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Tyrosine Hydroxylase Deficiency

Includes: Tyrosine Hydroxylase-Deficient Dopa-Responsive Dystonia (TH-Deficient DRD; Segawa Syndrome, Autosomal Recessive), Autosomal Recessive Infantile Parkinsonism

, MD and , MD, PhD.

Author Information
, MD
Associate Professor, Neurology
Adjunct Associate Professor, Pediatrics
Director, Pediatric Motor Disorders Research Program
University of Utah School of Medicine
Diplomate, American Board of Medical Genetics
Salt Lake City, Utah
, MD, PhD
Chairman, Department of Neurology
Juntendo Tokyo Koto Geriatric Medical Center
Professor, Department of Neurology, Faculty of Medicine
University & Postgraduate University of Juntendo
Tokyo, Japan

Initial Posting: .

Summary

Disease characteristics. Tyrosine hydroxylase (TH) deficiency is associated with a broad phenotypic spectrum ranging from TH-deficient dopa-responsive dystonia (DRD) at the mild end to a levodopa-unresponsive infantile parkinsonism or progressive infantile encephalopathy phenotype at the severe end. Findings in mild cases can be limited initially to unilateral or asymmetric limb dystonia, postural tremor, or gait "incoordination;" however, progression over time may result in the classic dopa-responsive dystonic gait disorder. Diurnal variation of motor symptoms may be present, worse in the afternoon or evening. Children at the severe end of the spectrum are profoundly disabled from early infancy with developmental motor delay, truncal hypotonia, limb rigidity, and hypokinesia. Ptosis and/or oculogyric crises are common. These infants are more difficult to treat and unusually prone to side effects (dyskinesias and gastrointestinal side effects) of levodopa therapy.

Diagnosis/testing. The patterns of cerebrospinal fluid (CSF) neurotransmitter metabolite and pterin studies help support the diagnosis of TH deficiency but are not by themselves diagnostic. Sequence analysis of TH, the only gene associated with TH deficiency, has identified mutations in all individuals reported to date.

Management. Treatment of manifestations: Levodopa improves motor function in the majority of mildly affected individuals. Starting with very low doses of levodopa and adequate amounts of carbidopa can help to minimize development of dyskinesias. The levodopa dose may need to be titrated slowly over weeks to months. In more severely affected infants with encephalopathy or parkinsonism phenotypes, immediate benefit with levodopa may be difficult to observe and dyskinesias may be dose-limiting; however, more prolonged treatment can ameliorate symptoms and allow additional developmental motor progress over time.

Prevention of primary manifestations: See Treatment of manifestations.

Prevention of secondary complications: Side effects associated with peak-dose levodopa such as gastroesophageal reflux, vomiting, or significant suppression of appetite leading to poor growth can be ameliorated with appropriate dosing.

Surveillance: neurologic evaluations every four to six months during childhood to assess medication dosing.

Agents/circumstances to avoid: Reglan® and other related antidopaminergic agents.

Evaluation of relatives at risk: Sibs of affected individuals should be examined for evidence of dystonia and/or motor incoordination, which could be evidence of mild involvement.

Genetic counseling. TH deficiency is inherited in an autosomal recessive manner. Heterozygotes (carriers) are generally asymptomatic; however, in rare instances heterozygotes can demonstrate a subtle phenotypic effect (i.e., exercise-induced stiffness responding to levodopa). At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both disease-causing alleles in a family are known.

Diagnosis

Clinical Diagnosis

The broad phenotypic spectrum of tyrosine hydroxylase (TH) deficiency ranges from a mild progressive dopa-responsive dystonic gait disorder to severe infantile parkinsonism with or without encephalopathy that may be unresponsive to levodopa treatment.

