{"id":{"repo_id":"birmingham","oai_identifier":"oai:etheses.bham.ac.uk:1126"},"canonical_url":"https://search.dev.ndltd.org/etd/birmingham/oai:etheses.bham.ac.uk:1126","repository":{"repo_id":"birmingham","name":"University of Birmingham","base_url":"https://etheses.bham.ac.uk/cgi/oai2"},"display":{"title":"Molecular genetic investigation of autosomal recessive neurodevelopmental disorders","abstract":"Development of the human brain occurs in a number of complex pre- and 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.","abstract_html":"Development of the human brain occurs in a number of complex pre- and 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.","abstract_has_math":false,"creators":["Kurian, Manju Ann"],"institution":"University of Birmingham","degree_name":"d_ph","degree_level":"d_ph","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-12","date_published":"2010-12","updated_at":"2026-07-24T01:11:23Z","subjects":["RJ Pediatrics"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.sponsor","label":"Sponsor","values":["na"]},{"key":"dc:creator","label":"Author","values":["Kurian, Manju Ann"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2010-12-01"]},{"key":"dc:date.issued","label":"Date","values":["2010-12"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["College of Medical & Dental Sciences","School of Clinical and Experimental Medicine"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Birmingham"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["http://etheses.bham.ac.uk//id/eprint/1126/"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["d_ph"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["d_ph"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["RJ Pediatrics"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://etheses.bham.ac.uk//id/eprint/1126/1/Decl_IS_Kurian_10_PhD.pdf","http://etheses.bham.ac.uk//id/eprint/1126/2/Kurian_10_PhD.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Development of the human brain occurs in a number of complex pre- and postnatal stages which are governed by both genetic and environmental factors. 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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."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Molecular genetic investigation of autosomal recessive neurodevelopmental disorders"]}]}],"canonical_facts":{"dc:contributor.sponsor":["na"],"dc:creator":["Kurian, Manju Ann"],"dc:date":["2010-12-01"],"dc:date.issued":["2010-12"],"dc:description.abstract":["Development of the human brain occurs in a number of complex pre- and 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."],"dc:format":["application/pdf"],"dc:identifier.uri":["http://etheses.bham.ac.uk//id/eprint/1126/1/Decl_IS_Kurian_10_PhD.pdf","http://etheses.bham.ac.uk//id/eprint/1126/2/Kurian_10_PhD.pdf"],"dc:publisher.department":["College of Medical & Dental Sciences","School of Clinical and Experimental Medicine"],"dc:publisher.institution":["University of Birmingham"],"dc:relation.isreferencedby":["http://etheses.bham.ac.uk//id/eprint/1126/"],"dc:subject":["RJ Pediatrics"],"dc:title":["Molecular genetic investigation of autosomal recessive neurodevelopmental disorders"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["d_ph"],"dc:type.qualificationname":["d_ph"]},"updated_at":"2026-07-24T01:11:23Z"}