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SLC6A3-Related Dopamine Transporter Deficiency Syndrome

Synonym: DAT Deficiency

, MA, MBBChir, PhD.

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Initial Posting: .

Estimated reading time: 17 minutes

Summary

Clinical characteristics.

SLC6A3-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/testing.

The 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.

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 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 counseling.

SLC6A3-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 testing or preimplantation genetic diagnosis for pregnancies at increased risk are options that can be considered.

GeneReview Scope

SLC6A3-Related Dopamine Transporter Deficiency Syndrome: Included Phenotypes
  • Classic early-onset dopamine transporter deficiency syndrome (DTDS)
  • Atypical later-onset DTDS

Diagnosis

SLC6A3-related dopamine transporter deficiency syndrome (DTDS) is a complex movement disorder in which the disease continuum comprises two phenotypes with overlapping clinical features:

  • Classic early-onset DTDS
  • Atypical later-onset DTDS

Suggestive Findings

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

Clinical Findings

Classic early-onset DTDS

  • Predominant features in infancy
    • Onset usually within the first six months of life
    • Early nonspecific clinical findings of irritability and difficulty feeding
    • Axial hypotonia
    • Delay in motor milestones
    • Hyperkinetic movement disorder (chorea, ballismus, dystonia, orolingual dyskinesia) typically evident in infancy and early childhood; may persist into late childhood and adolescence
    • Eye movement disorders including recurrent oculogyric crisis, saccade initiation failure, ocular flutter, and eyelid myoclonus (which is thought to be nonepileptic)
  • Predominant features in childhood/adolescence
    • Parkinsonism-dystonia including dystonic postures, resting and action tremor, difficulty initiating movements, bradykinesia, paucity of facial expression, and rigidity
    • Severe delay in motor milestones
    • Eye movement disorder (see classic early-onset DTDS)

Atypical later-onset DTDS: Predominant features

  • Onset from childhood to adulthood (4th decade)
  • Attention-deficit/hyperactivity disorder (ADHD)
  • Resting and action tremor
  • Dysarthria
  • Parkinsonism-dystonia

Laboratory Findings

CSF neurotransmitter analysis. To date, all individuals with classic early-onset SLC6A3-related DTDS have a distinct pattern:

  • Raised homovanillic acid level (HVA, metabolite derived from dopamine) with normal 5-hydroxyindoleacetic acid level (5-HIAA, metabolite derived from serotonin). The HVA:5-HIAA ratio in SLC6A3-related DTDS is >4.0 (range 5.0-13.0) (normal range 1.0-4.0)
  • Normal pterin profile

SPECT imaging using the ligand ioflupane (DaTScan). To date, all individuals with SLC6A3-related DTDS who were evaluated had very abnormal results with absent/reduced tracer uptake in the basal nuclei.

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 [Kurian et al 2011b], and biallelic pathogenic variants in SLC6A3 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and genomic testing (comprehensive genomic sequencing) depending on the phenotype.

Gene-targeted testing requires the clinician to broadly determine clinical phenotype and the gene(s) likely to be involved, whereas genomic testing does not. Children with the distinctive early-onset findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1) but may also be identified by genomic testing. Individuals with later-onset disease in which the phenotype may show overlap with other inherited neurologic disorders (ADHD, tremor, dysarthria, and/or parkinsonism-dystonia) may be identified through gene-targeted panels but may also be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of SLC6A3-related DTDS, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of SLC6A3 is performed first. Gene-targeted deletion/duplication analysis should be considered if only one or no pathogenic variant is found. To date, the majority of variants are intragenic single-nucleotide variants, insertions, or deletions detectable by Sanger sequencing. Two larger deletions that were detectable by deletion/duplication analysis have been identified [Kurian et al 2011b; Kurian, personal communication 2016].
  • A multigene panel that includes SLC6A3 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by ADHD, tremor, dysarthria, and/or parkinsonism-dystonia, molecular genetic testing approaches can include (when clinically available) comprehensive genomic testing, which includes exome sequencing and genome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in SLC6A3-Related Dopamine Transporter Deficiency Syndrome

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
SLC6A3Sequence analysis 3Most SLC6A3 pathogenic variants reported to date
Gene-targeted deletion/duplication analysis 4See footnote 5
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

Two individuals with deletions detectable by deletion/duplication analysis have been reported (see Molecular Pathogenesis, Pathogenic variants).

