Education effects on cognitive function in a healthy aged Arab population

Abstract Background-The Minimental State Examination (MMSE) has not been validated in Arabic speaking populations. The Brookdale Cognitive Screening Test (BCST) has been developed for use in low schooling populations. We investigated the influence of gender, education and occupation in a cognitively normal community sample assessed with an Arabic translation of the MMSE and the BCST

Epilepsy and mental retardation limited to females: an under-recognized disorder

Epilepsy and Mental Retardation limited to Females (EFMR) which links to Xq22 has been reported in only one family. We aimed to determine if there was a distinctive phenotype that would enhance recognition of this disorder.We ascertained four unrelated families (two Australian, two Israeli) where seizures in females were transmitted through carrier males. Detailed clinical assessment was performed on 58 individuals, using a validated seizure questionnaire, neurological examination and review of EEG and imaging studies. Gene localization was examined using Xq22 microsatellite markers. Twenty-seven affected females had a mean seizure onset of 14 months (range 6^36) typically presenting with convulsions. All had convulsive attacks at some stage, associated with fever in 17 out of 27 (63%). Multiple seizure types occurred including tonic-clonic (26), tonic (4), partial (11), absence (5), atonic (3) and myoclonic (4). Seizures ceased at mean 12 years. Developmental progress varied from normal (7), to always delayed (4) to normal followed by regression (12). Intellect ranged from normal to severe intellectual disability (ID), with 67% of females having ID or being of borderline intellect. Autistic (6), obsessive (9) and aggressive (7) features were prominent. EEGs showed generalized and focal epileptiform abnormalities. Five obligate male carriers had obsessional tendencies. Linkage to Xq22 was confirmed (maximum lod 3.5 at h = 0).We conclude that EFMR is a distinctive, under-recognized familial syndrome where girls present with convulsions in infancy, often associated with intellectual impairment and autistic features. The unique inheritance pattern with transmission by males is perplexing. Clinical recognition is straightforward in multiplex families due to the unique inheritance pattern; however, this disorder should be considered in smaller families where females alone have seizures beginning in infancy, particularly in the setting of developmental delay. In single cases, diagnosis will depend on identification of the molecular basis. Keywords: epilepsy; intellectual disability; females; X-linked inheritance; autistic features Abbreviations: BAC = bacterial artificial chromosome; CFNS = craniofrontonasal syndrome; EFMR = epilepsy and mental retardation limited to females; ID = intellectual disability

Unverricht-Lundborg disease in a five-generation Arab family: instability of dodecamer repeats.

BACKGROUND: Unverricht-Lundborg disease (ULD) is the prototypical form of progressive myoclonus epilepsy, and subjects are usually very photosensitive. ULD is caused by mutations in the cystatin B (CSTB) gene; the most common mutation is expansion of a dodecamer repeat near the promoter. The authors studied a five-generation Arab family with ULD lacking photosensitivity. METHODS: An Arab family from the Galilee region of Israel with progressive myoclonus epilepsy was clinically evaluated. Blood samples were obtained from three living affected and 16 unaffected individuals. Expansion of dodecamer repeat in the CSTB gene was examined. RESULTS: The three living affected individuals showed spontaneous and action myoclonus, ataxia, and mild dementia. EEG in two individuals showed generalized polyspike-wave without photosensitivity. The family structure with large sibships and multiple consanguineous loops allowed the authors to examine the gene over four generations of adults. The three living affected individuals were homozygous for repeat expansions and 11 of the 16 unaffected family members were heterozygous. Instability was demonstrated by the presence of expansions of different sizes occurring on the same haplotype background in this inbred family. Fragment size variations could be unequivocally detected in two sibships. The expansions were in the 49 to 54 dodecamer repeat range. Changes in one generation were small, 1 to 4 repeat units, consisting of either enlargements or contractions. CONCLUSIONS: Instability of the expanded dodecamer repeats in the cystatin B gene is frequent. Almost invariably, a small change is observed in parent-child transmission. The lack of photosensitivity in this family is unexplained.Case ReportsJournal Articleinfo:eu-repo/semantics/publishe

LGI1 mutations in temporal lobe epilepsies

Copyright © 2004 American Academy of NeurologyBackground and objectivesA number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich, glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations.MethodsThe authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1. ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4.ResultsFour families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 individuals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124T-->G; C42G) and 8 (c.1418C-->T; S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families.ConclusionIn TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.http://www.neurology.org/cgi/content/abstract/62/7/111

Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy

We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies

A new clinical and molecular form of Unverricht-Lundborg disease localized by homozygosity mapping.

Progressive myoclonus epilepsy (PME) has a number of causes, of which Unverricht-Lundborg disease (ULD) is the most common. ULD has previously been mapped to a locus on chromosome 21 (EPM1). Subsequently, mutations in the cystatin B gene have been found in most cases. In the present work we identified an inbred Arab family with a clinical pattern compatible with ULD, but mutations in the cystatin B gene were absent. We sought to characterize the clinical and molecular features of the disorder. The family was studied by multiple field trips to their town to clarify details of the complex consanguineous relationships and to personally examine the family. DNA was collected for subsequent molecular analyses from 21 individuals. A genome-wide screen was performed using 811 microsatellite markers. Homozygosity mapping was used to identify loci of interest. There were eight affected individuals. Clinical onset was at 7.3 +/- 1.5 years with myoclonic or tonic-clonic seizures. All had myoclonus that progressed in severity over time and seven had tonic-clonic seizures. Ataxia, in addition to myoclonus, occurred in all. Detailed cognitive assessment was not possible, but there was no significant progressive dementia. There was intrafamily variation in severity; three required wheelchairs in adult life; the others could walk unaided. MRI, muscle and skin biopsies on one individual were unremarkable. We mapped the family to a 15-megabase region at the pericentromeric region of chromosome 12 with a maximum lod score of 6.32. Although the phenotype of individual subjects was typical of ULD, the mean age of onset (7.3 years versus 11 years for ULD) was younger. The locus on chromosome 12 does not contain genes for any other form of PME, nor does it have genes known to be related to cystatin B. This represents a new form of PME and we have designated the locus as EPM1B.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Genetic architecture of idiopathic generalized epilepsy: Clinical genetic analysis of 55 multiplex families

