Segawa syndrome is an autosomal recessive neurologic disorder characterized by onset in infancy of dopa-responsive dystonia. There are 2 main phenotypes: one is a severe complex encephalopathy apparent in the perinatal period, with diurnal fluctuations and autonomic disturbances, ... Segawa syndrome is an autosomal recessive neurologic disorder characterized by onset in infancy of dopa-responsive dystonia. There are 2 main phenotypes: one is a severe complex encephalopathy apparent in the perinatal period, with diurnal fluctuations and autonomic disturbances, and the other shows a less severe course with onset in the first year of life of a progressive hypokinetic-rigid syndrome and generalized dystonia. The less severe type shows a better response to levodopa compared to the more severe type (summary by Stamelou et al., 2012). See also infantile parkinsonism-dystonia syndrome (613135), caused by mutation in the SLC6A3 gene (126455).
Brautigam et al. (1998) and Wevers et al. (1999) concluded that metabolic diagnosis of TH deficiency can only be made reliably by CSF measurement of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), metabolites of dopamine and norepinephrine, respectively. Decreased ... Brautigam et al. (1998) and Wevers et al. (1999) concluded that metabolic diagnosis of TH deficiency can only be made reliably by CSF measurement of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), metabolites of dopamine and norepinephrine, respectively. Decreased levels of these metabolites combined with normal 5-HIAA, the metabolite of serotonin, indicates a specific defect in tyrosine hydroxylase. Urinary measurements of these metabolites is not accurate. The authors noted that there is a steep rostral-caudal gradient for HVA and 5-HIAA in the CSF, as well as normal changes in values over the first months and years of life, and emphasized that standardized protocols and values are essential for correct diagnosis.
Ludecke et al. (1996) described an infant with jerky movements at the age of 3 months who developed generalized rigidity with very little spontaneous movement and continuing involuntary jerky movements. There was no diurnal variability in the symptoms. ... Ludecke et al. (1996) described an infant with jerky movements at the age of 3 months who developed generalized rigidity with very little spontaneous movement and continuing involuntary jerky movements. There was no diurnal variability in the symptoms. At the age of 6 months, the infant was noted to have an expressionless face, ptosis, drooling, and tremulous tongue movements. Tone in the limbs was variable and of the cogwheel type. Analysis of the cerebrospinal fluid (CSF) revealed a very low level of the dopamine metabolite homovanillic acid (HVA). Ocular instillation of phenylephrine led to dramatic improvement of the ptosis. Treatment with L-DOPA/cardidopa resulted in normalization of the CSF HVA and marked sustained improvement of the hypokinesia and other parkinsonian features. At the age of 3 years, the child was reported to have mild motor and speech delay with minimal gait ataxia. Brautigam et al. (1998) and Wevers et al. (1999) reported 4 unrelated Dutch patients with Segawa syndrome. All had normal pregnancies and deliveries. Between 3 and 7 months of age, the children developed progressive severe motor retardation with predominant extrapyramidal symptoms. They appeared hypokinetic with masked facies, rigidity of the limbs, and truncal hypotonia. There was no diurnal fluctuation of symptoms. Treatment with L-dopa resulted in marked clinical improvement. Brautigam et al. (1999) reported an Italian boy, born of consanguineous parents, with a severe form of Segawa syndrome. He was born prematurely and showed severe respiratory distress in the perinatal period. From birth, he showed progressive hypotonia, dysphagia, hypokinesia, and reduced facial mimicry. He also had prolonged diurnal periods of lethargy with increased sweating alternative with irritability and rare sporadic dystonic movements. Brain MRI at age 5 months showed cerebral atrophy. CSF HVA was undetectable. Response to L-dopa treatment was limited and not as favorable as reported in other patients with the disorder. De Lonlay et al. (2000) reported a patient who met all diagnostic criteria for Segawa syndrome, including homozygosity for a new mutation in the TH gene. The patient had extrapyramidal symptoms, but other symptoms were atypical. Periodic neurologic episodes were observed every 4 days beginning at 18 months of age, and were unresponsive to treatment with L-DOPA. These episodes were marked