Clinical Characteristics

Clinical Description

SLC6A3-related dopamine transporter deficiency syndrome (DTDS) typically presents in infancy and atypically later in childhood, adolescence, or adulthood [Hansen et al 2014, Ng et al 2014a, Kurian & Assmann 2015]. SLC6A3-related DTDS is rare, with fewer than 30 affected individuals (from ~21 families) identified to date [Kurian et al 2009, Kurian et al 2011b, Hansen et al 2014, Ng et al 2014a, Yildiz et al 2017].

Classic Early-Onset DTDS

Typically, infants present between birth and age six months [Kurian et al 2009, Kurian et al 2011b]. In the early stages, children manifest the nonspecific findings of irritability, feeding difficulties, axial hypotonia, and delayed motor development. In infancy a heterogeneous movement disorder is prominent, with features of chorea, dystonia, dystonia-parkinsonism, ballismus, and orolingual dyskinesia. Many infants also develop an eye movement disorder, which may manifest as recurrent oculogyric crises, saccade initiation failure, ocular flutter, or eyelid myoclonus. At this early age hyperkinetic features predominate.

The early hyperkinesia often becomes less prominent over time, with subsequent development of parkinsonism-dystonia. Bradykinesia progressing to akinesia is common, as well as dystonic posturing, distal tremor, rigidity, and hypomimia (reduced facial expression). Voluntary movements become limited, leading to severe motor delay.

During the first years of life some children have episodic status dystonicus. Prolonged periods of crying and irritability – without discernable triggers – are also described. Disrupted sleep patterns are common. Exacerbations of dystonia are also common, often related to intercurrent illness, infection, and/or dehydration.

Although more data are needed, it appears that many affected individuals show relative preservation of intellect with good cognitive development.

Secondary orthopedic, gastrointestinal, and respiratory complications are common [Kurian & Assmann 2015].

  • Many develop spinal deformities, often necessitating surgery. Fixed limb contractures, osteoporotic bone fractures, and hip dislocation are also described.
  • Alternative feeding strategies using nasogastric tubes or percutaneous endoscopic gastrostomy become necessary due to progressive bulbar dysfunction.
  • Reduced axial tone, spinal abnormalities, and bulbar dysfunction compromise respiratory function, leading to an increased risk for recurrent chest infections and aspiration pneumonia.
  • The majority develop anarthria, and need alternative and augmentative communication devices for effective communication.

A number of children with infantile-onset SLC6A3-related DTDS die in late childhood / early adolescence from unexplained sudden death in sleep or respiratory complications.

Atypical Later-Onset DTDS

To date, four individuals with atypical later-onset DTDS have been described. They had normal psychomotor development in infancy and early childhood, attaining independent ambulation and spoken language [Hansen et al 2014, Ng et al 2014a]. Later in childhood, adolescence, or adulthood, they developed manifestations of parkinsonism-dystonia with tremor, progressive bradykinesia, variable tone, and dystonic posturing.

Manifestations of ADHD in childhood have been reported.

Identification of additional individuals with later-onset DTDS will aid understanding of this atypical presentation.

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, severe early-onset disease have lower levels of residual transporter activity than those with the later-onset atypical phenotype [Hansen et al 2014, Ng et al 2014a].

Penetrance

SLC6A3-related DTDS shows complete penetrance with no discernible gender differences.

Prevalence

SLC6A3-related DTDS is rare, with fewer than 30 affected individuals (from ~21 families) currently identified [Kurian et al 2009, Kurian et al 2011b, Hansen et al 2014, Ng et al 2014a, Yildiz et al 2017].

