Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study.
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.


RESULTS
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.


CONCLUSIONS
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.
Department 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
Manju A
MA
Kurian
Yan
Y
Li
Juan
J
Zhen
Esther
E
Meyer
Nebula
N
Hai
Hans-Jürgen
HJ
Christen
Georg F
GF
Hoffmann
Philip
P
Jardine
Arpad
A
von Moers
Santosh R
SR
Mordekar
Finbar
F
O'Callaghan
Evangeline
E
Wassmer
Elizabeth
E
Wraige
Christa
C
Dietrich
Timothy
T
Lewis
Keith
K
Hyland
Simon
S
Heales
Terence
T
Sanger
Paul
P
Gissen
Birgit E
BE
Assmann
Maarten E A
ME
Reith
Eamonn R
ER
Maher
D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D002461:Cell Line, Transformed; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics*; D004421:Dystonia / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D015835:Ocular Motility Disorders / Q000235:genetics / Q000503:physiopathology; D020734:Parkinsonian Disorders / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D012189:Retrospective Studies; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D014162:Transfection / Q000379:methods
D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; D006897:Hydroxyindoleacetic Acid; D006719:Homovanillic Acid