Introduction. Clinical manifestations

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1 Tyrosine hydroxylase deficiency Roser Pons MD (Dr. Pons of the University of Athens in Greece has no relevant financial relationships to disclose.) Barry Wolf MD PhD, editor. (Dr. Wolf of Ann & Robert H. Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.) Originally released July 8, 2015; last reviewed March 30, 2016; expires March 30, 2019 Introduction This article includes discussion of tyrosine hydroxylase deficiency and autosomal recessive dopa responsive dystonia. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview Tyrosine hydroxylase deficiency is an autosomal recessively inherited inborn error of metabolism that involves the biosynthesis of catecholamines (dopamine, epinephrine, and norepinephrine). Patients often exhibit infantile parkinsonism and features of autonomic dysfunction. Diagnosis is based on the pattern of monoamine metabolites in CSF. Key points Tyrosine hydroxylase deficiency is an autosomal recessively inherited disorder that leads to a deficient production of catecholamines (dopamine, epinephrine, and norepinephrine). Patients usually exhibit developmental delay, infantile parkinsonism, dystonia, oculogyric crises, and features of autonomic dysfunction. Milder phenotypes may also occur. Tyrosine hydroxylase deficiency is diagnosed by detection of decreased CSF concentrations of the downstream metabolites of catecholamine degradation, homovanillic acid, and 3- methoxy-4-hydroxyphenylglycol. The treatment of choice is levodopa; alternatively, patients are treated with other dopaminergic drugs, mainly dopamine agonists and monoamine oxidase inhibitors. Historical note and terminology Tyrosine hydroxylase deficiency was first reported in 1971 in 2 brothers with early-onset progressive dopa-responsive dystonia (Castaigne et al 1971). Subsequently, young infants with a more severe phenotype were recognized (Hoffmann et al 2003). In 2010, Willemsen and colleagues described the largest series reported to date (36 patients) and proposed 2 phenotypes: type A, which is less severe, has a better prognosis, and is L-dopa responsive; and type B, which has an early onset, is more severe, and is poorly L-dopa responsive (Willemsen et al 2010). Currently, approximately 70 cases have been reported worldwide (Willemsen et al 2010; Fossbakk et al 2014). In 1996 the first mutations in the tyrosine hydroxylase gene were reported (Ludecke et al 1996). The spectrum of mutations is heterogenous with no hot spots detected (Kurian et al 2011; Fossbakk et al 2014). Two common mutations due to founder effects have been detected in the Greek population(c.707c>t) and in the Dutch population (c.698g>a) (van den Heuvel et al 1998; Pons 2009). Clinical manifestations Presentation and course The main clinical characteristics of tyrosine hydroxylase deficiency are infantile parkinsonism, dystonia, oculogyric crises, and features of autonomic dysfunction (Willemsen et al 2010; Kurian et al 2011). The age of presentation of tyrosine hydroxylase deficiency ranges from the neonatal period to childhood, and the clinical phenotype ranges from severe phenotypes to phenotypes reminiscent of dopa-responsive dystonia (Segawa

2 disease). Willemsen and colleagues reported a large cohort with tyrosine hydroxylase deficiency (36 patients) and defined 2 main phenotypes: type A (moderate phenotype) and type B (severe phenotype) (Willemsen et al 2010). Approximately 70% of patients present with the moderate phenotype. The majority manifest with infantile parkinsonism characterized by hypokinesia, bradykinesia, rigidity, dystonia, and oculogyric crises (episodes of intermittent upgaze deviation, without loss of consciousness, which lasts minutes to hours). Other patients present later in childhood with gait difficulties associated with dystonia or parkinsonian features (Furukawa et al 2004). Mild intellectual disability is frequently reported in patients with infantile-onset disorder whereas cognition is less affected in patients presenting during childhood (Willemsen et al 2010; Kurian et al 2011). Patients with the severe phenotype initially exhibit