Dopamine Transporter Deficiency Syndrome (DTDS): Expanding the Clinical Phenotype and Precision Medicine Approaches

• Published in: Cells (Basel, Switzerland) Vol. 12; no. 13; p. 1737
• Main Authors: Ng, Joanne, Barral, Serena, Waddington, Simon N, Kurian, Manju A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.06.2023; MDPI
• Subjects: Amino acid sequence; Attention deficit hyperactivity disorder; Autism; Basal ganglia; Bipolar disorder; Care and treatment; Cell surface; Central nervous system diseases; Cerebrospinal fluid; Children; Communication; DAT; Diagnosis; Dopamine; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine transporter; dopamine transporter deficiency syndrome; Drug therapy; Dyskinesia; Dystonia; Gene therapy; Genomic analysis; Genotype & phenotype; Glycosylation; infantile parkinsonism-dystonia; Mental disorders; Methods; Movement disorders; Neurodegeneration; Neurological diseases; neurotransmitter; Orthopedics; Ostomy; Parkinson's disease; Phenotype; Phenotypes; Precision Medicine; Protein transport; Review; SLC6A3; Tremor (Muscular contraction); United Kingdom; DAT; iPSC; gene therapy; infantile parkinsonism-dystonia; neurotransmitter; SLC6A3; dopamine transporter deficiency syndrome
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12131737

Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is an ultrarare childhood movement disorder caused by biallelic loss-of-function mutations in the gene. Advances in genomic analysis have revealed an evolving spectrum of -related neurological and neuropsychiatric disorders. Since the initial clinical and genetic characterisation of DTDS in 2009, there have been thirty-one published cases with a variety of protein-truncating variants (nonsense variants, splice-site changes, and deletions) and missense changes. Amino acid substitutions result in mutant proteins with impaired dopamine transporter function due to reduced transporter activity, impaired dopamine binding, reduced cell-surface expression, and aberrant posttranslational protein modification with impaired glycosylation. In this review, we provide an overview of the expanding clinical phenotype of DTDS and the precision therapies in development, including pharmacochaperones and gene therapy.