by generalized hypertonia with opisthotonos and conjugate upward deviations of both eyes lasting several minutes, followed by severe hypotonia, poor contact, and excessive salivation and perspiration for several hours. CSF biochemical abnormalities were severe. Uncharacteristically, a strikingly abnormal urinary catecholamine metabolite pattern was also consistently observed. De Lonlay et al. (2000) concluded that the atypical presentation of this patient shows that the clinical and metabolic phenotype of TH deficiency is more variable than formerly thought, and that the condition should no longer be considered a treatable disorder per se. Stamelou et al. (2012) reported a family in which 3 sibs had tyrosine hydroxylase deficiency. The mother was of British origin and the father was from Nigeria. The proband, who was described in detail, had severe hypotonia at age 6 months and never achieved motor milestones. She developed prominent and violent myoclonic jerks in all limbs, and dystonia in the upper limbs and face without diurnal variation. Treatment with levodopa at age 13 years resulted in marked improvement, and she learned to speak and drive an electric wheelchair. Cognition also improved and she attended school. At age 18 years, she had dystonic grimacing, dysarthria, generalized dystonia more prominent in the upper limbs, and action-induced myoclonus. There was no progression of symptoms over the next 9 years. EMG and EEG studies indicated a subcortical origin of the myoclonic jerks. Her 2 sibs had a similar phenotype, but showed better outcome than the proband because levodopa treatment was started earlier. Stamelou et al. (2012) noted that myoclonus was a major feature of the disorder in this family, suggesting that it should be considered part of the phenotypic spectrum of tyrosine hydroxylase deficiency.
In a Caucasian family in which 2 children were affected with Segawa syndrome, Ludecke et al. (1995) demonstrated a homozygous point mutation in the TH gene (191290.0001). One sister and both parents were heterozygous for the mutation. Symptoms ... In a Caucasian family in which 2 children were affected with Segawa syndrome, Ludecke et al. (1995) demonstrated a homozygous point mutation in the TH gene (191290.0001). One sister and both parents were heterozygous for the mutation. Symptoms disappeared promptly after administration of a low dose of levodopa in combination with a decarboxylase inhibitor. Former generations were not affected, suggesting that this was an autosomal recessive form of the disorder. Knappskog et al. (1995) showed that the mutant enzyme found in the 2 sibs had reduced affinity for L-tyrosine, and that it had residual activity of about 15% of normal at substrate concentrations prevailing in vivo, which was considered to be compatible with the clinical phenotype. In an infant with Segawa syndrome, Ludecke et al. (1996) identified a homozygous mutation in the TH gene (191290.0002). The parents were heterozygous for the mutation. In 3 unrelated Dutch patients with Segawa syndrome, Brautigam et al. (1998) and Wevers et al. (1999) identified a homozygous mutation in the TH gene (R233H; 191290.0003). A fourth patient was compound heterozygous for R233H and a truncating deletion in the TH gene (191290.0009). In an Italian boy with a severe form of Segawa syndrome, Brautigam et al. (1999) identified a homozygous mutation in the TH gene (191290.0011). In affected patients from each of 2 families, Swaans et al. (2000) found compound heterozygosity for novel missense mutations in the TH gene as the basis of infantile-onset parkinsonism (see 191290.0004-191290.0007). All 4 patients were in the fourth decade of life at the time of report and had been able to live a normal life with low-dose L-DOPA medication for more than 30 years. Verbeek et al. (2007) identified 3 different mutations in the promoter region of the TH gene (see, e.g., 191290.0010) in 7 patients with Segawa syndrome. The mutations all occurred within the highly conserved cAMP response element. Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family 8600041, they identified a homozygous missense mutation in the TH gene (191290.0012) in 3 sibs with severe intellectual disability and a phenotype compatible with autosomal recessive Segawa syndrome. The parents, who were first cousins, had 3 healthy children.
The broad phenotypic spectrum of tyrosine hydroxylase (TH) deficiency ranges from a mild progressive dopa-responsive dystonic gait disorder to severe infantile parkinsonism with or without encephalopathy that may be unresponsive to levodopa treatment....
