Familial hemiplegic migraine: linkage to chromosome 14q32 in a Spanish kindred

We sought to map the disease-causing gene in a large Spanish kindred with familial hemiplegic migraine (FHM). Patients were classified according to the ICHD-II criteria. After ruling out linkage to known migraine genetic loci, a single nucleotide polymorphism-based, 0.62-cM density genome-wide scan was performed. Among 13 affected subjects, FHM was the prevailing migraine phenotype in six, migraine with aura in four and migraine without aura in three. Linkage analysis revealed a disease locus in a 4.15-Mb region on 14q32 with a maximum two-point logarithm of odds (LOD) score of 3.1 and a multipoint parametric LOD score of 3.8. This genomic region does not overlap with the reported migraine loci on 14q21–22. Sequence analysis of three candidate genes in the region, SLC24A4, ATXN3 and ITPK1, failed to show disease-causing mutations in our patients. Genetic heterogeneity in FHM may be greater than previously suspected. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

The estrogen receptor 1 G594A polymorphism is associated with migraine susceptibility in two independent case/control groups

Migraine is a painful and debilitating disorder with a significant genetic component. Steroid hormones, in particular estrogen, have long been considered to play a role in migraine, as variations in hormone levels are associated with migraine onset in many sufferers of the disorder. Steroid hormones mediate their activity via hormone receptors, which have a wide tissue distribution. Estrogen receptors have been localized to the brain in regions considered to be involved in migraine pathogenesis. Hence it is possible that genetic variation in the estrogen receptor gene may play a role in migraine susceptibility. This study thus examined the estrogen receptor 1 (ESR) gene for a potential role in migraine pathogenesis and susceptibility. A population-based cohort of 224 migraine sufferers and 224 matched controls were genotyped for the G594A polymorphism located in exon 8 of the ESR1 gene. Statistical analysis indicated a significant difference between migraineurs and non-migraineurs in both the allele frequencies (P=0.003) and genotype distributions (P=0.008) in this sample. An independent follow-up study was then undertaken using this marker in an additional population-based cohort of 260 migraine sufferers and 260 matched controls. This resulted in a significant association between the two groups with regard to allele frequencies (P=8×10^–6) and genotype distributions (P=4×10^–5). Our findings support the hypothesis that genetic variation in hormone receptors, in particular the ESR1 gene, may play a role in migraine.     

Further localization of a multiple sclerosis susceptibility gene on chromosome 7q using a new T cell receptor beta-chain DNA polymorphism

Multiple sclerosis (MS) has been associated with particular HLA haplotypes and has recently been reported to also be associated with the T cell receptor (TCR) beta-chain complex. We have tried to determine the source of the TCR-beta/MS association by exploiting the pattern of linkage disequilibrium within the TCR-beta complex. We describe a new DNA polymorphism with the TCR variable region gene segment V beta 15 which appears to localize between the constant region and V beta 11. When the distribution of V beta 11-V beta 15 haplotypes in MS patients was compared to healthy controls, the strength of the V beta 11-V beta 15 MS association (p = 0.107) was much less than the MS association with the adjacent V beta 8-V beta 11 haplotype (p = 0.0010). On the basis we exclude an MS susceptibility gene telomeric to V beta 11. The reported MS association with the TCR-beta gene complex therefore does not appear to be due to genes within the diversity, joining, or constant region but more likely involves a specific gene(s) within the variable region.     

Familial hemiplegic migraine type 2 is linked to 0.9Mb region on chromosome 1q23

Familial hemiplegic migraine (FHM) is a rare autosomal dominant disorder characterized by episodes of transient hemiparesis followed by headache. Two chromosomal loci are associated to FHM: FHM1 on chromosome 19 and FHM2 on chromosome 1q21-23. Mutations of the alpha-1A subunit of the voltage gated calcium channel (CACNA1A) are responsible for FHM1. FHM2 critical region spans 28 cM, hence hampering the identification of the responsible gene. Here, we report the FHM2 locus refining by linkage analysis on two large Italian families affected by pure FHM. The new critical region covers a small area of 0.9Mb in 1q23 and renders feasible a positional candidate approach. By mutation analysis, we excluded the calsequestrin and two potassium channel genes mapping within the narrowed FHM2 locus.     