Affected individuals have been reported from a wide variety of ethnic backgrounds.

Differential Diagnosis

The following groups of disorders can present clinically with the manifestations of classic early-onset and atypical later-onset SLC6A3-related DTDS.

Cerebral palsy. The early hyperkinetic features of classic early-onset SLC6A3-related DTDS can mimic dyskinetic cerebral palsy and later features may be reminiscent of spastic/dystonic cerebral palsy. Details of the pre- and perinatal history and MRI, as well as the diagnostic testing specific for SLC6A3-related DTDS, may be helpful in differentiating these conditions.

Neurotransmitter disorders. The clinical features of progressive parkinsonism-dystonia, eye movement disorder, axial hypotonia, and delayed motor development may be similar to those seen in other neurotransmitter disorders [Kurian et al 2011a, Ng et al 2015], including autosomal recessive pterin defects (e.g., sepiapterin reductase deficiency and autosomal recessive GTP cyclohydrolase deficiency [OMIM 233910]), tyrosine hydroxylase deficiency, aromatic L-amino acid decarboxylase deficiency (OMIM 107930), and brain serotonin-dopamine deficiency caused by mutation of SLC18A2.

Mitochondrial diseases. The phenotypic features of the mitochondriocytopathies (including those caused by pathogenic variants in POLG, pyruvate dehydrogenase deficiency (OMIM 312170), and pyruvate carboxylase deficiency) overlap with SLC6A3-related DTDS [Garcia-Cazorla et al 2008]. In some mitochondrial disorders increased HVA levels are also observed [Pineda et al 2006, Hasselmann et al 2010].

Metabolic syndromes including lysosomal storage diseases, Niemann-Pick disease type C, GM1 gangliosidosis, Lesch-Nyhan syndrome, homocystinuria, and untreated phenylketonuria can mimic SLC6A3-related DTDS [Garcia-Cazorla & Duarte 2014].

Monogenic movement disorders associated with infantile-onset dyskinesia/hyperkinesia. Early disease manifestations of classic early-onset DTDS may be reminiscent of ADCY5-related dyskinesia, glucose transporter type 1 deficiency syndrome, PRRT2-related paroxysmal kinesigenic dyskinesia with infantile convulsions (see PRRT2-Associated Paroxysmal Movement Disorders), FOXG1-related syndrome (OMIM 613454), SYT1-related disorder (OMIM 185605), ATP1A3-related neurologic disorders, and GNAO1-related diseases (OMIM 615473).

Monogenic juvenile parkinsonism syndromes due to mutation of the following genes [Garcia-Cazorla & Duarte 2014] may mimic classic early-onset and atypical later-onset DTDS:

Disorders of brain metal accumulation. Wilson disease, neurodegeneration with brain iron accumulation (NBIA), and dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease may mimic SLC6A3-related DTDS. Brain MRI can assist in the diagnosis of these disorders [Tuschl et al 2012, Bandmann et al 2015]; see also Neurodegeneration with Brain Iron Accumulation.

Other. Meningoencephalitis; autoimmune, hypoxia, drug-induced, post-infectious, and monogenic causes of striatal necrosis; tumors; and Rett syndrome should be considered as well [Garcia-Cazorla & Duarte 2014].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a SLC6A3-related dopamine transporter deficiency syndrome (DTDS), the following evaluations are recommended:

  • Neurologic assessment of the movement disorder
  • Ophthalmology assessment of vision and eye movements
  • Evaluation of caloric intake and feeding by a nutritionist
  • Speech and language therapy assessment of communication and swallowing
  • Physiotherapy evaluation of postural issues and tone
  • Occupational therapy to provide suitable aids for communication, mobility, and home adaptations
  • Hip and spine x-rays to evaluate for hip dislocation and spinal deformity
  • Orthopedic review of any fixed contractures / joint dislocations
  • Pediatric physician-led care for evaluation of general issues such as drooling, gastroesophageal reflux disease, constipation, disturbed sleeping, and pressure sores
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

A multidisciplinary approach to the long-term management of this progressive disorder is optimal [Ng et al 2014b, Kurian & Assmann 2015].

