Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 1419 2023-07-06 11:40:15 |
2 only format change Meta information modification 1419 2023-07-07 04:39:31 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Ng, J.; Barral, S.; Waddington, S.N.; Kurian, M.A. Clinical Spectrum of Dopamine Transporter Deficiency Syndrome. Encyclopedia. Available online: https://encyclopedia.pub/entry/46511 (accessed on 22 June 2024).
Ng J, Barral S, Waddington SN, Kurian MA. Clinical Spectrum of Dopamine Transporter Deficiency Syndrome. Encyclopedia. Available at: https://encyclopedia.pub/entry/46511. Accessed June 22, 2024.
Ng, Joanne, Serena Barral, Simon N. Waddington, Manju A. Kurian. "Clinical Spectrum of Dopamine Transporter Deficiency Syndrome" Encyclopedia, https://encyclopedia.pub/entry/46511 (accessed June 22, 2024).
Ng, J., Barral, S., Waddington, S.N., & Kurian, M.A. (2023, July 06). Clinical Spectrum of Dopamine Transporter Deficiency Syndrome. In Encyclopedia. https://encyclopedia.pub/entry/46511
Ng, Joanne, et al. "Clinical Spectrum of Dopamine Transporter Deficiency Syndrome." Encyclopedia. Web. 06 July, 2023.
Clinical Spectrum of Dopamine Transporter Deficiency Syndrome
Edit

The clinical spectrum of dopamine-related conditions is broad, encompassing movement disorders and neuropsychiatric diseases such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), addiction, and bipolar disorder. Dopamine transporter deficiency syndrome (DTDS) is a primary neurotransmitter disorder due to defective dopamine reuptake. Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is an ultrarare childhood movement disorder caused by biallelic loss-of-function mutations in the SLC6A3 gene.

dopamine transporter deficiency syndrome spectrum

1. Introduction

The clinical spectrum of dopamine-related conditions is broad, encompassing movement disorders and neuropsychiatric diseases such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), addiction, and bipolar disorder [1]. The dopaminergic system is involved in controlling the initiation of motion, reinforcement, and motivation, as well as contributing to emotion and cognitive functions (learning, attention, and memory) [1].
Within clinical neurology, symptoms indicative of dopamine dysregulation include bradykinesia, tremor, hypomimia and dystonia, neuropsychiatric features (apathy, anxiety, and impulse control disorders), and cognitive impairment, as observed in Parkinson’s disease [2]. Parkinsonism may also present in infancy, often in combination with dystonia; in contrast to adult patients, many affected children are found to have an underlying genetic aetiology, leading either to dopaminergic neurodegeneration or the impairment of dopamine synthesis, breakdown, or transport [3]. Several primary dopamine synthesis disorders are also reported, including tyrosine hydroxylase deficiency, aromatic L-amino acid dopa-decarboxylase (AADC) deficiency, pterin defects (GTPCH, SR, and PTPS), vesicular monoamine transporter (VMAT2) deficiency, and DNAJC12 deficiency. These primary neurotransmitter disorders are associated with low cerebrospinal fluid dopamine metabolites [4]. Childhood disorders of dopaminergic deficiency may result from striatonigral neurodegeneration, as is evident in DNAJC6-related disease—one of many juvenile-onset forms of genetic parkinsonism—as well as numerous metabolic disorders, including the mitochondriocytopathies [5][6].
Dopamine transporter deficiency syndrome (DTDS) is a primary neurotransmitter disorder due to defective dopamine reuptake. Prior to gene discovery, the initial clinical description from 2004 reported three children presenting with infantile parkinsonism-dystonia and, paradoxically, raised cerebrospinal fluid (CSF) homovanillic acid (HVA) [7]. In 2009, with the identification of new patients—two cousins from consanguineous kindred and a separate singleton from another consanguineous family—further genetic analysis was possible. Through autozygosity mapping, the genetic interrogation of regions of homozygosity identified homozygous missense variants in SLC6A3, which encodes the dopamine transporter (DAT), in these two kindreds [8][9]. Since 2009, fifty-one patients have been identified worldwide with DTDS, with confirmed disease-causing biallelic variants in SLC6A3, which encodes DAT (Kurian personal communication).
DAT regulates dopamine homeostasis by transporting extracellular DA into the intracellular space that controls the synaptic levels of DA in the mesolimbic and nigrostriatal pathways [2]. In vitro modelling of DTDS-related SLC6A3 variants revealed impaired dopamine transporter function due to reduced transporter activity, with impaired dopamine binding, reduced cell-surface expression, and aberrant posttranslational modification with impaired glycosylation [8]. The effects of failed dopamine reuptake result in persistent synaptic dopamine and raised HVA, with subsequent intraneuronal dopamine reduction and downregulation of TH activity through aberrant feedback to presynaptic D2 receptors, as observed in the DAT knockout mouse model [10]. DAT is the principal regulator of synaptic DA transmission, and genetic variants in SLC6A3 alter expression, membrane localisation, hDAT density, dopamine reuptake activity, and dopamine neurotransmission dynamics, contributing to a pathophysiological spectrum from infantile to adult-onset parkinsonism-dystonia, termed DTDS. In addition, SLC6A3 variants are associated with neuropsychiatric diagnoses, including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and bipolar disorder [11][12][13][14].