The diagnosis of TH deficiency should be considered when the following signs or symptoms are observed in isolation or as part of a constellation of features:

  • Infantile hypotonia or dystonia with encephalopathy, hypokinesia and involuntary eye movements
  • Generalized dystonia
  • Torticollis
  • Limb dystonia
  • Progressive dystonic gait disorder
  • Involuntary eye movements or frank oculogyric crises
  • Involuntary tongue thrusting
  • Ptosis, miosis, blepharospasm
  • Increased lower extremity tone
  • Brisk reflexes and/or the striatal toe (dystonic extension of the great toe)
  • Diurnal variation of signs or symptoms: worse in the afternoon or evening, improved after sleep
  • Infantile or juvenile parkinsonism
  • Rigidity of extremities
  • Hypokinesia
  • Postural tremor
  • Developmental motor delay
  • Truncal hypotonia
  • Autonomic symptoms including hypothermia, gastrointestinal dysmotility, hypoglycemia, diaphoresis

Testing

Biochemical testing. The following patterns of cerebrospinal fluid (CSF) neurotransmitter metabolite and pterin studies help support the diagnosis of TH deficiency [Wevers et al 1999] but are not by themselves diagnostic.

  • Total biopterin (BP)* (most of which exists as tetrahydrobiopterin [BH4]). Normal
  • Total neopterin (NP). Normal
  • Homovanillic acid (HVA). Reduced
  • 5-hydroxyindoleacetic acid (5-HIAA). Normal
  • 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG; a metabolite of noradrenaline). Reduced

* If both BP and NP are low, GTP cyclohydrolase (GTPCH)-deficient dopa-responsive dystonia associated with mutations in GCH1 should be strongly considered [Furukawa et al 1996b, Furukawa et al 1998b]. Clinical phenotypes of GTPCH-deficient dopa-responsive dystonia (DRD) and mild TH deficiency overlap significantly.

Note: A biochemical enzymatic assay is not available for TH deficiency.

Molecular Genetic Testing

Gene. The only gene associated with TH deficiency is TH, which encodes TH, the rate-limiting enzyme in catecholamine biosynthesis.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Tyrosine Hydroxylase Deficiency

GeneTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
THSequence analysis/mutation scanning Sequence variants 2Unknown
Deletion analysis Exonic and whole-gene deletions

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband

  • CSF neurotransmitter metabolite and pterin pattern alone is not diagnostic of TH deficiency.
    • If CSF neurotransmitter metabolite and pterin analysis reveals a pattern of abnormalities consistent with TH deficiency in the setting of a characteristic phenotype, a clinical diagnosis of TH deficiency is strongly supported.
    • If CSF analysis reveals reduced BP and NP levels, GTPCH-deficient dopa-responsive dystonia (autosomal dominant Segawa syndrome [Segawa et al 1976, Ichinose et al 1994]) is more likely.
    • Secondary deficiencies of CSF neurotransmitter metabolites have been noted in other neurodegenerative disorders (see Differential Diagnosis).
  • Sequence analysis of the coding region (including the splice sites) and the CRE region of TH are helpful in confirming a suspected diagnosis of TH deficiency in a proband, especially in a simplex case (i.e., a single occurrence in a family) with one of the more severe infantile phenotypes that may not demonstrate a clear treatment effect with a levodopa trial.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in an an affected family member.

Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in an affected family member.

Clinical Description

Natural History

Tyrosine hydroxylase (TH) deficiency is associated with a broad phenotypic spectrum ranging from TH-deficient DRD, the mild form of the disorder, to an infantile parkinsonism or progressive infantile encephalopathy phenotype, the severe or very severe form. More data are needed to establish the major clinical characteristics of autosomal recessive TH deficiency [Furukawa et al 2004].

Mild form (TH-deficient dopa-responsive dystonia). Symptoms in mild cases can be limited to unilateral or asymmetric limb dystonia, postural tremor, or gait "incoordination." Progressive symptoms may ultimately result in the classic dopa-responsive dystonic gait disorder.

Typically, onset is in childhood with a lower-limb predominant dystonia and gait disturbance. Symptoms manifest after a variable period of apparently normal early motor development. Toe walking may be an early feature. Lower extremity tone and dystonic posturing increase with age. Diurnal variation of motor symptoms may be present, worse in the afternoon or evening. Prolonged exercise or fatigue may trigger symptoms in milder cases.

