Tyrosine Hydroxylase Deficiency Research Articles

The Genetics of Segawa Disease

Segawa disease is a dopa-responsive generalized dystonia, caused by abnormalities of the gene GCH-1 located on chromosomes 14q22.1–q22.2. Clinically, there are two types, postural type and action type, depending on the family. Cases of action type show focal or segmental dystonia after adolescence. In families of action type, there are cases starting with focal or segmental dystonia in adulthood or parkinsonism in older age. Both types show symptoms of dopamine decrement due to the deficiency of tyrosine hydroxylase in the terminal of the nigrostriatal dopamine neuron, which is caused by GCH-1 deficiency. With an onset in childhood, stagnation of body length develops. For these symptoms, L-dopa demonstrates dramatic effects. In early-onset cases, tryptophan hydroxylase is also affected and patients show symptoms of serotonine deficiency. More than 100 mutations of the GCH-1 gene are detected; they are particular for each family. However, there is no particular mutation for postural and action type.

Choreatic movement disorder due to tyrosine hydroxylase deficiency caused by a novel mutation in the TH gene

Introduction: Tyrosin hydroxylase (TH) catalyzes the synthesis of L-Dopa and plays a significant role in synthesis of dopamine. The responsible gene is located on chromosome 11 p. 15.5. TH deficiency (THD) is inherited in an autosomal recessive manner. THD has a broad phenotypic spectrum, but two main types can be defined:

Levodopa‐induced dyskinesias in tyrosine hydroxylase deficiency

The objective of this study was to characterize levodopa (l-dopa)-induced dyskinesias in patients with tyrosine hydroxylase deficiency. Clinical observation was carried out on 6 patients who were diagnosed with tyrosine hydroxylase deficiency and were treated with escalating doses of l-dopa. All 6 patients showed l-dopa-induced dyskinesias of variable intensity early in the course of treatment and regardless of the age of initiation. l-Dopa-induced dyskinesias were precipitated by increases in the dose of l-dopa and also by febrile illnesses and stress. They caused dysfunction and distress in 2 patients. The dyskinesias were improved by decreasing the l-dopa dose or by slowing its titration upward. Increasing the dose frequency was helpful in 2 patients, and introducing amantadine was helpful in another 2 patients. l-Dopa-induced dyskinesias are a common phenomenon in tyrosine hydroxylase deficiency. The current observations show that l-dopa-induced dyskinesias are frequent in a dopamine-deficient state in the absence of nigrostriatal degeneration. Although l-dopa-induced dyskinesias in tyrosine hydroxylase deficiency are phenomenologically similar to those that occur in Parkinson's disease, they are different in a number of other respects, suggesting intrinsic differences in the pathophysiologic basis of l-dopa-induced dyskinesias in the 2 conditions. © 2013 Movement Disorder Society.

Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency

To present a new family with tyrosine hydroxylase deficiency (THD) that presented with a new phenotype of predominant, levodopa-responsive myoclonus with dystonia due to compound heterozygosity of one previously reported mutation in the promoter region and a novel nonsynonymous mutation in the other allele, thus expanding the clinical and genetic spectrum of this disorder. We performed detailed clinical examination of the family and electrophysiology to characterize the myoclonus. We performed analysis of the TH gene and in silico prediction of the possible effect of nonsynonymous substitutions on protein structure. Electrophysiology suggested that the myoclonus was of subcortical origin. Genetic analysis of the TH gene revealed compound heterozygosity of a point mutation in the promoter region (c.1-71 C>T) and a novel nonsynonymous substitution in exon 12 (c.1282G>A, p.Gly428Arg). The latter is a novel variant, predicted to have a deleterious effect on the TH protein function and is the first pathogenic TH mutation in patients of African ancestry. We presented a THD family with predominant myoclonus-dystonia and a new genotype. It is important to consider THD in the differential diagnosis of myoclonus-dystonia, because early treatment with levodopa is crucial for these patients.

