cortical hyperexcitability, shown by the PPR and enlarged somatosensory evoked potentials, was a universal feature.

Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.

Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.

Electroencephalographic (EEG) Photoparoxysmal Responses Under 5 Years of Age: Diagnostic Implications and Peculiarities.

Electroencephalographic (EEG) photoparoxysmal response has been little investigated in very young patients. We studied 5055 patients aged less than 5 years with no acquired brain damage, who underwent EEG recording. We determined the prevalence and significance of photoparoxysmal response induced by 1 to 20 Hz photic stimulation. Fifty-three showed photoparoxysmal response and were diagnosed as having Dravet syndrome (11), epileptic encephalopathy with myoclonic seizures (8), neurodegenerative disorders (8), benign idiopathic epilepsies (9), and static disorders with a known or suspected genetic origin (17). Photoparoxysmal response occurred in response to 1 to 5 Hz trains in 41.5% subjects. In most patients with epileptic encephalopathies, photoparoxysmal response was a transient finding: in 53.2%, it failed to be replicated in the recordings performed more than 6 months after initial evaluation. Photoparoxysmal response is rare in patients aged less than 5 years and has some peculiarities such as occurrence with low-frequency stimuli. Its distribution in specific conditions indicates that photoparoxysmal response may be useful in diagnostic workup.

Seizures and EEG features in 74 patients with genetic-dysmorphic syndromes.

Epilepsy is one of the most common findings in chromosome aberrations. Types of seizures and severity may significantly vary both between different conditions and within the same aberration. Hitherto specific seizures and EEG patterns are identified for only few syndromes. We studied 74 patients with defined genetic-dysmorphic syndromes with and without epilepsy in order to assess clinical and electroencephalographic features, to compare our observation with already described electro-clinical phenotypes, and to identify putative electroencephalographic and/or seizure characteristics useful to address the diagnosis. In our population, 10 patients had chromosomal disorders, 19 microdeletion or microduplication syndromes, and 32 monogenic syndromes. In the remaining 13, syndrome diagnosis was assessed on clinical grounds. Our study confirmed the high incidence of epilepsy in genetic-dysmorphic syndromes. Moreover, febrile seizures and neonatal seizures had a higher incidence compared to general population. In addition, more than one third of epileptic patients had drug-resistant epilepsy. EEG study revealed poor background organization in 42 patients, an excess of diffuse rhythmic activities in beta, alpha or theta frequency bands in 34, and epileptiform patterns in 36. EEG was completely normal only in 20 patients. No specific electro-clinical pattern was identified, except for inv-dup15, Angelman, and Rett syndromes. Nevertheless some specific conditions are described in detail, because of notable differences from what previously reported. Regarding the diagnostic role of EEG, we found that--even without any epileptiform pattern--the generation of excessive rhythmic activities in different frequency bandwidths might support the diagnosis of a genetic syndrome.

Refractory absence epilepsy and glut1 deficiency syndrome: a new case report and literature review.

We report a 12-year-old female patient with a mild phenotype of glucose transporter type 1 deficiency syndrome (Glut1D). The clinical picture was characterized by refractory absence epilepsy, migraine, and learning disabilities. Absence seizures appeared at the age of 4 years, and electroencephalogram (EEG) showed irregular discharges of diffuse epileptic abnormalities. During the follow-up, seizures became drug resistant, cognitive evaluation revealed learning difficulties, and the patient complained migraine episodes. The evidence of seizure worsening before meals and the drug resistance suggested a Glut1D. Molecular analysis of SLC2A1 gene showed the presence of a pathogenic de novo mutation of the gene in heterozygosity (p.Ala275Thr, c.823G > A). Our case and the review of literature data on patients with Glut1D and absences provide a combination of clinical and EEG keys that should prompt the genetic analysis. The Glut1D should be suspected when absence seizures are associated with at least one among: irregular ictal EEG discharges, mild mental retardation, migraine, microcephaly, drug resistance, and worsening during fasting. An early diagnosis allows to establish one of the available ketogenic regimens which could modify the natural history of this treatable condition.

