Autosomal Recessive DOPA-Responsive Dystonia via the TH Gene

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).

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).

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).

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.