A new benign adult familial myoclonic epilepsy (BAFME) pedigree suggesting linkage to chromosome 2p11.1-q12.2

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant condition characterized by cortical tremor and generalized seizures, mapped on chromosome 8q24 by Japanese authors. Recently the same phenotype also was reported in European families, with linkage on chromosome 2. We present a new family with suggestion of linkage to chromosome 2p11.1-2q12.2 (lod score value, 1.55). This observation would confirm that BAFME is a worldwide, genetically heterogeneous condition, probably with Japanese families linked to 8q24 and European families to 2p11.1-q12.2.     

Absence of linkage to 8q23.3-q24.1 and 2p11.1-q12.2 in a new BAFME pedigree in China: indication of a third locus for BAFME

Benign adult familial myoclonic epilepsy (BAFME) were mapped on chromosome 8q24 and 8q23.3-q24.1 in Japanese pedigrees and mapped on 2p11.1-2q12.2 in European pedigrees, respectively. Recently, we recruited a large BAFME pedigree in China. After genotyping 11 microsatellite markers covering the two previously identified chromosome regions, we performed linkage analyses. However, evidence of negative linkage was found in the two previously reported candidate regions (LOD score <-3.0 at no recombination). Our data suggest that the causative gene responsible for BAFME in the Chinese pedigree may be located on a new region other than 8q23.3-q24.1 and 2p11.1-q12.2, indicating the presence of a third locus for BAFME.     

Benign adult familial myoclonic epilepsy (BAFME): evidence of an extended founder haplotype on chromosome 2p11.1-q12.2 in five Italian families

Benign adult familial myoclonic epilepsy (BAFME or FAME) is an autosomal dominant condition, characterized by shivering-like tremors of cortical origin, myoclonus, and epilepsy. Linkage to chromosomes 2p11.1-q12.2 and 8q23.1-q24.11 has been reported in Japanese and Italian families, respectively. We aimed to determine whether a common founder haplotype was shared by five BAFME families from southern Italy and attempted preliminary genotype-phenotype correlation analyses. Five Italian BAFME families were identified. One family has not been previously reported. DNA from 53 affected individuals was genotyped with highly polymorphic microsatellite markers spanning chromosomes 2p11.1-q12.2 and 8q23.1-q24.11. Multipoint linkage analysis was performed using LINKMAP 5.1 software assuming an autosomal dominant trait with 0.99 penetrance and frequency of 0.001. Significant linkage was found on chromosome 2p11.1-q12.2 and a maximum cumulative lod score of 18.5 was found for markers D2S2161 and D2S388. The haplotype "5332" of adjacent markers D2S388, D2S2216, D2S113, and D2S2175 segregates with the disease in all families indicating that the same mutation inherited from a common ancestor segregates in these families. Preliminary genotype-phenotype showed that patients carrying the disease haplotype show minor clinical differences, suggesting that expressivity of the founder mutation is not markedly influenced by other factors. The identification of causative mutations in BAFME requires an extensive and collaborative screening effort.     

Genetic fine mapping of the Miyoshi myopathy locus and exclusion of eight candidate genes

Miyoshi myopathy (MM) is an early adult-onset, autosomal recessive disorder characterized by weakness and muscular atrophy starting in the distal muscles. The disease locus has been previously mapped by linkage analysis to chromsome 2p using the microsatellite marker D2S291. Initial haplotype analysis of markers in families from three different origins (North American, Japanese, and Tunisian) suggested that the MM gene is located in a 4-cM region flanked by markers D2S292 on the telomeric side and D2S286 on the centromeric side. To delineate critical recombination events revealing a more refined localization of the MM gene, we have determined the pattern of segregation of 12 marker loci in two consanguineous families of Tunisian origin. In this study we have: (1) detected recombination events with the disease locus in one family, placing the MM gene most likely between markers D2S443 (CHLC.GGAA4D07.1876) and D2S2109; (2) generated a yeast artificial chromosome contig that spans approximately 3.8 megabases and extends from marker D2S358 to marker D2S286; (3) physically mapped 21 polymorphic markers, 5 genes, 3 STSs, and 1 EST within this contig; (4) detected and mapped a new polymorphism within this interval, allowing us to further reduce the MM locus to a 360-kilobase segment; (5) mapped the gene for the cytoskeletal protein β-adducin within the MM candidate region, failing to find a consistent pattern of mutation of this gene in our MM patients; (6) excluded seven other candidate myopathy genes from the Miyoshi locus. Accepted: August 14, 1997     

