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Disease Profile

Tyrosine hydroxylase deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 1 000 000

331 - 2,979

US Estimated

1-9 / 1 000 000

514 - 4,622

Europe Estimated

Age of onset

Infancy

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ICD-10

G24.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Parkinsonism, infantile, autosomal recessive; Dystonia, DOPA responsive, autosomal recessive; DOPA responsive dystonia, autosomal recessive;

Categories

Congenital and Genetic Diseases; Metabolic disorders; Nervous System Diseases

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]

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]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
30%-79% of people have these symptoms
Babinski sign
0003487
Bradykinesia
Slow movements
Slowness of movements

[ more ]

0002067
Brisk reflexes
0001348
Central hypotonia
0011398
Constipation
0002019
Decreased CSF homovanillic acid
0003785
Delayed speech and language development
Deficiency of speech development
Delayed language development
Delayed speech
Delayed speech acquisition
Delayed speech development
Impaired speech and language development
Impaired speech development
Language delay
Language delayed
Language development deficit
Late-onset speech development
Poor language development
Speech and language delay
Speech and language difficulties
Speech delay

[ more ]

0000750
Excessive salivation
Mouth watering
Oversalivation
Watery mouth

[ more ]

0003781
Feeding difficulties
Feeding problems
Poor feeding

[ more ]

0011968
Focal dystonia
0004373
Gait ataxia
Inability to coordinate movements when walking
0002066
Hypokinesia
Decreased muscle movement
Decreased spontaneous movement
Decreased spontaneous movements

[ more ]

0002375
Irritability
Irritable
0000737
Lethargy
0001254
Limb dystonia
0002451
Lower limb hyperreflexia
Overactive lower leg reflex
0002395
Motor delay
0001270
Myoclonus
0001336
Night sweats
0030166
Oculogyric crisis
0010553
Parkinsonism
0001300
Pes cavus
High-arched foot
0001761
Postural tremor
0002174
Ptosis
Drooping upper eyelid
0000508
Rigidity
Muscle rigidity
0002063
Talipes equinovarus
Club feet
Club foot
Clubfeet
Clubfoot

[ more ]

0001762
5%-29% of people have these symptoms
Fever
0001945
Generalized dystonia
0007325
Intellectual disability, mild
Mental retardation, borderline-mild
Mild and nonprogressive mental retardation
Mild mental retardation

[ more ]

0001256
1%-4% of people have these symptoms
Generalized hypotonia
Decreased muscle tone
Low muscle tone

[ more ]

0001290
Progressive encephalopathy
0002448
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance
0000007
Infantile onset
Onset in first year of life
Onset in infancy

[ more ]

0003593
Mask-like facies
Expressionless face
Lack of facial expression
Mask-like facial appearance

[ more ]

0000298
Muscular hypotonia of the trunk
Low muscle tone in trunk
0008936
Parkinsonism with favorable response to dopaminergic medication
0002548
Tremor
0001337
Variable expressivity
0003828

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]

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]

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

    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]

    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

      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

        In-Depth Information

        • 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.
        • 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.

          References

          1. Tyrosine hydroxylase deficiency. Genetic Home Reference. April 2009; https://ghr.nlm.nih.gov/condition/tyrosine-hydroxylase-deficiency.
          2. Tyrosine hydroxylase deficiency. NORD. April 2014; https://www.rarediseases.org/rare-disease-information/rare-diseases/byID/1245/viewAbstract.
          3. Yoshiaki Furukawa, MD, PhD and Stephen Kish, PhD. Tyrosine Hydroxylase Deficiency. GeneReviews. July 2014; https://www.ncbi.nlm.nih.gov/books/NBK1437/.

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