• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Tyrosine Hydroxylase Deficiency

, MD, PhD and , PhD.

Author Information
, 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
, PhD
Professor, Departments of Psychiatry and Pharmacology
University of Toronto
Head, Human Brain Laboratory
Research Imaging Centre
Centre for Addiction and Mental Health
Toronto, Ontario, Canada

Initial Posting: ; Last Update: July 17, 2014.

Summary

Disease characteristics. Tyrosine hydroxylase (TH) deficiency is associated with a broad phenotypic spectrum. Based on severity of symptoms/signs as well as responsiveness to levodopa therapy, clinical phenotypes caused by TH pathogenic variants are divided into (1) TH-deficient dopa-responsive dystonia (DRD: the mild form of TH deficiency [DYT5b]), (2) TH-deficient infantile parkinsonism with motor delay (the severe form), and (3) TH-deficient progressive infantile encephalopathy (the very severe form).

  • In individuals with TH-deficient DRD, onset is between age 12 months and six years; initial symptoms are typically lower-limb dystonia and/or difficulty in walking. Diurnal fluctuation of symptoms (worsening of the symptoms toward the evening and their alleviation in the morning after sleep) may be present.
  • In most individuals with TH-deficient infantile parkinsonism with motor delay, onset is between age three and 12 months. In contrast to TH-deficient DRD, motor milestones are overtly delayed in this severe form. Affected infants demonstrate truncal hypotonia and parkinsonian symptoms and signs (hypokinesia, rigidity of extremities, and/or tremor).
  • In individuals with TH-deficient progressive infantile encephalopathy, onset is before age three to six months. Fetal distress is reported in most. Affected individuals have marked delay in motor development, truncal hypotonia, severe hypokinesia, limb hypertonia (rigidity and/or spasticity), hyperreflexia, oculogyric crises, ptosis, mental retardation, and paroxysmal periods of lethargy (with increased sweating and drooling) alternating with irritability.

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 has identified biallelic TH pathogenic variants in all affected individuals reported to date.

Management. Treatment of manifestations:

  • All individuals with TH-deficient DRD demonstrate complete responsiveness of symptoms to levodopa (with a decarboxylase inhibitor).
  • Individuals with TH-deficient infantile parkinsonism with motor delay demonstrate a marked response to levodopa. However, in contrast to TH-deficient DRD, the responsiveness is generally not complete and/or it takes several months or even years before the full effects of treatment become established. Some individuals are hypersensitive to levodopa and prone to side effects (i.e., dopa-induced dyskinesias which develop at initiation of levodopa treatment).
  • Individuals with TH-deficient progressive infantile encephalopathy are extremely sensitive to levodopa therapy. In this very severe form, treatment with levodopa is often limited by intolerable dyskinesias.

Prevention of primary manifestations: See Treatment of manifestations.

Prevention of secondary complications: Side effects associated with levodopa (e.g., gastroesophageal reflux, vomiting, significant suppression of appetite) can be ameliorated with appropriate dosing.

Surveillance: Examination by a movement disorder specialist in pediatric or adult neurology at least several times yearly is recommended.

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

Evaluation of relatives at risk: Sibs of affected individuals should be examined for mild dystonic and/or parkinsonian symptoms or unexplained gait disorders. It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from treatment.

Genetic counseling. TH deficiency is inherited in an autosomal recessive manner. Heterozygotes (carriers) are generally asymptomatic. 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 TH pathogenic variants in a family are known.

GeneReview Scope

Tyrosine Hydroxylase Deficiency: Included Disorders
  • TH-deficient dopa-responsive dystonia
  • TH-deficient infantile parkinsonism with motor delay
  • TH-deficient progressive infantile encephalopathy

For synonyms and outdated names see Nomenclature.

Diagnosis

Tyrosine hydroxylase (TH) deficiency is associated with a wide phenotypic spectrum. Based on severity of symptoms and signs as well as responsiveness to levodopa therapy, the three clinical phenotypes attributable to TH pathogenic variants are: TH-deficient dopa-responsive dystonia (the mild form of TH deficiency [DYT5b]); TH-deficient infantile parkinsonism with motor delay (the severe form); and TH-deficient progressive infantile encephalopathy (the very severe form).

Since clinical suspicion is a key to the diagnosis of TH deficiency, physicians should be aware of this broad phenotypic spectrum.

Suggestive Findings

Clinical Signs and Symptoms

The diagnosis of tyrosine hydroxylase deficiency should be considered when the following symptoms and/or signs are recognized:

  • Lower limb dystonia
  • Generalized dystonia
  • Other forms of dystonia
  • Postural and/or rest tremor
  • Slowness of movements
  • Rigidity in affected limbs
  • Postural instability
  • Diurnal fluctuation (worsening of the symptoms toward the evening and their alleviation in the morning after sleep)
  • Hypokinesia
  • Truncal hypotonia
  • Developmental motor delay
  • Hyperreflexia
  • Spasticity in affected limbs
  • Extensor plantar responses
  • The striatal toe
  • Myoclonic jerks
  • Oculogyric crises
  • Bilateral ptosis
  • Mental retardation (intellectual disability)
  • Autonomic disturbances
  • Fetal distress
  • Feeding difficulties
  • Retarded somatic parameters (head circumference, height, and/or weight)
  • Dystonic crises
  • Lethargy-irritability crises

Cerebrospinal Fluid (CSF) Findings

The following pattern of cerebrospinal fluid (CSF) neurotransmitter metabolites and pterins supports the diagnosis of TH deficiency [Bräutigam et al 1998, Furukawa et al 1998a, Furukawa & Kish 1999, Wevers et al 1999, Willemsen et al 2010]:

  • Reduced homovanillic acid (HVA)
  • Normal 5-hydroxyindoleacetic acid (5-HIAA)
  • Reduced HVA/5-HIAA ratio
  • Reduced 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG; a metabolite of noradrenaline)
  • Normal total biopterin (BP) (most of which exists as tetrahydrobiopterin [BH4])
  • Normal total neopterin (NP) (the by-products of the GTP cyclohydrolase 1 [GTPCH1] reaction)

Interpretation of results:

  • If CSF neurotransmitter metabolite and pterin analyses reveal a pattern of abnormalities consistent with TH deficiency in the setting of a characteristic phenotype, a clinical diagnosis of TH deficiency is supported.
  • If CSF pterin analysis reveals low BP and NP levels, GTPCH1-deficient disorders (including GTPCH1-deficient DRD) should be considered; reduced levels of BP and NP have been confirmed in autopsied brains with GTPCH1 dysfunction [Furukawa et al 1999, Furukawa et al 2002].
  • Secondary deficiencies of CSF neurotransmitter metabolites have been noted in other neurodegenerative disorders (see Differential Diagnosis).