DiagnosisClinical DiagnosisThe broad phenotypic spectrum of tyrosine hydroxylase (TH) deficiency ranges from a mild progressive dopa-responsive dystonic gait disorder to severe infantile parkinsonism with or without encephalopathy that may be unresponsive to levodopa treatment.The diagnosis of TH deficiency should be considered when the following signs or symptoms are observed in isolation or as part of a constellation of features:Infantile hypotonia or dystonia with encephalopathy, hypokinesia and involuntary eye movements Generalized dystonia Torticollis Limb dystonia Progressive dystonic gait disorder Involuntary eye movements or frank oculogyric crises Involuntary tongue thrusting Ptosis, miosis, blepharospasm Increased lower extremity tone Brisk reflexes and/or the striatal toe (dystonic extension of the great toe) Diurnal variation of signs or symptoms: worse in the afternoon or evening, improved after sleep Infantile or juvenile parkinsonism Rigidity of extremities Hypokinesia Postural tremor Developmental motor delay Truncal hypotonia Autonomic symptoms including hypothermia, gastrointestinal dysmotility, hypoglycemia, diaphoresis TestingBiochemical testing. The following patterns of cerebrospinal fluid (CSF) neurotransmitter metabolite and pterin studies help support the diagnosis of TH deficiency [Wevers et al 1999] but are not by themselves diagnostic. Total biopterin (BP)* (most of which exists as tetrahydrobiopterin [BH4]). Normal Total neopterin (NP). Normal Homovanillic acid (HVA). Reduced 5-hydroxyindoleacetic acid (5-HIAA). Normal 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG; a metabolite of noradrenaline). Reduced * If both BP and NP are low, GTP cyclohydrolase (GTPCH)-deficient dopa-responsive dystonia associated with mutations in GCH1 should be strongly considered [Furukawa et al 1996b, Furukawa et al 1998b]. Clinical phenotypes of GTPCH-deficient dopa-responsive dystonia (DRD) and mild TH deficiency overlap significantly.Note: A biochemical enzymatic assay is not available for TH deficiency.Molecular Genetic TestingGene. The only gene associated with TH deficiency is TH, which encodes TH, the rate-limiting enzyme in catecholamine biosynthesis. Clinical testing Sequence analysis/mutation scanning. All reported individuals with recessively inherited TH deficiency have been homozygotes or compound heterozygotes for TH mutations. Most mutations have been single nucleotide substitutions [Ludecke & Bartholome 1995, Ludecke et al 1996, Ishiguro et al 1998, van den Heuvel et al 1998, Brautigam et al 1999, Wevers et al 1999, de Rijk-Van Andel et al 2000, Janssen et al 2000, Swaans et al 2000, Furukawa et al 2001, Grattan-Smith et al 2002, Hoffmann et al 2003, Schiller et al 2004, Diepold et al 2005, Moller et al 2005, Royo et al 2005], but single nucleotide deletions resulting in frameshift and protein truncation have also been reported [Wevers et al 1999, de Rijk-Van Andel et al 2000, Furukawa et al 2001]. Recently, mutations in the highly conserved cyclic adenosine monophosphate (cAMP) response element within the TH promoter have been found in six families with TH deficiency [Ribasés et al 2007, Verbeek et al 2007]; thus, the inclusion of the cAMP response element (CRE) region in sequence analysis/mutation scanning appears to improve the mutation detection frequency in TH deficiency.Deletion analysis. Deletion analysis is available as a clinical test. It is not clear whether use of this test method improves mutation detection frequency. Table 1. Summary of Molecular Genetic Testing Used in Tyrosine Hydroxylase DeficiencyView in own windowGeneTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityTHSequence analysis/mutation scanning Sequence variants 2Unknown ClinicalDeletion analysis Exonic and whole-gene deletions 1. The ability of the test method used to detect a mutation that is present in the indicated gene 2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm the diagnosis in a proband CSF neurotransmitter metabolite and pterin pattern alone is not diagnostic of TH deficiency. If CSF neurotransmitter metabolite and pterin analysis reveals a pattern of abnormalities consistent with TH deficiency in the setting of a characteristic phenotype, a clinical diagnosis of TH deficiency is strongly supported. If CSF analysis reveals reduced BP and NP levels, GTPCH-deficient dopa-responsive dystonia (autosomal dominant Segawa syndrome [Segawa et al 1976, Ichinose et al 1994]) is more likely. Secondary deficiencies of CSF neurotransmitter metabolites have been noted in other neurodegenerative disorders (see Differential Diagnosis). Sequence analysis of the coding region (including the splice sites) and the CRE region of TH are helpful in confirming a suspected diagnosis of TH deficiency in a proband, especially in a simplex case (i.e., a single occurrence in a family) with one of the more severe infantile phenotypes that may not demonstrate a clear treatment effect with a levodopa trial. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in an an affected family member. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in an affected family member. Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in TH.
