Autosomal Recessive DOPA-Responsive Dystonia via the TH Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
7845 TH 81406 81406,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7845TH81406 81406, 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

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Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Autosomal recessive Dopa-responsive dystonia (AR-DRD) is a rare progressive neurometabolic disorder. It is heterogeneous in regard to the age of onset, clinical features, progression rate, and response to levodopa therapy. Clinical features include limb dystonia, hypokinesia, bradykinesia, truncal hypotonia, tremor, myoclonus, rigidity of extremities, walking difficulties, oculogyric crises, inexpressive faces, ptosis, autonomic disturbances, lethargy-irritability crises, sleep disturbances, and psychomotor developmental delay. AR-DRD is usually more severe and more complex than autosomal dominant DRD. Two forms of the disease can be distinguished.

1. TH-deficient dopa-responsive dystonia is characterized by onset in infancy, usually during the first year of life, and diurnal fluctuation. Symptoms are mild in the mornings and exacerbate during the day. Patients with TH-deficient dopa-responsive dystonia are successfully treated with low-doses of L-DOPA in combination with a decarboxylase inhibitor. Patients are usually able to conduct a normal life (Schiller et al. 2004).

2. Infantile Parkinsonism is characterized by an earlier onset, usually during the first six months of life, and more rapid progression. Additional distinguishing symptoms include complicated perinatal history, seizures and developmental motor delay. Response to L-DOPA therapy is less effective and was absent in about one third of treated patients (Willemsen et al. 2010; Sun et al. 2014).

In addition to these two phenotypes, various intermediary phenotypes with overlapping features have been described (Hoffmann et al. 2003; Furukawa et al. 2004).

Autosomal recessive DRD is less common than the dominant form of DRD. About 50 families have been reported worldwide (Verbeek et al. 2007; Clot et al. 2009; Willemsen et al. 2010).

Genetics

Autosomal recessive DRD is genetically heterozygous. Two genes have been implicated in the disease: TH and SPR (Lüdecke et al. 1995; Bonafe et al. 2001).

To date, about 60 different pathogenic variants in the TH gene have been reported. Most variants are missense. However, several truncating variants, including splice site variants and small frameshift deletions were also reported. Large pathogenic deletions appear to be rare. Only one such deletion has been reported (Ormazabal et al. 2011). Several variants in the promoter region have been documented to be pathogenic (Ribasés et al. 2007; Verbeek et al. 2007). Although heterozygous carriers are usually asymptomatic, exercise-induced stiffness has been reported in heterozygous family members (Furukawa et al. 2001).

Pathogenic variants in the TH gene have been reported in patients with AR-DRD from various geographic and ethnic origins (Verbeek et al. 2007; Willemsen et al. 2010; Al-Muslamani et al. 2014).

The TH gene encodes the tyrosine hydroxylase enzyme, a rate-limiting enzyme in the biosynthesis of catecholamines, including dopamine. It is expressed mainly in the brain and adrenal medulla.

Pathogenic variants in the TH gene have been documented to result in reduced levels of the tyrosine hydroxylase enzyme, which lead to low levels of cerebral L-DOPA (Lüdecke et al. 1995).

Testing Strategy

This test provides full coverage of all coding exons of the TH gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Clinical Sensitivity - Sequencing with CNV PG-Select

This test will detect pathogenic variants in the TH gene in about 5% of patients with a clinical diagnosis of dystonia and marked and sustained response to levodopa treatment (Clot et al. 2009).

To date, only one large pathogenic deletion was reported in one patient (Ormazabal et al. 2011).

Indications for Test

Patients with infantile and childhood onset dystonia with a positive response to L-DOPA and no pathogenic variants in the GCH1 gene are candidates for this test.

Patients with atypical dystonia phenotypes and no pathogenic variants in the remaining genes associated with dystonia are also candidates (Sun et al. 2014).

This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in TH.

Gene

Official Gene Symbol OMIM ID
TH 191290
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Tyrosine Hydroxylase Deficiency AR 605407

Citations

  • Al-Muslamani A.M. et al. 2014. Sultan Qaboos University Medical Journal. 14: e397-400. PubMed ID: 25097778
  • Bonafé L. et al. 2001. American Journal of Human Genetics. 69: 269-77. PubMed ID: 11443547
  • Clot F. et al. 2009. Brain. 132: 1753-63. PubMed ID: 19491146
  • Furukawa Y. et al. 2001. Neurology. 56: 260-3. PubMed ID: 11160968
  • Furukawa Y. et al. 2004. Annals of Neurology. 55: 147-8. PubMed ID: 14705130
  • Hoffmann G.F. et al. 2003. Annals of Neurology. 54 Suppl 6: S56-65. PubMed ID: 12891655
  • Lüdecke B. et al. 1995. Human Genetics. 95: 123-5. PubMed ID: 7814018
  • Ormazabal A. et al. 2011. Movement Disorders. 26: 1558-60. PubMed ID: 21465550
  • Ribasés M. et al. 2007. Molecular Genetics and Metabolism. 92: 274-7. PubMed ID: 17698383
  • Schiller A. et al. 2004. Neurology. 63: 1524-6. PubMed ID: 15505183
  • Sun Z.F. et al. 2014. Plos One. 9: e106388. PubMed ID: 25181484
  • Verbeek M.M. et al. 2007. Annals of Neurology. 62: 422-6. PubMed ID: 17696123
  • Willemsen M.A. et al. 2010. Brain. 133: 1810-22. PubMed ID: 20430833

Ordering/Specimens

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