Confirming the Diagnosis

The diagnosis of tyrosine hydroxylase deficiency is confirmed by identification of biallelic pathogenic variants in TH, which encodes tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis (Table 1).

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

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
THSequence analysis 2Unknown 3
Deletion/duplication analysis 4Unknown, no deletions/duplications reported 5

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. The inclusion of the cAMP response element in the promoter region in TH sequence analysis appears to improve the mutation detection frequency in TH deficiency [Ribases et al 2007, Verbeek et al 2007, Stamelou et al 2012].

4. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. No deletions or duplications involving TH have been reported to cause tyrosine hydroxylase deficiency. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Clinical Description

Natural History

Tyrosine hydroxylase (TH) deficiency is associated with a wide phenotypic spectrum. Based on the severity of symptoms and signs as well as responsiveness to levodopa therapy, the three clinical phenotypes from mildest to most severe are: TH-deficient dopa-responsive dystonia (DRD) (DYT5b); TH-deficient infantile parkinsonism with motor delay; and TH-deficient progressive infantile encephalopathy (see Table 2). In addition, several atypical severe forms have been recognized.

None of the symptoms and signs of TH deficiency improve without proper treatment with levodopa (see Management).

Mild Form: TH-deficient DRD

Castaigne et al [1971] and Segawa et al [1971] first reported clinical characteristics of one family each with dopa-responsive dystonia (DRD). Advances in the genetics and biochemistry of DRD [Ichinose et al 1994, Ludecke et al 1995, Furukawa et al 1996, Bräutigam et al 1998] have shown that the former had autosomal recessive TH deficiency [Swaans et al 2000] and the latter had autosomal dominant GTP cyclohydrolase 1 (GTPCH1) deficiency (the major form of DRD) [Inagaki et al 1999, Segawa et al 2003] (See GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia [DYT5a]).

Clinical features of more than ten individuals with genetically proven TH-deficient DRD have been reported [Castaigne et al 1971, Rondot & Ziegler 1983, Rondot et al 1992, Knappskog et al 1995, Ludecke et al 1995, Swaans et al 2000, Furukawa et al 2001, Furukawa et al 2004b, Schiller et al 2004, Verbeek et al 2007, Wu et al 2008, Willemsen et al 2010, Haugarvoll & Bindoff 2011, Yeung et al 2011].

In individuals with TH-deficient DRD, the perinatal and postnatal periods are normal. Psychomotor development is normal. Onset of symptoms is generally between ages 12 months and six years.

In these individuals, initial symptoms are usually lower limb dystonia and/or difficulty in walking. In general, gradual progression to generalized dystonia occurs. Bradykinesia and tremor (mainly postural) can be observed. A variable degree of rigidity is detected in affected limbs. There is a tendency to fall. Without treatment individuals with TH-deficient DRD become wheelchair bound.

In addition to dystonic and parkinsonian elements, many affected individuals have some clinical features suggestive of pyramidal signs (hyperreflexia, spasticity, and/or extensor plantar responses). Plantar responses become flexor after beginning levodopa therapy, suggesting that the previous findings may be consistent with a dystonic phenomenon (the striatal toe) rather than a Babinski response.

Intellect is not impaired in individuals with TH-deficient DRD. Of note, Schiller et al [2004] have reported a TH-deficient DRD patient with mild cognitive impairment due to infantile rhesus incompatibility.

In rare instances, sustained upward ocular deviations (oculogyric crises) are observed.

Diurnal fluctuation of symptoms (worsening of the symptoms toward the evening and their alleviation in the morning after sleep) has been reported in approximately one third of the individuals with TH-deficient DRD, a much lower incidence than observed in GTPCH1-deficient DRD.

DRD is characterized by a dramatic and sustained response to relatively low doses of levodopa [Nygaard 1993, Furukawa 2004]. All individuals with TH-deficient DRD demonstrate complete responsiveness of symptoms to levodopa therapy. (Note: The term ‘levodopa therapy,’ without further specification, is herein used to indicate oral administration of levodopa with a decarboxylase inhibitor.) Such an excellent response in the absence of any motor adverse effects of chronic levodopa therapy (i.e., wearing-off and on-off phenomena and dopa-induced dyskinesias) for more than 30 years has been confirmed in at least five patients with TH-deficient DRD [Swaans et al 2000, Schiller et al 2004], including two affected brothers originally reported by Castaigne et al [1971].

Severe Form: TH-Deficient Infantile Parkinsonism with Motor Delay

More than 20 individuals with genetically proven TH-deficient infantile parkinsonism with motor delay have been reported [Ludecke et al 1996, Bräutigam et al 1998, Surtees & Clayton 1998, van den Heuvel et al 1998, Wevers et al 1999, de Rijk-van Andel et al 2000, Grattan-Smith et al 2002, Yeung et al 2006, Ribases et al 2007, Verbeek et al 2007, Clot et al 2009, Doummar et al 2009, Pons et al 2010, Willemsen et al 2010, Haugarvoll & Bindoff 2011, Najmabadi et al 2011, Yeung et al 2011, Chi et al 2012, Giovanniello et al 2012, Pons et al 2013].

In general, the pregnancies of affected individuals are uncomplicated. Perinatal and early postnatal periods are usually normal. Onset in most children is between ages three and 12 months. In contrast to TH-deficient DRD, in this severe form motor milestones are overtly delayed in infancy.

All affected individuals demonstrate truncal hypotonia as well as parkinsonian symptoms and signs (hypokinesia, rigidity of extremities, and/or tremor). Although dystonia is recognized in most, it tends to be less prominent. Brisk deep tendon reflexes, spasticity, and/or extensor plantar responses are frequently detected. Deep tendon reflexes have been reported to be normal or reduced in some.

Oculogyric crises are often observed. Ptosis and other features of mild autonomic dysfunction can be observed. Mental retardation is found in many of the affected individuals.

Typical diurnal fluctuation of symptoms is not observed in most patients with TH-deficient infantile parkinsonism with motor delay. Of note, diurnal variation of axial hypotonia but not of limb dystonia has been described in one affected individual [Clot et al 2009, Doummar et al 2009].