Tyrosine hydroxylase (TH) deficiency is associated with a broad phenotypic spectrum ranging from TH-deficient DRD, the mild form of the disorder, to an infantile parkinsonism or progressive infantile encephalopathy phenotype, the severe or very severe form. More data are needed to establish the major clinical characteristics of autosomal recessive TH deficiency [Furukawa et al 2004]....
Natural HistoryTyrosine hydroxylase (TH) deficiency is associated with a broad phenotypic spectrum ranging from TH-deficient DRD, the mild form of the disorder, to an infantile parkinsonism or progressive infantile encephalopathy phenotype, the severe or very severe form. More data are needed to establish the major clinical characteristics of autosomal recessive TH deficiency [Furukawa et al 2004].Mild form (TH-deficient dopa-responsive dystonia). Symptoms in mild cases can be limited to unilateral or asymmetric limb dystonia, postural tremor, or gait "incoordination." Progressive symptoms may ultimately result in the classic dopa-responsive dystonic gait disorder. Typically, onset is in childhood with a lower-limb predominant dystonia and gait disturbance. Symptoms manifest after a variable period of apparently normal early motor development. Toe walking may be an early feature. Lower extremity tone and dystonic posturing increase with age. Diurnal variation of motor symptoms may be present, worse in the afternoon or evening. Prolonged exercise or fatigue may trigger symptoms in milder cases.More severely affected children may demonstrate involuntary eye movements consisting of brief upward eye-rolling movements, or frank oculogyric crises.Motor symptoms in children with the relatively mild phenotypes typically respond readily to treatment with levodopa. However, delayed diagnosis and therapy may be associated with progressive motor disability and an increased predisposition to dyskinesias at initiation of levodopa treatment.In several families, a sustained response to treatment with levodopa without apparent adverse motor effects has been documented in periods ranging from 30 to 35 years [Furukawa 2004, Schiller et al 2004].Severe form (infantile parkinsonism). Children with the infantile parkinsonism variant are profoundly disabled from early infancy. Typically, onset of this form is before age six months. Features included developmental motor delay, truncal hypotonia, limb rigidity, and hypokinesia [Furukawa 2003, Hoffmann et al 2003, Furukawa 2004]. Ptosis and/or oculogyric crises are common. Associated neuropsychiatric features can include attention deficit or impulsivity, sometimes with associated learning disabilities. Speech delay or difficulty with articulation has been noted in more severely affected children. Excessive anxiety, depression, or obsessive-compulsive symptoms have also been reported.Autonomic dysfunction may be manifest in the most severe infantile cases by constipation, reflux, poor feeding, temperature instability, hypoglycemia, and difficulty regulating blood pressure [de Lonlay et al 2000, de Rijk-Van Andel et al 2000].More severely affected children have intellectual disability and hyperprolactinemia (dopamine is a prolactin-inhibiting factor at the level of the hypothalamus) [Furukawa et al 2005].These infants are more difficult to treat and unusually prone to side effects (dyskinesias and gastrointestinal side effects) of levodopa therapy as well as other dopaminergic agonists. A much more gradual response to pharmacologic interventions may be noted [de Rijk-Van Andel et al 2000, Hoffmann et al 2003].Progressive infantile encephalopathy. Another phenotype associated with mutations in TH is a progressive infantile encephalopathy in which children have persistent encephalopathy and motor disability in spite of directed treatment of the underlying dopamine deficiency state. In rare cases, no apparent benefit has been noted in spite of directed treatment with levodopa [Hoffmann et al 2003]. Neuroimaging. Brain CT and MRI to date have not revealed structural or signal abnormality in individuals with TH-deficient DRD who have been on treatment for as long as 35 years [Schiller et al 2004]. Cerebral and cerebellar atrophy was found in a severely affected individual with TH deficiency [Hoffmann et al 2003]. Neuropathology. No autopsies of individuals with TH deficiency have been reported.
