Expansion of the genotypic and phenotypic spectrum of hereditary Dopamine transporter deficiency syndrome.

Background: Dopamine transporter deficiency syndrome (DTDS) is a hereditary disorder characterised by dystonia-parkinsonism, raised CSF HVA:HIAA ratio and mutations in SLC6A3, the gene encoding the dopamine transporter (DAT). We describe the clinical, genetic and functional features of newly identified DTDS cases. Methods: Patients presenting with a biochemical profile suggestive of DTDS underwent detailed clinical phenotyping and SLC6A3 mutation analysis. Mutant constructs of human DAT (hDAT) were used for in-vitro functional analysis of dopamine uptake and cocaine–analogue binding. Results: We report five patients presenting in early infancy (2-9 months) with a progressive movement disorder characterised by hyperkinesia, chorea, dystonia and hypokinetic-rigid features. One patient is still alive at 35 years with features of classical parkinsonism. Patients had markedly raised CSF HVA: 5 HIAA ratios ranging from 6.8 to 31.9 (normal 1.0-3.7). Mutations in SLC6A3 were identified in all cases, including novel missense and splice site mutations. In vitro functional investigation of mutant hDAT showed that studied mutations resulted in loss of DAT function. Conclusion: DTDS is a newly described clinical disorder. Our new case cohort of further DTDS patients expands the clinical phenotype and range of mutations identified in DTDS, thereby increasing the clinical and molecular understanding of this disorder.