Individuals with TH-deficient infantile parkinsonism with motor delay demonstrate a marked response to levodopa. However, in contrast to TH-deficient DRD, the responsiveness is generally not complete and/or it takes several months or even years for the full effects of treatment to become established. For example,

  • Four individuals reported by de Rijk-van Andel et al [2000] still had clumsy gait and intellectual impairment four to five years after beginning levodopa therapy.
  • One child, who had received levodopa from age six months, showed motor and speech delay even at age three years [Ludecke et al 1996]. Subsequently, this child was reported to have no developmental delay and no neurologic abnormalities when examined at age four years [Surtees & Clayton 1998].

Some affected individuals are hypersensitive to levodopa (combined with a decarboxylase inhibitor) and are prone to intolerable side effects (i.e., severe dopa-induced dyskinesias which develop at initiation of levodopa treatment); because of this hypersensitivity, such patients require very low initial doses of levodopa [Grattan-Smith et al 2002, Yeung et al 2006, Clot et al 2009, Doummar et al 2009, Yeung et al 2011].

Very Severe Form: TH-Deficient Progressive Infantile Encephalopathy

More than ten individuals with genetically proven TH-deficient progressive infantile encephalopathy have been reported [Bräutigam et al 1999, de Lonlay et al 2000, Dionisi-Vici et al 2000, Janssen et al 2000, Haussler et al 2001, Hoffmann et al 2003, Moller et al 2005, Zafeiriou et al 2009, Willemsen et al 2010, Yeung et al 2011, Chi et al 2012, Szentivanyi et al 2012, Pons et al 2013].

TH-deficient progressive infantile encephalopathy begins before age three to six months. Fetal distress is reported in most; infants with this neonatal-onset form may demonstrate feeding difficulties, hypotonia, and/or retarded somatic parameters (head circumference, height, and/or weight) from birth. Determining the age of onset is sometimes difficult because of complicated perinatal events.

Affected individuals have marked delay in motor development, truncal hypotonia, severe hypokinesia, limb hypertonia (rigidity and/or spasticity), hyperreflexia with extensor plantar responses, oculogyric crises, bilateral ptosis, mental retardation, and paroxysmal periods of lethargy (with increased sweating and drooling) alternated with irritability (so-called lethargy-irritability crises [Willemsen et al 2010]).

In general, dystonia is not a prominent clinical feature of TH-deficient progressive infantile encephalopathy; however, in the most severely affected infants, dystonic crises (every 4-5 days) have been reported [Zafeiriou et al 2009, Willemsen et al 2010]. Other abnormal involuntary movements (tremor and/or myoclonic jerks) can be observed in some.

Although autonomic disturbances occur, especially in the periods of lethargy-irritability crises, the clinical characteristics of impaired production of peripheral catecholamines (e.g., abnormalities in the maintenance of blood pressure) are not present [Hoffmann et al 2003, Willemsen et al 2010].

Usually, typical diurnal fluctuation of symptoms is not recognized in TH-deficient progressive infantile encephalopathy.

Individuals with TH-deficient progressive infantile encephalopathy are extremely sensitive to levodopa therapy; thus, treatment with levodopa is often limited by intolerable dyskinesias. Some develop severe dyskinesias even at doses of 0.2 to 1.5 mg/kg/day levodopa (combined with a decarboxylase inhibitor); no or only minimum improvement can be detected in these patients [de Lonlay et al 2000, Hoffmann et al 2003, Zafeiriou et al 2009]. Two such patients died at ages 2.5 years and nine years [Hoffmann et al 2003, Willemsen et al 2010].

Table 2. Characteristics of the Three Phenotypes of TH Deficiency

Clinical PhenotypeSeverityAge at OnsetEffect of Levodopa
TH-deficient dopa-responsive dystoniaMild12 mos-6 yrsDramatic and sustained
TH-deficient infantile parkinsonism with motor delaySevere3-12 mosIncomplete 1
TH-deficient progressive infantile encephalopathyVery severe<3-6 mosLittle to none 2

1. Generally incomplete and/or levodopa treatment takes months/years to achieve full effect.

2. Levodopa treatment is often limited by intolerable dopa-induced dyskinesias which develop at initiation of the therapy.

Atypical Severe Forms

TH-deficient myoclonus-dystonia. Stamelou et al [2012] reported three sibs with severe TH deficiency who presented with truncal hypotonia, developmental motor delay, generalized dystonia, and prominent myoclonic jerks in infancy. The proband in this family had a normal birth but was floppy with poor head control at age six months. After beginning levodopa treatment at age 13 years, all of her symptoms (including cognitive dysfunction) markedly improved. She could walk some steps with help but had generalized dystonia, choreoathetoid movements, slowing in finger-tapping, and myoclonic jerks even five years after starting levodopa therapy.

TH deficiency with a biphasic clinical course. Giovanniello et al [2007] reported one individual with moderate-severe TH deficiency showing a biphasic course. Psychomotor development was normal in early infancy. In the second year of life he demonstrated toe-walking, frequent falls, and developmental language delay. At age 11 years, he developed involuntary movements over the course of a few months. When examined at age 13 years, he had generalized choreoathetosis, myoclonic jerks, expressionless face, dysarthria, gaze paresis, oculogyric crises, and borderline IQ. He showed hypersensitivity to levodopa and could be treated only with very low doses.

TH deficiency with exacerbation by viral infections. Diepold et al [2005] reported one individual with developmental psychomotor delay, truncal hypotonia, parkinsonism, and dystonic posturing of the hands. These symptoms were induced and/or exacerbated by viral infections (e.g., exanthema subitum, an active infection of Epstein-Barr virus). Although he demonstrated a remarkable response to levodopa, this patient still had truncal hypotonia and developmental delay six months after starting levodopa treatment.

Neuroimaging

In all individuals with TH-deficient DRD and in most individuals with TH-deficient infantile parkinsonism with motor delay brain MRI is normal. Brain MRI demonstrated no abnormalities in the basal ganglia of two patients with TH-deficient DRD even 38 and 43 years after onset of the disorder [Schiller et al 2004].

In individuals with TH-deficient progressive infantile encephalopathy, brain MRI often reveals mild-moderate cerebral and/or cerebellar atrophy. In one individual with this very severe form, no abnormalities were observed on two brain MRIs in the first year of life; however, the third brain MRI at age 2.5 years showed periventricular white matter changes and symmetric high signal abnormalities in the superior cerebellar peduncles and dorsal pons [Zafeiriou et al 2009].

