What is Tyrosine Hydroxylase Deficiency?

Tyrosine Hydroxylase (TH) deficiency (also known as Recessive Dopa- Responsive Dystonia) is a rare metabolic disorder characterized by the lack of the enzyme involved in converting the amino acid tyrosine to Ldopa.

TH is a critical enzyme in normal dopamine production. Lack of this enzyme means neurotransmitters are blocked from signaling one another appropriately. The neurotransmitters dopamine, norepinepherine, epinepherine (collectively known as catecholamines) and serotinin are deficient in the central nervous system and periphery.

Patients with TH Deficiency can develop movement disorders, autonomic symptoms (blood pressure instability, temperature irregularities), abnormal eye movements and neurological impairment.

What symptoms are associated with TH Deficiency?

A wide range of symptoms can be associated with TH Deficiency, and involvement can vary from mild, moderate to severe.

Mild:

In the mildest cases, walking or running may be clumsy but little else may be noticed initially. Symptoms may progress slowly as the child gets older. One side of the body may seem weaker, or the child may begin to walk up on their tiptoes due to some tightness of the leg muscles. Attention difficulties in school are common.

Children with mild symptoms are often treated successfully with medication.

Moderate:

In moderately affected cases, the child may not be able to walk at all, or walking may be extremely difficult. Unusual arm posturing or positions of their arms with attempts to walk or walk on their toes is common. Abnormal eye movements, tremor and speech delay may be present. Children with moderate symptoms often respond well to treatment but full benefit may take many months.

Severe:

In the most severe cases children are physically disabled and affected from early infancy. This is sometimes known as the Infantile Parkinson’s disease variant. Patients may demonstrate all or some of the following symptoms;

• Muscle tightness (rigidity, spasticity)
• Abnormal posturing (arching of the back)
• Tremor
• Poor muscle control
• Abnormal eye movements (eye deviation upward, downward or towards the nose)
• Strabismus (cross-eyed)
• Ptosis (droopiness of the eyelids)
• Speech delay
• Difficulties feeding or swallowing
• Constipation
• Torticollis (involuntary deviation of the head and neck)
• Intermittent color changes
• Unexplained low body temperatures or fevers
• Low blood sugar
• Difficulty regulating blood pressure

Children who are severely affected are more difficult to treat, and several medications may be needed. They are unusually vulnerable to side effects of the medications, which can result in excessive movement >and irritability. Response may be slow, with some continued benefit over months to years, but may not result in the complete resolution of all symptoms. Symptoms may present or worsen during other illnesses the child might experience.

Children with TH Deficiency are often considered clumsy or uncoordinated and are often initially diagnosed with cerebral palsy.

What causes TH Deficiency?

TH Deficiency is inherited as an autosomal recessive trait. In recessive disorders, the condition does not occur unless an individual inherits the same defective gene for the same trait from each parent. A child who receives one normal gene and one gene for the disease will be a carrier but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder is 25%. The risk is the same for each pregnancy.

Who gets TH Deficiency?

It is unclear at present whether males or females are affected any differently.

Only a few dozen cases have been identified to date worldwide as of 2003. It is suspected that many cases either go unrecognized or misdiagnosed.

How is TH Deficiency diagnosed?

A diagnosis of TH Deficiency is based upon a two stage testing procedure:

STAGE 1

A lumbar puncture (spinal tap) to determine abnormalities of neurotransmitter metabolites.

Note: Testing for PND’s is not a routine procedure and requires< specific guidelines. Should the treating physician or consultant require more information on laboratories please refer to the Pediatric

Neurotransmitter Disease Association at www.pndassociation.org

or contact:

Keith Hyland PhD
Director
Medical Neurogenetics, LLC
Atlanta, GA.
Phone (678) 225-0222
Fax (678) 225-0212
[email protected]
[email protected]

Teodoro Bottiglieri, PhD
Principle Investigator, Director of Neuropharmacology
Adjunct Professor of Biomedical Studies
Baylor University Medical Center
Institute of Metabolic Disease
Phone (214) 820 4748
Fax (214) 820 4853
Web: http://www.baylorhealth.edu/imd/
[email protected]

STAGE 2

Once the diagnosis is suspected on the basis of cerebrospinal fluid studies, the diagnosis should be confirmed by analysis of the TH gene itself. This is done via a blood sample and results can take some time.

There are again specific guidelines for blood sampling/shipping and adherence is critical to the accurate diagnosis of TH Deficiency. For information on how to collect and where to send the samples, or to receive a testing packet please refer to the above information. If possible samples should be collected from all family members.

Note: If abnormalities of neurotransmitter metabolites are displayed in the Stage 1 testing procedure but are not conclusive to TH Deficiency, then consideration should be given to other Pediatric Neurotransmitter Diseases.

How is TH Deficiency treated?

Presently, the most well established treatment of TH Deficiency is medication to help restore normal dopamine levels. Dopamine itself cannot cross the blood-brain barrier directly and so it is necessary to treat with a compound called L-Dopa in combination with another medication called carbidopa. Sinemet is a commercially available medication which contains both carbidopa and L-dopa together in a single tablet.

However, Sinemet was designed to treat adults with Parkinson’s disease and the available dosages are much too high for many infants and young children with TH Deficiency. It is imperative that the pharmacist compound special doses of L-dopa and carbidopa for children. Children with the TH Deficiency can experience excessive movement or irritability with low doses of L-dopa and extreme irritability, sleeplessness, and vomiting or persistent abnormal movements with excessive doses.

It is important to work closely with the physician to maximize the results of medications and reduce side effects.

In children who are severely affected, less than one year of age, or prove intolerant of low dose L-dopa therapy, additional medications may be beneficial. They include:

• Anticholinergic Agents - Artane
• Monoamine Oxidase B Inhibitors - Selegeline
• Serotonergic Medications
• Gastrointestinal Medications
• Miscellaneous category
• Physical and occupational therapy is recommended. Speech therapy
• has also been effective in some children
• Medical advancements made in gene therapy or stem cell transplantation
• may someday provide an avenue to cure the disorder.