Comprehensive educational plan for patients with epilepsy and comorbidity (EDU-COM): a pragmatic randomised trial.

BACKGROUND: The impact of educational strategies in the management of adverse treatment effects and drug interactions in adult patients with epilepsy with comorbidities remains undetermined. OBJECTIVE: The EDU-COM study is a randomised, pragmatic trial investigating the effect of a patient-tailored educational plan in patients with epilepsy with comorbidity. METHODS: 174 adult patients with epilepsy with chronic comorbidities, multiple-drug therapy and reporting at least one adverse treatment effect and/or drug interaction at study entry were randomly assigned to the educational plan or usual care. The primary endpoint was the number of patients becoming free from adverse treatment events and/or drug interactions after a 6-month follow-up. The number of adverse treatment events and drug interactions, health-related quality of life (HRQOL) summary score changes and the monetary costs of medical contacts and drugs were assessed as secondary outcomes. RESULTS: The primary endpoint was met by 44.0% of patients receiving the educational plan versus 28.9% of those on usual care (p=0.0399). The control group reported a significantly higher risk not to meet successfully the primary endpoint at the end of the study: OR (95% CI) of 2.29 (1.03 to 5.09). A separate analysis on drug adverse effects and drug interactions showed that the latter were more sensitive to the effect of educational treatment. Quality of life and costs were not significantly different in the two groups. CONCLUSIONS: A patient-tailored educational strategy is effective in reducing drug-related problems (particularly drug interactions) in epilepsy patients with chronic comorbidities, without adding significant monetary costs. Registered at ClinicalTrials.gov, identifier NCT01804322, (http://www.clinicaltrials.gov).

Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1 mutations.

PURPOSE: In relatively small series, autosomal dominant lateral temporal epilepsy (ADLTE) has been associated with leucine-rich, glioma-inactivated 1 (LGI1) mutations in about 50% of the families, this genetic heterogeneity being probably caused by differences in the clinical characteristics of the families. In this article we report the overall clinical and genetic spectrum of ADLTE in Italy with the aim to provide new insight into its nosology and genetic basis. METHODS: In a collaborative study of the Commission of Genetics of the Italian League Against Epilepsy (LICE) encompassing a 10-year period (2000-2010), we collected 33 ADLTE families, selected on the basis of the following criteria: presence of at least two members concordant for unprovoked partial seizures with prominent auditory and or aphasic symptoms, absence of any known structural brain pathology or etiology, and normal neurologic examination. The clinical, neurophysiologic, and neuroradiologic findings of all patients were analyzed and a genealogic tree was built for each pedigree. The probands' DNA was tested for LGI1 mutations by direct sequencing and, if negative, were genotyped with single-nucleotide polymorphism (SNP) array to search for disease-linked copy-number variation CNV. The disease penetrance in mutated and nonmutated families was assessed as a proportion of obligate carriers who were affected. KEY FINDINGS: The 33 families included a total of 127 affected individuals (61 male, 66 female, 22 deceased). The age at onset ranged between 2 and 60 years (mean 18.7 years). Ninety-one patients (72%) had clear-cut focal (elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 68% of the cases. Other symptoms included complex visual hallucinations, vertigo, and déjà vu. Aphasic seizures, associated or not with auditory features, were observed in 20% of the cases, whereas tonic-clonic seizures occurred in 86% of the overall series. Sudden noises could precipitate the seizures in about 20% of cases. Seizures, which usually occurred at a low frequency, were promptly controlled or markedly improved by antiepileptic treatment in the majority of patients. The interictal electroencephalography (EEG) studies showed the epileptiform temporal abnormalities in 62% of cases, with a slight predominance over the left region. Magnetic resonance imaging (MRI) or computerized tomography (CT) scans were negative. LGI1 mutations (missense in nine and a microdeletion in one) were found in only 10 families (30%). The patients belonging to the mutated and not mutated groups did not differ except for penetrance estimate, which was 61.3% and 35% in the two groups, respectively (chi-square, p = 0.017). In addition, the disease risk of members of families with mutations in LGI1 was three times higher than that of members of LGI1-negative families (odds ratio [OR] 2.94, confidence interval [CI] 1.2-7.21). SIGNIFICANCE: A large number of ADLTE families has been collected over a 10-year period in Italy, showing a typical and homogeneous phenotype. LGI1 mutations have been found in only one third of families, clinically indistinguishable from nonmutated pedigrees. The estimate of penetrance and OR, however, demonstrates a significantly lower penetrance rate and relative disease risk in non-LGI1-mutated families compared with LGI1-mutated pedigrees, suggesting that a complex inheritance pattern may underlie a proportion of these families.

