Inaug.-Diss.--Zürich.

The Hereditary Spastic Paraplegias (HSP) comprise a group of neurodegenerative diseases characterized by progressive lower limb spasticity. This disease, with a prevalence ranging from 1 to 20 in 100,000 individuals, is currently untreatable. The neuropathological hallmark is axonal degeneration of motor neurons in the corticospinal tract. However, the mechanisms of pathogenesis underlying this neurodegeneration remain poorly understood. Over the last decade, genetic studies of HSP have identified 33 loci including 14 genes. The main objective of this dissertation was to identify and characterize genes in a large North American HSP cohort. Mutation analysis of the two most common genes implicated in HSP, SPG3 and SPG4, led to the detection of nine novel mutations, including an ancestral SPG4 mutation in five French Canadian families. This screen also allowed for the molecular characterization of the p.del436N mutation in SPG3, which suggests a previously unidentified dominant-negative mechanism. Furthermore, a novel deletion in the VPS9 domain of the ALS2 gene was identified in a family with severe infantile onset HSP. In addition, linkage analysis and whole genome scan efforts resulted in the successful mapping of two novel HSP loci, SPG27 and SAX1. SAX1 represents the first locus for autosomal dominant spastic ataxia, a complicated form of HSP, with a common ancestor in Newfoundland. Finally, a positional candidate gene strategy at the SPG8 locus identified three missense mutations in a novel gene encoding strumpellin. Two mutations failed to rescue an axonal phenotype induced by morpholino knock-down of the SPG8 gene in zebrafish. Our efforts to identify and characterize HSP genes determined the underlying genetic cause in 36% of our cohort. These genetic causes include two novel loci and a novel gene. The findings are a major contribution to the characterization of the pathophysiology of HSP and significantly broaden the knowledge in the field of motor neuron disease. Analysis of the 15 known HSP genes suggests a common disease mechanism involving disrupted axonal membrane protein trafficking. Unraveling this mechanism will elucidate the functional maintenance of neurons in the corticospinal tract and will facilitate the development of therapies for HSP and related diseases.

Thesis (Ph.D.) - University of Queensland, 2006. / Includes bibliographical references.

No description available.

Thesis (M.S.W.)--University of Hong Kong, 1994. / Includes bibliographical references (leaves 87-91).

MPH / Department of Public Health / Worldwide there are millions of children and adolescents with adisability. The United Nations Children’s Fund estimates the worldwide prevalence to be 150 million children under 18 years older, the World Health Organization also estimates that there are 93 million children with impairment. This study focused at describing the impact of rehabilitation programme for the young adult living with cerebral palsy admitted in a care centre Mopani District, South Africa. The study utilized a quantitative, descriptive cross-sectional survey method. Data was collected using an observational check list. The target population is young adults’ aged 18- 35 yearswith cerebral palsy in a Care Centre. Sampling was not necessary in this study since the targeted population was small in number. Confidentiality of respondents’ information was maintained where study subjects wereidentifiedusing codes. Data were analysed using descriptive statistics and the results of the analysis are presented in the form of tables and charts to enhance clarity. The results are presented according to the objectives. The conclusion and recommendationswere made based on the findings. The study results show that there were more females than males (ratio 3:1) and the range of age distribution was 20 to 37 years. The study also finds out that cerebral palsy condition was accompanied by other complications such as blindness, mental retardation, epilepsy and hydrocephalus. The study indicated that rehabilitation can only have minimal effects but it can improve the quality of life of the patient. With regard to communication outcome of the rehabilitation programme it indicates progress following rehabilitation between 57% and 80% could use expressive language and follow basic instructions. The study also observed that patients made a steady improvement right through from those who spent 4 to 8 years to those who had been there for long, 15 years and above. Since cerebral palsy can affect motor development as well as social development, the rehabilitation seems beneficial to focus on intervention programme on the cognitive stimulation of children and young adults with cerebral palsy. / NRF