Clinical characteristics: SLC6A3-related dopamine transporter deficiency syndrome (DTDS) is a complex movement disorder with a continuum that ranges from classic early-onset DTDS (by age 6 months) to atypical later-onset DTDS (in childhood, adolescence, or adulthood).

Classic early-onset 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 later-onset DTDS: Normal psychomotor development in infancy and early childhood. Attention-deficit/hyperactivity disorder (ADHD) is reported in childhood followed by later-onset manifestations of parkinsonism-dystonia with tremor, progressive bradykinesia, variable tone, and dystonic posturing. The long-term prognosis of this form of DTDS is currently unknown.

Diagnosis/testing: The diagnosis of SLC6A3-related DTDS is established in a proband with characteristic clinical, laboratory, and imaging findings and either biallelic loss-of-function pathogenic variants in SLC6A3 or, rarely, a heterozygous dominant-negative pathogenic variant in SLC6A3 identified by molecular genetic testing.

Management: Treatment 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 the dopamine agonists 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. Movement disorders can be exacerbated by pain or discomfort, so diagnosis and treatment of all sources of pain and discomfort (e.g., dental caries, hip dislocation, scoliosis, pressure sores) is essential. Supportive management and developmental support includes: nutrition management and feeding support for oral feeding issues; alternative and augmentative communication devices when needed; medical management of tone issues and regular physical therapy to reduce the risk of contractures and fractures; focal botulinum toxin for contractures; standard treatments for pulmonary infections; influenza vaccine, prophylactic antibiotics, and chest physiotherapy to prevent pulmonary infections; chloral hydrate, melatonin, and other sedatives as needed for sleep issues; anti-serotoninergic agents for vomiting; standard treatments for gastroesophageal reflux, constipation, and ADHD.

Surveillance: Every six to 12 months: neurologic assessment; nutrition, swallowing, and speech-language assessment; physiotherapy evaluation for postural and tone issues; evaluation for hip dislocation and spinal deformity; physical and occupational therapy evaluation to assess mobility, activities of daily living, and need for adaptive devices; assessment of the frequency of respiratory infections and presence of sleep issues; assessment for vomiting, gastrointestinal reflux, and constipation; assessment for manifestations of ADHD. Annually: ophthalmology examination for eye movement disorders and refractive errors.

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 movement disorders. The antiemetics metoclopramide, prochlorperazine, and other medicines with anti-dopaminergic effects may exacerbate movement disorders.

Genetic counseling: In most individuals reported to date, SLC6A3-related DTDS is caused by biallelic loss-of-function pathogenic variants and inherited in an autosomal recessive manner. Autosomal dominant SLC6A3-related DTDS caused by a heterozygous dominant-negative SLC6A3 pathogenic variant has been reported in one individual to date.

Autosomal recessive inheritance: If both parents are known to be heterozygous for an SLC6A3 loss-of-function pathogenic variant, each sib of an affected individual has at conception 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. Carrier testing for at-risk relatives requires prior identification of the SLC6A3 pathogenic variants in the family.

Autosomal dominant inheritance: Each child of an individual with SLC6A3-related DTDS has a 50% chance of inheriting the dominant-negative SLC6A3 pathogenic variant.

Once the SLC6A3 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.