Neuropathology

No autopsies of individuals with any of the forms of TH deficiency have been reported.

Genotype-Phenotype Correlations

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

It is known, however, that all of the affected individuals who have at least one point mutation in the promoter region of TH (homozygotes or compound heterozygotes) have never developed the very severe form of TH deficiency [Ribases et al 2007, Verbeek et al 2007, Stamelou et al 2012].

Penetrance

Penetrance appears to be complete in individuals with biallelic TH pathogenic variants.

In contrast to autosomal dominant GTPCH1-deficient DRD [Furukawa et al 1998b, Segawa et al 2003], there is no predominance of clinically affected females in autosomal recessive TH-deficient DRD.

Prevalence

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

Nomenclature

DYT5a is another designation for GTP cyclohydrolase 1-deficient dopa-responsive dystonia.

DYT5b is another designation for TH-deficient dopa-responsive dystonia (see Dystonia Overview).

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 80% of individuals with DRD have sequence variants or exon deletions in GCH1 [Furukawa et al 2013], the gene encoding the enzyme GTPCH1. The enzyme GTPCH1 catalyzes the first step in the biosynthesis of tetrahydrobiopterin (BH4), the essential cofactor for TH. Brain and CSF concentrations of total BP (most of which exists as BH4) and total NP (the by-products of the GTPCH1 reaction) are low in GTPCH1-deficient DRD [Furukawa 2003] (see Diagnosis, Cerebrospinal Findings, Interpretation of results).

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.

Autosomal recessive sepiapterin reductase (SR)-deficient DRD (OMIM 612716). Arrabal et al [2011] reported one family with a strikingly mild phenotype (without motor and cognitive delay) of SR deficiency associated with compound heterozygous pathogenic variants in SPR (which encodes SR). One pathogenic variant was a missense mutation and the other a partially penetrant splicing mutation. In this family with autosomal recessive SR-deficient DRD, an affected family member showed markedly decreased levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in CSF.

Early-onset primary dystonia (DYT1). A GAG deletion in 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 it 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. 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) [Furukawa et al 2013].
  • Measurement of the concentration of both BP and NP in CSF is useful in distinguishing the following three disorders responsive to levodopa [Furukawa et al 1998a, 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) pathogenic variants

See Parkin Type of Early-Onset 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, including recessively inherited GTPCH1 deficiency). Individuals with recessively inherited BH4 deficiencies develop BH4-dependent hyperphenylalaninemia (HPA) in the first six months of life; an exception is autosomal recessive sepiapterin reductase (SR) deficiency (in which BH4 is synthesized through the salvage pathway in peripheral tissue). Individuals with autosomal recessive BH4 deficiencies typically present with severe neurologic dysfunction (e.g., psychomotor retardation, convulsions, microcephaly, swallowing difficulties, hypersomnia, cognitive impairment, truncal hypotonia, limb hypertonia, paroxysmal stiffening, involuntary movements, oculogyric crises); diurnal fluctuation of symptoms and dystonia partially responding to levodopa can be seen in some, especially those with SR deficiency [Hanihara et al 1997, Furukawa & Kish 1999, Bonafe et al 2001, Furukawa 2004, Neville et al 2005, Abeling et al 2006, Roze et al 2006, Arrabal et al 2011, Dill et al 2012, Marras et al 2012] (see Autosomal recessive SR-deficient DRD). For individuals with autosomal recessive SR deficiency, oral administration of both levodopa and 5-hydroxytryptophan is necessary because of very low levels of the neurotransmitter metabolites HVA and 5-HIAA in CSF. BH4 treatment and neurotransmitter replacement therapy (levodopa and 5-hydroxytriptophan) 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

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

  • Clinical examination to assess the severity of motor disturbances
  • Evaluation for associated psychiatric symptoms or cognitive impairments
  • Medical genetics consultation

Treatment of Manifestations

In patients with TH deficiency, initial use of a levodopa (combined with a decarboxylase inhibitor) dose of 0.5-3 mg/kg (body weight)/day, divided into three to six doses, has been recommended [Willemsen et al 2010, Yeung et al 2011, Pons et al 2013]. Nevertheless, it is possible that even at the lowest initial dosage recommended (i.e., 0.5 mg/kg/day), some individuals with the very severe form of TH deficiency (Table 2) will develop intolerable dyskinesias [Zafeiriou et al 2009, Pons et al 2013].

When tolerated, the dose of levodopa can be increased gradually. However, with the exception of those with mild TH-deficient DRD (see Table 2), it is often difficult to increase levodopa doses smoothly in affected individuals due to the risk of developing severe dyskinesias. In such cases, combined administration of levodopa and selegiline (a monoamine oxidase B inhibitor, which inhibits dopamine degradation) has been recommended [Dionisi-Vici et al 2000, Haussler et al 2001, Willemsen et al 2010, Yeung et al 2011].

As reported in compound heterozygotes for GCH1 pathogenic variants [Furukawa et al 2004a], amantadine (an N-methyl-D-aspartate receptor antagonist) can suppress dopa-induced dyskinesias, which develop at initiation of levodopa therapy, in some patients with TH deficiency [Pons et al 2013].

Mild form (TH-deficient DRD [DYT5b]). Patients demonstrate complete responsiveness of symptoms to levodopa treatment. Such an excellent response without any motor adverse effects of chronic levodopa therapy for more than 30 years has been confirmed in some patients with TH-deficient DRD [Swaans et al 2000, Schiller et al 2004].

Severe form (TH-deficient infantile parkinsonism with motor delay). Patients show a marked response to levodopa. However, in contrast to TH-deficient DRD, the responsiveness is generally not complete and/or it takes several months or even years before full effects of treatment become established. Some patients with the severe form of TH deficiency are hypersensitive to levodopa and are prone to intolerable dyskinesias at initiation of levodopa therapy; this hypersensitivity necessitates use of very low initial doses of levodopa [Grattan-Smith et al 2002, Yeung et al 2006, Clot et al 2009, Doummar et al 2009, Yeung et al 2011].

Very severe form (TH-deficient progressive infantile encephalopathy). Patients are extremely sensitive to levodopa. Accordingly, treatment with levodopa is often limited by severe dyskinesias. Some patients with the very severe form of TH deficiency develop intolerable dyskinesias even at doses of 0.2 to 1.5 mg/kg/day levodopa and no or only minimum improvement is observed [De Lonlay et al 2000, Hoffmann et al 2003, Zafeiriou et al 2009].