More severely affected children may demonstrate involuntary eye movements consisting of brief upward eye-rolling movements, or frank oculogyric crises.

Motor symptoms in children with the relatively mild phenotypes typically respond readily to treatment with levodopa. However, delayed diagnosis and therapy may be associated with progressive motor disability and an increased predisposition to dyskinesias at initiation of levodopa treatment.

In several families, a sustained response to treatment with levodopa without apparent adverse motor effects has been documented in periods ranging from 30 to 35 years [Furukawa 2004, Schiller et al 2004].

Severe form (infantile parkinsonism). Children with the infantile parkinsonism variant are profoundly disabled from early infancy. Typically, onset of this form is before age six months. Features included developmental motor delay, truncal hypotonia, limb rigidity, and hypokinesia [Furukawa 2003, Hoffmann et al 2003, Furukawa 2004]. Ptosis and/or oculogyric crises are common.

Associated neuropsychiatric features can include attention deficit or impulsivity, sometimes with associated learning disabilities. Speech delay or difficulty with articulation has been noted in more severely affected children. Excessive anxiety, depression, or obsessive-compulsive symptoms have also been reported.

Autonomic dysfunction may be manifest in the most severe infantile cases by constipation, reflux, poor feeding, temperature instability, hypoglycemia, and difficulty regulating blood pressure [de Lonlay et al 2000, de Rijk-Van Andel et al 2000].

More severely affected children have intellectual disability and hyperprolactinemia (dopamine is a prolactin-inhibiting factor at the level of the hypothalamus) [Furukawa et al 2005].

These infants are more difficult to treat and unusually prone to side effects (dyskinesias and gastrointestinal side effects) of levodopa therapy as well as other dopaminergic agonists. A much more gradual response to pharmacologic interventions may be noted [de Rijk-Van Andel et al 2000, Hoffmann et al 2003].

Progressive infantile encephalopathy. Another phenotype associated with mutations in TH is a progressive infantile encephalopathy in which children have persistent encephalopathy and motor disability in spite of directed treatment of the underlying dopamine deficiency state. In rare cases, no apparent benefit has been noted in spite of directed treatment with levodopa [Hoffmann et al 2003].

Neuroimaging. Brain CT and MRI to date have not revealed structural or signal abnormality in individuals with TH-deficient DRD who have been on treatment for as long as 35 years [Schiller et al 2004]. Cerebral and cerebellar atrophy was found in a severely affected individual with TH deficiency [Hoffmann et al 2003].

Neuropathology. No autopsies of individuals with TH deficiency have been reported.

Genotype-Phenotype Correlations

No correlations between specific clinical features and types of mutations in TH have been established.

Penetrance

Penetrance of TH deficiency in families reported to date has been complete. However, variable expressivity has been noted within the same family, such that sibs have both severe phenotypes and milder phenotypes that could be manifest only as modest incoordination or clumsiness [Swoboda 2006].

An increase in penetrance for motor symptoms in females with TH deficiency has not been clearly documented, in contrast to that observed in families with GTPCH-deficient DRD [Furukawa et al 1998a, Steinberger et al 1998]. However, the autosomal recessive nature of the disorder (and hence the lack of large multiplex families) as well as the relatively small number of familial cases reported to date would make such an observation difficult. Nevertheless, restless leg symptoms (i.e., uncomfortable sensations in the lower extremities, often described as crawling, prickling, and which are typically relieved by movement, hence the term "restless legs") in obligate female carriers in three families may warrant a more detailed evaluation of gender-dependent penetrance [Swoboda 2006].

Prevalence

The prevalence of TH deficiency has not been clearly documented. In primary dystonia in childhood or adolescence, the TH-deficient form and the GTPCH-deficient form of DRD account for an estimated 5%-10% of cases [Nygaard et al 1988].

Differential Diagnosis

The major differential diagnoses for tyrosine hydroxylase (TH) deficiency include several types of dystonia, early-onset parkinsonism, cerebral palsy or spastic paraplegia, and primary and secondary deficiencies of CSF neurotransmitter metabolites.

