Clinical 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 pathogenic variants in TH are divided into (1) TH-deficient dopa-responsive dystonia (the mild form of TH deficiency), (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 dopa-responsive dystonia (DYT5b, DYT-TH), onset is between age 12 months and 12 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, intellectual disability, and paroxysmal periods of lethargy (with increased sweating and drooling) alternating with irritability.

Diagnosis/testing.

The diagnosis of TH deficiency is established in a proband by identification of biallelic pathogenic variants in TH by molecular genetic testing.

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: 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 this type of TH deficiency and biallelic TH pathogenic variants have been reported.

Prevention of secondary complications: Side effects associated with levodopa (e.g., gastroesophageal reflux, vomiting, significant suppression of appetite) may be ameliorated with dose adjustment and supportive intervention.

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

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, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if both TH pathogenic variants in a family are known.

Suggestive Findings

The diagnosis of TH deficiency should be suspected in an individual with the following clinical and laboratory features.

Clinical

• 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
• Intellectual disability
• Autonomic disturbances
• Fetal distress
• Feeding difficulties
• Growth retardation (head circumference, height, and/or weight)
• Dystonic crises
• Lethargy-irritability crises

Laboratory (cerebrospinal fluid)

• 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)

This pattern of CSF neurotransmitter metabolites and pterins supports the clinical diagnosis of TH deficiency [Bräutigam et al 1998, Furukawa et al 1998a, Furukawa & Kish 1999, Wevers et al 1999, Willemsen et al 2010].

If CSF pterin analysis reveals low BP and NP levels, GTPCH1-deficient disorders (including GTPCH1-deficient dopa-responsive dystonia; see Differential Diagnosis) 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].

Establishing the Diagnosis

The diagnosis of TH deficiency is established in a proband by identification of biallelic pathogenic variants in TH (see Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of TH is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes TH and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

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, DYT-TH); 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).

Genotype-Phenotype Correlations

Individuals who are homozygous or compound heterozygous for a single-nucleotide variant in the promoter region of TH have not developed the very severe form of TH deficiency [Ribasés et al 2007, Verbeek et al 2007, Ormazabal et al 2011, Stamelou et al 2012, Ortez et al 2015].

No additional genotype-phenotype correlations have been identified in individuals with TH deficiency.

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. DRD has been reported to account for an estimated 5%-10% of primary dystonia in childhood or adolescence [Nygaard et al 1988].

Nomenclature

DYT5b and DYT-TH are other designations for TH-deficient dopa-responsive dystonia (see Dystonia Overview).

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 if they have not already been completed:

• Clinical examination to assess the severity of motor disturbances
• Evaluation for associated psychiatric symptoms or cognitive impairments
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

In individuals 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 (see 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 individuals, combined administration of levodopa and selegiline (a monoamine oxidase B inhibitor, which inhibits dopamine degradation) has been recommended [Dionisi-Vici et al 2000, Häussler et al 2001, Willemsen et al 2010, Yeung et al 2011, Leuzzi et al 2017].

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 individuals with TH deficiency [Pons et al 2013].

Mild form (TH-deficient DRD). Individuals 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 individuals with TH-deficient DRD [Swaans et al 2000, Schiller et al 2004].

Severe form (TH-deficient infantile parkinsonism with motor delay). Individuals 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 individuals 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). Individuals are extremely sensitive to levodopa. Accordingly, treatment with levodopa is often limited by severe dyskinesias. Some individuals 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 minimal 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 this type of TH deficiency and 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 prompt initiation of treatment.

Evaluations include:

• Clinical examination to identify mild dystonic and/or parkinsonian symptoms or unexplained gait disorders;
• Molecular genetic testing 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 in the US and EU Clinical Trials Register in Europe 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.

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 (i.e., carriers of one TH pathogenic variant).
• 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.
• Heterozygotes (carriers) are generally asymptomatic.

Offspring of a proband. Unless an individual with TH deficiency has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in TH.

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

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/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the TH pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Prenatal diagnosis of TH deficiency has been reported [Møller et al 2005].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular 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 neuropsychological function and impaired motor control and operant learning. In humans, homozygous or compound heterozygous pathogenic variants can result in reduced TH enzyme function.

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 (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.

