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Background: The NOTCH4 gene is located at 6p21.3, a site shown in several studies to have significant linkage with Alzheimer’s disease. Objective: To investigate the potential impact of two polymorphisms within this gene on the risk of developing Alzheimer’s disease. Methods: Genotyping of promoter and 5′-UTR polymorphisms was done in Scottish, English, and French populations. The potential functionality of the 5′-UTR polymorphism was assessed by testing its impact on Aβ load in Alzheimer brains and also by undertaking electrophoretic mobility shift assays and transfection experiments. Results: No association of the Notch4 polymorphisms alone with the disease was observed in any of the populations. However, an interaction of the 5′-UTR C/T polymorphism with the e4 allele of the APOE gene was detected in United Kingdom populations but not in the French. No relation between the 5′-UTR polymorphism and Aβ loads was detected overall or in the presence or absence of the e4 allele. No DNA protein specific binding was found with proteins from neuroblastoma, glioma, or astrocytoma cells, and no allele dependent transcriptional activity was detected. Conclusions: No association between two NOTCH4 polymorphisms alone and Alzheimer’s disease was observed in the three populations, but there was evidence of an increased risk associated with the 5′-UTR CC genotype in e4 bearers in the United Kingdom. As no functionality for this polymorphism could be determined, it is likely that the interaction is spurious or results from a linkage disequilibrium of this 5′-UTR polymorphism with another marker elsewhere in the 6p21.3 locus.

Allele frequencies for 15 STR markers included in the AmpFISTR Identifiler kit (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818, and FGA) were obtained from a sample of 561 unrelated individuals from Sao Paulo, Brazil.

Background: Northern Ireland has a high and rising prevalence rate of multiple sclerosis (MS). The most recent survey in 1996 found a rate of 168.7/100 000. Recorded prevalence rates for the south of Ireland, including County Wexford, have been markedly lower and seemed to suggest the existence of a prevalence gradient within the island. Objectives: To compare the prevalence of multiple sclerosis in Co. Wexford in the south east of Ireland and Co. Donegal in the north west, and to establish whether a variation in prevalence of MS exists within Ireland. Methods: Patients were referred from multiple sources. Review of clinical case records and/or patient examination confirmed the diagnosis. Results: In Co. Wexford, 126 patients were found to have clinically definite or probable multiple sclerosis with a prevalence rate of 120.7/100 000 (95% confidence intervals (CI) 100.6 to 143.8), which is similar to other areas of similar latitude within the British Isles. In Co. Donegal, 240 people had clinically definite or probable MS with a prevalence rate of 184.6/100 000 (95% CI 162.0 to 209.5). The difference in prevalence rates is statistically significant (Z = 3.94, p = Conclusion: There is a latitudinal variation in the prevalence rate of MS between the north and the south of Ireland. The increased prevalence of MS seen in Co. Wexford is likely to represent better case ascertainment and improved diagnostic accuracy rather than an actual increase in prevalence. The north/south variation in prevalence may represent a variation in the genetic predisposition to MS between the background populations of the two counties.

Objective: Spinocerebellar ataxia type 2 (SCA2) has been reported as the commonest dominant hereditary ataxia in India. However, India is an ethnically and religiously diverse population. Previous studies have not clearly indicated exact ethnic and religious origins, and must therefore be interpreted with caution. The purpose of this study was to determine the prevalence of different SCA mutations in a relatively homogeneous population from eastern India. Methods: We identified 28 families with autosomal dominant cerebellar ataxia from eastern India. Each underwent full clinical evaluation and were analysed for the presence of SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, and SCA17 mutations. In addition, haplotype analysis was carried out in seven of the 16 families with SCA2. Results: Seven patients from four (14%) families were positive for an expansion in SCA1 and 26 patients from 16 (57%) families were positive for an expansion in SCA2. No mutations were detected in the remaining eight families (29%). Most of the SCA1 and SCA2 families were Hindu from the state of Bihar. Five out of 26 SCA2 patients in this study did not have slow saccades. In addition, four of seven SCA1 patients had slow saccades. We found an association between the SCA2 CAG repeat expansion and the 285 base pair (bp) allele of microsatellite marker D12S1672, and also data supportive of the association between the expansion and the 225 bp allele of D12S1333, which has been previously described. Conclusions: We conclude that (1) although slow ocular saccades are highly suggestive of SCA2, that they are not universal, nor are they exclusive to this disorder and (2) SCA2 is likely to be the commonest dominant ataxia in eastern India, with further evidence for a founder effect.

Objectives: Hereditary spastic paraparesis (HSP) is clinically and genetically heterogeneous. “Pure” autosomal dominant (AD) HSP is most common and eight genetic loci are identified to date. Previous studies have included autosomal recessive and sporadic cases in prevalence calculations. This study aimed to determine the prevalence and features of pure ADHSP in the island of Ireland. Methods: Index cases were identified from a 5 year survey of all adult and paediatric neurologists, clinical geneticists, hospital records, and hospital inpatient enquiry system data in Ireland, north and south. Families were examined by two neurologists and classified as affected or unaffected according to specific criteria. The prevalence date was set at 1 June 2000 and the midyear population estimate for the previous year was 5.436 million. Results: Eighty two patients with pure ADHSP and a further 12 obligate carriers from 19 families were identified. In total 69 patients with pure ADHSP were alive and resident in Ireland at the prevalence date. Twenty nine per cent of these were asymptomatic but with signs of paraparesis. Conclusions: The prevalence of ADHSP in Ireland to estimated to be 1.27/100 000 population. The high proportion of asymptomatic cases and obligate carriers means that this condition is likely to be underdiagnosed.