Dystonia. For a differential diagnosis of dystonia, see Dystonia Overview.

GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. The average age of onset is approximately six years. This disorder typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms. In general, gradual progression to generalized dystonia is observed. Inheritance is autosomal dominant.

More than 60% of individuals with DRD have sequence variants or exon deletions in GCH1, the gene encoding the enzyme GTPCH1. The enzyme GTPCH1 catalyzes the first step in the biosynthesis of tetrahydrobiopterin (BH4), the essential cofactor for TH. The concentrations of total BP (most of which exists as BH4) and total NP (the byproducts of the GTPCH1 reaction) in CSF are low in GTPCH1-deficient DRD (see Clinical Diagnosis, Biochemical Testing).

When the phenotypes associated with GTPCH-deficient DRD and TH-deficient DRD overlap significantly, the two disorders can be distinguished by molecular genetic testing and the pattern of CSF pterins and neurotransmitter metabolites.

Early-onset primary dystonia (DYT1). A GAG deletion in DYT1 (TOR1A) that results in loss of a glutamic acid residue in a novel ATP-binding protein (torsinA) has been identified in many individuals with chromosome 9q34-linked early-onset primary dystonia, regardless of ethnic background. This heterozygous deletion cannot be found in some families with typical DYT1 phenotype (early-onset limb dystonia spreading to at least one other limb but not to cranial muscles). However, the dramatic and sustained response to low doses of levodopa in DRD distinguishes DRD from all other forms of dystonia.

Early-onset parkinsonism. Individuals with early-onset parkinsonism responding to levodopa, especially those with onset before age 20 years, often develop gait disturbance attributable to foot dystonia as the initial symptom [Furukawa et al 1996a]. Thus, early in the disease course, clinical differentiation between individuals with early-onset parkinsonism with dystonia and individuals with DRD is difficult.

  • The most reliable clinical distinction between early-onset parkinsonism and DRD is the subsequent occurrence of motor-adverse effects of chronic levodopa therapy (wearing-off and on-off phenomena and dopa-induced dyskinesias) in early-onset parkinsonism. Under optimal doses, individuals with DRD on long-term levodopa treatment do not develop these complications. However, this is a retrospective difference.
  • An investigation of the nigrostriatal dopaminergic terminals by positron emission tomography (PET) or single photon emission computed tomography (SPECT) can differentiate early-onset parkinsonism (markedly reduced) from DRD (normal or near normal) [Snow et al 1993, Jeon et al 1998, O'Sullivan et al 2001].
  • Measurement of the concentration of both BP and NP in CSF is useful in distinguishing the following three disorders responsive to levodopa [Furukawa & Kish 1999]:
    • GTPCH1-deficient DRD (reduced concentration of BP and NP)
    • TH-deficient DRD (normal concentration of BP and NP)
    • Early-onset parkinsonism (reduced concentration of BP associated with normal concentration of NP), including the autosomal recessive form caused by PARK2 (the gene encoding parkin) mutations

See Parkin Type of Juvenile Parkinson Disease and Parkinson Disease Overview).

Cerebral palsy or spastic paraplegia. Some individuals with DRD are initially diagnosed as having cerebral palsy or spastic paraplegia [Tassin et al 2000, Furukawa et al 2001, Grimes et al 2002]. Dystonic extension of the big toe (the striatal toe), which occurs spontaneously or is induced by plantar stimulation, may be misinterpreted as an extensor plantar response (see Hereditary Spastic Paraplegia Overview).

