Pet studies of parkinsonism associated with mutation in the α-synuclein gene

Objective: To assess the pattern of dopaminergic abnormalities in a Greek-American kindred (family H) with autosomal dominantly inherited, levodopa-responsive parkinsonism caused by a mutation of the gene encoding α-synuclein. Background: Mutations of α-synuclein have been associated recently with dominantly inherited, levodopa-responsive parkinsonism. The pattern of dopamine deficiency and status of postsynaptic dopamine receptors in this condition have not been reported previously. The authors followed a large, six-generation family in whom the affected members carry the recently reported G209A mutation in the gene encoding α-synuclein. Methods: The authors studied four affected and two clinically unaffected gene-negative members of family H using [¹⁸F]-6-fluoro-L-dopa (FD) and [¹¹C]-raclopride (RAC) PET to assess presynaptic dopaminergic function and dopamine D2 receptors. The results were compared with normal subjects and patients with sporadic, idiopathic PD (IP). Results: In affected individuals, FD uptake was reduced in both the caudate and the putamen, but the putamen was affected more severely than the caudate, as seen in IP. RAC binding was within the normal range, but the ratio of RAC binding in the putamen to that in the caudate was increased in affected members of family H. This pattern is similar to that seen in IP. Conclusions: PET of the nigrostriatal system in parkinsonism associated with a mutation in the α-synuclein gene indicates that it results in a pattern of dopamine deficiency, with preserved D2 binding, indistinguishable from IP.