Prevention of Primary Manifestations

As described in Treatment of Manifestations, appropriate levodopa therapy can reverse symptoms and signs of TH-deficient DRD; thus, levodopa treatment from early infancy may not be required to prevent disease manifestations in this mild form of TH deficiency.

Levodopa therapy from early infancy may prevent manifestations of some symptoms and signs in TH-deficient infantile parkinsonism with motor delay; however, no levodopa trials in the early postnatal period of infants with biallelic TH pathogenic variants have been reported.

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 dosing in conjunction with appropriate supportive intervention as needed help in management.

Surveillance

Examination by a movement disorder specialist in pediatric or adult neurology at least several times yearly is recommended.

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

It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from treatment.

  • Sibs of affected individuals should be examined for mild dystonic and/or parkinsonian symptoms or unexplained gait disorders.
  • Molecular genetic testing may be available to at-risk sibs if the TH pathogenic variants have been identified in the family.

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 a proband are obligate heterozygotes, and thus carry one mutant allele.
  • Heterozygotes (carriers) are generally asymptomatic.

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 TH pathogenic variant.
  • If the reproductive partner of the proband is an asymptomatic carrier of a TH pathogenic variant, 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

Carrier testing for at-risk relatives requires prior identification of the TH pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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, are carriers, or are at risk of being carriers.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the TH pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing. Prenatal diagnosis of TH deficiency has been reported [Moller et al 2005].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the TH pathogenic variants 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 pathogenic variants exhibit defects in neuropsychologic function and impaired motor control and operant learning. In humans, homozygous or compound heterozygous pathogenic variants resulting in reduced TH enzyme function associated with diminished catecholamine biosynthesis underlie all published cases to date.

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Some normal TH variants exist; the p.Val112Met substitution of isoform a (NP_954986.2; see Table 3) 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).

Pathogenic allelic variants. More than 50 TH pathogenic variants (including single nucleotide variants in the cAMP response element of the TH promoter) have been reported in individuals with TH deficiency; approximately 15% of these TH pathogenic variants may lead to protein truncation [Knappskog et al 1995, Ludecke et al 1995, Ludecke et al 1996, Bräutigam et al 1998, Surtees & Clayton 1998, van den Heuvel et al 1998, Bräutigam 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, Haussler et al 2001, Grattan-Smith et al 2002, Hoffmann et al 2003, Schiller et al 2004, Diepold et al 2005, Moller et al 2005, Yeung et al 2006, Giovanniello et al 2007, Ribases et al 2007, Verbeek et al 2007, Wu et al 2008, Clot et al 2009, Doummar et al 2009, Zafeiriou et al 2009, Pons et al 2010, Willemsen et al 2010, Haugarvoll & Bindoff 2011, Najmabadi et al 2011, Yeung et al 2011, Chi et al 2012, Giovanniello et al 2012, Stamelou et al 2012, Szentivanyi et al 2012, Pons et al 2013].

Table 3. Selected TH Allelic Variants

Variant ClassificationDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequence
Benignc.334G>Ap.Val112MetNM_199292​.2
NP_954986​.2
Pathogenicc.698G>A 1p.Arg233His
c.707T>C 2p.Leu236Pro

Note on variant classification: Variants listed in the table have been provided by the authors. 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.

