Khan, N.L.; (2006) Familial parkinsonism [Parkinson's disease and early onset parkinsonism]: a genetic, clinical study and 18F-dopa pet study. Doctoral thesis , University of London.

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Abstract

This thesis reports a study of familial parkinsonism using diverse scientific tools of both molecular genetics and positron emission tomography functional imaging. Population-based allelic association studies are also described. Molecular and clinical characterisation of the largest British kindred with autosomal Parkinson's disease (PD). Genome wide linkage analysis was used to map the sub-chromosomal location of the disorder as the first step for disease-gene identification. The disease mapped to a 50cM region on the short arm of chromosome 12 overlapping a locus, PARK8 that had just been reported in a Japanese kindred, with an identical phenotype. A detailed clinical study of the British kindred identified unilateral onset of tremor in the leg, prominent foot dystonia and behavioural disorder. Intact cognition and sustained levodopa response, was observed despite lengthy disease duration. Phenotypic study of PARK2 / parkin disease This case series reports a detailed clinical assessment of twenty four cases of early onset parkinsonism with mutations in PARK2, emphasising the clinical features, atypical phenotypes including cervical dystonia, autonomic dysfunction, peripheral neuropathy, pure exercise-induced dystonia and behavioural disorder prior to the onset of parkinsonism. Olfaction was normal compared to a group of parkin negative patients and idiopathic PD cohorts. A number of unaffected relatives who were parkin heterozygotes had psychiatric symptoms and some had extrapyramidal signs that did not fulfil Queen Square Brain Bank criteria. 18F-dopa Positron Emission Tomography in Familial Parkinsonism. Functional imaging in cohorts of patients with parkin (PARK2) and PINK1 (PARK6) mutations identified patterns of nigrostriatal dysfunction that was bilateral and uniform unlike that seen in idiopathic PD. Serial 18F-dopa PET used to assess disease progression in parkin disease over a ten year period, showed that the rate of loss of dopaminergic function was slower compared to idiopathic PD. Asymptomatic parkin and PINK1 heterozygotes also had nigrostriatal dysfunction implying that the gene products exhibited 'haploinsufficiency'. Population based Allelic Association studies. A large study using pathologically proven PD cases and controls failed to replicate a report of positive association between an alpha synuclein polymorphism and PD. In a separate study the angiotensin converting enzyme gene was used as a candidate disease gene. Familial parkinsonism encompasses a heterogeneous group of diseases. Familial 'parkinsonism' was observed in early onset, recessive disease with atypical phenotypes, normal smell and patterns of nigrostriatal dysfunction and rate of progression of functional imaging unlike that seen in idiopathic PD. Functional imaging in asymptomatic heterozygotes suggested that parkin and PINK1 proteins exhibited the phenomenon of haploinsufficiency. Familial Parkinson's disease, however, with a typical phenotype and pattern of 18F-dopa uptake similar to PD was observed in an autosomal dominant British kindred. This thesis also confirmed locus heterogeneity in autosomal dominant Parkinson's disease and studied a putative susceptibility allele, ACE, in a population-based study.

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