Primary deficiencies of CSF neurotransmitter metabolites include autosomal recessive BH4-related enzyme deficiencies (so-called BH4 deficiencies [Blau et al 2002], including recessively inherited GTPCH1 deficiency). Individuals with recessively inherited BH4 deficiencies generally manifest BH4-dependent hyperphenylalaninemia (HPA) in the first six months of life (an exception is autosomal recessive sepiapterin reductase (SR) deficiency [Bonafe et al 2001]). The typical presentation includes severe neurologic dysfunction (e.g., psychomotor retardation, convulsions, microcephaly, swallowing difficulties, truncal hypotonia, limb hypertonia, involuntary movements, oculogyric crises); diurnal fluctuation of symptoms and dystonia partially responding to levodopa can be found in some individuals, especially those with SR deficiency [Furukawa & Kish 1999, Bonafe et al 2001, Furukawa 2004, Neville et al 2005, Abeling et al 2006, Roze et al 2006]. Oral administration of both levodopa and 5-hydroxytryptophan is necessary for individuals with autosomal recessive SR deficiency. BH4 treatment and neurotransmitter replacement therapy (levodopa and 5-hydroxytryptophan) are indispensable for those with other autosomal recessive BH4-related enzyme deficiencies.

Secondary deficiencies of CSF neurotransmitter metabolites have been observed in other neurodegenerative disorders including spinocerebellar ataxia type 2, neuronal ceroid-lipofuscinosis, Menkes kinky hair disease (see ATP7A-Related Copper Transport Disorders), and in association with hypoxic ischemic encephalopathy.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with tyrosine hydroxylase (TH) deficiency, the following are recommended:

  • Clinical examination to assess the severity of the associated movement disorder
  • Evaluation for associated psychiatric symptoms or cognitive impairments

Treatment of Manifestations

Patients with TH deficiency can be extremely sensitive to the initiation of dopamine-precursor therapy.

Development of dyskinesias can be minimized by starting with very low doses of levodopa therapy and maintaining adequate amounts of carbidopa to block the peripheral aromatic L-amino acid decarboxylase and thus limit peripheral side effects. This may require compounded dosing of the individual ingredients rather than use of a tablet formulation with a fixed levodopa to carbidopa ratio.

Titrating the levodopa dose slowly over weeks to months may be necessary, particularly in those who are most severely affected or in whom a significant delay in diagnosis has occurred. In mild cases, minimal titration of dosing is needed, dyskinesias are absent, and a sustained response to low-dose levodopa treatment can be expected.

Optimism regarding significant improvement in motor function is warranted in most cases, with the exception of the most severely affected infants. However, if diagnosis is significantly delayed, caution is warranted: delayed diagnosis can be associated with lifelong cognitive impairment and dyskinesias that are quite refractory to moderation of levodopa dosage.

In more severely affected infants with encephalopathy or parkinsonism phenotypes, immediate benefit with levodopa may be difficult to observe and dyskinesias may be dose-limiting; however, more prolonged treatment can ameliorate symptoms and allow additional developmental motor progress over time.

Prevention of Primary Manifestations

Levodopa. Primary manifestations in patients with TH-deficient DRD are predominantly motor; these symptoms are most effectively treated with levodopa. Optimal dosing requirements may vary with age, physical activity, and growth.

Levodopa must be used in conjunction with an inhibitor of amino acid decarboxylase activity such as carbidopa to allow the precursor to effectively cross the blood-brain barrier, where it can be converted to dopamine in neuronal cells.

In more severely affected individuals who have levodopa dose-related dyskinesia, other therapies may help augment the levodopa therapy, thus reducing the sometimes significant peak-and-trough fluctuations in motor function associated with the short levodopa half-life. Slow-release formulations are available for adults but not children.

Other. The monoamine oxidase B (MAO-B) inhibitor selegiline slows the catabolism of dopamine and significantly augments the effectiveness of levodopa/carbidopa therapy in some individuals.

Anticholinergic agents, such as trihexyphenidyl and amantidine, have also proved modestly helpful in this regard.

Prevention of Secondary Complications

Additional side effects associated with peak-dose levodopa include gastroesophageal reflux, vomiting, or significant suppression of appetite leading to poor growth. Although these problems may be most evident in the first few weeks of onset of levodopa treatment, close monitoring of symptoms and ongoing adjustment of levodopa/carbidopa dosing in conjunction with appropriate supportive intervention as needed helps in management.

Surveillance

Neurologic evaluations every four to six months during childhood are useful to assess medication dosing.