2. Clinical Spectrum of DTDS

DTDS is a primary neurotransmitter disorder that presents with infantile parkinsonism-dystonia due to biallelic loss-of-function mutations in the SLC6A3 gene (OMIM # 613135). The detailed clinical characterisation of eleven children with DTDS established the classical features and progression of DTDS over time. Since 2011, there have been thirty-one DTDS patients reported in the literature [8][9][15][16][17][18][19][20][21][22][23][24], and a further unpublished twenty patients reported to the centre (Kurian personal communication).

2.1. Classical Early Onset DTDS

The classical DTDS phenotype typically manifests during early infancy with irritability, feeding difficulties, hypotonia, and delayed motor development [8][9][15][25]. A hyperkinetic movement disorder develops with features of chorea, dystonia, ballismus, and orolingual dyskinesia [8][9][15][25]. Over time, the condition evolves to parkinsonism-dystonia with the development of dystonic posturing, bradykinesia, distal tremor, rigidity, and hypomimia. The movement disorder progresses to akinesia in late childhood/early adolescence [8][9][15][25]. Some children also experience episodic status dystonicus and eye movement disorders with oculogyric crisis, ocular flutter, eyelid myoclonus, and saccade initiation failure [8][9][15][25]. Although the children present with a severe movement disorder with motor and speech delays, many individuals are reported to have relative preservation of intellect and good cognitive development [9][25]. Cognition in children with severe motor impairment, as seen in DTDS, is difficult to assess, but children with DTDS are thought to remain relatively cognitively intact, showing good working memory, communication with eye-gaze devices, accurate recognition of familiar information, and empathy and social awareness [9]. Secondary orthopaedic complications such as scoliosis and joint contractures are also described. Reported classical early onset DTDS individuals have a distinct CSF neurotransmitter analysis profile, with raised HVA (a stable metabolite of dopamine) and normal hydroxyindoleacetic acid levels (5-HIAA, a stable metabolite of serotonin). The HVA:HIAA ratio is raised at 5.0–13.0 (normal range: 1.0–4.0) [8][9][15]. MRI brain imaging can be normal or show subtle nonspecific abnormalities, such as mild delayed myelination, white matter abnormalities (such as periventricular leukomalacia), and prominence of external frontotemporal spaces. Single-photon emission computerised tomography (SPECT) with 123Ioflupane (DaTScan) imaging shows either absent or significantly reduced tracer uptake in the basal nuclei [9].
With over a decade of experience in treating early onset DTDS patients, it is evident that there is limited response to standard pharmacotherapies [9][15]. Palliative treatment endeavours to control symptoms; this includes the use of tetrabenazine and benzodiazepines to treat chorea and dyskinesia early in the disease, and dopamine agonists such as pramipexole and ropinirole [9][15][25]. There is limited or no response to levodopa treatment. Gabapentin has been useful in easing stiffness and reducing hyperkinesia in some cases (Kurian personal communication). Focal treatment with botulinum toxin injections for dystonia and orthopaedic intervention for severe contractures have been tried in some patients [9][15][25]. Episodes of status dystonicus can be life-threatening, with associated rhabdomyolysis requiring emergency intensive care management. Neurosurgical interventions such as deep brain stimulation and intrathecal baclofen have been used in older patients, with limited therapeutic benefit [9]. The associated bulbar dysfunction and feeding difficulties contribute to poor weight gain, and most patients require gastrostomy feeding. Affected patients are at significant risk of respiratory problems, such as chest infections and aspiration pneumonia; eight children have died from cardiorespiratory complications. Although the long-term outcome of DTDS remains to be fully characterised, it is clearly associated with a significant risk of morbidity and premature mortality, with a mean age of death of 10.4 years old (range: 3–16.2) [9][15] Kurian personal communication). The oldest surviving early onset DTDS patients are now in their fourth decade of life [11][21].

