DOPAMINE TRANSPORTER DENSITY MEASURED BY [I-123] BETA-CIT SINGLE-PHOTON EMISSION COMPUTED-TOMOGRAPHY IS NORMAL IN DOPA-RESPONSIVE DYSTONIA

The clinical distinction between dopa-responsive dystonia (DRD) and ju venile Parkinson's disease (JPD) can pose a diagnostic challenge. Both conditions are dopa responsive. However, long-term L-dopa benefit is very different between the two. The difference in the prognosis is due to presence or absence of nigral cell loss. In JPD, there is degenera tive nigral cell loss, whereas there are enzymatic defects in dopamine synthesis without cell loss in DRD. Mutations have been found in the GTP cyclohydrolase I (GCH-I) and tyrosine hydroxylase genes in DRD. As the discovered mutations are multiple and more are expected to be fou nd, it is difficult to confirm or exclude DRD by mutation studies. Mea surement of cerebrospinal fluid (CSF) neopterin will detect DRD from m utations in the GCH-I gene but not from mutations in tyrosine hydroxyl ase. The dopamine transporter (DAT) is a protein in the dopaminergic n erve terminals. (1R)-2 beta-Carbomethoxy-3 beta-(4-[I-123]iodophenyl)t ropane ([I-123]beta-CIT) is a ligand for the DAT, and it was shown to be a useful nuclear imaging marker for neurons that degenerate in Park inson's disease (PD). As DRD was shown to have a normal DAT without ni gral cell loss in a postmortem study, we predicted that the DAT measur ed in vivo by nuclear imaging will be normal in DRD and will different iate DRD from JPD. Therefore, we performed [I-123]beta-CIT single-phot on emission computed tomography ([I-123]beta-CIT SPECT) in clinically diagnosed DRD, PD, and JPD, and examined whether DAT imaging can diffe rentiate DRD fi om PD and JPD. We then examined whether DAT imaging ca n provide a screening tool for molecular genetic studies, by studying mutations in the candidate gene GCH-I and measuring CSF neopterin. Fiv e females (4 from two families, and 1 sporadic) were diagnosed as DRD based on early-onset foot dystonia and progressive parkinsonism beginn ing at ages 7 to 12. All patients were functioning normally on L-dopa 100 to 250 mg/day for up to 8 years. SPECT imaging was obtained after intravenous injection of [I-123]beta-CIT; 15 healthy volunteers served as normal control, and 6 PD and 1 JPD as disease controls. [I-123]bet a-CIT striatal binding was normal in DRD, whereas it was markedly decr eased in PD and JPD. Gene analysis showed a novel nonsense mutation in the GCH-I gene in one family. No mutation was found in the other fami ly or in the sporadic case. CSF neopterin was markedly decreased in th e 4 tested patients. [I-123] P-CIT SPECT is a sensitive method for pro bing the integrity of nigrostriatal dopaminergic nerve terminals. A no rmal striatal DAT in a parkinsonian patient is evidence for a nondegen erative cause of parkinsonism and differentiates DRD from JPD. Finding a new mutation in one family and failure to demonstrate mutations in the putative gene in other cases supports the usefulness of DAT imagin g in diagnosing DRD.