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....
Differential DiagnosisThe major differential diagnoses for tyrosine hydroxylase (TH) deficiency include several types of dystonia, early-onset parkinsonism, cerebral palsy or spastic paraplegia, and primary and secondary deficiencies of CSF neurotransmitter metabolites.Dystonia. For a differential diagnosis of dystonia, see Dystonia Overview. GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. The average age of onset is approximately six years. This disorder typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms. In general, gradual progression to generalized dystonia is observed. Inheritance is autosomal dominant. More than 60% of individuals with DRD have sequence variants or exon deletions in GCH1, the gene encoding the enzyme GTPCH1. The enzyme GTPCH1 catalyzes the first step in the biosynthesis of tetrahydrobiopterin (BH4), the essential cofactor for TH. The concentrations of total BP (most of which exists as BH4) and total NP (the byproducts of the GTPCH1 reaction) in CSF are low in GTPCH1-deficient DRD (see Clinical Diagnosis, Biochemical Testing).When the phenotypes associated with GTPCH-deficient DRD and TH-deficient DRD overlap significantly, the two disorders can be distinguished by molecular genetic testing and the pattern of CSF pterins and neurotransmitter metabolites.Early-onset primary dystonia (DYT1). A GAG deletion in DYT1 (TOR1A) that results in loss of a glutamic acid residue in a novel ATP-binding protein (torsinA) has been identified in many individuals with chromosome 9q34-linked early-onset primary dystonia, regardless of ethnic background. This heterozygous deletion cannot be found in some families with typical DYT1 phenotype (early-onset limb dystonia spreading to at least one other limb but not to cranial muscles). However, the dramatic and sustained response to low doses of levodopa in DRD distinguishes DRD from all other forms of dystonia. Early-onset parkinsonism. Individuals with early-onset parkinsonism responding to levodopa, especially those with onset before age 20 years, often develop gait disturbance attributable to foot dystonia as the initial symptom [Furukawa et al 1996a]. Thus, early in the disease course, clinical differentiation between individuals with early-onset parkinsonism with dystonia and individuals with DRD is difficult. The most reliable clinical distinction between early-onset parkinsonism and DRD is the subsequent occurrence of motor-adverse effects of chronic levodopa therapy (wearing-off and on-off phenomena and dopa-induced dyskinesias) in early-onset parkinsonism. Under optimal doses, individuals with DRD on long-term levodopa treatment do not develop these complications. However, this is a retrospective difference. An investigation of the nigrostriatal dopaminergic terminals by positron emission tomography (PET) or single photon emission computed tomography (SPECT) can differentiate early-onset parkinsonism (markedly reduced) from DRD (normal or near normal) [Snow et al 1993, Jeon et al 1998, O'Sullivan et al 2001]. Measurement of the concentration of both BP and NP in CSF is useful in distinguishing the following three disorders responsive to levodopa [Furukawa & Kish 1999]: GTPCH1-deficient DRD (reduced concentration of BP and NP) TH-deficient DRD (normal concentration of BP and NP) Early-onset parkinsonism (reduced concentration of BP associated with normal concentration of NP), including the autosomal recessive form caused by PARK2 (the gene encoding parkin) mutations See Parkin Type of Juvenile Parkinson Disease and Parkinson Disease Overview).Cerebral palsy or spastic paraplegia. Some individuals with DRD are initially diagnosed as having cerebral palsy or spastic paraplegia [Tassin et al 2000, Furukawa et al 2001, Grimes et al 2002]. Dystonic extension of the big toe (the striatal toe), which occurs spontaneously or is induced by plantar stimulation, may be misinterpreted as an extensor plantar response (see Hereditary Spastic Paraplegia Overview). Primary deficiencies of CSF neurotransmitter metabolites include autosomal recessive BH4-related enzyme deficiencies (so-called BH4 deficiencies [Blau et al 2002], including recessively inherited GTPCH1 deficiency). Individuals with recessively inherited BH4 deficiencies generally manifest BH4-dependent hyperphenylalaninemia (HPA) in the first six months of life (an exception