2.2. Atypical Later-Onset DTDS

Since the first description of early onset classical DTDS, there has been an expansion of the clinical phenotype, with the identification of patients with a milder, more slowly progressive condition associated with biallelic missense variants in SLC6A3. Such patients with later-onset atypical DTDS usually have a history of normal early neurodevelopment in infancy and early childhood (achieving independent ambulation and spoken language), presenting later in the second decade of life with tremor, progressive bradykinesia, dystonic posturing, and variable tone [15]. The first reported atypical DTDS kindred identified three brothers who presented at 10–11 years old with head tremor. The brothers were diagnosed at 16, 26, and 28 years old, respectively, with the older brothers developing progressive symptoms in their 20s with tremor affecting the head, arms, cervical dystonia and hypomimia, and speech deterioration [15]. All three individuals harboured homozygous missense variant Ala314Val, that on in vitro analysis retained 8% dopamine uptake activity, relatively higher than missense variants identified in classical infantile onset DTDS [15]. Another adult with atypical later-onset DTDS was reported; he initially presented with childhood failure to thrive as well as learning and behavioural problems in school. He presented with insidious right-sided tremor at 28 years old, which progressed to severe coarse tremor in all limbs and the trunk, with rigidity and bradykinesia, and was diagnosed with early onset PD at 35 years of age [16]. Molecular genetic investigation identified compound heterozygous missense variants Ile312Phe and Asp421Asn [16]. In vitro modelling of these variants showed both DAT variants exhibited markedly reduced dopamine uptake capacity (33% of the wildtype transporter) but preserved membrane targeting, consistent with impaired catalytic activity [16]. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission [16]. The long-term outcome of these individuals with atypical later-onset DTDS parkinsonism-dystonia is currently unknown.

