Clinical Guidance

Individuals who are homozygous or compound heterozygous for a single-nucleotide variant in the promoter region of TH have not developed the very severe form of TH deficiency [, , , , ]. No additional genotype-phenotype correlations have been identified in individuals with TH deficiency.

Source: GeneReviews — "Tyrosine Hydroxylase Deficiency"

Penetrance

Penetrance appears to be complete in individuals with biallelic TH pathogenic variants. In contrast to autosomal dominant GTPCH1-deficient DRD , there is no predominance of clinically affected females in autosomal recessive TH-deficient DRD.

Source: GeneReviews — "Tyrosine Hydroxylase Deficiency"

Diagnostic Criteria

Tyrosine hydroxylase (TH) deficiency is associated with a wide phenotypic spectrum. Based on severity of symptoms and signs as well as responsiveness to levodopa therapy, the three clinical phenotypes attributable to pathogenic variants in TH are: TH-deficient dopa-responsive dystonia (DYT5b, DYT-TH ; the mild form of TH deficiency); TH-deficient infantile parkinsonism with motor delay (the severe form); and TH-deficient progressive infantile encephalopathy (the very severe form). Since clinical suspicion is a key to the diagnosis of TH deficiency, physicians should be aware of this broad phenotypic spectrum.

Suggestive Findings

The diagnosis of TH deficiency should be suspected in an individual with the following clinical and laboratory features.

Clinical

Source: GeneReviews — "Tyrosine Hydroxylase Deficiency"

Differential Diagnosis

The major differential diagnoses for tyrosine hydroxylase (TH) deficiency include several types of dystonia, early-onset parkinsonism, cerebral palsy or spastic paraplegia, and primary and secondary deficiencies of CSF neurotransmitter metabolites. Dystonia. For a differential diagnosis of dystonia, see Dystonia Overview. GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD, DYT5a, DYT-GCH1) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. The average age of onset is approximately six years. This disorder typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms.

Source: GeneReviews — "Tyrosine Hydroxylase Deficiency"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with tyrosine hydroxylase (TH) deficiency, the following are recommended if they have not already been completed:

• Clinical examination to assess the severity of motor disturbances

• Evaluation for associated psychiatric symptoms or cognitive impairments

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

In individuals with TH deficiency, initial use of a levodopa (combined with a decarboxylase inhibitor) dose of 0.5-3 mg/kg (body weight)/day, divided into three to six doses, has been recommended . Nevertheless, it is possible that even at the lowest initial dosage recommended (i.e., 0.5 mg/kg/day), some individuals with the very severe form of TH deficiency will develop intolerable dyskinesias . When tolerated, the dose of levodopa can be increased gradually. However, with the exception of those with mild TH-deficient DRD , it is often difficult to increase levodopa doses smoothly in affected individuals due to the risk of developing severe dyskinesias. In such individuals, combined administration of levodopa and selegiline (a monoamine oxidase B inhibitor, which inhibits dopamine degradation) has been recommended [, , , , ].

Source: GeneReviews — "Tyrosine Hydroxylase Deficiency"

Clinical Guidance

The prokinetic agent Reglan®, commonly used for treatment of bowel dysmotility, is contraindicated in individuals with TH deficiency because of its antidopaminergic activity. Use of Reglan® or related antidopaminergic agents, including some antipsychotic medications, could result in a dystonic crisis.

Source: GeneReviews — "Tyrosine Hydroxylase Deficiency"

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.

Source: GeneReviews — "Tyrosine Hydroxylase Deficiency"

Surveillance Guidelines

Examination by a movement disorder specialist in pediatric or adult neurology at least several times yearly is recommended.

Source: GeneReviews — "Tyrosine Hydroxylase Deficiency"