‘That DAT’ gene that causes dystonia-parkinsonism: broadening the phenotype

Abstract

Dopamine transporter (DAT) deficiency, a recessive disorder due to mutations in the encoding SLC63 gene, was first described by Kurian et al. (2009, 2011). The typical phenotype originally reported was infantile dystonia-parkinsonism with a characteristic metabolic profile in the CSF, namely a raised homovanillic acid: 5-hydroxyindoleacetic acid (HVA:5-HIAA) ratio, usually in excess of 4.0. Presynaptic DAT, expressed by dopaminergic neurons, is responsible for reuptake of extracellular dopamine in a Na+/Cl−dependent manner (Torres et al., 2003). In this issue of Brain, Ng et al. (2014) describe a new cohort of patients with dopamine transporter deficiency syndrome (DTDS) and evaluate the functional consequences of SLC6A3 mutations using in vitro heterologous expression. The clinical significance of this paper is the new phenotypic associations. In addition to the classical presenation—infantile-onset progressive parkinsonism-dystonia—Ng et al. (2014) report cases who presented atypically, later in childhood and with a milder disease course. The new cohort consisted of eight cases with a median age at diagnosis of 13 years; one patient was diagnosed at 34 years. All eight patients had either homozygous or compound heterozygous missense or splice site mutations in the SLC63 gene. Three of eight cases, from one kindred, had juvenile onset progressive parkinsonism-dystonia. Notably, all three brothers had a normal birth history and neonatal course, and achieved normal early developmental milestones in infancy. At 10–11 years of age, they all developed a tremor affecting the head, with progression of symptoms in their 20 s. Another case, despite having infantile onset, survived into his fourth decade. Ng et al. (2014) also present evidence for dysfunction of the DAT gene in the new cases. In vitro studies of mutant transporter showed several defects in dopamine transporter function, including absent or reduced dopamine uptake, reduced DAT cell surface expression, and reduced affinity for dopamine. Loss of post-translational dopamine transporter glycosylation and failure of amphetamine-mediated dopamine efflux were also detected. The degree of dysfunction was greater for mutations causing infantile-onset than for those causing juvenile-onset disease. For example, the A314V mutation associated with atypical DTDS exhibited the highest residual dopamine uptake capacity compared with the mutations causing infantile DTDS. This report expands the phenotypic spectrum of DTDS, which includes presentation in infancy (early onset, rapidly-progressive disease), and in childhood/adolescence (later onset, slower disease progression). Genotype–phenotype analysis in this cohort, consistent with several other enzymatic recessive disorders, suggests that the higher residual dopamine transporter activity contributed to postponing disease presentation or slowing down progression in these late-onset cases. What is the significance of this report for clinicians, in particular paediatric neurologists and movement disorders specialists? DTDS is probably under-recognized. To date, apart from the original report (Kurian et al., 2009, 2011), there has been only one other study describing similar early-onset cases (Henriksen et al., 2012), and overall there are only a handful of cases in the literature. This study highlights the need to consider DTDS in the differential diagnosis for both infantile- and juvenile-onset movement disorders presenting with tremor and dystonia-parkinsonism. Some of these cases may be masquerading as cerebral palsy or other conditions that present with juvenile dystonia and parkinsonism (Schneider and Bhatia, 2010). Given that some of the patients with DTDS have oculogyric crises, other disorders in the dopamine synthesis pathway such as tyrosine hydroxylase deficiency and sepiapterin reductase deficiency enter into the differential diagnosis. Moreover, because tremor was common, juvenile parkinsonism needs to be kept in mind, particularly due to parkin gene mutations. However, in this regard, the DAT SPECT scan is normal in DTDS, whereas most cases of degenerative juvenile parkinsonism, including those arising from parkin gene mutations, will have an abnormal DAT scan. Hence the combination of the CSF analysis, showing a raised HVA/HIAA ratio, and a normal DAT scan, should be a clear pointer for DTDS, which of course can be confirmed on genetic testing. Finally, it is interesting to note that the cases described by Ng et al. (2014) are not only from an Asian background, but also include Italian and mixed European ancestry, and it is likely that these conditions are present in all countries. The message for clinicians is, when faced with a patient with infantile or adolescent dystonia-parkinsonsim, even if presenting in adulthood, don’t forget to consider ‘that DAT’ gene.