References

  1. Iversen, S.D.; Iversen, L.L. Dopamine: 50 years in perspective. Trends Neurosci. 2007, 30, 188–193.
  2. Stoker, T.B.; Barker, R.A. Recent developments in treatments in Parkinson’s Disease. F1000Research 2020, 9, F1000, Faculty Rev-862.
  3. Brennenstuhl, H.; Jung-Klawitter, S.; Assmann, B.; Opladen, T. Inherited Disorders of Neurotransmitters: Classification and Practical Approaches for Diagnosis and Treatment. Neuropediatrics 2019, 50, 2–14.
  4. Ng, J.; Papandreou, A.; Heales, S.J.; Kurian, M.A. Monoamine neurotransmitter disorders—Clinical advances and future perspectives. Nat. Rev. Neurol. 2015, 11, 567–584.
  5. Ng, J.; Cortès-Saladelafont, E.; Abela, L.; Termsarasab, P.; Mankad, K.; Sudhakar, S.; Gorman, K.M.; Heales, S.J.R.; Pope, S.; Biassoni, L.; et al. DNAJC6 Mutations Disrupt Dopamine Homeostasis in Juvenile Parkinsonism-Dystonia. Mov. Disord. 2020, 35, 1357–1368.
  6. Niemann, N.; Jankovic, J. Juvenile Parkinsonism: Differential diagnosis, genetics and treatment. Park. Relat. Disord. 2019, 67, 74–89.
  7. Assmann, B.E.; Robinson, R.O.; Surtees, R.A.; Bräutigam, C.; Heales, S.J.; Wevers, R.A.; Zschocke, J.; Hyland, K.; Sharma, R.; Hoffmann, G.F. Infantile Parkinsonism-dystonia and elevated dopamine metabolites in CSF. Neurology 2004, 62, 1872–1874.
  8. Kurian, M.A.; Zhen, J.; Cheng, S.Y.; Li, Y.; Mordekar, S.R.; Jardine, P.; Morgan, N.V.; Meyer, E.; Tee, L.; Pasha, S.; et al. Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia. J. Clin. Investig. 2009, 119, 1595–1603.
  9. Kurian, M.A.; Li, Y.; Zhen, J.; Meyer, E.; Hai, N.; Christen, H.J.; Hoffmann, G.F.; Jardine, P.; von Moers, A.; Mordekar, S.R.; et al. Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: An observational cohort and experimental study. Lancet Neurol. 2011, 10, 54–62.
  10. Jones, S.R.; Gainetdinov, R.; Jaber, M.; Giros, B.; Wrightman, R.M.; Caron, M.G. Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc. Natl. Acad. Sci. USA 1998, 95, 4029–4034.
  11. Hamilton, P.J.; Campbell, N.G.; Sharma, S.; Erreger, K.; Herborg, H.F.; Saunders, C.; Belovich, A.N.; Daly, M.J.; Gibbs, R.A.; Boerwinkle, E.; et al. De Novo Mutation in the Dopamine Transporter gene associates dopamine dysfunction with Autism Spectrum Disorder. Mol. Psychiatry 2013, 18, 1315–1323.
  12. Campbell, N.G.; Shekar, A.; Aguilar, J.I.; Peng, D.; Navratna, V.; Yang, D.; Morley, A.N.; Duran, A.M.; Galli, G.; O’Grady, B.; et al. Structural, Functional, and Behavioral insights of Dopamine dysfunction revealed by a deletion in SLC6A3. Proc. Natl. Acad. Sci. USA 2019, 116, 3853–3862.
  13. Sakrikar, D.; Mazei-Robison, M.S.; Mergy, M.A.; Richtand, N.W.; Han, Q.; Hamilton, P.J.; Bowton, E.; Galli, A.; VeenstraVanderWeele, J.; Gill, M.; et al. Attention Deficit/Hyperactivity Disorder-Derived Coding Variation in the Dopamine Transporter disrupts microdomain targeting and trafficking Regulation. J. Neurosci. 2012, 32, 5385–5397.
  14. Reith, M.E.A.; Kortagere, S.; Wiers, C.E.; Sun, H.; Kurian, M.A.; Galli, A.; Volkow, N.D.; Lin, Z.C. The dopamine transporters gene SLC6A3: Multidisease risks. Mol. Psychiatry 2022, 27, 1031–1046.
  15. Ng, J.; Zhen, J.; Meyer, E.; Erreger, K.; Li, Y.; Kakar, N.; Ahmad, J.; Thiele, H.; Kubisch, C.; Rider, N.L.; et al. Dopamine transporter deficiency syndrome: Phenotypic spectrum from infancy to adulthood. Brain 2014, 137, 1107–1119.
  16. Hansen, F.H.; SkjØrringe, T.; Yasmeen, S.; Arends, N.V.; Sahai, M.A.; Erreger, K.; Andreassen, T.F.; Holy, M.; Hamilton, P.J.; Neergheen, V.; et al. Missense dopamine transporter mutations associate with adult parkinsonism and ADHD. J. Clin. Investig. 2014, 124, 3107–3120.
  17. Yildiz, Y.; Pektas, E.; Tokatli, E.; Haliloglu, G. Hereditary dopamine transporter deficiency syndrome: Challenges in diagnosis and treatment. Neuropediatrics 2017, 48, 49–52.
  18. Schiff, M.; Cano, A.; Amsallem, D.; Barnerias, C.; Chaumette, B.; Plaze, M.; Slama, A.; Ioos, C.; Desguerre, I.; Lebre, A.S.; et al. Diagnostic approach to neurotransmitter monoamine disorders: Experience from clinical, biochemical, and genetic profiles. J. Inherit. Metab. Dis. 2018, 41, 129–139.
  19. Galiart, A.; Weber, P.; Datta, A.N. Infantile dystonia parkinsonism caused by mutations in SLC6A3: Case report of three siblings. Neuropediatrics 2017, 48, S1–S45.
  20. Heidari, E.; Razmara, E.; Hosseinpour, S.; Tavasoli, A.R.; Garshasbi, M. Homozygous in-frame variant of SCL6A3 causes dopamine transporter deficiency syndrome in a consanguineous family. Ann. Hum. Genet. 2020, 84, 315–323.
  21. Baga, M.; Spagnioli, C.; Soliano, L.; Salerno, G.G.; Rizzi, S.; Frattini, D.; Pisani, F.; Fusco, C. Early-onset dopamine transporter deficiency syndrome: Long-term follow-up. Can. J. Neurol. Sci. 2021, 48, 285–286.
  22. Nasehi, M.M.; Nikkah, A.; Salari, M.; Soltani, P.; Shirzadi, S. Dopamine transporter deficiency syndrome: A case with hyper- and hypokinetic extremes. Mov. Disord. Clin. Pract. 2020, 7, S57–S60.
  23. Tehreem, B.; Kornitzer, J. Expanding the phenotypic spectrum of dopamine transporter deficiency syndrome with a novel mutation. Neurology 2020, 94 (Suppl. 15).
  24. Davletshina, R.; Kopishinskaia, S.; Vorontsova, E. The first case of a child with a dopamine transporter deficiency associated with SLC6A3 in Russia. Eur. J. Neurol. 2021, 28 (Suppl. 1), 907.
  25. Kurian, M.A. SLC6A3-Related Dopamine Transporter Deficiency Syndrome; GeneReviews® ; University of Washington: Seattle, WA, USA, 2017. Available online: https://www.ncbi.nlm.nih.gov/books/ (accessed on 20 February 2023).
More
Information
Subjects: Neurosciences
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , , ,
View Times: 293
Revisions: 2 times (View History)
Update Date: 07 Jul 2023
1000/1000
Video Production Service