Multiple Applications of L-DOPA Therapy in Children with Neurological Disorders - 25 Year Review (P04.178)

Objective: L -Dopa is well known for its use in childhood neurological disorders. formost is Dopa-responsive dystonia, Segawa9s Disease, and its variants. L-Dopa has increasingly been cited in many other childhood neurological diosrders in the literature. This review summarizes athe applications of L-Dopa in childhood based upon extensive computerized literature review expanding the clinical applications in and young adults. Background Previously isloated reports have cited the application of L Dopa in childhood movement disorders but no single review has comprehensively reviewed all the disorders in which L Dopa has been used. Design/Methods: Summarization of medical literature in the past 25 years searching the term L-Dopa in childhood, L -Dopa in Childhood movement disorders, L Dopa in children utilizing Pubmed database and a Cochrane Review was performed.Citations were grouped upon frequency of citation and applicability to clincial practice. Both well known applications and less commonly cited therapies were included. Results: Over 25 years at least 26 different disorders have been reported in childhood utilizing L-Dopa. Most frequent are the disorders related to Dopa responsive dystonia, (Segawa9s disease)and its variants. This includes disorders in dopamine synthesis including tyrosine hydroxylase deficiency and tetrahydrobiopterin pathway disorders. Significant citations also include: Juvenile Parkinson9s disease, Myoclonus- Dystonia, Familial paroxysmal Dystonia, PKAN, Lower Limb Dystonia, Chediak -Hegashi synsdrome, Dystonia-Parkinsonism, Benign Paroxysmal Tonic Upgaze of Childhood, Amblyopia, Aromatic l-aminoacid decarboxylase Deficiency, Restless Legs Syndrome and Attention Deficit Hyperactivity Syndrome, and potential application in Angelman Syndrome. Conclusions: In the past 25 years, over 26 childhood neurological disorders have been described that are responsive to L-Dopa therapy. While many are well known an expanded current application is summarized. This summary brings up to date the prevalent citations and provides a review of the many less commonly and less frequently recognized disorders in childhood for which L-Dopa therapy plays a major role. Disclosure: Dr. Lavenstein has nothing to disclose. Dr. Hecht has nothing to disclose.

Tyrosine Hydroxylase Deficiency in Taiwanese Infants

We analyzed the clinical manifestations, genetic mutations, treatment responses to L-dopa, and long-term neurologic outcomes in Taiwanese infants with tyrosine hydroxylase deficiency. From 1999 to May 2011, we enrolled six infants who had been diagnosed with tyrosine hydroxylase deficiency by identifying point mutations on the tyrosine hydroxylase gene. Two patients manifested fetal distress during the perinatal period. Four patients exhibited generalized tremor as their first observed neurologic sign at age 3 months. All presented brisk reflexes, hypokinesia, rigidity, distal chorea, and athetosis. We identified a novel missense mutation, I382T, and report on the first patient, to the best of our knowledge, with a homozygous R153X nonsense mutation. Five of six patients responded to L-dopa at a dose of 4.2-34.7 mg/kg/day combined with biperiden or selegiline or both. Long-term neurologic outcomes (median follow-up, 5 years and 10.5 months) revealed two patients demonstrated slightly low intelligence quotients, three demonstrated mild to moderate psychomotor retardation, and one died of respiratory failure. A higher dose of L-dopa, together with alternative therapies, may lead to improvements in motor function. However, several years of observation may be needed to reach definitive conclusions about neurologic outcomes.

Novel Mutations in the Tyrosine Hydroxylase Gene in the First Czech Patient with Tyrosine Hydroxylase Deficiency

Tyrosine hydroxylase deficiency manifests mainly in early childhood and includes two clinical phenotypes: an infantile progressive hypokinetic-rigid syndrome with dystonia (type A) and a neonatal complex encephalopathy (type B). The biochemical diagnostics is exclusively based on the quantitative determination of the neurotransmitters or their metabolites in cerebrospinal fluid (CSF). The implementation of neurotransmitter analysis in clinical praxis is necessary for early diagnosis and adequate treatment. Neurotransmitter metabolites in CSF were analyzed in 82 children (at the age 1 month to 17 years) with clinical suspicion for neurometabolic disorders using high performance liquid chromatography (HPLC) with electrochemical detection. The CSF level of homovanillic acid (HVA) was markedly decreased in three children (64, 79 and 94 nmol/l) in comparison to age related controls (lower limit 218-450 nmol/l). Neurological findings including severe psychomotor retardation, quadruspasticity and microcephaly accompanied with marked dystonia, excessive sweating in the first patient was compatible with the diagnosis of tyrosine hydroxylase (TH) deficiency (type B) and subsequent molecular analysis revealed two novel heterozygous mutations c.636A>C and c.1124G>C in the TH gene. The treatment with L-DOPA/carbidopa resulted in the improvement of dystonia. Magnetic resonance imaging studies in two other patients with microcephaly revealed postischaemic brain damage, therefore secondary HVA deficit was considered in these children. Diagnostic work-up in patients with neurometabolic disorders should include analysis of neurotransmitter metabolites in CSF.

