Dopamine transporter defect: Infantile parkinsonism-dystonia with elevated dopamine metabolites in cerebrospinal fluid is genetically resolved

Aim of the study: To describe the clinical features and underlying etiology of a group of patients with a unique complex movement disorder.

Methods: The clinical features (including video footage) and results of CSF investigation of 10 patients (from 9 distinct unrelated kindreds) were reviewed. Autozygosity mapping studies were undertaken in order to identify the disease-causing gene.

Results: The movement disorder is heterogeneous, especially in infancy. However, some features are almost universally present, such as intense and frequent dystonic crises during the first years of life, development of severe swallowing difficulties and anarthria. The movement disorder in infancy is characterised by both hyperkinetic and hypokinetic features, however severe hypokinesia/akinesia and rigidity predominate later in childhood. Over time some children develop ocular flutter and saccade initiation failure. Whereas the motor disorder is progressive (4 patients died at ages 9, 13, 14 and 16 years respectively) cognitive function is relatively spared. Numerous treatment strategies have shown limited therapeutic response. Magnetic resonance imaging studies (including in-vivo spectroscopy in one patient) did not reveal abnormalities in most patients although periventricular white matter changes were evident in 3 patients. Investigations of cerebrospinal fluid (CSF) revealed paradoxically elevated concentrations of dopamine metabolites (ratios of dopamine metabolite homovanillic acid (HVA) [nmol/l]/serotonine metabolite 5-Hydroxy-inddole acetic acid (HIAA) [nmol/l] between 5 an 13, normal ratios between 1.5 and 4). Molecular genetic investigation identified the gene encoding the pre-synaptic dopamine transporter (DAT), SLC6A3 as the causative gene and germline mutations were identified in all 10 patients. DAT scan (undertaken in one patient) showed almost complete loss of basal nuclei DAT activity.

Conclusions: Genetic DAT deficiency is identified as a new cause of a complex extrapyramidal movement disorder evolving into severe parkinsonism-dystonia with paradoxically elevated dopamine metabolites in CSF.