Copyright © 2004 International League Against EpilepsySummary: Purpose: In families with idiopathic generalized epilepsy (IGE), multiple IGE subsyndromes may occur. We performed a genetic study of IGE families to clarify the genetic relation of the IGE subsyndromes and to improve understanding of the mode(s) of inheritance. Methods: Clinical and genealogic data were obtained on probands with IGE and family members with a history of seizures. Families were grouped according to the probands' IGE subsyndrome: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with tonic–clonic seizures only (IGE-TCS). The subsyndromes in the relatives were analyzed. Mutations in genes encoding α1 and γ2 γ-aminobutyric acid (GABA)-receptor subunits, α1 and β1 sodium channel subunits, and the chloride channel CLC-2 were sought. Results: Fifty-five families were studied. 122 (13%) of 937 first- and second-degree relatives had seizures. Phenotypic concordance within families of CAE and JME probands was 28 and 27%, respectively. JAE and IGE-TCS families had a much lower concordance (10 and 13%), and in the JAE group, 31% of relatives had CAE. JME was rare among affected relatives of CAE and JAE probands and vice versa. Mothers were more frequently affected than fathers. No GABA-receptor or sodium or chloride channel gene mutations were identified. Conclusions: The clinical genetic analysis of this set of families suggests that CAE and JAE share a close genetic relation, whereas JME is a more distinct entity. Febrile seizures and epilepsy with unclassified tonic–clonic seizures were frequent in affected relatives of all IGE individuals, perhaps representing a nonspecific susceptibility to seizures. A maternal effect also was seen. Our findings are consistent with an oligogenic model of inheritance.Carla Marini, Ingrid E. Scheffer, Kathryn M. Crossland, Bronwyn E. Grinton, Fiona L. Phillips, Jacinta M. McMahon, Samantha J. Turner, Joanne T. Dean, Sara Kivity, Aziz Mazarib, Miriam Y. Neufeld, Amos D. Korczyn, Louise A. Harkin, Leanne M. Dibbens, Robyn H. Wallace, John C. Mulley, and Samuel F. Berkovic

Multiplex families with epilepsy: success of clinical and molecular genetic characterization

Objective: To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis. Methods: Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate. Results: A total of 211 families were ascertained over an 11-year period in Israel. A total of 169 were classified into broad familial epilepsy syndrome groups: 61 generalized, 22 focal, 24 febrile seizure syndromes, 33 special syndromes, and 29 mixed. A total of 42 families remained unclassified. Pathogenic variants were identified in 49/211 families (23%). The majority were found in established epilepsy genes (e.g., SCN1A, KCNQ2, CSTB), but in 11 families, this cohort contributed to the initial discovery (e.g., KCNT1, PCDH19, TBC1D24). We expand the phenotypic spectrum of established epilepsy genes by reporting a familial LAMC3 homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and a pathogenic SCN1A variant in a family where in 5 siblings the phenotype was broadly consistent with Dravet syndrome, a disorder that usually occurs sporadically. Conclusion: A total of 80% of families were successfully classified, with pathogenic variants identified in 23%. The successful characterization of familial electroclinical and inheritance patterns has highlighted the value of studying multiplex families and their contribution towards uncovering the genetic basis of the epilepsies.Zaid Afawi, Karen L. Oliver, Sara Kivity, Aziz Mazarib, Ilan Blatt, Miriam Y. Neufeld, Katherine L. Helbig, Hadassa Goldberg-Stern, Adel J. Misk, Rachel Straussberg, Simri Walid, Muhammad Mahajnah, Tally Lerman-Sagie, Bruria Ben-Zeev, Esther Kahana, Rafik Masalha, Uri Kramer, Dana Ekstein, Zamir Shorer, Robyn H. Wallace, Marie Mangelsdorf, James N. MacPherson, Gemma L. Carvill, Heather C. Mefford, Graeme D. Jackson, Ingrid E. Scheffer, Melanie Bahlo, Jozef Gecz, Sarah E. Heron, Mark Corbett, John C. Mulley, Leanne M. Dibbens, Amos D. Korczyn and Samuel F. Berkovi

Neuronal Sodium-Channel α1-Subunit Mutations in Generalized Epilepsy with Febrile Seizures Plus

Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by the presence of febrile and afebrile seizures. The first gene, GEFS1, was mapped to chromosome 19q and was identified as the sodium-channel β1-subunit, SCN1B. A second locus on chromosome 2q, GEFS2, was recently identified as the sodium-channel α1-subunit, SCN1A. Single-stranded conformation analysis (SSCA) of SCN1A was performed in 53 unrelated index cases to estimate the frequency of mutations in patients with GEFS+. No mutations were found in 17 isolated cases of GEFS+. Three novel SCN1A mutations—D188V, V1353L, and I1656M—were found in 36 familial cases; of the remaining 33 families, 3 had mutations in SCN1B. On the basis of SSCA, the combined frequency of SCN1A and SCN1B mutations in familial cases of GEFS+ was found to be 17%