Familial cortical myoclonic tremor with epilepsy (FCMTE): Clinical characteristics and exclusion of linkages to 8q and 2p in a large French family

Introduction

Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by an autosomal-dominant inheritance, adult onset of myoclonus of the extremities, infrequent epileptic seizures, a non-progressive course, polyspikes on electroencephalography (EEG), photosensitivity, giant somatosensory-evoked potentials (SEP), enhancement of C-reflex and a premyoclonus spike detected by jerk-locked EEG back-averaging. Two genes yet to be identified are mapped to 8q23.3-q24.1 and 2p11.1-q12.2.

Methods

The present study involved five generations of a French family presenting with FCMTE, including 76 family members. Clinical analyses were performed in 39 living subjects and electrophysiological studies in five patients. Altogether, 27 relatives (21 living and six deceased) had the clinical characteristics of FCMTE, 17 of whom were analyzed. Linkage analyses were performed with microsatellites encompassing the two known loci (8q 23.3-q24.1 and 2p11.1-q12.2).

Results

Mean age at onset in the 17 living patients was 28.8 years (range 24-41). All had myoclonus/cortical tremor, and 11/17 had generalized tonic-clonic seizures. Other clinical symptoms were photosensitivity (16 cases), partial seizures (five cases), sensitivity to starvation/exercise (six cases) and vibration (four cases), ophthalmic migraine (six cases) and gait disorders (10 cases). Electrophysiological studies confirmed the FCMTE diagnosis in the five studied patients. Of the remaining relatives, 14 were considered healthy (asymptomatic subjects aged more than 40 years) and eight were of unknown status (asymptomatic aged lesser than 40 years). The pattern of inheritance was consistent with autosomal-dominant inheritance, although the two loci responsible for FCMTE were excluded.

Conclusion

This large family highlights some unusual clinical characteristics and suggests the presence of a third gene. Genetic research is ongoing to identify the mutated gene.     

A Dutch family with 'familial cortical tremor with epilepsy'. Clinical characteristics and exclusion of linkage to chromosome 8q23.3-q24.1

Objectives: To describe the clinical characteristics of a large Dutch family with cortical tremor with epilepsy (FCTE) and to test for genetic linkage of FCTE to chromosome 8q23.3–q24.1. Background: FCTE is an idiopathic generalised epilepsy of adult onset with autosomal dominant inheritance. It is characterised by kinesiogenic tremor and myoclonus of the limbs, generalised seizures, and electrophysiological findings consistent with cortical reflex myoclonus. Genetic analysis has been performed in five Japanese families. In all families, linkage was shown to chromosome 8q23.3–q24.1. Methods: Clinical and electrophysiological data of a four-generation family, suspected of autosomal dominant inherited FCTE, were collected and linkage analysis was performed. Results Clinical and electrophysiological findings were consistent with a diagnosis of FCTE. Of 41 relatives examined, 13 subjects were considered to be definitely affected, three were probably affected and ten were unaffected. In 15 relatives, the diagnosis could not be established. Linkage to chromosome 8q23.3–q24.1 was excluded. Conclusions: In this family with autosomal dominant FCTE, specific clinical and electrophysiological features were identified. Exclusion of linkage to chromosome 8q23.3–q24.1 indicates that genetic heterogeneity exists for FCTE. Received: 5 September 2001, Received in revised form: 21 November 2001, Accepted: 29 November 2001     

