SLC6A3-Related Dopamine Transporter Deficiency Syndrome

Clinical characteristicsSLC6A3-related dopamine transporter deficiency syndrome (DTDS) is a complex movement disorder with a continuum that ranges from classic early-onset DTDS (in the first 6 months) to atypical later-onset DTDS (in childhood, adolescence, or adulthood). Classic DTDS. Infants typically manifest nonspecific findings (irritability, feeding difficulties, axial hypotonia, and/or delayed motor development) followed by a hyperkinetic movement disorder (with features of chorea, dystonia, ballismus, orolingual dyskinesia). Over time, affected individuals develop parkinsonism-dystonia characterized by bradykinesia (progressing to akinesia), dystonic posturing, distal tremor, rigidity, and reduced facial expression. Limitation of voluntary movements leads to severe motor delay. Episodic status dystonicus, exacerbations of dystonia, and secondary orthopedic, gastrointestinal, and respiratory complications are common. Many affected individuals appear to show relative preservation of intellect with good cognitive development. Atypical DTDS. Normal psychomotor development in infancy and early childhood is followed by later-onset manifestations of parkinsonism-dystonia with tremor, progressive bradykinesia, variable tone, and dystonic posturing. The long-term outcome of this form is currently unknown.Diagnosis/testingThe diagnosis of SLC6A3-related DTDS is established in a proband with characteristic clinical, laboratory, and imaging findings and biallelic pathogenic variants in SLC6A3 identified by molecular genetic testing.ManagementTreatment of manifestations: Treatment to control chorea and dyskinesia in early stages of the disease includes tetrabenazine and benzodiazepines. Dystonia is more difficult to control and treatment often includes pramipexole and ropinirole as first-line agents; adjuncts such as trihexyphenidyl, baclofen, gabapentin, and clonidine for severe dystonia; and chloral hydrate and benzodiazepines for exacerbations of dystonia or status dystonicus. Prevention of secondary complications: Regular physiotherapy to reduce the risk of contractures; early referral for management of feeding difficulties; use of influenza vaccine, prophylactic antibiotics, and chest physiotherapy for patients prone to chest infections, especially in the winter months. Surveillance: Evaluation every six to 12 months for early evidence of hip dislocation and/or spinal deformity; regular assessment of swallowing to evaluate risk for aspiration; regular nutrition assessment to ensure adequate caloric intake. Agents/circumstances to avoid: Although the dopamine agonists bromocriptine and pergolide could be considered, the associated increased risk of pulmonary, retroperitoneal, and pericardial fibrosis makes them less desirable than the newer dopamine agonists. Drugs with anti-dopaminergic side effects (e.g., some antihistamines, sedatives, and dimenhydrinate) may exacerbate the movement disorder. For the treatment of vomiting, anti-emetics such as the anti-serotoninergic agents (e.g., ondansetron) potentially have fewer side effects than other agents.Genetic counselingSLC6A3-related DTDS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SLC6A3 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.