Clinical characteristics: Tyrosine hydroxylase (TH) deficiency is associated with a broad phenotypic spectrum. Based on severity of symptoms/signs as well as responsiveness to levodopa therapy, clinical phenotypes caused by pathogenic variants in TH are divided into (1) TH-deficient dopa-responsive dystonia (the mild form of TH deficiency), (2) TH-deficient infantile parkinsonism with motor delay (the severe form), and (3) TH-deficient progressive infantile encephalopathy (the very severe form).

1. In individuals with TH-deficient dopa-responsive dystonia (DYT5b, DYT-TH), onset is between age 12 months and 12 years; initial symptoms are typically lower-limb dystonia and/or difficulty in walking. Diurnal fluctuation of symptoms (worsening of the symptoms toward the evening and their alleviation in the morning after sleep) may be present.

2. In most individuals with TH-deficient infantile parkinsonism with motor delay, onset is between age three and 12 months. In contrast to TH-deficient DRD, motor milestones are overtly delayed in this severe form. Affected infants demonstrate truncal hypotonia and parkinsonian symptoms and signs (hypokinesia, rigidity of extremities, and/or tremor).

3. In individuals with TH-deficient progressive infantile encephalopathy, onset is before age three to six months. Fetal distress is reported in most. Affected individuals have marked delay in motor development, truncal hypotonia, severe hypokinesia, limb hypertonia (rigidity and/or spasticity), hyperreflexia, oculogyric crises, ptosis, intellectual disability, and paroxysmal periods of lethargy (with increased sweating and drooling) alternating with irritability.

Diagnosis/testing: The diagnosis of TH deficiency is established in a proband by identification of biallelic pathogenic variants in TH by molecular genetic testing.

Management: Treatment of manifestations:

1. All individuals with TH-deficient DRD demonstrate complete responsiveness of symptoms to levodopa (with a decarboxylase inhibitor).

2. Individuals with TH-deficient infantile parkinsonism with motor delay demonstrate a marked response to levodopa. However, in contrast to TH-deficient DRD, the responsiveness is generally not complete and/or it takes several months or even years before the full effects of treatment become established. Some individuals are hypersensitive to levodopa and prone to side effects (i.e., dopa-induced dyskinesias which develop at initiation of levodopa treatment).

3. Individuals with TH-deficient progressive infantile encephalopathy are extremely sensitive to levodopa therapy. In this very severe form, treatment with levodopa is often limited by intolerable dyskinesias.

Prevention of primary manifestations: Levodopa therapy from early infancy may prevent manifestations of some symptoms and signs in TH-deficient infantile parkinsonism with motor delay; however, no levodopa trials in the early postnatal period of infants with this type of TH deficiency and biallelic TH pathogenic variants have been reported.

Prevention of secondary complications: Side effects associated with levodopa (e.g., gastroesophageal reflux, vomiting, significant suppression of appetite) may be ameliorated with dose adjustment and supportive intervention.

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

Agents/circumstances to avoid: The prokinetic agent Reglan^® and other related antidopaminergic agents.

Evaluation of relatives at risk: Sibs of affected individuals should be examined for mild dystonic and/or parkinsonian symptoms or unexplained gait disorders. It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from treatment.

Genetic counseling: TH deficiency is inherited in an autosomal recessive manner. Heterozygotes (carriers) are generally asymptomatic. 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. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if both TH pathogenic variants in a family are known.