Further examination of the candidate genes in chromosome 12p13 locus for late-onset Alzheimer disease

A broad region on chromosome 12p13 has been intensely investigated for novel genetic variants associated with Alzheimer disease (AD). We examined this region with 23 microsatellite markers using 124 North European (NE) families and 209 Caribbean Hispanic families with late-onset AD (FAD). Significant evidence for linkage was present in a 5-cM interval near 20 cM in both the NE FAD (LOD = 3.5) and the Caribbean Hispanic FAD (LOD = 2.2) datasets. We further investigated these families and an independent NE case–control dataset using 14 single nucleotide polymorphisms (SNPs). The initial screening of the region at ∼20 cM in the NE case–control dataset revealed significant association between AD and seven SNPs in several genes, with the strongest result for rs2532500 in TAPBPL (p = 0.006). For rs3741916 in GAPDH, the C allele, rather than the G allele as was observed by Li et al. (Proc Natl Acad Sci U S A 101(44):15688–15693, 2004), was the risk allele. When the two family datasets were examined, none of the SNPs were significant in NE families, but two SNPs were associated with AD in Caribbean Hispanics: rs740850 in NCAPD2 (p = 0.0097) and rs1060620 in GAPDH (p = 0.042). In a separate analysis combining the Caribbean Hispanic families and NE cases and controls, rs740850 was significant after correcting for multiple testing (empirical p = 0.0048). Subsequent haplotype analyses revealed that two haplotype sets—haplotype C-A at SNPs 6–7 within NCAPD2 in Caribbean Hispanics, and haplotypes containing C-A-T at SNPs 8–10 within GAPDH in Caribbean Hispanic family and NE case–control datasets—were associated with AD. Taken together, these SNPs may be in linkage disequilibrium with a pathogenic variant(s) on or near NCAPD2 and GAPDH. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1

Migraine is the most common type of chronic episodic headache. To find novel susceptibility genes for familial migraine with and without aura, a genomewide screen was performed in a large family from northern Sweden. Evidence of linkage was obtained on chromosome 6p12.2-p21.1, with a maximum two-point lod score of 5.41 for marker D6S452. The patients with migraine shared a common haplotype of 10 Mb between markers D6S1650 and D6S1960.     

Clinical and genetic heterogeneity in chromosome 9p associated hereditary inclusion body myopathy: exclusion of GNE and three other candidate genes

We have previously reported a new autosomal dominant inclusion body myopathy clinically resembling limb girdle muscular dystrophy, associated with Paget disease of bone in the majority and frontotemporal dementia in a third of individuals. The critical locus for this unique disorder now termed IBMPFD is 9 p21.1-p12, spans 5.5 Mb and contains the gene responsible for the recessive quadriceps-sparing inclusion body myopathy (IBM2). Mutation analysis of the GNE gene associated with IBM2 in affected individuals from four IBMPFD families did not identify any mutations, indicating that the two disorders are not allelic. Expression studies indicate that GNE has a tissue-specific splice pattern, with four splice variants. Mutation analysis in three other candidate genes (beta-tropomyosin, NDUFB6 and SMU1) did not identify any mutations.     

A new locus for autosomal dominant generalized epilepsy associated with mild mental retardation on chromosome 3p