symptoms during the neonatal period or in infancy. They manifest with severe parkinsonism and dystonia leading to profound developmental delay. Patients experience oculogyric crises that may be severe and associated with axial and limb dystonia. They are often irritable and show profound hypokinesia, truncal hypotonia, fluctuating limb rigidity, dystonic posturing, hypomimia, and ptosis. Sleep disturbances, often in the form of excessive sleep, are also reported. Nonprogressive cognitive impairment is characteristically seen (Willemsen et al 2010; Kurian et al 2011; Pons et al 2013). Overall, these 2 phenotypes show substantial overlap (Willemsen et al 2010; Kurian et al 2011). Thus, a phenotypic continuum of severity has been proposed, a characteristic that also applies to other monoamine neurotransmitter disorders (Pons 2009). In all phenotypes of tyrosine hydroxylase deficiency, motor symptoms often show a pattern of diurnal variation and sleep benefit, with aggravation of symptoms late in the day or improvement by evening. Additionally, oculogyric crises occur mainly in the afternoon or in the evening (Willemsen et al 2010; Kurian et al 2011; Pons et al 2013). Other motor symptoms include tremor and chorea (Grattan-Smith 2002; Chi 2012; Pons 2013). Furthermore, atypical cases, including early-onset spastic paraplegia and dopa-responsive myoclonus-dystonia, have also been described (Furukawa et al 2001; Ormazabal et al 2011; Stamelou et al 2012). Signs of autonomic dysfunction, such as excessive sweating, temperature instability and nasal congestion, occur often in infants with tyrosine hydroxylase deficiency (Willemsen et al 2010; Kurian et al 2011; Pons et al 2013). Hormonal manifestations that may occur in tyrosine hydroxylase deficiency include growth retardation and delayed bone age (Hoffmann et al 2003). In addition, hyperprolactinemia is also a characteristic feature because dopamine inhibits prolactin secretion. Galactorrhea has been reported in several patients with tyrosine hydroxylase deficiency (Yeung et al 2006). Prognosis and complications The response to L-dopa therapy in tyrosine hydroxylase deficiency depends on the severity of the phenotype, which in turn is reflected by the concentrations of homovanillic acid and the HVA/5-HIA ratio in CSF (Willemsen et al 2010). Response to treatment varies from minimal or no response in severe phenotypes to slow and gradual responses with escalation of L-dopa dose in moderate phenotypes and dramatic favorable response within days in phenotypes reminiscent of Segawa disease. Responders show improvement in hypokinesia, tremor, rigidity, and dystonia whereas oculogyric crises decrease in frequency and severity and may eventually disappear (Willemsen et al 2010; Yeung et al 2011; Pons et al 2013). It is generally accepted that early diagnosis and prompt treatment improves the final motor and cognitive outcome in tyrosine hydroxylase-deficient patients (Willemsen et al 2010; Kurian et al 2011). Some patients with phenotypes of mild and moderate severity and favorable response to L-dopa therapy reach full normalization of neurologic condition whereas others continue having some mild motor impairments. Generally, response to L-dopa remains stable over the years, and patients do not experience motor fluctuations. Patients who experienced dyskinesias induced by L-dopa tend to improve with time, and, in certain cases, dyskinesias may subside with no need for further management (Willemsen et al 2010; Yeung et al 2011; Pons et al 2013). Patients with severe phenotypes show a worse but variable outcome. A number of them show minimal or no response in motor function, whereas others show a slow and gradual response and are able to gain motor milestones over the course of months to years. They usually show variable degrees of motor impairment, and their condition remains stable over the years with no evidence of progressive disease. Although these patients generally show more problems with L-dopa-induced dyskinesias, their tolerance improves over time (Willemsen et al 2010; Yeung et al 2011; Pons et