A narcolepsy susceptibility locus maps to a 5 Mb region of chromosome 21q

The genetic basis of human narcolepsy remains poorly understood. Multiplex families with full-blown narcolepsy-cataplexy are rare, whereas families with both narcolepsy-cataplexy and excessive daytime sleepiness without cataplexy are more common. We performed a genomewide linkage analysis in a large French family with four members affected with narcolepsy-cataplexy and 10 others with isolated recurrent naps or lapses into sleep. Only three regions showed logarithm of odds (LOD) scores greater than 1 in two-point linkage analysis (D6S1960, D11S2359, and D21S228). Genotyping additional markers provided support for linkage to 9 markers on chromosome 21 (maximum two-point LOD score, 3.36 at D21S1245). The multipoint linkage analysis using SimWalk2 provided further evidence for linkage to the same region (maximum parametric LOD score, 4.00 at 21GT26K). A single haplotype was shared by all affected individuals and informative crossovers indicated that the elusive gene that confers susceptibility to narcolepsy is likely to be located between markers D21S267 and ABCG1, in a 5.15 Mb region of 21q.     

Familial hemiplegic migraine: clinical features and probable linkage to chromosome 1 in an Italian family

We describe an Italian family with familial hemiplegic migraine (FHM), subtle cerebellar signs and probable linkage to chromosome 1. FHM is genetically heterogeneous; in about 50% of families it is caused by mutations within the CACNA1A gene on chromosome 19. Linkage to 1q31 and 1g21–23 has also been established. Other families do not link either to chromosome 19 or 1. Chromosome 19-linked FHM may display nystagmus and cerebellar ataxia. Affected family members were neurologically examined; linkage analysis was performed with markers for chromosomes 19p13, 1q21–23, and 1q32. Five family members had hemiplegic migraine, and 3 displayed additional cerebellar signs (scanning speech and nystagmus). In 1 patient, episodes of hemiplegic migraine triggered by mild head trauma. Epilepsy and mental retardation were also found in 1 affected relative each. Lod scores for linkage to 19p13 were negative, while the maximum two-point lod score was 1.81 to 1q21–23. This family with FHM and associated subtle cerebellar signs, epilepsy and mental retardation showed probable linkage to 1q21–23. Received: 27 December 2001 / Accepted in revised form: 27 February 2002     

No proof of linkage between schizophrenia-related disorders including schizophrenia and chromosome 2q21 region

Summary We examined linkage between schizophrenia and schizophrenia-related disorders and five genetic markers on chromosome 2 in fourteen families ascertained through affected probands in St. Louis and Vienna. The chromosomal region 2q21 was considered a candidate locus for schizophrenia because of a report of a balanced translocation 2;18 (q21;q23) in a schizophrenia family. Linkage analyses were conducted for three disease models: a narrow model including schizophrenia only; an intermediate model including a spectrum of schizophrenia-related disorders; and a broad model including major affective disorders. Multipoint linkage analyses excluded linkage across the region (about 50cM) for the intermediate disease model. The same was generally true for the broad affection status model. None of the two-point and multipoint analyses showed definite linkage of schizophrenia to any marker. The most prominent positive association was between D2S44 and a broad affection status model, giving a two-point lod score of 1.71 at 0.20 recombination fraction.     

偏头痛患者外周血淋巴细胞5—羟色胺1D受体基因表达的研究

目的探讨５－羟色胺１Ｄ（５－ＨＴ１Ｄ）受体基因表达与５－ＨＴ在偏头痛发作中的作用。方法采用反转录－聚合酶链反应技术，检测３２例偏头痛患者外周血淋巴细胞５－ＨＴ１Ｄ受体基因表达、血浆５－ＨＴ含量的变化。结果偏头痛患者发作期５－ＨＴ１Ｄ受体基因表达阳性率为９３．８％，对照组表达为５．０％，两者比较差异有显著意义；间歇期受体表达为５３．３％，与发作期比较差异有显著意义；发作期血浆５－ＨＴ含量明显低于对照组和间歇期。结论５－ＨＴ含量异常可能是偏头痛的发病基础，５－ＨＴ１Ｄ受体可能是偏头痛发作的参与者，５－ＨＴ１Ｄ受体基因表达对偏头痛的诊断有重要意义。     