1. Founder mutation in Dutch population [van den Heuvel et al 1998]

2. Founder mutation in Greek population [Pons et al 2010]

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 pathogenic variants 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 pathogenic variant, 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. Arrabal L, Teresa L, Sánchez-Alcudia R, Castro M, Medrano C, Gutiérrez-Solana L, Roldán S, Ormazábal A, Pérez-Cerdá C, Merinero B, Pérez B, Artuch R, Ugarte M, Desviat LR. Genotype-phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant. Neurogenetics. 2011;12:183–91. [PubMed: 21431957]
  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]
  4. Bräutigam C, Steenbergen-Spanjers GC, Hoffmann GF, Dionisi-Vici C, van den Heuvel LP, Smeitink JA, Wevers RA. Biochemical and molecular genetic characteristics of the severe form of tyrosine hydroxylase deficiency. Clin Chem. 1999;45:2073–8. [PubMed: 10585338]
  5. Bräutigam C, Wevers RA, Jansen RJ, Smeitink JA, de Rijk-van Andel JF, Gabreëls FJ, Hoffmann GF. Biochemical hallmarks of tyrosine hydroxylase deficiency. Clin Chem. 1998;44:1897–904. [PubMed: 9732974]
  6. Castaigne P, Rondot P, Ribadeau-Dumas JL, Saïd G. Progressive extra-pyramidal disorder in 2 young brothers. Remarkable effects of treatment with L-dopa. Rev Neurol (Paris). 1971;124:162–6. [PubMed: 5564861]
  7. Chi C-S, Lee H-F, Tsai C-R. Tyrosine hydroxylase deficiency in Taiwanese infants. Pediatr Neurol. 2012;46:77–82. [PubMed: 22264700]
  8. Clot F, Grabli D, Cazeneuve C, Roze E, Castelnau P, Chabrol B, Landrieu P, Nguyen K, Ponsot G, Abada M, Doummar D, Damier P, Gil R, Thobois S, Ward AJ, Hutchinson M, Toutain A, Picard F, Camuzat A, Fedirko E, Sân C, Bouteiller D, LeGuern E, Durr A, Vidailhet M, Brice A. French Dystonia Network.; Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia. Brain. 2009;132:1753–63. [PubMed: 19491146]
  9. de Lonlay P, Nassogne MC, van Gennip AH, van Cruchten AC, Billatte de Villemeur T, Cretz M, Stoll C, Launay JM, Steenberger-Spante GC, van den Heuvel LP, Wevers RA, Saudubray JM, Abeling NG. Tyrosine hydroxylase deficiency unresponsive to L-dopa treatment with unusual clinical and biochemical presentation. J Inherit Metab Dis. 2000;23:819–25. [PubMed: 11196107]
  10. de Rijk-van Andel JF, Gabreels FJ, Geurtz B, Steenbergen-Spanjers GC, van Den Heuvel LP, Smeitink JA, Wevers RA. L-dopa-responsive infantile hypokinetic rigid parkinsonism due to tyrosine hydroxylase deficiency. Neurology. 2000;55:1926–8. [PubMed: 11134401]
  11. Diepold K, Schutz B, Rostasy K, Wilken B, Hougaard P, Guttler F, Romstad A, Birk Moller L. Levodopa-responsive infantile parkinsonism due to a novel mutation in the tyrosine hydroxylase gene and exacerbation by viral infections. Mov Disord. 2005;20:764–7. [PubMed: 15747353]
  12. Dill P, Wagner M, Somerville A, Thöny B, Blau N, Weber P. Paroxysmal stiffening, upward gaze, and hypotonia: hallmarks of sepiapterin reductase deficiency. Neurology. 2012;78:e29–32. [PubMed: 22291068]
  13. Dionisi-Vici C, Hoffmann GF, Leuzzi V, Hoffken H, Brautigam C, Rizzo C, Steebergen-Spanjers GC, Smeitink JA, Wevers RA. Tyrosine hydroxylase deficiency with severe clinical course: clinical and biochemical investigations and optimization of therapy. J Pediatr. 2000;136:560–2. [PubMed: 10753262]
  14. Doummar D, Clot F, Vidailhet M, Afenjar A, Durr A, Brice A, Mignot C, Guet A, de Villemeur TB, Rodriguez D. Infantile hypokinetic-hypotonic syndrome due to two novel mutations of the tyrosine hydroxylase gene. Mov Disord. 2009;24:943–5. [PubMed: 19224593]
  15. Furukawa Y. Genetics and biochemistry of dopa-responsive dystonia: significance of striatal tyrosine hydroxylase protein loss. Adv Neurol. 2003;91:401–10. [PubMed: 12442699]
  16. Furukawa Y. Update on dopa-responsive dystonia: locus heterogeneity and biochemical features. Adv Neurol. 2004;94:127–38. [PubMed: 14509665]
  17. Furukawa Y, Filiano JJ, Kish SJ. Amantadine for levodopa-induced choreic dyskinesia in compound heterozygotes for GCH1 mutations. Mov Disord. 2004a;19:1256–58. [PubMed: 15389992]
  18. Furukawa Y, Graf WD, Wong H, Shimadzu M, Kish SJ. Dopa-responsive dystonia simulating spastic paraplegia due to tyrosine hydroxylase (TH) gene mutations. Neurology. 2001;56:260–3. [PubMed: 11160968]
  19. Furukawa Y, Guttman M, Nakamura S, Kish SJ. Dopa-responsive dystonia. In: Frucht SJ, ed. Current Clinical Neurology: Movement Disorder Emergencies: Diagnosis and Treatment. 2 ed. New York, NY: Springer (Humana Press); 2013:319-40.
  20. Furukawa Y, Kapatos G, Haycock JW, Worsley J, Wong H, Kish SJ, Nygaard TG. Brain biopterin and tyrosine hydroxylase in asymptomatic dopa-responsive dystonia. Ann Neurol. 2002;51:637–41. [PubMed: 12112113]
  21. Furukawa Y, Kish SJ. Dopa-responsive dystonia: recent advances and remaining issues to be addressed. Mov Disord. 1999;14:709–15. [PubMed: 10495030]
  22. Furukawa Y, Kish SJ, Bebin EM, Jacobson RD, Fryburg JS, Wilson WG, Shimadzu M, Hyland K, Trugman JM. Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations. Ann Neurol. 1998a;44:10–6. [PubMed: 9667588]
  23. Furukawa Y, Kish SJ, Fahn S. Dopa-responsive dystonia due to mild tyrosine hydroxylase deficiency. Ann Neurol. 2004b;55:147–8. [PubMed: 14705130]
  24. Furukawa Y, Lang AE, Trugman JM, Bird TD, Hunter A, Sadeh M, Tagawa T, St George-Hyslop PH, Guttman M, Morris LW, Hornykiewicz O, Shimadzu M, Kish SJ. Gender-related penetrance and de novo GTP-cyclohydrolase I gene mutations in dopa-responsive dystonia. Neurology. 1998b;50:1015–20. [PubMed: 9566388]
  25. Furukawa Y, Nygaard TG, Gütlich M, Rajput AH, Pifl C, DiStefano L, Chang LJ, Price K, Shimadzu M, Hornykiewicz O, Haycock JW, Kish SJ. Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia. Neurology. 1999;53:1032–41. [PubMed: 10496263]
