A Thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy / Pterygium, a wing-shaped fibrovascular growth of the conjunctiva onto the cornea, can impair vision and be cosmetically unacceptable. Its frequency varies in Africa and postsurgical recurrence in blacks may be high. Determinants of pterygium occurrence and recurrence in rural Africans are not known. This study aimed to establish the determinants of pterygium occurrence and recurrence in rural blacks. The case controlled study comprised 230 patients and 157 controls. Interviews and eye examination were conducted; however, data from 150 patients and 150 controls were analyzed as pre-calculated. Families of 51 cases and 50 controls were studied. Surgery was done on 200 eligible patients. Those who experienced post-surgical recurrence were subclassified as cases and those who did not, controls. Immunohistochemistry was done on 59 pterygium sections and 7 controls. Family history of pterygium was present in 46 cases (30.6%) of 150, and 15 controls (10%) of 150; Odds ratio (OR) =3.93; p <0.01. Traditional eye medication was used by 79 cases (52.6%) of 150, and 60 controls (40%) of 150; OR =2.03; p <0.01. The tear film was unstable in 10 cases (6.6%) of 150, and 26 controls (17.3%) of 150; OR =0.30; p <0.01. Groups of 3-5 individuals per household were pterygium-affected in 36 pterygium families (70.5%) of 51 vs. 1 control (2%) of 50. After surgery, only 190 patients completed followup for a minimum duration of 6 months, and 52 (27.4%) experienced post-surgical recurrence. Of the 52 cases, 21 (40%) had grade 2 pterygia v. 8 post-surgical controls having grade 2 pterygia (6%) of 138; OR =9.1; p <0.01. The limbal basal epithelium expressed p53 in 11 pterygia (18.6%) of 59 v. 5 controls (71.4%) of 7; p <0.01. It expressed matrixmetalloproteinase-1 (MMP1) in 14 pterygia (23.7%) of 59 v. 5 controls (71.4%) of 7; p =0.02. MMP2 and MMP3 were detected in 16 cases (27.1%) of 59 v. 5 controls (71.4%) of 7; p =0.03. Pterygium occurred in families and was associated with traditional eye medication. Pterygium occurrence was not associated with unstable tear film, p53, and MMPs. Postsurgical recurrence was connected to grade 2 pterygia.

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.

No description available.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease which results from the degeneration of upper and lower motor neurons in the brainstem, spinal cord and motor cortex. Tragically there is no treatment to prevent ALS. The drug Riluzole acts to delay progression, but only by a month or so in this disease that has a survival length of three to five years. The identification of genes that are mutated in patients with ALS would help devise novel therapeutic strategies as much remains to be discovered about the genetics of ALS. Familial forms of the disease account for only 5-10% of patients. Among these familial cases, about 15-20% are caused by mutations in the zinc/copper superoxide dismutase gene, but the genetic basis of the remaining familial cases and the many sporadic cases continues to be largely unknown. / Altogether, the results presented in this thesis came from the use of several strategies to establish the genetic cause of ALS and the related motor neuron disorders like hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). A concerted and collaborative effort was put forth to identify the gene causative for ALS3 on chromosome 18. In addition, a recently reported locus has been confirmed on chromosome 9p for patients that present both ALS and frontotemporal dementia. The major finding involves the discovery of eight mutations in the TARDBP gene in nine patients with sporadic and familial ALS. Furthermore, a large association study evaluated the role of common polymorphisms in the paraoxonase gene cluster in susceptibility to the development of ALS. In the analysis of upper motor neuron diseases, mutations in a novel gene, KIAA0196, were identified for the HSP locus SPG8 on chromosome 8. Finally, the first locus for PLS was discovered on the p-arm of chromosome 4 following genome scan analysis of a large Quebec family with PLS. / These genetic discoveries all contributed novel advances to the field of motor neuron disorders. As more is elucidated regarding the biochemical function of these the proteins encoded by these genes, a more comprehensive picture of ALS and other motor neuron disorders will hopefully emerge.

No description available.