Molecular Genetic Investigation of Autosomal Recessive Neurodevelopmental Disorders

Development of the human brain occurs in a number of complex preand postnatal stages which are governed by both genetic and environmental factors. Aberrant brain development due to inherited defects may result in a wide spectrum of neurological disorders which are commonly encountered in the clinical field of paediatric neurology. In the work for this thesis, I have investigated the molecular basis and defined the clinical features of three autosomal recessive neurological syndromes. I studied a cohort of children with early onset epileptic encephalopathy and, in one family, identified a novel homozygous pathogenic mutation of PLCB1. I have also utilised autozygosity mapping techniques to study consanguineous families with a complex motor disorder, infantile parkinsonism-dystonia, and identified loss-of-function mutations in the gene encoding the dopamine transporter (SLC6A3). Subsequent acquisition of a cohort of similarly affected children allowed detailed clinical and molecular characterisation of this novel disorder, dopamine transporter deficiency syndrome. Finally I have delineated the clinical and genetic features of PLA2G6-associated neurodegeneration. The identification of disease-causing genes contributes greatly to understanding the disease mechanisms underlying such early-onset disorders, and also provides novel insights into normal human neurodevelopment. I would like to dedicate this thesis to my husband, David and our beautiful daughter, Imogen. I am forever indebted to you both for your constant love and support which has enabled me to bring this work to completion. Over the years, I have been privileged to work with a number of neurologically impaired children and their families, who have taught me so much, and continue to be a constant source of inspiration. Given the nature of this thesis, no dedication would be complete without a tribute to their courage, patience and perseverance.