3 al 2013). Cognitive development is impaired in many patients with tyrosine hydroxylase deficiency. Although systematic assessment of cognitive profiles is lacking, Willemsen and colleagues reported mild to moderate intellectual disability in 91% of patients with severe phenotypes and in 33% with mild-to-intermediate phenotypes. Long-term follow up did not reveal any signs of further cognitive decline in any of the tested patients (Willemsen et al 2010). Clinical vignette The patient, a female, was the product of an uncomplicated pregnancy and an unremarkable perinatal period. At 2.5 months of age, she exhibited hand and leg tremors when crying. At 3 to 4 months of life, she started having episodes of eye rolling upwards associated with limb posturing (oculogyric crises). These episodes lasted 2 to 6 hours and occurred mainly in the late afternoon every 4 days. EEG recording during these paroxysmal episodes did not show any epileptiform activity, but she was treated with antiepileptic drugs with no favorable response. Her brain MRI was normal. At the age of 2 years, she had not achieved any motor development. She had no head or trunk control. She was able to hold an object in her hand, but she could not reach. Although her motor performance was minimal, her parents noted that she was more active in the mornings and after a nap. She understood simple commands and babbled occasionally. On review of systems, she had increased sweating, a chronically stuffed nose, and constipation. Her vital signs were stable. Her head circumference was 50 cm. She had a narrow and long face, tented mouth, small hands, and mild gingival hypertrophy and was perspiring profusely. She was alert and appeared oriented and aware of her surroundings. She had bilateral ptosis with full extraocular movements and poor facial expression. Her cry was strong. She had no head control, and her spontaneous movements were minimal. Mild twitching of fingers and face was noted consistent with chorea. Although she appeared hypotonic when in her mother's arms, she developed dystonic posturing and stiffness of limbs and neck when manipulated. Her deep tendon reflexes were hyperactive, and she had spontaneous up-going toes. No tremor was noted. The parents stated that the tremor previously noted had disappeared gradually during the first year of life. Neurotransmitter metabolites were measured in CSF. A marked reduction of homovanillic acid concentrations with normal serotonin metabolites as detected. Sequencing analysis of the tyrosine hydroxylase gene revealed a homozygous mutation in exon 6 (c.707t>c). She was started on L-dopa-carbidopa at 1 mg kg-1 d-1, and the dose was increased gradually every month. Despite the gradual increase in the L-dopa dose, she developed jaw opening dystonia and generalized dyskinesias. Amantadine (4 mg kg-1 d-1) was added at 3.5 years of age, and this was followed by a reduction of dyskinesias, which allowed further increases in the L-dopa dose. Her motor development gradually improved. She walked independently at the age of 5 years, and she speaks with dysarthria and attends special education classes at the age of 10 years. She is fidgety, her gait is mildly dyskinetic, and she is independent in all her daily activities. Biological basis Etiology and pathogenesis Tyrosine hydroxylase deficiency is caused by mutations in the tyrosine hydroxylase gene on chromosome 11p15.5. Tyrosine hydroxylase is a specific tetrabiopterin-dependent amino acid hydroxylase that converts tyrosine to dihydroxyphenylalanine (L-dopa), the rate-limiting step in the synthesis of catecholamines, dopamine, epinephrine, and norepinephrine (Kurian 2011). In the brain, tyrosine hydroxylase is mainly expressed in dopaminergic neurons in the ventral tegmental area and substantia nigra pars compacta and in the noradrenergic neurons of the locus coeruleus. In the periphery, tyrosine hydroxylase is mainly found in sympathetic neurons and in the adrenal medulla (Fossbakk et al 2014). Monoamine neurotransmitters include serotonin and catecholamines. They play important roles in modulation of psychomotor function and hormone secretion as well as cardiovascular, respiratory, and gastrointestinal control, sleep mechanisms, body temperature, and pain.