偏头痛与5-羟色胺转运体基因多态性的相关性研究

目的研究5-羟色胺转运体(5-hydroxytryptamine transporter,5-HTT)基因多态性频率在汉族偏头痛人群的分布,探讨该基因多态性与偏头痛的相关性。方法采集40例偏头痛患者(实验组)和40例健康成人(对照组)的肘静脉血,通过DNA-PCR扩增等分子生物学技术,观察5-HTT基因多态性的基因型和等位基因频率在两组中的分布特点。结果5-HTT基因多态性的基因型和等位基因频率在实验组和对照组中的分布无统计学差异(P>0.05),在偏头痛各临床特征中的分布也无统计学差异(P>0.05)。结论5-HTT基因是否在汉族人群偏头痛发病中起作用,有待进一步研究。     

Familial partial epilepsy with variable foci: clinical features and linkage to chromosome 22q12

BACKGROUND: Familial partial epilepsy with variable foci (FPEVF) is an autosomal dominant syndrome characterized by partial seizures originating from different brain regions in different family members in the absence of detectable structural abnormalities. A gene for FPEVF was mapped to chromosome 22q12 in two distantly related French-Canadian families. METHODS: We describe the clinical features and performed a linkage analysis in a Spanish kindred and in a third French-Canadian family distantly related to the original pedigrees. RESULTS: Onset of seizures was typically in middle childhood, and attacks were usually easy to control. Seizure semiology varied among family members but was constant for each individual. In some, a pattern of nocturnal frontal lobe seizures led to consideration of the diagnosis of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). The Spanish family was mapped to chromosome 22q (multipoint lod score, 3.4), and the new French-Canadian family had a multipoint lod score of 2.97 and shared the haplotype of the original French-Canadian families. CONCLUSIONS: Identification of the various forms of familial partial epilepsy is challenging, particularly in small families, in which insufficient individuals exist to identify a specific pattern. We provide clinical guidelines for this task, which will eventually be supplanted by specific molecular diagnosis. We confirmed linkage of FPEVF to chromosome 22q12 and redefined the region to a 5.2-Mb segment of DNA.     

偏头痛患者5-羟色胺2A受体启动子区T102C基因多态性的研究

目的 探讨5-羟色胺2A受体(5-HT2AR)基因T102C多态性与哈尔滨地区汉族人偏头痛的关系.方法 应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法,检测204例偏头痛患者及186例健康对照者5-HT2AR基因启动子区域T102C多态性.结果 偏头痛患者中T/T,T/C,C/C分布为29.9%,53.9%和16.2%,正常对照中T/T,T/C,C/C分布为35.0%,48.9%和16.1%,两组间无显著性差异(P>0.05).偏头痛患者的等位基因频率为102T 56.9%,102C 43.1%,正常对照组为102T 59.4%,102C 40.6%,两组间无显著性差异(P>0.05).结论 5-HT2AR基因启动子区域T102C基因多态性与哈尔滨地区汉族人偏头痛的发生无相关性.

Abstract：

Objective To investigate the association between 5-HT2A receptor (5-HT2AR) promoter T102C gene polymorphism and migraine in Han nationality, Harbin. Methods Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP)analysis were applied to determine the genotypes at the promoter 102 of 5-HT2AR gene in 204 migraine patients and 186 controls. The genotype distribution and allele frequencies among different groups were compared. Results The genotype T/T,T/C,C/C distribution of the 5-HT2AR were 29.9% ,53.9% and 16.2% in migraine patients,and were 35.0% ,48.9% and 16.1% in controls (P > 0.05). The allele frequencies of 5-HT2AR in migraine patients were 56.9% for 102T,43.1% for 102C,and 59.4% for 102T,40.6% for 102C in controls (P > 0.05 ).Conclusion The polymorphism of 5-HT2AR promoter T102C gene was not significantly associated with migraine among Han nationality,in Harbin, China.     

