ABSTRACT:Hereditary spastic paraplegia (HSP) describes a heterogeneous group of inherited neurodegenerative disorders in which the cardinal pathological feature is upper motor neurone degeneration leading to progressive spasticity and weakness of the lower limbs. Using samples from a large Omani family we recently mapped a gene for a novel autosomal recessive form of HSP (SPG35) in which the spastic paraplegia was associated with intellectual disability and seizures. Magnetic resonance imaging of the brain of SPG35 patients showed white matter abnormalities suggestive of a leukodystrophy. Here we report homozygous mutations in the fatty acid 2-hydroxylase gene (FA2H) in the original family used to define the SPG35 locus (p.Arg235Cys) as well as in a previously unreported Pakistani family with a similar phenotype (p.Arg53_Ile58del). Measurement of enzyme activity in vitro revealed significantly reduced enzymatic function of FA2H associated with these mutations. These results demonstrate that mutations in FA2H are associated with SPG35, and that abnormal hydroxylation of myelin galactocerebroside lipid components can lead to a severe progressive phenotype, with a clinical presentation of complicated HSP and radiological features of leukodystrophy. ©2010 Wiley-Liss, Inc.

The FHQ identified most informants with genetic risks that are appropriately addressed in primary care-those with a family history of premature coronary heart disease, those warranting specialist referral, and those who might appropriately be offered carrier testing. However, it was less effective in identifying those with a possible Mendelian disorder for whom more information was required.

The present paper examines the professional and scientific views on the social, ethical and legal issues that impact on genetic information and testing in insurance and employment in Europe. For this purpose, many aspects have been considered, such as the concerns of medical geneticists, of the insurers and employers, of the public, as well as the regulatory frameworks and unresolved issues. The method used was primarily the review of the technical, social, economical and ethical aspects of advances in genetics and the concerns of parties who are involved, that is, the insurers, the employers and the public. The existing guidelines and legislation on this topic were also reported. Then, the method was to examine the issues debated by these parties in Europe, as well as by 47 experts from 14 European countries invited to an international workshop organized by the European Society of Human Genetics Public and Professional Policy Committee in Manchester, UK, 25-27 February 2000. The result of this was that the most important issues raised by genetic information and testing in insurance and employment in Europe include a need for clear definitions of terms used in genetics, declaring the grounds on which genetic information is or is not used, and promoting confidence between the public and the insurance industry. There is currently very little use of genetic information in relation to employment, but the situation should be kept under review.

We have identified an alternative pathway of tumorigenesis in sporadic colon cancer, involving microsatellite instability due to mismatched repair methylation, which may be driven by mutations in the BRAF gene (V600E). Colorectal cancer (CRC) is the most common cancer in the world, and African Americans show a higher incidence than other populations in the United States. We analyzed sporadic CRCs in Omani (of African origin, N = 61), Iranian (of Caucasian origin, N = 53) and African American (N = 95) patients for microsatellite instability, expression status of mismatched repair genes (hMLH1, hMSH2) and presence of the BRAF (V600E) mutation. In the Omani group, all tumors with BRAF mutations were located in the left side of the colon, and for African Americans, 88% [7] of tumors with BRAF mutations were found in the right side of the colon. In African Americans, 31% of tumors displayed microsatellite instability at two or more markers (MSI-H), while this rate was 26% and 13% for tumors in the Iranian and Omani groups, respectively. A majority of these MSI-H tumors were located in the proximal colon (right side) in African American and Iranian subjects, whereas most were located in the distal colon (left side) in Omani subjects. Defects in hMLH1 gene expression were found in 77% of MSI-H tumors in both African Americans and Iranians and in 38% of tumors in Omanis. BRAF mutations were observed in all subjects: 10% of tumors in African Americans (8/82), 2% of tumors in Iranians (1/53), and 19% of tumors in Omanis (11/59). Our findings suggest that CRC occurs at a younger age in Omani and Iranian patients, and these groups showed a lower occurrence of MSI-H than did African American patients. Our multivariate model suggests an important and significant role of hMLH1 expression and BRAF mutation in MSI-H CRC in these populations. The high occurrence of MSI-H tumors in African Americans may have significant implications for treatment, since patients with MSI-H lesions display a different response to chemotherapeutic agents such as 5-fluorouracil.

We have mapped the chromosomal location of a novel gene responsible for a form of hereditary spastic paraplegia (HSP) (SPG35) and defined its clinical presentation.