Agents/Circumstances to Avoid

The prokinetic agent Reglan®, commonly used for treatment of bowel dysmotility, is contraindicated in individuals with TH deficiency because of its antidopaminergic activity. Use of Reglan® or related antidopaminergic agents, including some antipsychotic medications, could result in a dystonic crisis.

Evaluation of Relatives at Risk

Sibs of affected individuals should be examined for evidence of dystonia and/or motor incoordination, which could be evidence of more mild involvement.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Direct dopaminergic receptor agonists may not be recommended for TH deficiency because the primary biochemical deficiency includes dopamine and a host of downstream catecholamine metabolites. Because dopaminergic receptor agonists may selectively activate only a subset of dopamine receptors, they may not be as effective as levodopa in treating the associated systemic catecholamine deficiency.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Tyrosine hydroxylase (TH) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes, and thus carry one mutant allele.
  • Heterozygotes (carriers) are generally asymptomatic; in rare instances, heterozygotes can demonstrate a subtle phenotypic effect (i.e., exercise-induced stiffness responding to levodopa).

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Offspring of a proband

  • The offspring of an individual with TH deficiency are obligate heterozygotes (carriers) for a mutation in TH.
  • If the reproductive partner of the proband is an asymptomatic carrier of a TH mutation, the children have a 50% chance of being affected and a 50% chance of being heterozygotes (unaffected).

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing. Carrier testing is possible once the mutations have been identified in the family.

Biochemical genetic testing. The reliability of biochemical testing for carrier detection has not yet been determined. However, low CSF HVA concentrations were documented in three carriers (mothers of affected children), all of whom had symptoms consistent with restless leg syndrome [Swoboda 2006].

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It may be appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Prenatal diagnosis of TH deficiency has been reported [Moller et al 2005].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Dystonia Medical Research Foundation
    One East Wacker Drive
    Suite 2810
    Chicago IL 60601-1905
    Phone: 800-377-3978 (toll-free); 312-755-0198
    Fax: 312-803-0138
    Email: dystonia@dystonia-foundation.org
  • Dystonia Society
    89 Albert Embankment
    3rd Floor
    London SE1 7TP
    United Kingdom
    Phone: 0845 458 6211; 0845 458 6322 (Helpline)
    Fax: 0845 458 6311
    Email: support@dystonia.org.uk
  • Pediatric Neurotransmitter Disease Association
    498 Lillian Court
    PO Box 180622
    Delafield WI 53018
    Phone: 603-733-8409
    Email: pnd@pndassoc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Tyrosine Hydroxylase Deficiency: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
TH11p15​.5Tyrosine 3-monooxygenaseTH homepage - Mendelian genesTH

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Tyrosine Hydroxylase Deficiency (View All in OMIM)

191290TYROSINE HYDROXYLASE; TH
605407SEGAWA SYNDROME, AUTOSOMAL RECESSIVE

Molecular Genetic Pathogenesis

Tyrosine hydroxylase (TH) (tyrosine 3-monooxygenase) catalyzes the initial and rate-limiting step in the synthesis of catecholamine, including dopamine, adrenaline (epinephrine), and noradrenaline (norepinephrine).

Complete disruption of TH function in mice results in severe catecholamine deficiency and perinatal lethality. Mice heterozygous for Th mutations exhibit defects in neuropsychologic function and impaired motor control and operant learning. In humans, homozygous or compound heterozygous mutations resulting in reduced TH enzyme function associated with diminished catecholamine biosynthesis underlie all published cases to date.

Normal allelic variants. Human TH consists of 14 exons spanning approximately 8.5 kb [Grima et al 1987, Kaneda et al 1987]. Four types of mRNA are produced through alternative splicing from a single primary transcript (now, several additional types of mRNA are known [Furukawa 2004, Kobayashi & Nagatsu 2005]). Type 1 mRNA and type 4 mRNA contain the coding regions of 1491 and 1584 base pairs, encoding 497 and 528 amino acid residues, respectively. Type 1 mRNA encodes TH isoform b and type 4 mRNA encodes TH isoform a (see Entrez Gene).