As first principle, risk factors that exacerbate the movement disorder should be avoided, including patient discomfort, poor body positioning, and pain (e.g., from constipation, urinary retention, pressure sores, undetected fractures). Early referral for nasogastric feeding or percutaneous gastrostomy is appropriate if oral feeding becomes problematic.

Treatment for the palliative control of symptoms includes the following [Ng et al 2014b, Kurian & Assmann 2015]:

  • Tetrabenazine and benzodiazepines may be useful in controlling chorea and dyskinesia in early stages of the disease. Chloral hydrate may also help during exacerbations or to aid sleep.
  • Dystonia is more difficult to control and treatment often includes pramipexole and ropinirole as first-line agents (as few patients respond to levodopa/carbidopa and any response is usually modest and not sustained).
    Adjuncts, such as the anticholinergic trihexyphenidyl, are often needed. Baclofen, gabapentin, and clonidine may also be tried for severe dystonia.
    Benzodiazepines and chloral hydrate can be useful for exacerbations of dystonia or status dystonicus. Although the role of atypical tranquilizers (e.g., zopiclone) is not yet established, they have been used successfully in individual cases.
  • Surgical interventions such as intrathecal baclofen and deep brain stimulation have been used on rare occasions late in the disease course when dystonia is severe; therapeutic benefit is limited [Kurian et al 2009].
  • Optimum management of tone with medical therapies and regular physiotherapy evaluation reduce risk of contracture development. Focal botulinum toxin may be considered for emerging limb contractures and to prevent hip dislocation.
  • For the treatment of vomiting, anti-emetics such as the anti-serotoninergic agents (e.g., ondansetron) potentially have fewer side effects than other agents.

Treatment of status dystonicus. Standard protocols are used in an intensive care setting. Anesthetic agents, GABA-ergic medication (including GABA-A receptor agonists such as benzodiazepines, GABA-enhancing medications such as gabapentin or phenobarbitone, and GABA-B receptor agonists like baclofen), further anticholinergics, and alpha adrenergic agents such as clonidine may be used. For severe life-threatening or medically intractable status dystonicus, intrathecal baclofen and pallidal deep brain stimulation may be considered.

Prevention of Secondary Complications

Consider influenza vaccine, prophylactic antibiotics, and chest physiotherapy for patients prone to chest infections especially during winter months.

Surveillance

The following are appropriate:

  • Evaluation every six to 12 months for early evidence of hip dislocation and/or spinal deformity
  • Regular swallowing assessment to evaluate risk for aspiration
  • Regular assessment by a dietitian/nutritionist to ensure adequate caloric intake

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 the movement disorder.

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

SLC6A3-related dopamine transporter deficiency syndrome (DTDS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are usually obligate heterozygotes (i.e., carriers of one SLC6A3 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • 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.
  • Heterozygotes (carriers) 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 DTDS having children, but this may be a theoretic possibility for those with the atypical form of disease.
  • The offspring of an individual with SLC6A3-related DTDS would be obligate heterozygotes (carriers) for a pathogenic variant (based on the assumption that the offspring's partner is not a carrier).

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 (Heterozygote) Detection

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

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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 carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SLC6A3 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for SLC6A3-related DTDS are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for SLC6A3-Related Dopamine Transporter Deficiency Syndrome have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

SLC6A3-Related Dopamine Transported Deficiency Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
SLC6A35p15​.33Sodium-dependent dopamine transporterSLC6A3 @ LOVDSLC6A3SLC6A3

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for SLC6A3-Related Dopamine Transported Deficiency Syndrome (View All in OMIM)

126455SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, DOPAMINE), MEMBER 3; SLC6A3
613135PARKINSONISM-DYSTONIA, INFANTILE, 1; PKDYS1