Purpose: Generalized epilepsies are clinically and genetically heterogeneous syndromes. Idiopathic generalized epilepsy (IGE), which has a strong genetic background, is not associated with any additional clinical features, such as mental retardation (MR). Herein we report results of linkage analysis in a large family with autosomal dominant (AD) generalized epilepsy associated with MR. Methods: We identified a four‐generation kindred with several affected members with generalized epilepsy without any evidence for secondary causes. Electroencephalography (EEG) studies and magnetic resonance imaging (MRI) results were reviewed when available. We performed a genome‐wide linkage analysis. Key Findings: Fourteen individuals were classified as affected and an additional three were considered as nonpenetrant obligatory carriers. Thirteen affected individual had a history of generalized tonic–clonic seizures, and absence seizures were reported in nine affected individuals. There was no history of preceding febrile seizures. MR was present in nine affected individuals with epilepsy but the other affected individuals had normal intelligence. Neuroimaging did not reveal any structural abnormalities and EEG studies were consistent with IGE rather than symptomatic generalized epilepsy. Genetic analysis detected a group of markers with logarithmic (base 10) of odds (LOD) score >3 on chromosome 3p spanning a 5.5 Mbp region. Sequencing of several candidate genes, including dynein light chain‐A, golgin subfamily a4, leucine rich repeat (in FLII) interacting gene, serine/threonine‐protein kinase DCAMKL3 (doublecortin‐ like and CAM kinase‐like 3), laforin (EPM2A) interacting protein 1 (EPM2AIP1, programmed cell death 6 interacting protein, and CLIP‐associating protein 2 (cytoplasmic linker‐associated protein 2) (hOrbit2) genes did not identify the disease‐causing mutations. Significance: We report the identification of a genetic locus for generalized epilepsy associated with MR on chromosome 3p. Affected individuals have a form of genetic epilepsy with generalized seizures variably associated with MR. Despite the presence of MR in several affected patients, epilepsy phenotype was not fully consistent with symptomatic epilepsy and suggests a biologic continuum between symptomatic epilepsies and IGE.     

Clinical and experimental studies of epilepsy associated with focal cortical dysplasia

The results of clinical and experimental studies on epilepsy associated with focal cortical dysplasia (FCD) are presented. We have been interested in the findings of abnormal increases in the numbers of small vessels in specimens of FCD resected from epilepsy patients. In the clinical study of 13 patients with epilepsy, specimens of FCD or dysembryoplastic neuroepithelial tumor (DNT) were examined using immunohistochemistry. The number of vessels in both lesions were greater than those in cortical specimens of autopsy cases without epilepsy. Because the vessels showed negative staining of VEGF, it was thought that the phenomenon of increase in the number of vessels was simply a hypervascularity, not a neovascularity. The local hypervascularity was expected to show local hyperperfusion in CBF-SPECT study, but interictal SPECT demonstrated local hypoperfusion and ictal SPECT showed hyperperfusion. This may have been caused by a functional change in those vessels. In the experimental study, we tried to make a new animal model of FCD to study epileptogenicity of FCD. When kainic acid had been infused into the neocortex in the neonatal rats, FCD was induced in adult Wistar rats. Histopathological examination revealed cortical dyslamination and abnormal neurons. On EEG, local spike bursts were elicited from the lesions, however, clinical seizures were not detected. Although the data are preliminary and observation over a longer period is required to determine whether spontaneous seizures will occur in this model, it is expected that this new model will be useful for studying epilepsy associated with FCD.     

局灶性皮质发育不良相关癫痫的诊疗进展

局灶性皮质发育不良（FCD）是临床中常见的局灶性癫痫的病理类型之一,多数FCD患者在癫痫起病后即表现出耐药性,成为难治性癫痫。2011年国际抗癫痫联盟提出了新的FCD病理分型后,让大家对FCD有了更进一步的认识。近几年随着医学检测技术、病理研究及神经影像技术的发展,针对不同病理亚型的研究使得临床医生对FCD致病机制及治疗措施的决策有了新的理解。该文综合近年相关文献,对FCD不同亚型临床特点、治疗方法及相关预后作一综述,以期为临床决策提供帮助。     

Refractory coeliac disease associated with late onset epilepsy, ataxia, tremor and progressive myoclonus with giant cortical evoked potentials--a case report and review of literature

Population-based screening studies suggest an overall prevalence of coeliac disease in Western populations of about 1%. A variety of neurological problems have been associated with coeliac disease occurring in up to 10% of cases of adult coeliac disease. We report an interesting case of a patient with coeliac disease who subsequently developed neurological symptoms several years later. Furthermore, a literature review of all cases to date was performed.