  26. Furukawa Y, Shimadzu M, Rajput AH, Shimizu Y, Tagawa T, Mori H, Yokochi M, Narabayashi H, Hornykiewicz O, Mizuno Y, Kish SJ. GTP-cyclohydrolase I gene mutations in hereditary progressive amd dopa-responsive dystonia. Ann Neurol. 1996;39:609–17. [PubMed: 8619546]
  27. Giovanniello T, Claps D, Carducci C, Carducci C, Blau N, Vigevano F, Antonozzi I, Leuzzi V. A new tyrosine hydroxylase genotype associated with early-onset severe encephalopathy. J Child Neurol. 2012;27:523–5. [PubMed: 21940685]
  28. Giovanniello T, Leuzzi V, Carducci C, Carducci C, Sabato ML, Artiola C, Santagata S, Pozzessere S, Antonozzi I. Tyrosine hydroxylase deficiency presenting with a biphasic clinical course. Neuropediatrics. 2007;38:213–5. [PubMed: 18058633]
  29. Goodwill KE, Sabatier C, Marks C, Raag R, Fitzpatrick PF, Stevens RC. Crystal structure of tyrosine hydroxylase at 2.3 A and its implications for inherited neurodegenerative diseases. Nat Struct Biol. 1997;4:578–85. [PubMed: 9228951]
  30. Grattan-Smith PJ, Wevers RA, Steenbergen-Spanjers GC, Fung VS, Earl J, Wilcken B. Tyrosine hydroxylase deficiency: clinical manifestations of catecholamine insufficiency in infancy. Mov Disord. 2002;17:354–9. [PubMed: 11921123]
  31. Grima B, Lamouroux A, Boni C, Julien JF, Javoy-Agid F, Mallet J. A single human gene encoding multiple tyrosine hydroxylases with different predicted functional characteristics. Nature. 1987;326:707–11. [PubMed: 2882428]
  32. Grimes DA, Barclay CL, Duff J, Furukawa Y, Lang AE. Phenocopies in a large GCH1 mutation positive family with dopa responsive dystonia: confusing the picture? J Neurol Neurosurg Psychiatry. 2002;72:801–4. [PMC free article: PMC1737930] [PubMed: 12023430]
  33. Hanihara T, Inoue K, Kawanishi C, Sugiyama N, Miyakawa T, Onishi H, Yamada Y, Osaka H, Kosaka K, Iwabuchi K, Owada M. 6-Pyruvoyl-tetrahydropterin synthase deficiency with generalized dystonia and diurnal fluctuation of symptoms: a clinical and molecular study. Mov Disord. 1997;12:408–11. [PubMed: 9159737]
  34. Haugarvoll K, Bindoff LA. A novel compound heterozygous tyrosine hydroxylase mutation (p.R441P) with complex phenotype. J Parkinsons Dis. 2011;1:119–22. [PubMed: 23939262]
  35. Haussler M, Hoffmann GF, Wevers RA. L-dopa and selegiline for tyrosine hydroxylase deficiency. J Pediatr. 2001;138:451–2. [PubMed: 11241071]
  36. Hoffmann GF, Assmann B, Bräutigam C, Dionisi-Vici C, Häussler M, de Klerk JB, Naumann M, Steenbergen-Spanjers GC, Strassburg HM, Wevers RA. Tyrosine hydroxylase deficiency causes progressive encephalopathy and dopa-nonresponsive dystonia. Ann Neurol. 2003;54 Suppl 6:56–65. [PubMed: 12891655]
  37. Ichinose H, Ohye T, Takahashi E, Seki N, Hori T, Segawa M, Nomura Y, Endo K, Tanaka H, Tsuji S, Fujita K, Nagatsu T. Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet. 1994;8:236–42. [PubMed: 7874165]
  38. Inagaki H, Ohye T, Suzuki T, Segawa M, Nomura Y, Nagatsu T, Ichinose H. Decrease in GTP cyclohydrolase I gene expression caused by inactivation of one allele in hereditary progressive dystonia with marked diurnal fluctuation. Biochem Biophys Res Commun. 1999;260:747–51. [PubMed: 10403837]
  39. Ishiguro H, Arinami T, Saito T, Akazawa S, Enomoto M, Mitushio H, Fujishiro H, Tada K, Akimoto Y, Mifune H, Shiozuka S, Hamaguchi H, Toru M, Shibuya H. Systematic search for variations in the tyrosine hydroxylase gene and their associations with schizophrenia, affective disorders, and alcoholism. Am J Med Genet. 1998;81:388–96. [PubMed: 9754624]
  40. Janssen RJ, Wevers RA, Haussler M, Luyten JA, Steenbergen-Spanjers GC, Hoffmann GF, Nagatsu T, Van den Heuvel LP. A branch site mutation leading to aberrant splicing of the human tyrosine hydroxylase gene in a child with a severe extrapyramidal movement disorder. Ann Hum Genet. 2000;64:375–82. [PubMed: 11281275]
  41. Kaneda N, Kobayashi K, Ichinose H, Kishi F, Nakazawa A, Kurosawa Y, Fujita K, Nagatsu T. Isolation of a novel cDNA clone for human tyrosine hydroxylase: alternative RNA splicing produces four kinds of mRNA from a single gene. Biochem Biophys Res Commun. 1987;146:971–5. [PubMed: 2887169]
  42. Knappskog PM, Flatmark T, Mallet J, Ludecke B, Bartholome K. Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene. Hum Mol Genet. 1995;4:1209–12. [PubMed: 8528210]
  43. Kobayashi K, Nagatsu T. Molecular genetics of tyrosine 3-monooxygenase and inherited diseases. Biochem Biophys Res Commun. 2005;338:267–70. [PubMed: 16105653]
  44. Ludecke B, Bartholome K. Frequent sequence variant in the human tyrosine hydroxylase gene. Hum Genet. 1995;95:716. [PubMed: 7789962]
  45. Ludecke B, Dworniczak B, Bartholome K. A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome. Hum Genet. 1995;95:123–5. [PubMed: 7814018]
  46. Ludecke B, Knappskog PM, Clayton PT, Surtees RA, Clelland JD, Heales SJ, Brand MP, Bartholome K, Flatmark T. Recessively inherited L-DOPA-responsive parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene. Hum Mol Genet. 1996;5:1023–8. [PubMed: 8817341]
  47. Marras C, Lohmann K, Lang A, Klein C. Fixing the broken system of genetic locus symbols: Parkinson disease and dystonia as examples. Neurology. 2012;78:1016–24. [PMC free article: PMC3310311] [PubMed: 22454269]
  48. Moller LB, Romstad A, Paulsen M, Hougaard P, Ormazabal A, Pineda M, Blau N, Guttler F, Artuch R. Pre- and postnatal diagnosis of tyrosine hydroxylase deficiency. Prenat Diagn. 2005;25:671–5. [PubMed: 16049992]
  49. Najmabadi H, Hu H, Garshasbi M, Zemojtel T, Abedini SS, Chen W, Hosseini M, Behjati F, Haas S, Jamali P, Zecha A, Mohseni M, Püttmann L, Vahid LN, Jensen C, Moheb LA, Bienek M, Larti F, Mueller I, Weissmann R, Darvish H, Wrogemann K, Hadavi V, Lipkowitz B, Esmaeeli-Nieh S, Wieczorek D, Kariminejad R, Firouzabadi SG, Cohen M, Fattahi Z, Rost I, Mojahedi F, Hertzberg C, Dehghan A, Rajab A, Banavandi MJ, Hoffer J, Falah M, Musante L, Kalscheuer V, Ullmann R, Kuss AW, Tzschach A, Kahrizi K, Ropers HH. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011;478:57–63. [PubMed: 21937992]
