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Published on: September 21, 2017
Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational
Manju A Kurian1, Yan Li, Juan Zhen
1Department of Medical and Molecular Genetics, University of Birmingham School of Medicine, Institute of Biomedical Research, and Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Birmingham, UK. manju_dave@hotmail.com
Insights
Dopamine transporter deficiency syndrome, caused by SLC6A3 gene mutations, leads to early-onset parkinsonism in children. This genetic disorder impairs dopamine transporter function, highlighting the role of dopamine in neurological disease.
Area of Science:
- Neuroscience
- Genetics
- Pediatric Neurology
Background:
- Dopamine transporter deficiency syndrome (DTDS) is the first identified genetic parkinsonian disorder.
- It results from genetic alterations in the dopamine transporter (DAT), encoded by the SLC6A3 gene.
- Understanding DTDS is crucial for diagnosing and managing pediatric movement disorders.
Purpose of the Study:
- To improve the clinical and molecular characterization of children with DTDS.
- To reduce diagnostic delays and misdiagnoses in affected children.
- To gain insights into the pathophysiological mechanisms of DTDS.
Main Methods:
- A cohort of 11 children with suspected DTDS was studied across multiple pediatric neurology centers.
- Methods included detailed clinical phenotyping, biochemical and neuroradiological assessments, and SLC6A3 mutation analysis.
- In-vitro functional studies of mutant dopamine transporter constructs were performed.
Main Results:
- Children presented in infancy with hyperkinesia, parkinsonism, or mixed movement disorders, often initially misdiagnosed.
- Severe parkinsonism-dystonia, eye movement abnormalities, and pyramidal tract signs developed during childhood.
- All patients had elevated homovanillic acid to 5-hydroxyindoleacetic acid ratios in cerebrospinal fluid and SLC6A3 mutations, with loss of DAT function confirmed in vitro and via DaTSCAN imaging.
Conclusions:
- DTDS is a newly recognized autosomal recessive disorder caused by impaired dopamine transporter function.
- Characterizing DTDS offers insights into dopamine homeostasis and its role in human neurological diseases.
- Understanding DTDS pathophysiology may guide future drug development for related disorders.
Background:
dopamine transporter deficiency syndrome is the first identified parkinsonian disorder caused by genetic alterations of the dopamine transporter. We describe a cohort of children with mutations in the gene encoding the dopamine transporter (SLC6A3) with the aim to improve clinical and molecular characterisation, reduce diagnostic delay and misdiagnosis, and provide insights into the pathophysiological mechanisms.
Methods:
11 children with a biochemical profile suggestive of dopamine transporter deficiency syndrome were enrolled from seven paediatric neurology centres in the UK, Germany, and the USA from February, 2009, and studied until June, 2010. The syndrome was characterised by detailed clinical phenotyping, biochemical and neuroradiological studies, and SLC6A3 mutation analysis. Mutant constructs of human dopamine transporter were used for in-vitro functional analysis of dopamine uptake and cocaine-analogue binding.
Findings:
children presented in infancy (median age 2·5 months, range 0·5-7) with either hyperkinesia (n=5), parkinsonism (n=4), or a mixed hyperkinetic and hypokinetic movement disorder (n=2). Seven children had been initially misdiagnosed with cerebral palsy. During childhood, patients developed severe parkinsonism-dystonia associated with an eye movement disorder and pyramidal tract features. All children had raised ratios of homovanillic acid to 5-hydroxyindoleacetic acid in cerebrospinal fluid, of range 5·0-13·2 (normal range 1·3-4·0). Homozygous or compound heterozygous SLC6A3 mutations were detected in all cases. Loss of function in all missense variants was recorded from in-vitro functional studies, and was supported by the findings of single photon emission CT DaTSCAN imaging in one patient, which showed complete loss of dopamine transporter activity in the basal nuclei.
Interpretation:
dopamine transporter deficiency syndrome is a newly recognised, autosomal recessive disorder related to impaired dopamine transporter function. Careful characterisation of patients with this disorder should provide novel insights into the complex role of dopamine homoeostasis in human disease, and understanding of the pathophysiology could help to drive drug development.
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