Some normal TH variants exist and the p.Val112Met substitution of isoform a (NP_954986.2; see Table 2) has been identified frequently [Ludecke & Bartholome 1995, Ishiguro et al 1998]. Note that this normal variant is also known as the p.Val81Met substitution of isoform b (reference sequence NP_000351.2).

Pathologic allelic variants. More than 20 pathologic mutations (including point mutations in the CRE within the TH promoter) have been reported in individuals with TH deficiency [Ludecke et al 1995, Ludecke et al 1996, van den Heuvel et al 1998, Brautigam et al 1999, Wevers et al 1999, de Lonlay et al 2000, de Rijk-van Andel et al 2000, Dionisi-Vici et al 2000, Janssen et al 2000, Swaans et al 2000, Furukawa et al 2001, Grattan-Smith et al 2002, Hoffmann et al 2003, Schiller et al 2004, Moller et al 2005, Ribasés et al 2007, Verbeek et al 2007]. One of them, p.Arg233His, has been found repeatedly in unrelated families [Furukawa 2003].

Table 2. Selected TH Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequence
Normalc.334G>Ap.Val112MetNM_199292​.2
NP_954986​.2
Pathologicc.698G>Ap.Arg233His

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The normal product is the TH (EC 1.14.16.2) protein. The enzyme TH, a BH4-dependent monooxygenase, catalyzes the rate-limiting step (the formation of dopa from tyrosine) in the biosynthesis of catecholamines (dopamine, noradrenaline, adrenaline). The native TH enzyme is a tetramer of four identical subunits [Goodwill et al 1997].

Abnormal gene product. Because null TH mutations are lethal in Th(-/-) knockout mice [Zhou et al 1995], it appears that both homozygotes and compound heterozygotes for TH mutations have some residual enzyme activity.

  • In one family with TH-deficient DRD and homozygosity for a missense TH mutation, the mutant enzyme had approximately 15% of specific activity compared with the wild-type in an in vitro coupled transcription-translation assay system [Knappskog et al 1995, Ludecke et al 1995].
  • In an individual with infantile parkinsonism and developmental motor delay and a homozygous TH mutation, the mutant enzyme revealed 0.3%-16% of wild-type enzyme activity in three complementary expression systems [Ludecke et al 1996].

References

Literature Cited

  1. Abeling NG, Duran M, Bakker HD, Stroomer L, Thony B, Blau N, Booij J, Poll-The BT. Sepiapterin reductase deficiency an autosomal recessive DOPA-responsive dystonia. Mol Genet Metab. 2006;89:116–20. [PubMed: 16650784]
  2. Hyland K, Cotton RGH, Thoeny B, Blau N. Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 78. Available at www​.ommbid.com. Accessed 2-14-11.
  3. Bonafe L, Thony B, Penzien JM, Czarnecki B, Blau N. Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia. Am J Hum Genet. 2001;69:269–77. [PMC free article: PMC1235302] [PubMed: 11443547]
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Suggested Reading

  1. Pearl PL, Wallis DD, Gibson KM. Pediatric neurotransmitter diseases. Curr Neurol Neurosci Rep. 2004;4:147–52. [PubMed: 14984687]
  2. Swoboda KJ. Diagnosis and treatment of neurotransmitter disorders. In: Swaiman KF, Ashwal S, Ferriero DM, eds. Pediatric Neurology: Principles and Practice. 4th ed. Philadelphia, PA: Mosby Elsevier; 2006:759-69.

Chapter Notes

Acknowledgments

Pediatric Neurotransmitter Disorders Association

Revision History

  • 8 February 2008 (me) Review posted to live Web site
  • 15 February 2007 (me) Scope of Dopa-Responsive Dystonia GeneReview changed as part of update process -> GTP cyclohydrolase 1-deficient dopa-responsive dystonia and tyrosine hydroxylase-deficient dopa-responsive dystonia.
  • 15 June 2004 (me) Comprehensive update posted to live Web site
  • 5 March 2004 (me) Comprehensive update posted to live Web site
  • 21 February 2002 (me) Review posted to live Web site as Dopa-Responsive Dystonia
  • 30 June 2001 (yf) Original submission
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