Tyrosine hydroxylase (TH) deficiency is a rare inherited condition that affects the nervous system. There are three different forms of the condition that vary in severity. The mild form is called TH-deficient dopa-responsive dystonia and typically develops between age twelve months and six years. The two severe forms, which are called infantile parkinsonism and progressive infantile encephalopathy, often begin shortly after birth or during early infancy. Although there is some overlap of features among the three forms, each is associated with unique signs and symptoms. TH deficiency is caused by changes (mutations) in the TH gene and is inherited in an autosomal recessive manner. Affected people are usually treated with levodopa therapy.

TH gene. This gene encodes an enzyme that helps convert certain amino acids (building blocks of protein) to dopamine. Dopamine is a chemical that is important to the function of the nervous system. For example, it helps the brain control movement by acting as a messenger to the other parts of the body. Dopamine can also be made into other chemicals that play an important role in the functioning of the autonomic nervous system. Mutations in the TH gene result in reduced levels of dopamine, which leads to the many signs and symptoms associated with TH deficiency.

and not be a carrier.

The severe form of TH deficiency is called infantile parkinsonism. Children affected by this form generally begin developing features of the condition between age three to twelve months. Signs and symptoms of infantile parkinsonism may include:

• Delayed motor milestones (i.e. sitting up, crawling, walking)
• Intellectual disability
• Speech problems
• Muscle stiffness, especially in the arms and legs
• Unusual positioning of body
• Ptosis
• Abnormal, involuntary eye movements
• Constipation
• Gastroesophageal reflux
• Difficulty regulating body temperature, blood sugar and blood pressure
• Mental health conditions (i.e. depression, anxiety, or obsessive-compulsive behaviors)

The very severe form of TH deficiency which is called progressive infantile encephalopathy, generally develops before age three to six months. Early symptoms may include fetal distress; feeding difficulties; low muscle tone; and small head circumference, height and/or weight from birth. Babies affected by this form generally have severe physical and intellectual disability due to underlying brain dysfunction and structural abnormalities. Other signs and symptoms include severe delay in motor milestones; rigidity and/or spasticity of arms and legs; ptosis of both eye lids; and episodes of profuse sweating, lethargy, irritability and/or excessive drooling.

Unfortunately, children with infantile parkinsonism or progressive infantile encephalopathy (the two severe forms of TH deficiency) may have an incomplete response to levodopa, or it may take several months to several years to see an improvement in symptoms. In many cases, affected children are also extremely sensitive to the drug and may experience negative side affects such as difficulties in performing voluntary movements (dyskinesia), vomiting and appetite suppression of appetite.

Unfortunately, babies affected by infantile parkinsonism or progressive infantile encephalopathy generally experience more severe signs and symptoms than those affected by TH-deficient dopa-responsive dystonia. These severe forms of TH deficiency are also more difficult to effectively treat and therefore, tend to have a worse prognosis.