GeneReviews^® [Internet].

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 ofSLC6A3-related DTDS is established in aproband with characteristic clinical, laboratory, and imaging findings and eitherbiallelicloss-of-function pathogenic variants inSLC6A3 or, rarely, aheterozygousdominant-negativepathogenic variant inSLC6A3 identified bymolecular 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 bybiallelicloss-of-function pathogenic variants and inherited in anautosomal recessive manner. Autosomal dominantSLC6A3-related DTDS caused by aheterozygousdominant-negativeSLC6A3pathogenic variant has been reported in one individual to date.

Autosomal recessive inheritance: If both parents are known to beheterozygous for anSLC6A3loss-of-functionpathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomaticcarrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives requires prior identification of theSLC6A3 pathogenic variants in the family.

Autosomal dominant inheritance: Each child of an individual withSLC6A3-related DTDS has a 50% chance of inheriting thedominant-negativeSLC6A3pathogenic variant.

Once theSLC6A3pathogenic variant(s) have been identified in an affected family member, prenatal andpreimplantation genetic testing are possible.

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Suggestive Findings

Classic early-onset and atypical later-onsetSLC6A3-related dopamine transporter deficiency syndrome (DTDS)should be suspected in individuals with the following clinical and laboratory findings.

Establishing the Diagnosis

The diagnosis ofSLC6A3-related DTDSis established in aproband 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 bymolecular genetic testing (seeTable 1):

• Biallelicloss-of-function pathogenic (orlikely pathogenic) variants inSLC6A3

OR

• Aheterozygousdominant-negativeSLC6A3pathogenic variant known to causeautosomal dominant DTDS (e.g.,p.Lys619Asn)

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology 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 thisGeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) ofuncertain 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 ofgene-targeted testing (single gene testing,multigene panel) andcomprehensivegenomic testing (exome sequencing,genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (seeOption 1), whereas comprehensive genomic testing does not (seeOption 2).

Clinical Description

SLC6A3-related dopamine transporter deficiency syndrome (DTDS) typically presents in infancy and atypically later in childhood, adolescence, or adulthood. In early-onsetSLC6A3-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-onsetSLC6A3-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 whethergenotype-phenotype correlations exist forSLC6A3-related DTDS. From published functional data on pathogenicmissense 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].

Table 2.

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Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with aSLC6A3-related DTDS, the evaluations summarized inTable 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure forSLC6A3-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 (seeTable 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 inTable 5 are recommended.

Agents/Circumstances to Avoid

Although dopamine agonists are used as first-line treatment of dystonia inSLC6A3-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

SeeGenetic Counseling for issues related to testing of at-risk relatives forgenetic counseling purposes.

Therapies Under Investigation

SearchClinicalTrials.gov in the US andEU 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 bybiallelicloss-of-function pathogenic variants and inherited in anautosomal recessive manner. Autosomal dominantSLC6A3-related DTDS caused by aheterozygousdominant-negativeSLC6A3pathogenic variant has been reported in one individual to date.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of aproband

• The parents of a child withautosomal recessiveSLC6A3-related DTDS are presumed to beheterozygous for anSLC6A3loss-of-functionpathogenic variant.
• Molecular genetic testing is recommended for the parents of theproband to confirm that both parents areheterozygous for anSLC6A3pathogenic variant and to allow reliablerecurrence risk assessment.
• If apathogenic 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 theproband occurred as ade novo event in the proband or as apostzygoticde novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to havehomozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexondeletion in theproband that was not detected bysequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parentalchromosome with thepathogenic variant that resulted in homozygosity for the pathogenic variant in theproband.
• Individuals who areheterozygous for anSLC6A3loss-of-functionpathogenic variant are asymptomatic and are not at risk of developing the disorder.

Sibs of aproband

• If both parents are known to beheterozygous for anSLC6A3pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomaticcarrier, and a 25% chance of being unaffected and not a carrier.
• Individuals who areheterozygous for anSLC6A3loss-of-functionpathogenic variant are asymptomatic and are not at risk of developing the disorder.

Offspring of aproband

• To date, there are no reports of individuals withSLC6A3-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 hasSLC6A3-related DTDS or is acarrier, offspring will be obligate heterozygotes (carriers) for apathogenic variant inSLC6A3.

Other family members. Each sib of theproband's parents is at a 50% risk of being acarrier of anSLC6A3pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of theSLC6A3 pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of aproband

• In the one individual reported to dateautosomal dominantSLC6A3-related DTDS, theproband had the disorder as the result of a paternally inheriteddominant-negativeSLC6A3pathogenic variant (clinical data are not available for theheterozygous father) [Herborg et al 2021].
• If aproband withautosomal dominantSLC6A3-related DTDS appears to be the only affected family member (i.e., asimplex case),molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliablerecurrence risk counseling.
• If thepathogenic variant identified in theproband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • Theproband has ade novopathogenic variant.
  • Theproband inherited apathogenic variant from a parent withgermline (or somatic and germline)mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances ofsomatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

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

• If a parent of theproband is affected and/or is known to have thepathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If theSLC6A3pathogenic variant identified in theproband cannot be detected in the leukocyte DNA of either parent, therecurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parentalgermline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for theSLC6A3pathogenic variant but are clinically unaffected, sibs of aproband with clinically unaffected parents are still presumed to be at increased risk forSLC6A3-related DTDS because of the possibility of reducedpenetrance in aheterozygous parent or parentalgermline mosaicism.

Offspring of aproband. Each child of an individual withautosomal dominantSLC6A3-related DTDS has a 50% chance of inheriting theSLC6A3pathogenic variant.

Other family members. The risk to other family members depends on the status of theproband's parents: if a parent has theSLC6A3pathogenic 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 offergenetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, areheterozygous, or are at risk of being heterozygous.

Prenatal Testing and Preimplantation Genetic Testing

Once theSLC6A3pathogenic variant(s) have been identified in an affected family member, prenatal andpreimplantation genetic testing are possible.

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

Table A.

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Table B.

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Molecular Pathogenesis

To date, functional investigations indicate thatSLC6A3-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 ofnonsense variants,splice site changes, and deletions have been reported inSLC6A3-related DTDS, and it is likely that for these pathogenic variants nonsense-mediated decay or absent/truncated protein are mechanistic factors in disease. Reportedmissense 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-dystoniaphenotype in humans [Giros et al 1996]. Recent preclinical studies investigating targetedgene 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 tobiallelicSLC6A3 pathogenic variants. One individual withheterozygousSLC6A3pathogenic variantp.Lys619Asn presented with atypical later-onset DTDS; functional modeling of the variant demonstrateddominant-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 withSLC6A3-related dopamine transporter deficiency syndrome (DTDS). She would be happy to communicate with persons who have any questions regarding diagnosis ofSLC6A3-related DTDS or other considerations.

Contact Prof Kurian to inquire about review ofSLC6A3 variants ofuncertain significance.

Acknowledgments

The authors would like to thank and acknowledge the families and patients withSLC6A3-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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