4 The starting substrate for the formation of catecholamines is tyrosine and for serotonin is tryptophan. Tyrosine is converted to L-dopa by tyrosine hydroxylase and tryptophan to 5-hydroxytryptophan by tryptophan hydroxylase. L- dopa and 5-hydroxytryptophan undergo decarboxylation through the action of aromatic amino acid decarboxylase, leading to the formation of dopamine and serotonin, respectively. Within noradrenergic neurons, dopamine is converted to norepinephrine, and within the adrenal medulla, norepinephrine is methylated to form epinephrine. Dopamine and serotonin are released and rapidly catabolized. Through the action of monoamine oxidase and catechol- O-methyltransferase, 5-hydroxyindolacetic acid (5-HIAA) is produced from serotonin, homovanillic acid from dopamine, and 3-methoxy-4-hydroxyphenylglycol from norepinephrine (Pons 2009). Disorders of monoamine biosynthesis lead to reduced synthesis of specific neurotransmitters, and their clinical manifestations are caused by the deficiency of these neurotransmitters in the brain and peripheral nervous system. Tyrosine hydroxylase deficiency leads to reduced synthesis of all catecholamines. Reduced concentrations of dopamine are thought to be the cause of the motor symptoms, given dopamine's role in coordination and regulation of movement. Norepinephrine and epinephrine deficiency are responsible for the manifestations of autonomic sympathetic dysfunction. Given the role of monoamines on hormonal function, endocrine dysfunction may also occur. Some clinical manifestations, such as cognitive disturbances, cannot be attributed to the deficit of a specific neurotransmitter. The early effects of dopamine deficiency in the developing brain may account for these disturbances. This is supported by animal models that have shown structural abnormalities in brain development, particularly in the growth and laminar organization of the cerebral cortex (Pons 2009). Another factor that has been implicated in the pathophysiology of tyrosine hydroxylase deficiency and other defects of monoamine synthesis is neurotransmitter imbalance. Oculogyric crises are thought to be due to reduced dopaminergic transmission and excessive cholinergic activity (Pons 2009). Further pathophysiological mechanisms include changes in receptor sensitivity implicated in the drug-induced dyskinesias that are often observed in these patients (Pons et al 2013). Epidemiology" Tyrosine hydroxylase deficiency is a rare disorder. Currently, approximately 70 cases have been reported worldwide (Willemsen et al 2010; Pons et al 2010; Pons et al 2013; Ormazabal et al 2011; Yeung et al 2011; Szentivanyi et al 2012; Chi et al 2012; Giovanniello et al 2012; Stamelou et al 2012). Prevention Only parents who are asymptomatic heterozygous carriers for tyrosine hydroxylase deficiency have a 1 in 4 chance of having an affected fetus with each pregnancy. Genetic counseling for a family with a previously documented proband is recommended. Tyrosine hydroxylase is not expressed in amniotic fluid cells or in chorionic villus; therefore, prenatal diagnosis by measurement of enzyme activity is not possible. Prenatal diagnosis by sequencing the tyrosine hydroxylase gene for mutations in chorionic villus has been performed successfully (Moller et al 2005). Differential diagnosis Differential diagnosis of tyrosine hydroxylase deficiency includes other disorders of monoamine synthesis, such as aromatic amino acid decarboxylase deficiency and pterin disorders. These disorders lead to severe dopamine deficiency from early infancy, which may manifest with infantile parkinsonism, oculogyric crises, and autonomic dysfunction. In moderate phenotypes of tyrosine hydroxylase deficiency that present in childhood with gait disorders and dystonia, differential diagnosis also includes Segawa disease. Associated clinical manifestations and biochemical findings, including blood phenylalanine concentration and CSF pattern of monoamine catabolites and pterins, allow the differentiation of these defects. Measurement of enzyme activity in some cases and molecular studies can confirm the diagnosis (Pons 2009; Kurian et al 2011). Epileptic encephalopathy is also considered in the differential diagnosis of severe cases of tyrosine hydroxylase deficiency because oculogyric crises are associated with prominent dystonic posturing that may be misdiagnosed as seizures. Unresponsiveness to antiepileptic drugs and the presence of infantile parkinsonism and autonomic dysfunction together, with the lack of EEG correlate during episodes, should suggest a defect in monoamine synthesis