Familial partial epilepsy with variable foci: A new family with suggestion of linkage to chromosome 22q12

Familial partial epilepsy with variable foci (FPEVF) is an autosomal dominant form of partial epilepsy characterized by the presence of epileptic seizures originating from different cerebral lobes in different members of the same family. Linkage to chromosomes 22q12 and 2q36 has been reported, although only six families have been published. We studied a new FPEVF family including nine affected individuals. The phenotype in this family was similar to that previously described and consisted of nocturnal and daytime seizures with semiology suggesting a frontal lobe origin. A video‐EEG (electroencephalography) recording of the proband’s seizures is presented and revealed hyperkinetic seizures of frontal lobe origin preceded by left frontal spikes. We excluded linkage to chromosome 2q36 and found a suggestion of linkage to chromosome 22q12 with a lod score of 2.64 (θ = 0) for marker D22S689.     

A novel hereditary spastic paraplegia with dystonia linked to chromosome 2q24‐2q31

Spastic paraplegias (HSPs) and dystonias (DYTs) typically localize to different neuroanatomic systems. We report clinical and genetic data from large Ohio kindred with autosomal dominant (AD) HSP and DYT. Single and multipoint linkage using microsatellite and single nucleotide polymorphism array genotyping were performed on a large, multigenerational family with a novel, AD, highly penetrant neurological disease causing spasticity and DYT. Age of onset of spasticity and weakness is from the first year to the sixth decade, and age of onset of DYT from the first to third decade. There is no ataxia or apparent cognitive involvement. Neuroimaging and peripheral neurophysiology are normal. Generalized DYT improved markedly with deep brain stimulation in 1 child. The disease locus was mapped to a region on chromosome 2q 24–31, flanked by markers rs1424937–rs1559510, proximal to SPG13, in a region where there are no known HSP or DYT genes. A secondary analysis for candidate genes segregating with the DYT phenotype revealed two candidate regions with parametric lod scores above 2.0. On the basis of clinical presentation and linkage results, we conclude that this disease is a novel neurological disorder. Identifying the causative gene may elucidate an important pathway for pyramidal and extrapyramidal disorders. © 2008 Movement Disorder Society     

A locus for generalized tonic-clonic seizure susceptibility maps to chromosome 10q25-q26

Inheritance patterns in twins and multiplex families led us to hypothesize that two loci were segregating in subjects with juvenile myoclonic epilepsy (JME), one predisposing to generalized tonic-clonic seizures (GTCS) and a second to myoclonic seizures. We tested this hypothesis by performing genome-wide scan of a large family (Family 01) and used the results to guide analyses of additional families. A locus was identified in Family 01 that was linked to GTCS (10q25-q26). Model-based multipoint analysis of the 10q25-q26 locus showed a logarithm of odds (LOD) score of 2.85; similar results were obtained with model-free analyses (maximum nonparametric linkage [NPL] of 2.71; p = 0.0019). Analyses of the 10q25-q26 locus in 10 additional families assuming heterogeneity revealed evidence for linkage in four families; model-based and model-free analyses showed a heterogeneity LOD (HLOD) of 2.01 (alpha = 0.41) and maximum NPL of 2.56 (p = 0.0027), respectively, when all subjects with GTCS were designated to be affected. Combined analyses of all 11 families showed an HLOD of 4.04 (alpha = 0.51) and maximum NPL score of 4.20 (p = 0.000065). Fine mapping of the locus defined an interval of 4.45Mb. These findings identify a novel locus for GTCS on 10q25-q26 and support the idea that distinct loci underlie distinct seizure types within an epilepsy syndrome such as JME.     

A novel candidate region for ALS on chromosome 14q11.2

Sequence variations with biologic effect in ALS have been identified in the gene for vascular endothelial growth factor (VEGF). The gene for a related protein, angiogenin, lies on chromosome 14q11.2. Analysis of the angiogenin (ANG) gene in the authors' population has demonstrated a significant allelic association with the rs11701 single nucleotide polymorphism (SNP) and identified a novel mutation in two individuals with sporadic ALS that potentially inhibits angiogenin function. These observations propose a candidate region for ALS on chromosome 14q11.2 and suggest that other genes with similar function to VEGF may be important in the pathogenesis of ALS.