is autosomal recessive sepiapterin reductase (SR) deficiency [Bonafe et al 2001]). The typical presentation includes severe neurologic dysfunction (e.g., psychomotor retardation, convulsions, microcephaly, swallowing difficulties, truncal hypotonia, limb hypertonia, involuntary movements, oculogyric crises); diurnal fluctuation of symptoms and dystonia partially responding to levodopa can be found in some individuals, especially those with SR deficiency [Furukawa & Kish 1999, Bonafe et al 2001, Furukawa 2004, Neville et al 2005, Abeling et al 2006, Roze et al 2006]. Oral administration of both levodopa and 5-hydroxytryptophan is necessary for individuals with autosomal recessive SR deficiency. BH4 treatment and neurotransmitter replacement therapy (levodopa and 5-hydroxytryptophan) are indispensable for those with other autosomal recessive BH4-related enzyme deficiencies. Secondary deficiencies of CSF neurotransmitter metabolites have been observed in other neurodegenerative disorders including spinocerebellar ataxia type 2, neuronal ceroid-lipofuscinosis, Menkes kinky hair disease (see ATP7A-Related Copper Transport Disorders), and in association with hypoxic ischemic encephalopathy.
To establish the extent of disease in an individual diagnosed with tyrosine hydroxylase (TH) deficiency, the following are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with tyrosine hydroxylase (TH) deficiency, the following are recommended:Clinical examination to assess the severity of the associated movement disorder Evaluation for associated psychiatric symptoms or cognitive impairments Treatment of ManifestationsPatients with TH deficiency can be extremely sensitive to the initiation of dopamine-precursor therapy.Development of dyskinesias can be minimized by starting with very low doses of levodopa therapy and maintaining adequate amounts of carbidopa to block the peripheral aromatic L-amino acid decarboxylase and thus limit peripheral side effects. This may require compounded dosing of the individual ingredients rather than use of a tablet formulation with a fixed levodopa to carbidopa ratio.Titrating the levodopa dose slowly over weeks to months may be necessary, particularly in those who are most severely affected or in whom a significant delay in diagnosis has occurred. In mild cases, minimal titration of dosing is needed, dyskinesias are absent, and a sustained response to low-dose levodopa treatment can be expected.Optimism regarding significant improvement in motor function is warranted in most cases, with the exception of the most severely affected infants. However, if diagnosis is significantly delayed, caution is warranted: delayed diagnosis can be associated with lifelong cognitive impairment and dyskinesias that are quite refractory to moderation of levodopa dosage.In more severely affected infants with encephalopathy or parkinsonism phenotypes, immediate benefit with levodopa may be difficult to observe and dyskinesias may be dose-limiting; however, more prolonged treatment can ameliorate symptoms and allow additional developmental motor progress over time.Prevention of Primary ManifestationsLevodopa. Primary manifestations in patients with TH-deficient DRD are predominantly motor; these symptoms are most effectively treated with levodopa. Optimal dosing requirements may vary with age, physical activity, and growth. Levodopa must be used in conjunction with an inhibitor of amino acid decarboxylase activity such as carbidopa to allow the precursor to effectively cross the blood-brain barrier, where it can be converted to dopamine in neuronal cells.In more severely affected individuals who have levodopa dose-related dyskinesia, other therapies may help augment the levodopa therapy, thus reducing the sometimes significant peak-and-trough fluctuations in motor function associated with the short levodopa half-life. Slow-release formulations are available for adults but not children.Other. The monoamine oxidase B (MAO-B) inhibitor selegiline slows the catabolism of dopamine and significantly augments the effectiveness of levodopa/carbidopa therapy in some individuals. Anticholinergic agents, such as trihexyphenidyl and amantidine, have also proved modestly helpful in this regard.Prevention of Secondary ComplicationsAdditional side effects associated with peak-dose levodopa include gastroesophageal reflux, vomiting, or significant suppression of appetite leading to poor growth. Although these problems may be most evident in the first few weeks of onset of levodopa treatment, close monitoring of symptoms and ongoing adjustment of levodopa/carbidopa dosing in conjunction with appropriate supportive intervention as needed helps in management.SurveillanceNeurologic evaluations every four to six months during childhood are useful to assess medication dosing.Agents/Circumstances to AvoidThe 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 RiskSibs of affected individuals should be examined for evidence of dystonia and/or motor incoordination, which could be evidence of more mild involvement.