Focal epilepsies in adult patients attending two epilepsy centers: classification of drug-resistance, assessment of risk factors, and usefulness of "new" antiepileptic drugs.

PURPOSE: To classify the grade of antiepileptic drug (AED) resistance in a cohort of patients with focal epilepsies, to recognize the risk factors for AED resistance, and to estimate the helpfulness of "new-generation" AEDs. METHODS: We included 1,155 adults with focal epilepsies who were observed consecutively after 1990 and followed regularly at two epilepsy centers. We systematically collected the clinical, diagnostic, and therapeutic data using a custom-written database. We classified the patients as seizure-free or AED resistant according to the International League Against Epilepsy (ILAE) criteria, and we evaluated the risk factors associated with AED resistance using logistic regression analysis. We further grouped AED-resistant patients in different grades (I, II, and III) according to the number of AEDs already tried as proposed by Perucca. KEY FINDINGS: AED resistance occurred in 57.8% of the 729 patients with symptomatic focal epilepsies and was positively associated with electroencephalography (EEG) abnormalities, seizure type, and the presence of mesial temporal sclerosis. Among 426 patients without detectable causes, the percentage of AED resistance was significantly lower (39.2%) and correlated with EEG abnormalities and psychiatric symptoms. Among AED-resistant patients, the majority (64.6%) had tried three or more AEDs, which fit the more severe grade III proposed by Perucca. Among seizure-free patients, more than one-half (57%) needed to try two or more AEDs before reaching seizure control (14.9% needed three or more AEDs). Furthermore, among seizure-free patients who could be previously classified as resistant to two or more AEDs, 52.2% reached seizure freedom while receiving treatment with "new generation" AEDs. SIGNIFICANCE: The ILAE classification of AED resistance, as well the graded classification proposed by Perucca, was easily exploitable in our patients, although these classifications systems appear to have a limited value in predicting seizure outcome. Actually, a small but not negligible percentage of patients reached seizure freedom after trying several AEDs (including "new" AEDs), suggesting repeated trials may be necessary for seizure control.

Paroxysmal non-epileptic motor events in childhood: a clinical and video-EEG-polymyographic study.

AIM: The aim of this article was to describe the phenomenology and polymyographic features of paroxysmal non-epileptic motor events (PNMEs) observed in a series of typically developing and children with neurological impairment. METHOD: We conducted a retrospective evaluation of 63 individuals (29 females; 34 males) affected by PNMEs at the National Neurological Institute 'C. Besta' between 2006 and 2008. Individuals were included in the study if they had PNMEs documented by a video-electroencephalography-polymyographic study and were aged between 1 month and 18 years (mean age at the time of video-electroencephalography-polymyography: 5y 10mo). RESULTS: In 45 of the 63 participants (71%), PNMEs were associated with other neurological conditions (secondary) including epilepsy, whereas in 18 participants PNME was the only neurological symptom (primary). Clinical features allowed classification of the motor disturbance into usual movement disorder categories in 31 individuals (49%); in the remaining 32 (51%), the movement disorder was characterized on the basis of polymyographic pattern of 'jerks' or 'sustained contraction'. The most frequent PNMEs were paroxysmal dyskinesias, followed by startle, stereotypies, shuddering, sleep myoclonus, psychogenic movement disorders, and benign myoclonus of early infancy; the last syndrome was also observed in children with neurological impairment. In eight participants, PNMEs remained unclassified. INTERPRETATION: PNMEs may occur in both healthy and children with neurological impairment and are caused by a wide range of static and progressive conditions. In the majority of children with neurological impairment with associated epilepsy, the PNMEs do not fit into the usual movement disorders categories. A video-electroencephalography-polymyography is therefore useful for characterizing them.

