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.

Suggestive Findings

Classic early-onset and atypical later-onset SLC6A3-related dopamine transporter deficiency syndrome (DTDS) should be suspected in individuals with the following clinical and laboratory findings.

Establishing the Diagnosis

The diagnosis of SLC6A3-related DTDS is established in a proband with characteristic clinical findings (especially parkinsonism-dystonia), CSF HVA:5-HIAA ratio >4.0, DaTSCAN showing reduced tracer uptake (supportive but not essential for diagnosis) [Kurian et al 2011b], and either of the following identified by molecular genetic testing (see Table 1):

• Biallelic loss-of-function pathogenic (or likely pathogenic) variants in SLC6A3

OR

• A heterozygous dominant-negative SLC6A3 pathogenic variant known to cause autosomal dominant DTDS (e.g., p.Lys619Asn)

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis. (3) Although the CSF HVA:5-HIAA ratio is almost universally elevated, an atypical presentation without elevated CSF HVA:5-HIAA ratio has been described.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

SLC6A3-related dopamine transporter deficiency syndrome (DTDS) typically presents in infancy and atypically later in childhood, adolescence, or adulthood. In early-onset SLC6A3-related DTDS, nonspecific findings of irritability, feeding difficulties, axial hypotonia, and/or delayed motor development are followed by onset of hyperkinetic movement disorder, abnormal eye movements, and childhood parkinsonism-dystonia. Later-onset SLC6A3-related DTDS is characterized by 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. SLC6A3-related DTDS is rare, with fewer than 60 affected individuals identified to date [Kurian et al 2009, Kurian et al 2011b, Hansen et al 2014, Ng et al 2014b, Yildiz et al 2017, Herborg et al 2021, Ng et al 2021, Ng et al 2023].

Genotype-Phenotype Correlations

It is not yet clear whether genotype-phenotype correlations exist for SLC6A3-related DTDS. From published functional data on pathogenic missense variants, children with classic early-onset DTDS have lower levels of residual transporter activity than those with the atypical later-onset DTDS [Hansen et al 2014, Ng et al 2014b].

Prevalence

While there are no current estimates on prevalence, SLC6A3-related DTDS is ultra-rare, with fewer than 60 affected individuals identified to date [Kurian et al 2009, Kurian et al 2011b, Hansen et al 2014, Ng et al 2014b, Yildiz et al 2017, Herborg et al 2021, Ng et al 2021, Ng et al 2023].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a SLC6A3-related DTDS, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for SLC6A3-related DTDS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4) [Ng et al 2014a, Kurian & Assmann 2015].

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Agents/Circumstances to Avoid

Although dopamine agonists are used as first-line treatment of dystonia in SLC6A3-related DTDS, bromocriptine and pergolide are generally avoided due to increased risk of pulmonary, retroperitoneal, and pericardial fibrosis.

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 and alternatives should be used (e.g., anti-serotonergic agents).

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

In most individuals reported to date, SLC6A3-related dopamine transporter deficiency syndrome (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 – Risk to Family Members

Parents of a proband

• The parents of a child with autosomal recessive SLC6A3-related DTDS are presumed to be heterozygous for an SLC6A3 loss-of-function pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an SLC6A3 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygous for an SLC6A3 loss-of-function pathogenic variant are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an SLC6A3 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.
• Individuals who are heterozygous for an SLC6A3 loss-of-function pathogenic variant are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• To date, there are no reports of individuals with SLC6A3-related classic early-onset DTDS having children, but this may be a theoretic possibility for those with atypical later-onset DTDS.
• Unless an affected individual's reproductive partner also has SLC6A3-related DTDS or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in SLC6A3.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC6A3 pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the SLC6A3 pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• In the one individual reported to date autosomal dominant SLC6A3-related DTDS, the proband had the disorder as the result of a paternally inherited dominant-negative SLC6A3 pathogenic variant (clinical data are not available for the heterozygous father) [Herborg et al 2021].
• If a proband with autosomal dominant SLC6A3-related DTDS appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the SLC6A3 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the SLC6A3 pathogenic variant but are clinically unaffected, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SLC6A3-related DTDS because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant SLC6A3-related DTDS has a 50% chance of inheriting the SLC6A3 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the SLC6A3 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

