What are the other Names for this Condition? (Also known as/Synonyms)

• Autosomal Recessive Infantile Parkinsonism
• DOPA Responsive Dystonia, Autosomal Recessive type
• Progressive Infantile Encephalopathy

What is Tyrosine Hydroxylase Deficiency? (Definition/Background Information)

• 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 severe form is called infantile Parkinsonism, and begins manifesting at 3-12 months of age
  • The very severe form progressive infantile encephalopathy, often begin shortly after birth or during early infancy (before a child is 3-6 months old)
• 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 theTH gene and is inherited in an autosomal recessive manner
• Affected people are usually treated with levodopa therapy

(Source: Tyrosine Hydroxylase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Tyrosine Hydroxylase Deficiency? (Age and Sex Distribution)

• Tyrosine Hydroxylase Deficiency is a rare congenital disorder. The presentation of symptoms differ, depending on the type of disease, and occur as:
  • Mild form - between 1-6 years old
  • Severe form - between 3-12 months old
  • Very severe - before 3-6 months old

(Source: Tyrosine Hydroxylase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Tyrosine Hydroxylase Deficiency? (Predisposing Factors)

• A positive family history may be an important risk factor, since Tyrosine Hydroxylase Deficiency can be inherited

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Tyrosine Hydroxylase Deficiency? (Etiology)

• Tyrosine Hydroxylase Deficiency is caused by changes (mutations) in theTH gene
• The disorder is inherited in an autosomal recessive manner

(Source: Tyrosine Hydroxylase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected

What are the Signs and Symptoms of Tyrosine Hydroxylase Deficiency?

The signs and symptoms of Tyrosine Hydroxylase Deficiency vary, depending on the severity of disease.

The signs and symptoms of the mild form of Tyrosine Hydroxylase Deficiency, also known as DOPA-Responsive Dystonia include:

• An abnormal gait (manner of walking)
• Lack of coordination when walking or running
• Repetitive, involuntary movements of the arms and/or legs
• Unusual positioning of limbs
• Postural tremor (shaking when holding a position)
• Abnormal, involuntary eye movements 

The signs and symptoms of the severe form of Tyrosine Hydroxylase Deficiency, also known as Infantile Parkinsonism:

• 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 signs and symptoms of the very severe form of Tyrosine Hydroxylase Deficiency, also known as Progressive Infantile Encephalopathy:

• Fetal distress
• Feeding difficulties
• Low muscle tone
• Small head circumference, height and/or weight from birth
• Severe physical and intellectual disability due to underlying brain dysfunction and structural abnormalities 
• Severe delay in motor milestones 
• Rigidity and/or spasticity of arms and legs
• Ptosis of both eye lids 
• Episodes of profuse sweating, lethargy, irritability and/or excessive drooling

(Source: Tyrosine Hydroxylase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Tyrosine Hydroxylase Deficiency Diagnosed?

• A diagnosis of Tyrosine Hydroxylase Deficiency is typically suspected based on the presence of characteristic signs and symptoms 
• Analysis of a small sample of cerebrospinal fluid may be recommended to support the diagnosis and to rule out other conditions associated with similar features
• Identification of a disease-causing change (mutation) in each copy of theTH gene confirms a diagnosis of TH deficiency

(Source: Tyrosine Hydroxylase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Tyrosine Hydroxylase Deficiency?

The complications of Tyrosine Hydroxylase Deficiency may include:

• Progressive worsening of symptoms
• Not responding to treatment, in case of the severe forms of the disease
• Delay in achieving developmental milestones
• Low self-esteem
• Depression

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Tyrosine Hydroxylase Deficiency Treated?

• People affected by Tyrosine Hydroxylase Deficiency are generally treated with a medication called levodopa
• The effectiveness of levodopa therapy varies significantly depending on the severity of the condition 
• People affected by the mild form of TH deficiency (TH-deficient dopa-responsive dystonia) generally respond well to treatment. In most cases, this medication is able to drastically improve or even completely alleviate associated symptom
• 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

(Source: Tyrosine Hydroxylase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How can Tyrosine Hydroxylase Deficiency be Prevented?

• Currently, Tyrosine Hydroxylase Deficiency may not be preventable, since it is a genetic disorder
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders
• Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of Tyrosine Hydroxylase Deficiency? (Outcomes/Resolutions)

• The long-term outlook (prognosis) for people with TH deficiency varies based on the severity of the condition
• The mild form of TH deficiency (TH-deficient dopa-responsive dystonia) is generally associated with a good prognosis. People affected by this form usually respond quickly and completely to treatment with levodopa, often seeing a full reversal of symptoms 
• 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

(Source: Tyrosine Hydroxylase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Additional and Relevant Useful Information for Tyrosine Hydroxylase Deficiency:

Tyrosine Hydroxylase Deficiency is also known by the following additional names: 

• Autosomal Recessive Segawa Syndrome
• Infantile, Autosomal Recessive Parkinsonism

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/