5 (Pons 2009; Kurian et al 2011). Because severe forms of tyrosine hydroxylase deficiency can be associated with perinatal complications, a differential diagnosis with neonatal infectious, hypoxic ischemic, epileptic, and metabolic disorders must be considered. Given the profound hypotonia and hypokinesia associated with ptosis and hypomimia that these patients show, neuromuscular disorders are also considered in the differential diagnosis. Finally, moderate forms of tyrosine hydroxylase deficiency can also mimic cerebral palsy and hereditary or acquired forms of juvenile parkinsonism. Medical history, clinical manifestations, and biochemical and genetic investigations can confirm the diagnosis (Kurian et al 2011). Diagnostic workup Concentrations of the monoamine neurotransmitter catabolites reflect the turnover of these neurotransmitters in the brain. Therefore, the diagnosis of tyrosine hydroxylase deficiency relies on the measurement of the monoamine catabolites homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, and 5-HIAA in CSF. The typical biochemical pattern is a decreased homovanillic acid and 3-methoxy-4-hydroxyphenylglycol concentrations and low HVA/5-HIAA ratios (Pons et al 2013). Given the differential diagnosis includes other defects of monoamine synthesis, concentrations of individual pterin species should also be measured. It is important to note that collection and handling of CSF must be performed under appropriate conditions given the rostro-caudal gradient of these metabolites and the tendency for oxidation of some of them (Kurian et al 2011). Measurements of dopamine precursor amino acids or catecholamines in blood or urine are in general noninformative. However, if differential diagnosis with other disorders of monoamine synthesis are considered, measurement of phenylalanine concentrations and analysis of tyrosine and phenylalanine concentrations after a load of phenylalanine may be necessary. Plasma prolactin measurement is an indicator of dopamine status because dopamine downregulates prolactin synthesis by the hypothalamus; thus, hyperprolactinemia is expected when dopamine deficiency occurs (Kurian et al 2011). Neuroimaging is nondiagnostic. Brain MRI is normal in most patients with tyrosine hydroxylase deficiency, but some children with severe phenotypes may show nonspecific white-matter abnormalities and increased extracerebral CSF spaces (Kurian et al 2011). Molecular analysis of the tyrosine hydroxylase gene confirms the diagnosis. To date, 40 different disease-related missense mutations, 5 nonsense mutations, and 3 mutations in the promoter region have been reported (Willemsen et al 2010). Most mutations are private, except for the 707T>C mutation in patients of Greek origin, and the 698G>A mutation in Dutch patients (van den Heuvel et al 1998; Pons et al 2010). Genotype-phenotype correlations have been difficult to demonstrate because patients are often compound heterozygotes. Furthermore, homozygosity for the common c.698g>a and c.707t>c mutations have been detected in both severe and moderate phenotypes (Willemsen et al 2010; Pons et al 2013). Management The mainstay of treatment in tyrosine hydroxylase deficiency is restoring dopaminergic neurotransmission by administering L-dopa, the primary metabolite that is deficient in this condition. Response and tolerance to L-dopa therapy is variable and depends on the severity of the phenotype. For this reason, therapy in tyrosine hydroxylasedeficient patients needs to be tailored on an individual basis. The starting dose of L-dopa, its escalation