Association of intronic variants of the KCNAB1 gene with lateral temporal epilepsy.

The KCNAB1 gene is a candidate susceptibility factor for lateral temporal epilepsy (LTE) because of its functional interaction with LGI1, the gene responsible for the autosomal dominant form of LTE. We investigated association between polymorphic variants across the KCNAB1 gene and LTE. The allele and genotype frequencies of 14 KCNAB1 intronic SNPs were determined in 142 Italian LTE patients and 104 healthy controls and statistically evaluated. Single SNP analysis revealed one SNP (rs992353) located near the 3'end of KCNAB1 slightly associated with LTE after multiple testing correction (odds ratio=2.25; 95% confidence interval 1.26-4.04; P=0.0058). Haplotype analysis revealed two haplotypes with frequencies higher in cases than in controls, and these differences were statistically significant after permutation tests (Psim=0.047 and 0.034). One of these haplotypes was shown to confer a high risk for the syndrome (odds ratio=12.24; 95% confidence interval 1.32-113.05) by logistic regression analysis. These results support KCNAB1 as a susceptibility gene for LTE, in agreement with previous studies showing that this gene may alter susceptibility to focal epilepsy.

ADAM23, a Gene Related to LGI1, Is Not Linked to Autosomal Dominant Lateral Temporal Epilepsy.

Autosomal dominant lateral temporal epilepsy (ADTLE) is an inherited epileptic syndrome characterized by ictal auditory symptoms or aphasia, negative MRI findings, and relatively benign evolution. Mutations responsible for ADLTE have been found in the LGI1 gene. The functions of the Lgi1 protein apparently are mediated by interactions with members of the ADAM protein family: it binds the postsynaptic receptor ADAM22 to regulate glutamate-AMPA currents at excitatory synapses and also the ADAM23 receptor to promote neurite outgrowth in vitro and dendritic arborization in vivo. Because alteration of each of these neuronal mechanisms may underlie ADLTE, ADAM22 and ADAM23 are candidate genes for this syndrome. In a previous work, we excluded a major role of ADAM22 in the aetiology of ADLTE. Here, we performed linkage analysis between microsatellite markers within or flanking the ADAM23 gene and ADLTE in 13 Italian families. The results exclude ADAM23 as major causative gene for ADLTE.

Myoclonus in Creutzfeldt-Jakob disease: polygraphic and video-electroencephalography assessment of 109 patients.

We used electroencephalography (EEG)-polygraphic recordings to classify myoclonus in 109 patients with Creutzfeldt-Jakob disease (CJD) on the basis of its electromyography (EMG) pattern, time course, distribution, and EEG correlates. We recorded myoclonic jerks in 55 patients (50.4%), and we classified them as periodic myoclonus in 28, rhythmic in 13, and irregular in 20 (6 patients showed two types of myoclonus). Myoclonus occurred as a prominently negative event (interrupting the EMG discharge) in 10. Periodic sharp-wave complexes (PSWCs) were present in all but one patient with myoclonic jerks but were time-locked with EMG-bursts only in case of periodic myoclonus. Jerk-locked back averaging revealed a variable EEG-EMG transfer-time commonly exceeding that characterizing cortical myoclonus. Myoclonus was frequently associated with Met/Met polymorphism at codon 129 of the prion protein gene, but it was also observed in association with Met/Val or Val/Val polymorphisms provided that the EEG showed the presence of the PSWC pattern. The presence of enlarged somatosensory evoked potentials significantly correlated with the myoclonic presentation, as did MR signal hyperintensity involving the cortical mantle. Our observations on the basis of standard polygraphic criteria suggest that CJD associates with a remarkable variety of myoclonic jerks, and therefore different brain structures are probably involved as generators. The significant association between the presence of all myoclonus types with PSWCs suggests that hyperexcitable corticosubcortical loops are always required to generate (or allow) both myoclonus and the EEG complexes, either they are time locked or not.