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.OtherDirect 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTH11p15.5Tyrosine 3-monooxygenaseTH homepage - Mendelian genesTHData 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) View in own window 191290TYROSINE HYDROXYLASE; TH 605407SEGAWA SYNDROME, AUTOSOMAL RECESSIVEMolecular Genetic PathogenesisTyrosine hydroxylase (TH) (tyrosine 3-monooxygenase) catalyzes the initial and rate-limiting step in the synthesis of catecholamine, including dopamine, adrenaline (epinephrine), and noradrenaline (norepinephrine).Complete disruption of TH function in mice results in severe catecholamine deficiency and perinatal lethality. Mice heterozygous for Th mutations exhibit defects in neuropsychologic function and impaired motor control and operant learning. In humans, homozygous or compound heterozygous mutations resulting in reduced TH enzyme function associated with diminished catecholamine biosynthesis underlie all published cases to date.Normal allelic variants. Human TH consists of 14 exons spanning approximately 8.5 kb [Grima et al 1987, Kaneda et al 1987]. Four types of mRNA are produced through alternative splicing from a single primary transcript (now, several additional types of mRNA are known [Furukawa 2004, Kobayashi & Nagatsu 2005]). Type 1 mRNA and type 4 mRNA contain the coding regions of 1491 and 1584 base pairs, encoding 497 and 528 amino acid residues, respectively. Type 1 mRNA encodes TH isoform b and type 4 mRNA encodes TH isoform a (see Entrez Gene). Some normal TH variants exist and the p.Val112Met substitution of isoform a (NP_954986.2; see Table 2) has been identified frequently [Ludecke & Bartholome 1995, Ishiguro et al 1998]. Note that this normal variant is also known as the p.Val81Met substitution of isoform b (reference sequence NP_000351.2).Pathologic allelic variants. More than 20 pathologic mutations (including point mutations in the CRE within the TH promoter) have been reported in individuals with TH deficiency [Ludecke et al 1995, Ludecke et al 1996, van den Heuvel et al 1998, Brautigam et al 1999, Wevers et al 1999, de Lonlay et al 2000, de Rijk-van Andel et al 2000, Dionisi-Vici et al 2000, Janssen et al 2000, Swaans et al 2000, Furukawa et al 2001, Grattan-Smith et al 2002, Hoffmann et al 2003, Schiller et al 2004, Moller et al 2005, Ribasés et al 2007, Verbeek et al 2007]. One of them, p.Arg233His, has been found repeatedly in unrelated families [Furukawa 2003].Table 2. Selected TH Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequenceNormalc.334G>Ap.Val112MetNM_199292.2 NP_954986.2 Pathologicc.698G>Ap.Arg233HisSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).Normal gene product. The normal product is the TH (EC 1.14.16.2) protein. The enzyme TH, a BH4-dependent monooxygenase, catalyzes the rate-limiting step (the formation of dopa from tyrosine) in the biosynthesis of catecholamines (dopamine, noradrenaline, adrenaline). The native TH enzyme is a tetramer of four identical subunits [Goodwill et al 1997]. Abnormal gene product. Because null TH mutations are lethal in Th(-/-) knockout mice [Zhou et al 1995], it appears that both homozygotes and compound heterozygotes for TH mutations have some residual enzyme activity. In one family with TH-deficient DRD and homozygosity for a missense TH mutation, the mutant enzyme had approximately 15% of specific activity compared with the wild-type in an in vitro coupled transcription-translation assay system [Knappskog et al 1995, Ludecke et al 1995]. In an individual with infantile parkinsonism and developmental motor delay and a homozygous TH mutation, the mutant enzyme revealed 0.3%-16% of wild-type enzyme activity in three complementary expression systems [Ludecke et al 1996].