Tyrosine hydroxylase deficiency

Title

Other Names:

Parkinsonism, infantile, autosomal recessive; Dystonia, DOPA responsive, autosomal recessive; DOPA responsive dystonia, autosomal recessive; Parkinsonism, infantile, autosomal recessive; Dystonia, DOPA responsive, autosomal recessive; DOPA responsive dystonia, autosomal recessive; Segawa syndrome, autosomal recessive See More

Categories:

Congenital and Genetic Diseases; Metabolic disorders; Nervous System Diseases

Summary Summary

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.^[1]^[2]^[3]

Last updated: 2/16/2015

Symptoms Symptoms

There are three different forms of tyrosine hydroxylase (TH) deficiency that vary in severity. The mild form of the condition is called TH-deficient dopa-responsive dystonia. Children affected by this form typically develop features of the condition between age twelve months and six years. Symptoms may 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); and abnormal, involuntary eye movements. The features of TH-deficient dopa-responsive dystonia tend to get worse over time but are generally responsive to treatment.^[1]^[3]

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:^[1]^[3]

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.^[2]^[3]

Last updated: 2/16/2015

The Human Phenotype Ontology (HPO) provides the following list of features that have been reported in people with this condition. Much of the information in the HPO comes from Orphanet, a European rare disease database. If available, the list includes a rough estimate of how common a feature is (its frequency). Frequencies are based on a specific study and may not be representative of all studies. You can use the MedlinePlus Medical Dictionary for definitions of the terms below.

Signs and Symptoms	Approximate number of patients (when available)
Myoclonus	Occasional (present in 5%-29% of cases)
Autosomal recessive inheritance	-
Decreased CSF homovanillic acid	-
Delayed speech and language development	-
Gait ataxia	-
Hypokinesia	-
Infantile onset	-
Limb dystonia	-
Mask-like facies	-
Motor delay	-
Muscular hypotonia of the trunk	-
Parkinsonism	-
Parkinsonism with favorable response to dopaminergic medication	-
Ptosis	-
Rigidity	-
Tremor	-
Variable expressivity	-

Last updated: 9/1/2017

Cause Cause

Tyrosine hydroxylase (TH) deficiency is caused by changes (mutations) in the 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.^[1]

Last updated: 2/16/2015

Inheritance Inheritance

Tyrosine hydroxylase deficiency is inherited in an autosomal recessive manner.^[3] This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Last updated: 2/16/2015

Diagnosis Diagnosis

A diagnosis of tyrosine hydroxylase (TH) 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 the TH gene confirms a diagnosis of TH deficiency.^[2]^[3]

Last updated: 2/16/2015

Testing Resources

The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
Orphanet lists international laboratories offering diagnostic testing for this condition.

Treatment Treatment

People affected by tyrosine hydroxylase (TH) 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 symptoms.^[2]^[3]

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.^[2]^[3]

Last updated: 2/16/2015

Management Guidelines

GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.

Prognosis Prognosis

The long-term outlook (prognosis) for people with tyrosine hydroxylase (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.^[1]^[2]^[3]

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.^[2]^[3]

Last updated: 2/16/2015

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Organizations Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Dystonia Medical Research Foundation
1 East Wacker Drive
Suite 1730
Chicago, IL 60601-1905
Toll-free: 800-377-3978
Telephone: 312-755-0198
Fax: 312-803-0138
E-mail: dystonia@dystonia-foundation.org
Website: http://www.dystonia-foundation.org
Pediatric Neurotransmitter Disease Association
28 Prescott Place
Old Bethpage, NY 11804
Telephone: 603-733-8409
E-mail: pnd@pndassociation.org
Website: http://www.pndassoc.org/

Do you know of an organization? Send us your suggestions.

Living With Living With

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Genetics Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by GeneTests, the American College of Medical Genetics, and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.

Learn More Learn More

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

Genetics Home Reference (GHR) contains information on Tyrosine hydroxylase deficiency. This website is maintained by the National Library of Medicine.
The National Institute of Neurological Disorders and Stroke (NINDS) collects and disseminates research information related to neurological disorders. Click on the link to view information on this topic.
The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
PubMed is a searchable database of medical literature and lists journal articles that discuss Tyrosine hydroxylase deficiency. Click on the link to view a sample search on this topic.

News & Events News & Events

News

Don’t Miss the NCATS Toolkit for Patient-Focused Therapy Development Event
August 31, 2017
Funding Opportunities Now Available for the Undiagnosed Diseases Network (UDN) Phase II
August 30, 2017
IRDiRC Goals 2017-2027: New Rare Disease Research Goals for the Next Decade
August 10, 2017

NCATS Co-Sponsored Conferences

Nutritional Challenges in the High-Risk Infant Monday, September 14, 2009 - Tuesday, September 15, 2009
Location: DC Metro Area,
Description: Evidence was critically evaluated at this workshop. Current gaps in knowledge in this area were identified and research priorities were formulated. The workshop summary will provide NICHD and the scientific community a template to address the scientific and clinical issues related to nutrition and neonatal care.

Contact: Dr. Rosemary D. Higgins, NICHD 301-435-7909

Co-funding Institute(s): National Institute of Child Health and Human Development

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The following diseases are related to Tyrosine hydroxylase deficiency. If you have a question about any of these diseases, you can contact GARD.

Dopa-responsive dystonia

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