Pathogenic variants. Approximately 60 TH pathogenic variants (including single-nucleotide variants in the cAMP response element of the TH promoter) have been reported in individuals with TH deficiency [Knappskog et al 1995, Lüdecke et al 1995, Lüdecke 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, Häussler et al 2001, Grattan-Smith et al 2002, Hoffmann et al 2003, Schiller et al 2004, Diepold et al 2005, Møller et al 2005, Yeung et al 2006, Giovanniello et al 2007, Ribasés 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, Ormazabal et al 2011, Yeung et al 2011, Chi et al 2012, Giovanniello et al 2012, Stamelou et al 2012, Szentiványi et al 2012, Pons et al 2013, Sun et al 2014, Ortez et al 2015, Tristán-Noguero et al 2016, Leuzzi et al 2017, Yan et al 2017, Zhang et al 2017]. Founder effects have been described for the c.698G>A pathogenic variant in the Dutch population [van den Heuvel et al 1998] and for the c.707T>C pathogenic variant in the 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 TH null variants 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 TH missense variant, the mutated 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, Lüdecke et al 1995].
• In an individual with TH-deficient infantile parkinsonism with motor delay and a homozygous TH pathogenic variant, the mutated enzyme revealed 0.3%-16% of wild-type enzyme activity in three complementary expression systems [Lüdecke et al 1996].

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

• 11 May 2017 (sw) Comprehensive update posted live
• 17 July 2014 (me) Comprehensive update posted live
• 8 February 2008 (me) Review posted live
• 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 live
• 5 March 2004 (me) Comprehensive update posted live
• 21 February 2002 (me) Review posted live as Dopa-Responsive Dystonia
• 30 June 2001 (yf) Original submission