and dosing frequency, and the need for the addition of other agents to potentiate dopamine transmission are different in each patient (Pons et al 2013). The second most often used pharmacological strategy to potentiate dopaminergic neurotransmission involves inhibition of dopamine catabolism via the selective type B monoamine oxidase inhibitor, selegiline. Other inhibitors of dopamine degradation, such as catechol-o-methyl transferase inhibitors, and dopamine receptor agonists, ropinirole, pramipexole, bromocriptine, have only been tried sporadically in tyrosine hydroxylase-deficient patients (Dionisi-Vici et al 2000; Willemsen et al 2010; Stamelou et al 2012). Symptomatic management of movement disorders, mainly dystonia and oculogyric crises, can be treated with anticholinergic drugs and benzodiazepines (Hoffmann et al 2003; Yeung et al 2011; Pons et al 2013). Management of autonomic dysfunction has not been necessary in these patients because initiation of L-dopa

6 treatment, even at very small doses, usually corrects sympathetic dysfunction (Pons et al 2013). Some of the first patients with tyrosine hydroxylase deficiency underwent serial lumbar punctures in order to monitor treatment efficacy biochemically. Irrespective of the clinical response, homovanillic acid concentrations increased with treatment but rarely reached normal concentrations (Willemsen et al 2011; Yeung et al 2011). Currently, serial monitoring of metabolites in CSF is performed in selected cases. Determination of prolactin concentrations has been proposed as a functional parameter to tailor therapy in dopamine deficiency disorders. However, there are marked fluctuations of prolactin during the day that cannot be attributed to variations in L-dopa dosing. Thus, determination of prolactin is used as an indicator of insufficient dopamine production (Hoffmann et al 2003). L-dopa. L-dopa is coadministered with a peripheral decarboxylase inhibitor carbidopa or benserazide in order to prevent conversion of L-dopa to dopamine peripherally, thus, increasing L-dopa brain bioavailability and decreasing its peripheral dose-related side effects. Tolerance to L-dopa treatment usually refers to the appearance of dyskinesias that may manifest with small doses of L-dopa even at the initiation of treatment, especially in children with the severe infantile disorder (Willemsen et al 2010; Pons et al 2013). On the other hand, common dose-dependent adverse effects of L-dopa, such as nausea, vomiting, and hypotension, are rarely seen in these patients. Disabling L-dopa-related panic attacks were reported in one case (Schiller et al 2004). In general, older children with phenotypes resembling Segawa disease are treated with L-dopa at 150 to 250 mg/d (Furukawa et al 2001; Schiller et al 2004), whereas younger patients with infantile parkinsonism are treated with starting doses of L-dopa at 0.1 to 1 mg/k/d divided in 3 to 6 doses a day. L-dopa is then increased gradually according to its tolerance. The final L-dopa dose is variable among patients, ranging from 0.8 mg/k/d to 30 mg/k/d (Willemsen et al 2010; Tormentini et al 2011; Yeung et al 2011; Chin et al 2012; Giovanniello et al 2012; Pons et al 2013). Monoamine oxidase inhibitors. In patients with poor response and tolerance to L-dopa, treatment with selegiline, a selective monoamine oxidase B inhibitor, provides benefit and may allow further increases, even doubling of the L- dopa dose (Dionisi-Vici et al 2000; Hoffmann et al 2003; Yeung et al 2011; Chi et al 2012; Giovanniello et al 2012). It has been postulated that the early introduction of selegiline in poor L-dopa-responder patients improves the overall treatment outcome (Yeung 2011). However, despite some favorable reports, selegiline has been ineffective in other patients (de Lonlay et al 2000; Zafeiriou et al 2009). Selegiline is usually administered once daily, with reported dose ranges from 2.5 to 15 mg daily or 0.1 to 0.4 mg/k/d. Dose-dependent side effects reported in tyrosine hydroxylase deficient patients include hyperkinesia, rigidity, and sleep disorder (Chi et al 