Molecular Pathogenesis

To date, functional investigations indicate that SLC6A3-related DTDS results from loss of transporter function [Kurian et al 2009, Kurian et al 2011b, Hansen et al 2014, Ng et al 2014a]. 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). The transporter 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 transporter function through a number of mechanisms including (i) reduced transporter activity, (ii) impaired dopamine recognition and/or binding affinity, (iii) decreased cell surface expression of the transporter, and (iv) abnormal posttranslational protein modification with impaired glycosylation [Kurian et al 2009, Kurian et al 2011b, Hansen et al 2014, Ng et al 2014a]. 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 HVA, which can be detected on 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 a number of features described in humans, including reduced growth, early hyperkinesia, and difficulties with feeding. Over time they develop abnormal clasping and kyphosis with progressive bradykinesia, reminiscent of the parkinsonism-dystonia phenotype in humans [Giros et al 1996].

Gene structure. The protein-coding transcript NM_001044.4 (ENST00000270349) comprises 15 exons in total, 14 of which are coding.

Pathogenic variants. To date, 20 individuals have been identified with biallelic (i.e., homozygous or compound heterozygous) pathogenic variants in SLC6A3.

Pathogenic variants have been identified throughout the entire coding region and flanking splice sites. No mutation hot spots or recurrent/common pathogenic variants have been identified. In these 20 individuals, 41 pathogenic variants including 27 missense changes, one pathogenic nonsense variant, seven splice site variants, and four intra-exon small deletions have been described. Large deletions have been described: a homozygous multiexon deletion [Kurian et al 2011b] and a microdeletion/translocation encompassing SLC6A3 [Kurian, personal communication 2016].

Note that rare missense variants in SLC6A3 have been reported in individuals with bipolar disorder, attention-deficit/hyperactivity disorder, and autism spectrum disorder [Hayden & Nurnberger 2006, Hamilton et al 2013, Bowton et al 2014] leading to the proposal that – through currently unknown mechanisms – this gene may confer risk for multiple complex psychiatric disorders [Bowton et al 2014]. However, parents of individuals with DTDS have not manifested attention-deficit disorder or psychiatric diseases.

Normal gene product. The gene transcript encodes a protein of 620 amino acids (NP_001035.1). The dopamine transporter (DAT) is one of the solute carrier 6 (SLC6) transporters [Bröer & Gether 2012]. Based on the crystal structure of a prokaryotic homolog [Singh et al 2007], DAT comprises 12 transmembrane helices connected by a series of interconnecting extracellular and intracellular loops from the N- to C-terminus. The protein undergoes posttranslational modification prior to being expressed at the cell surface of the presynaptic membrane. Its role in the translocation of dopamine requires tandem transport of sodium and chloride ions across the cell membrane.

Abnormal gene product. Pathogenic variants in the gene are postulated to lead to loss of transporter function and a number of pathogenic variants reported in the literature are pathogenic nonsense variants, splice site variants, or deletions.

Functional studies indicate that for pathogenic missense variants, mutated DAT displays impaired transporter function through a number of mechanisms including (i) reduced transporter activity, (ii) impaired dopamine recognition and binding affinity, (iii) decreased cell surface expression of the transporter, and (iv) abnormal posttranslational protein modification with impaired glycosylation [Kurian et al 2009, Kurian et al 2011b, Hansen et al 2014, Ng et al 2014a].

References

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Chapter Notes

Author Notes

Dr Manju Kurian
Developmental Neurosciences, UCL Institute of Child Health, London
Web: iris.ucl.ac.uk/iris/browse/profile?upi=MKURI59

Acknowledgments

The author would like to thank and acknowledge the families and patients with DTDS. MAK is funded by a Wellcome Trust Intermediate Clinical Fellowship and receives funding from Rosetrees Trust.

Revision History

  • 27 July 2017 (bp) Review posted live
  • 30 June 2015 (mak) Original submission
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