To date, functional investigations indicate that SLC6A3-related dopamine transporter deficiency syndrome (DTDS) results from loss of transporter function [Kurian et al 2009, Kurian et al 2011b, Hansen et al 2014, Ng et al 2014b, Ng et al 2021]. SLC6A3 encodes the dopamine transporter (DAT) that is expressed predominantly within the substantia nigra (projecting to the striatum) and in the midbrain ventral tegmental area (projecting to the hippocampus, nucleus accumbens, and corticolimbic areas). DAT has a crucial role in mediating reuptake of dopamine from the synaptic cleft, thereby controlling dopamine homeostasis by regulating the duration and amplitude of synaptic dopaminergic transmission.

A number of nonsense variants, splice site changes, and deletions have been reported in SLC6A3-related DTDS, and it is likely that for these pathogenic variants nonsense-mediated decay or absent/truncated protein are mechanistic factors in disease. Reported missense substitutions result in mutated proteins that impair DAT through a number of mechanisms including (1) reduced transporter activity, (2) impaired dopamine recognition and/or binding affinity, (3) decreased cell surface expression or accelerated turnover of the transporter, and (4) abnormal post-translational protein modification with impaired glycosylation [Kurian et al 2009, Kurian et al 2011b, Hansen et al 2014, Ng et al 2014b, Herborg et al 2021, Ng et al 2021]. Abnormal DAT protein folding and transporter oligomerization are also postulated to play a role.

SLC6A3 pathogenic variants therefore impair the normal physiologic recycling of dopamine leading to presynaptic dopamine depletion. Excess dopamine in the synaptic cleft is metabolized to homovanillic acid (HVA), which can be detected on cerebrospinal fluid (CSF) analysis. High levels of synaptic dopamine may have downstream signaling effects on postsynaptic dopamine receptors and are also likely to suppress tyrosine hydroxylase activity through action on D2 autoreceptors, thereby inhibiting presynaptic dopamine synthesis [Blackstone 2009].

A DAT knockout mouse model shows several features described in humans, including reduced growth, early hyperkinesia, and difficulties with feeding. Over time, the mice develop abnormal clasping and kyphosis with progressive bradykinesia, reminiscent of the parkinsonism-dystonia phenotype in humans [Giros et al 1996]. Recent preclinical studies investigating targeted gene therapy delivered to the midbrain of knockout mice has shown rescue of the motor phenotype [Ng et al 2021].

Mechanism of disease causation. In most individuals the mechanism is loss of transporter function due to biallelic SLC6A3 pathogenic variants. One individual with heterozygous SLC6A3 pathogenic variant p.Lys619Asn presented with atypical later-onset DTDS; functional modeling of the variant demonstrated dominant-negative reduction in transporter function [Herborg et al 2021].

Author Notes

Dr Robert Spaull
Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, UK
Web page: iris.ucl.ac.uk/iris/browse/profile?upi=RSPAU38

Professor Manju Kurian
Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, UK
Web page: iris.ucl.ac.uk/iris/browse/profile?upi=MKURI59

Prof Kurian (ku.ca.lcu@nairuk.ujnam) is actively involved in clinical research regarding individuals with SLC6A3-related dopamine transporter deficiency syndrome (DTDS). She would be happy to communicate with persons who have any questions regarding diagnosis of SLC6A3-related DTDS or other considerations.

Contact Prof Kurian to inquire about review of SLC6A3 variants of uncertain significance.

Acknowledgments

The authors would like to thank and acknowledge the families and patients with SLC6A3-related DTDS. Robert Spaull is funded by an award from Great Ormond Street Hospital Children's Charity and LifeArc. Manju Kurian is funded by an NIHR Professorship, The Sir Jules Thorn Biomedical Award for Research, and Rosetrees Trust.

Revision History

• 28 September 2023 (sw) Comprehensive update posted live
• 27 July 2017 (bp) Review posted live
• 30 June 2015 (mak) Original submission

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