Homozygous in‐frame variant of SCL6A3 causes dopamine transporter deficiency syndrome in a consanguineous family

2020 ◽  
Vol 84 (4) ◽  
pp. 315-323 ◽  
Author(s):  
Erfan Heidari ◽  
Ehsan Razmara ◽  
Sareh Hosseinpour ◽  
Ali Reza Tavasoli ◽  
Masoud Garshasbi
Keyword(s):  
Dopamine Transporter ◽  
Deficiency Syndrome ◽  
Consanguineous Family ◽  
Transporter Deficiency

scholarly journals Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism

2021 ◽  
Vol 13 (594) ◽  
pp. eaaw1564
Author(s):  
Joanne Ng ◽  
Serena Barral ◽  
Carmen De La Fuente Barrigon ◽  
Gabriele Lignani ◽  
Fatma A. Erdem ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Dopamine Transporter ◽  
Premature Death ◽  
Deficiency Syndrome ◽  
Loss Of Function ◽  
Knockout Mouse Model ◽  
Partial Restoration ◽  
Transporter Deficiency ◽  
Induced Pluripotent ◽  
Motor Phenotype

Most inherited neurodegenerative disorders are incurable, and often only palliative treatment is available. Precision medicine has great potential to address this unmet clinical need. We explored this paradigm in dopamine transporter deficiency syndrome (DTDS), caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter (DAT). Patients present with early infantile hyperkinesia, severe progressive childhood parkinsonism, and raised cerebrospinal fluid dopamine metabolites. The absence of effective treatments and relentless disease course frequently leads to death in childhood. Using patient-derived induced pluripotent stem cells (iPSCs), we generated a midbrain dopaminergic (mDA) neuron model of DTDS that exhibited marked impairment of DAT activity, apoptotic neurodegeneration associated with TNFα-mediated inflammation, and dopamine toxicity. Partial restoration of DAT activity by the pharmacochaperone pifithrin-μ was mutation-specific. In contrast, lentiviral gene transfer of wild-type human SLC6A3 complementary DNA restored DAT activity and prevented neurodegeneration in all patient-derived mDA lines. To progress toward clinical translation, we used the knockout mouse model of DTDS that recapitulates human disease, exhibiting parkinsonism features, including tremor, bradykinesia, and premature death. Neonatal intracerebroventricular injection of human SLC6A3 using an adeno-associated virus (AAV) vector provided neuronal expression of human DAT, which ameliorated motor phenotype, life span, and neuronal survival in the substantia nigra and striatum, although off-target neurotoxic effects were seen at higher dosage. These were avoided with stereotactic delivery of AAV2.SLC6A3 gene therapy targeted to the midbrain of adult knockout mice, which rescued both motor phenotype and neurodegeneration, suggesting that targeted AAV gene therapy might be effective for patients with DTDS.

Hereditary Dopamine Transporter Deficiency Syndrome: Challenges in Diagnosis and Treatment

2016 ◽  
Vol 48 (01) ◽  
pp. 049-052 ◽  
Author(s):  
Emine Pektas ◽  
Aysegul Tokatli ◽  
Goknur Haliloglu ◽  
Yilmaz Yildiz
Keyword(s):  
Dopamine Transporter ◽  
Deficiency Syndrome ◽  
Diagnosis And Treatment ◽  
Transporter Deficiency

scholarly journals Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood

Brain ◽  
2014 ◽  
Vol 137 (4) ◽  
pp. 1107-1119 ◽  
Author(s):  
Joanne Ng ◽  
Juan Zhen ◽  
Esther Meyer ◽  
Kevin Erreger ◽  
Yan Li ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
Deficiency Syndrome ◽  
Phenotypic Spectrum ◽  
Transporter Deficiency

Early-onset Dopamine Transporter Deficiency Syndrome: Long-term Follow-up

2020 ◽  
pp. 1-2
Author(s):  
Margherita Baga ◽  
Carlotta Spagnoli ◽  
Luca Soliani ◽  
Grazia Gabriella Salerno ◽  
Susanna Rizzi ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
Early Onset ◽  
Deficiency Syndrome ◽  
Long Term Follow Up ◽  
Transporter Deficiency

scholarly journals Dopamine Transporter Deficiency Syndrome: A Case with Hyper‐ and Hypokinetic Extremes

2020 ◽  
Vol 7 (S3) ◽  
Author(s):  
Mohammad M. Nasehi ◽  
Ali Nikkhah ◽  
Mehri Salari ◽  
Pegah Soltani ◽  
Saeed Shirzadi
Keyword(s):  
Dopamine Transporter ◽  
Deficiency Syndrome ◽  
Transporter Deficiency
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