  50. Neville BG, Parascandalo R, Farrugia R, Felice A. Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder. Brain. 2005;128:2291–6. [PubMed: 16049044]
  51. Nygaard TG. Dopa-responsive dystonia: delineation of the clinical syndrome and clues to pathogenesis. Adv Neurol. 1993;60:577–85. [PubMed: 8420194]
  52. Nygaard TG, Marsden CD, Duvoisin RC. Dopa-responsive dystonia. Adv Neurol. 1988;50:377–84. [PubMed: 3041760]
  53. Pons R, Serrano M, Ormazabal A, Toma C, Garcia-Cazorla A, Area E, Ribasés M, Kanavakis E, Drakaki K, Giannakopoulos A, Orfanou I, Youroukos S, Cormand B, Artuch R. Tyrosine hydroxylase deficiency in three Greek patients with a common ancestral mutation. Mov Disord. 2010;25:1086–90. [PubMed: 20198643]
  54. Pons R, Syrengelas D, Youroukos S, Orfanou I, Dinopoulos A, Cormand B, Ormazabal A, Garzía-Cazorla A, Serrano M, Artuch R. Levodopa-induced dyskinesias in tyrosine hydroxylase deficiency. Mov Disord. 2013;28:1058–63. [PubMed: 23389938]
  55. Ribases M, Serrano M, Fernandez-Alvarez E, Pahisa S, Ormazabal A, Garcia-Cazorla A, Perez-Duenas B, Campistol J, Artuch R, Cormand B. A homozygous tyrosine hydroxylase gene promoter mutation in a patient with dopa-responsive encephalopathy: clinical, biochemical and genetic analysis. Mol Genet Metab. 2007;92:274–7. [PubMed: 17698383]
  56. Rondot P, Aicardi J, Goutières F, Ziegler M. Dopa-sensitive dystonia. Rev Neurol (Paris). 1992;148:680–6. [PubMed: 1303557]
  57. Rondot P, Ziegler M. Dystonia--L-dopa responsive or juvenile parkinsonism? J Neural Transm Suppl. 1983;19:273–81. [PubMed: 6583312]
  58. Roze E, Vidailhet M, Blau N, Moller LB, Doummar D, de Villemeur TB, Roubergue A. Long-term follow-up and adult outcome of 6-pyruvoyl-tetrahydropterin synthase deficiency. Mov Disord. 2006;21:263–6. [PubMed: 16161143]
  59. Schiller A, Wevers RA, Steenbergen GC, Blau N, Jung HH. Long-term course of L-dopa-responsive dystonia caused by tyrosine hydroxylase deficiency. Neurology. 2004;63:1524–6. [PubMed: 15505183]
  60. Segawa M, Nomura Y, Nishiyama N. Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol. 2003;54 Suppl 6:S32–45. [PubMed: 12891652]
  61. Segawa M, Ohmi K, Itoh S, Aoyama N, Hayakawa H. Childhood basal ganglia disease with remarkable response to L-Dopa: hereditary progressive basal ganglia disease with marked fluctuation. Shinryo (Tokyo). 1971;24:667–72.
  62. Stamelou M, Mencacci NE, Cordivari C, Batla A, Wood NW, Houlden H, Hardy J, Bhatia KP. Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency. Neurology. 2012;79:435–41. [PMC free article: PMC3405253] [PubMed: 22815559]
  63. Surtees R, Clayton P. Infantile parkinsonism-dystonia: tyrosine hydroxylase deficiency. Mov Disord. 1998;13:350.
  64. Swaans RJ, Rondot P, Renier WO, Van Den Heuvel LP, Steenbergen-Spanjers GC, Wevers RA. Four novel mutations in the tyrosine hydroxylase gene in patients with infantile parkinsonism. Ann Hum Genet. 2000;64:25–31. [PubMed: 11246459]
  65. Szentiványi K, Hansíková H, Krijt J, Vinšová K, Tesařová M, Rozsypalová E, Klement P, Zeman J, Honzík T. Novel mutations in the tyrosine hydroxylase gene in the first Czech patient with tyrosine hydroxylase deficiency. Prague Med Rep. 2012;113:136–46. [PubMed: 22691284]
  66. Tassin J, Durr A, Bonnet AM, Gil R, Vidailhet M, Lucking CB, Goas JY, Durif F, Abada M, Echenne B, Motte J, Lagueny A, Lacomblez L, Jedynak P, Bartholome B, Agid Y, Brice A. Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations? Brain. 2000;123:1112–21. [PubMed: 10825351]
  67. van den Heuvel LP, Luiten B, Smeitink JA, de Rijk-van Andel JF, Hyland K, Steenbergen-Spanjers GC, Janssen RJ, Wevers RA. A common point mutation in the tyrosine hydroxylase gene in autosomal recessive L-DOPA-responsive dystonia in the Dutch population. Hum Genet. 1998;102:644–6. [PubMed: 9703425]
  68. Verbeek MM, Steenbergen-Spanjers GC, Willemsen MA, Hol FA, Smeitink J, Seeger J, Grattan-Smith P, Ryan MM, Hoffmann GF, Donati MA, Blau N, Wevers RA. Mutations in the cyclic adenosine monophosphate response element of the tyrosine hydroxylase gene. Ann Neurol. 2007;62:422–6. [PubMed: 17696123]
  69. Wevers RA, de Rijk-van Andel JF, Brautigam C, Geurtz B, van den Heuvel LP, Steenbergen-Spanjers GC, Smeitink JA, Hoffmann GF, Gabreels FJ. A review of biochemical and molecular genetic aspects of tyrosine hydroxylase deficiency including a novel mutation (291delC). J Inherit Metab Dis. 1999;22:364–73. [PubMed: 10407773]
  70. Willemsen MA, Verbeek MM. et al. Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. Brain. 2010;133:1810–22. [PubMed: 20430833]
  71. Wu ZY, Lin Y, Chen WJ, Zhao GX, Xie H, Murong SX, Wang N. Molecular analyses of GCH-1, TH and parkin genes in Chinese dopa-responsive dystonia families. Clin Genet. 2008;74:513–21. [PubMed: 18554280]
  72. Yeung WL, Wong VC, Chan KY, Hui J, Fung CW, Yau E, Ko CH, Lam CW, Mak CM, Siu S, Low L. Expanding phenotype and clinical analysis of tyrosine hydroxylase deficiency. J Child Neurol. 2011;26:179–87. [PubMed: 20823027]
  73. Yeung WL, Lam CW, Hui J, Tong SF, Wu SP. Galactorrhea-a strong clinical clue towards the diagnosis of neurotransmitter disease. Brain Dev. 2006;28:389–91. [PubMed: 16376043]
  74. Zafeiriou DI, Willemsen MA, Verbeek MM, Vargiami E, Ververi A, Wevers R. Tyrosine hydroxylase deficiency with severe clinical course. Mol Genet Metab. 2009;97:18–20. [PubMed: 19282209]
  75. Zhou QY, Quaife CJ, Palmiter RD. Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development. Nature. 1995;374:640–3. [PubMed: 7715703]

Chapter Notes

Author History

Yoshiaki Furukawa, MD, PhD (2001-present)
Stephen Kish, PhD (2014-present)
Kathryn Swoboda, MD, University of Utah School of Medicine (2008-2014)

Revision History

  • 17 July 2014 2014 (me) Comprehensive update posted live
  • 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
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1437PMID: 20301610
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...