2012). Additional side effects include nausea, dizziness, dryness of the mouth, confusion, and orthostatic hypotension. Monoamine oxidase hypertensive crisis precipitated by food rich in tyramine do not occur with selegiline doses below 10 mg/d. Because patients with tyrosine hydroxylase deficiency rarely take more than 10 mg/d, they do not need to be on a tyramine-restricted diet; it can be given safely in combination with L-dopa (Pons et al 2013). Management of L-dopa induced dyskinesias. Poor tolerance to L-dopa manifesting in the form of L-dopa-induced dyskinesias is a common feature of defects of dopamine synthesis; such movements may be intolerable and preclude treatment. Dyskinesias can also be induced by other dopaminergic agents (Pons 2009; Kurian et al 2011). In tyrosine hydroxylase-deficient patients, L-dopa-induced dyskinesias are of variable intensity and appear early in the course of treatment regardless of the age at which treatment was initiated. They have been characterized as chorea of the face, limbs, and trunk of variable intensity, and more rarely by prominent ballism. They are precipitated by increases in the dose of L-dopa and also by febrile illnesses and stress. Occasionally, they can be intolerable, especially in those cases presenting in the form of ballism (Pons et al 2013). L-dopa-induced dyskinesias in tyrosine hydroxylase-deficient patients are initially managed by slowing down the escalation of L-dopa dose either by decreasing the L-dopa to the previously tolerated dose or by postponing further increases of L-dopa until dyskinesias decrease or recede. When these measures are insufficient, amantadine may be added (Pons et al 2013). Amantadine is used in patients with Parkinson disease suffering from motor fluctuations and dyskinesias. Its mechanism of action is not completely clear. Side effects include nausea, vomiting, and livedo reticularis. Amantadine at 4 to 6 mg/k/d has been tried in 2 tyrosine hydroxylase-deficient patients with L-dopa-induced dyskinesias that were

7 severe enough to prevent escalation of their L-dopa therapy. Patients showed a favorable response with no adverse effects, and the dose of L-dopa could then be further increased (Pons et al 2013). Symptomatic treatment. Treatment with anticholinergics and benzodiazepines has been used in individual with tyrosine hydroxylase deficiency for the symptomatic management of dystonia and oculogyric crises. However, the response to these drugs is often disappointing (Hoffmann et al 2003; Zafiriou et al 2009; Chi et al 2012; Stamelou et al 2012). In addition to pharmacological therapy, patients are placed on a rehabilitation program including physical, occupational, and speech therapy. Other therapeutic strategies. Bilateral subthalamic nucleus deep brain stimulation was performed in a 6-year-old child with tyrosine hydroxylase deficiency exhibiting prominent dystonia and infantile parkinsonism that was medically intractable. After surgery, his condition improved significantly and his L-dopa treatment could be reduced (Tormenti et al 2011). Although it is too soon to know, deep-brain stimulation may be an option for tyrosine hydroxylase-deficient patients with minimal or no response to dopaminergic treatment or with intolerable L-dopa-induced dyskinesias. References cited Castaigne P, Rondot P, Ribadeau-Dumas JL, Said G. Progressive extra-pyramidal disorder in 2 young brothers: remarkable eff ects of treatment with L-dopa. Rev Neurol 1971;124: PMID Chi CS, Lee HF, Tsai CR. Tyrosine hydroxylase deficiency in Taiwanese infants. Pediatr Neurol 2012;46(2): PMID de Lonlay P, Nassogne MC, van Gennip AH, et al. Tyrosine hydroxylase deficiency unresponsive to L-dopa treatment with unusual clinical and biochemical presentation. J Inherit Metab Dis 2000; 23: PMID Dionisi-Vici C, Hoffmann GF, Leuzzi V, et al. Tyrosine hydroxylase deficiency with severe clinical course: clinical and biochemical investigations and optimization of therapy. J Pediatr 2000;136: PMID Fossbakk A, Kleppe R, Knappskog PM, Martinez A, Haavik J. Functional studies of tyrosine hydroxylase