Thesis (M. Sc.)--University of New South Wales, 2005. / Also available online.

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2007. / Title from first page of PDF file (viewed January 8, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 75-84).

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

BACKGROUND: Mitochondrial complex I deficiency often leads to a devastating neurodegenerative disorder of childhood. In most cases, the underlying genetic defect is unknown. Recessive nuclear gene mutations, rather than mitochondrial DNA mutations, account for the majority of cases. AIM: Our aim was to identify the genetic basis of complex I deficiency in 34 patients with isolated complex I deficiency, by studying six of the 39 nuclear encoded complex I subunit genes (NDUFV1, NDUFS1, NDUFS2, NDUFS4, NDUFS7 and NDUFS8). These genes have been conserved throughout evolution and carry out essential aspects of complex I function. METHODS: RNA was extracted from patient fibroblasts and cDNA made by reverse transcription. Overlapping amplicons that together spanned the entire coding area of each gene were amplified by PCR. The genes were screened for mutations using denaturing High Performance Liquid Chromatography (dHPLC). Patient samples with abnormal dHPLC profiles underwent direct DNA sequencing. RESULTS: Novel mutations were identified in six of 34 (18%) patients with isolated complex I deficiency. Five patients had two mutations identified and one patient had a single mutation in NDUFS4 identified. All patients with mutations had a progressive encephalopathy and five out of six had Leigh syndrome or Leigh like syndrome. Mutations were found in three nuclear encoded subunit genes, NDUFV1, NDUFS2 and NDUFS4. Three novel NDUFV1 mutations were identified (R386H, K111E and P252R). The R386H mutation was found in two apparently unrelated patients. Four novel NDUFS2 mutations were identified (R221X, M292T, R333Q and IVS9+4A&ltG). The novel NDUFS4 mutation c.221delC was found in two patients - one in homozygous form and the other heterozygous. Specific genotype and phenotype correlations were not identified. CONCLUSIONS: Nuclear encoded complex I subunit gene mutations are an important contributor to the aetiology of isolated complex I deficiency in childhood. Screening of these genes is an essential part of the investigation of complex I deficiency.

18q- is a chromosomal deletion disorder caused by missing genetic material from the long arm of the 18th chromosome. The extensive impairments associated with 18qmay be a significant source of stress to parents. Research on families of handicapped children suggests that these families experience additional stress related to challenges such as increased caregiving demands, changes in social support systems, and financial burdens related to medical needs and decreased income. Changes in the family environment are also implicated in families coping with a disabled child. Some studies reveal highly cohesive environments within these families, while others reveal decreased levels of expressiveness and cohesion and increases in conflict. The present study compared variables of parenting stress and family environment in families of children with and without disabilities. Group 1 consisted of 24 primary caregivers of children with 18q-. Group 2 consisted of 32 primary caregivers of children with DS. Group 3 consisted of 32 primary caregivers of typically developing children. A one-way, between groups multivariate analysis of variance (MANOVA) was conducted to investigate differences in parenting stress on three subscales of the Parenting Stress Index. A significant difference between groups was found. Post hoc pairwise comparisons indicated that the DS group reported statistically significantly more stress than the Control group on both the Isolation and Spouse subscales. The 18q- group was not found to be statistically significantly different from either the Control or DS group on any of the three PSI subscales. A one-way, between groups multivariate analysis of variance (MANOVA) was also conducted to investigate differences in family environment on three subscales of the Family Environment Scale. A significant difference between groups was found. Post hoc pairwise comparisons indicated that the DS group showed statistically significantly less amounts of cohesion in the family environment than both the 18q- and Control groups. The 18q- group showed similar levels of cohesion to the Control group. There were no significant differences between groups on the other two FES subscales. Findings from the study provide important information about the role of family environment and parenting stress in families of children with disabilities. Limitations of the study and implications for future research and practice are discussed. / text