Literature Cited

• 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]
• 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]
• Bonafé 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]
• 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]
• 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]
• 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]
• Chi C-S, Lee H-F, Tsai C-R. Tyrosine hydroxylase deficiency in Taiwanese infants. Pediatr Neurol. 2012;46:77–82. [PubMed: 22264700]
• 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, et al. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with dopa-responsive dystonia. Brain. 2009;132:1753–63. [PubMed: 19491146]
• 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]
• 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]
• Diepold K, Schutz B, Rostasy K, Wilken B, Hougaard P, Güttler F, Romstad A, Birk Møller 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]
• 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]
• 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]
• 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 Apr 30;24:943–5. [PubMed: 19224593]
• Friedman J, Roze E, Abdenur JE, Chang R, Gasperini S, Saletti V, Wali GM, Eiroa H, Neville B, Felice A, Parascandalo R, Zafeiriou DI, Arrabal-Fernandez L, Dill P, Eichler FS, Echenne B, Gutierrez-Solana LG, Hoffmann GF, Hyland K, Kusmierska K, Tijssen MA, Lutz T, Mazzuca M, Penzien J, Poll-The BT, Sykut-Cegielska J, Szymanska K, Thöny B, Blau N. Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann Neurol. 2012;71:520–30. [PubMed: 22522443]
• Friedman JR. What is not in the name? Dopa-responsive dystonia may respond to more than L-dopa. Pediatr Neurol. 2016;59:76–80. [PubMed: 27080360]
• Furukawa Y. Update on dopa-responsive dystonia: locus heterogeneity and biochemical features. Adv Neurol. 2004;94:127–38. [PubMed: 14509665]
• 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]
• 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]
• 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.
• 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]
• Furukawa Y, Kish SJ. Dopa-responsive dystonia: recent advances and remaining issues to be addressed. Mov Disord. 1999;14:709–15. [PubMed: 10495030]
• Furukawa Y, Kish SJ. Parkinsonism in GTP cyclohydrolase 1-deficient DOPA-responsive dystonia. Brain. 2015;138:e351. [PMC free article: PMC5963400] [PubMed: 25416181]
• 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]
• Furukawa Y, Kish SJ, Fahn S. Dopa-responsive dystonia due to mild tyrosine hydroxylase deficiency. Ann Neurol. 2004b;55:147–8. [PubMed: 14705130]
• 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]
• 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]
• Furukawa Y, Rajput AH, Tong J, Tomizawa Y, Hornykiewicz O, Kish SJ. A marked contrast between serotonergic and dopaminergic changes in dopa-responsive dystonia. Neurology. 2016;87:1060–1. [PMC free article: PMC5027808] [PubMed: 27488599]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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]
• Häussler M, Hoffmann GF, Wevers RA. L-dopa and selegiline for tyrosine hydroxylase deficiency. J Pediatr. 2001;138:451–2. [PubMed: 11241071]
• 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:S56–65. [PubMed: 12891655]
• Janssen RJ, Wevers RA, Häussler 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]
• 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]
• Knappskog PM, Flatmark T, Mallet J, Lüdecke B, Bartholomé 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]
• Kobayashi K, Nagatsu T. Molecular genetics of tyrosine 3-monooxygenase and inherited diseases. Biochem Biophys Res Commun. 2005;338:267–70. [PubMed: 16105653]
• Leuzzi V, Mastrangelo M, Giannini MT, Carbonetti R, Hoffmann GF. Neuromotor and cognitive outcomes of early treatment in tyrosine hydroxylase deficiency type B. Neurology. 2017;88:501–2. [PubMed: 28039315]
• Lüdecke B, Dworniczak B, Bartholomé K. A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome. Hum Genet. 1995;95:123–5. [PubMed: 7814018]
• Lüdecke B, Knappskog PM, Clayton PT, Surtees RA, Clelland JD, Heales SJ, Brand MP, Bartholomé 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]
• 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]
• Møller LB, Romstad A, Paulsen M, Hougaard P, Ormazabal A, Pineda M, Blau N, Güttler F, Artuch R. Pre- and postnatal diagnosis of tyrosine hydroxylase deficiency. Prenat Diagn. 2005;25:671–5. [PubMed: 16049992]
• 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]
• 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]
• Nygaard TG. Dopa-responsive dystonia: delineation of the clinical syndrome and clues to pathogenesis. Adv Neurol. 1993;60:577–85. [PubMed: 8420194]
• Nygaard TG, Marsden CD, Duvoisin RC. Dopa-responsive dystonia. Adv Neurol. 1988;50:377–84. [PubMed: 3041760]
• Ormazabal A, Serrano M, Garcia-Cazorla A, Campistol J, Artuch R, Castro de Castro P, Barredo-Valderrama E, Armstrong J, Toma C, Cormand B. Deletion in the tyrosine hydroxylase gene in a patient with a mild phenotype. Mov Disord. 2011;26:1558–60. [PubMed: 21465550]
• Ortez C, Duarte ST, Ormazábal A, Serrano M, Pérez A, Pons R, Pineda M, Yapici Z, Fernández-Álvarez E, Domingo-Jiménez R, De Castro P, Artuch R, García-Cazorla A. Cerebrospinal fluid synaptic proteins as useful biomarkers in tyrosine hydroxylase deficiency. Mol Genet Metab. 2015;114:34–40. [PubMed: 25468651]
• 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]
• 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]
• Ribasés 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]
• Rondot P, Aicardi J, Goutières F, Ziegler M. Dopa-sensitive dystonia. Rev Neurol (Paris). 1992;148:680–6. [PubMed: 1303557]
• Rondot P, Ziegler M. Dystonia--L-dopa responsive or juvenile parkinsonism? J Neural Transm Suppl. 1983;19:273–81. [PubMed: 6583312]
• Roze E, Vidailhet M, Blau N, Møller 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]
• 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]
• 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]
• 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]
• Sun ZF, Zhang YH, Guo JF, Sun QY, Mei JP, Zhou HL, Guan LP, Tian JY, Hu ZM, Li JD, Xia K, Yan XX, Tang BS. Genetic diagnosis of two dopa-responsive dystonia families by exome sequencing. PLoS One. 2014;9:e106388. [PMC free article: PMC4152247] [PubMed: 25181484]
• Surtees R, Clayton P. Infantile parkinsonism-dystonia: tyrosine hydroxylase deficiency. Mov Disord. 1998;13:350.
• 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]
• 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]
• 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, Bartholomé B, Agid Y, Brice A. Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations? Brain. 2000;123:1112–21. [PubMed: 10825351]
• Tristán-Noguero A, Díez H, Jou C, Pineda M, Ormazábal A, Sánchez A, Artuch R, Garcia-Cazorla À. Study of a fetal brain affected by a severe form of tyrosine hydroxylase deficiency, a rare cause of early parkinsonism. Metab Brain Dis. 2016;31:705–9. [PubMed: 26686676]
• 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]
• 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]
• 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]
• Willemsen MA, Verbeek MM, Kamsteeg EJ, de Rijk-Van Andel JF, Aeby A, Blau N, Burlina A, Donati MA, Geurtz B, Grattan-Smith PJ, Haeussler M, Hoffmann GF, Jung H, de Klerk JB, van der Knaap MS, Kok F, Leuzzi V, de Lonlay P, Megarbane A, Monaghan H, Renier WO, Rondot P, Ryan MM, Seeger J, Smeitink JA, Steenbergen-Spanjers GC, Wassmer E, Weschke B, Wijburg FA, Wilcken B, Zafeiriou DI, Wevers RA. Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. Brain. 2010;133:1810–22. [PubMed: 20430833]
• 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]
• Yan YP, Zhang B, Mao YF, Guo ZY, Tian J, Zhao GH, Pu JL, Luo W, Ouyang ZY, Zhang BR. A novel tyrosine hydroxylase variant in a group of Chinese patients with dopa-responsive dystonia. Int J Neurosci. 2017;127:694–700. [PubMed: 27619486]
• 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]
• 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]
• 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]
• Zhang W, Zhou Z, Li X, Huang Y, Li T, Lin Y, Shao Y, Hu H, Liu H, Liu L. Dopa-responsive dystonia in Chinese patients: Including a novel heterozygous mutation in the GCH1 gene with an intermediate phenotype and one case of prenatal diagnosis. Neurosci Lett. 2017;644:48–54. [PubMed: 28087438]
• 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]