missense variants reveal distinct patterns of molecular defects in Dopa-responsive dystonia. Hum Mutat 2014;35(7): PMID 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(2):260-3.PMID Furukawa Y, Kish SJ, Fahn S. Dopa-responsive dystonia due to mild tyrosine hydroxylase deficiency. Ann Neurol 2004;55(1): PMID Giovanniello T, Claps D, Carducci C, et al. A new tyrosine hydroxylase genotype associated with early-onset severe encephalopathy. J Child Neurol 2012;27(4): PMID 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: PMID Hoffmann GF, Assmann B, Brautigam C, et al. Tyrosine hydroxylase deficiency causes progressive encephalopathy and dopa-nonresponsive dystonia. Ann Neurol 2003;54(suppl 6):S56-65.PMID Kurian MA, Gissen P, Smith M, Heales S Jr, Clayton PT. The monoamine neurotransmitter disorders: an expanding range of neurological syndromes. Lancet Neurol 2011;10(8): PMID Ludecke B, Knappskog PM, Clayton PT, et al. Recessively inherited L-DOPA-responsive parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene. Hum Mol Genet 1996;5(7): PMID Moller LB, Romstad A, Paulsen M, et al. Pre- and postnatal diagnosis of tyrosine hydroxylase deficiency. Prenat Diagn 2005;25(8): PMID Ormazabal A, Serrano M, Garcia-Cazorla A, et al. Deletion in the tyrosine hydroxylase gene in a patient with a mild

8 phenotype. Mov Disord 2011;26(8): PMID Pons R. The phenotypic spectrum of paediatric neurotransmitter diseases and infantile parkinsonism. J Inherit Metab Dis 2009;32(3): PMID Pons R, Serrano M, Ormazabal A, et al. Tyrosine hydroxylase deficiency in three Greek patients with a common ancestral mutation. Mov Disord 2010;25(8): PMID Pons R, Syrengelas D, Youroukos S, Orfanou I, Dinopoulos A, Cormand B, et al. Levodopa-Induced dyskinesias in tyrosine hydroxylase deficiency. Mov Disord 2013;28(8): PMID 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(8): PMID Stamelou M, Mencacci NE, Cordivari C, et al. Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency. Neurology 2012;79(5): PMID Szentivanyi K, Hansíková H, Krijt J, et al. Novel mutations in the tyrosine hydroxylase gene in the first Czech patient with tyrosine hydroxylase deficiency. Prague Med Rep 2012;113(2): PMID Tormenti MJ, Tomycz ND, Coffman KA, Kondziolka D, Crammond DJ, Tyler-Kabara EC. Bilateral subthalamic nucleus deep brain stimulation for dopa-responsive dystonia in a 6-year-old child. EC. J Neurosurg Pediatr 2011;7(6): PMID van den Heuvel LP, Luiten B, Smeitink JA, et al. A common point mutation in the tyrosine hydroxylase gene in autosomal recessive L-DOPA-responsive dystonia in the Dutch population. Hum Genet 1998;102(6): PMID Willemsen MA, Verbeek MM, Kamsteeg EJ, et al. Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. Brain 2010;133(pt 6): PMID 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(6): PMID Yeung WL, Wong VC, Chan KY, et al. Expanding phenotype and clinical analysis of tyrosine hydroxylase deficiency. J Child Neurol 2011;26(2): PMID Zafeiriou DI, Willemsen MA, Verbeek MM, Vargiami E, Ververi A, Wevers R. Tyrosine hydroxylase deficiency with severe clinical course. Mol Genet Metab 2009;97: PMID **References especially recommended by the author or editor for general reading. ICD and OMIM codes ICD codes ICD-9: Other specified disorders of metabolism: ICD-10: Metabolic disorders: E70-E90 OMIM numbers Tyrosine hydroxylase; TH: * Profile Age range of presentation 0-01 month

9 01-23 months years years Sex preponderance male=female Family history family history may be obtained Heredity autosomal recessive Population groups selectively affected none selectively affected Occupation groups selectively affected none selectively affected Differential diagnosis list Disorders of monoamine neurotransmitter synthesis Early infantile epileptic encephalopathy Cerebral palsy Neuromuscular disorders Congenital myasthenia Metabolic disorders Other topics to consider Abnormalities of tetrahydrobiopterin metabolism Aromatic L-amino acid decarboxylase deficiency Childhood movement disorders Dopa responsive dystonia Copyright MedLink Corporation. All rights reserved.