A New Tyrosine Hydroxylase Genotype Associated With Early-Onset Severe Encephalopathy

We describe a boy affected by an early-onset severe encephalopathy (stagnation of psychomotor development, paroxysmal dystonic postures and movements of limbs, hypokinesia) due to tyrosine hydroxylase deficiency. High blood prolactin and low homovanillic acid in cerebrospinal fluid suggested the diagnosis. Genetic analysis revealed 3 new missense mutations on tyrosine hydroxylase gene: [c.752C>T(p.P251L) and c.887G>A(p.R296Q] harbored by the father and c.836G>T (p.C279F) of maternal origin. Bioinformatics tools have been helpful in predicting the pathogenic role of p.P251L and p.C279F substitutions, while a weak pathogenic effect was ascribed to p.R296Q.

Bilateral subthalamic nucleus deep brain stimulation for dopa-responsive dystonia in a 6-year-old child

Tyrosine hydroxylase (TH) deficiency is a rare autosomal recessive metabolic disease that results in the decreased production of catecholamines. Standard treatment relies on combinations of levodopa and carbidopa, anticholinergic agents, serotonergic agonists, and monamine oxidase B inhibitors. Unfortunately, severely affected children often require escalating doses of medication and suffer from dyskinesias as well as significant on/off symptomatology. The authors present a case of medically intractable dopa-responsive dystonia in a 6-year-old boy whose condition significantly improved with bilateral subthalamic nucleus deep brain stimulation. This case is unique in its novel approach to tyrosine hydroxylase deficiency and the young age of the patient.

Expanding Phenotype and Clinical Analysis of Tyrosine Hydroxylase Deficiency

This study included 12 Chinese patients with a wide spectrum of phenotypes of tyrosine hydroxylase deficiency. Seven females and 5 males, aged 2.2 to 41 years, had phenotypes ranging from severe type with onset at infancy to mild type with onset after 3 years of age. Patients with the severe type had encephalopathy with poor treatment response or infantile parkinsonism with motor delay. Patients with the less common mild type had dopa-responsive dystonia or a newly recognized predominant symptom of myopathy. Female siblings had more severe phenotypes. The phenotype and treatment outcomes were strongly related to a homovanillic acid level and homovanillic acid/5-hydroxyindolacetic acid ratio of less than 1 in the cerebrospinal fluid. Hyperprolactinemia was found in 50% of the severe cases. Levodopa was the mainstay of treatment, and early addition of selegiline resulted in a remarkable response in some patients. Treatment response for mild-type patients is universally good even with a treatment delay of 10 years after onset of neurological symptoms.

Tyrosine hydroxylase deficiency in three Greek patients with a common ancestral mutation

We present the clinical, biochemical, and molecular findings of three Greek patients with tyrosine hydroxylase (TH) deficiency. All patients presented with a severe clinical phenotype characterized by prominent motor delay, infantile parkinsonism, oculogyric crises, and signs of autonomic dysfunction. Cerebrospinal fluid analysis disclosed reduced dopamine metabolites and normal pterins. Response to levodopa was favorable though not dramatic. All patients were homozygous for a previously reported mutation (p.L236P). SNP haplotype analysis was consistent with a common ancestral mutation, thus indicating a founder effect in Greek patients with TH deficiency.

Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis

Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dopa.

Disorders of monoamine metabolism: inherited disorders frequently misdiagnosed as epilepsy

Pediatric neurotransmitter diseases are new emerging neurological diseases in children. They include tyrosine hydroxylase (TH) deficiency, aromatic L-amino acid decarboxylase (AADC) deficiency, succinic semialdehyde dehydrogenase (SSADH) deficiency, gua-nosine triphosphate cyclohydrolase I deficiency, sepiapterin reductase (SR) deficiency and cerebral folate deficiency. Of these, monoamine biosynthesis and metabolism disorders are one group of inherited disorders usually requiring specific diagnostic procedures. Children with disorders of neurotransmitters often present with psychomotor retardation, hypotonia and microcephaly. Although seizures may be more common in patients with SR deficiency, patients with TH or AADC deficiency only occasionally have non-epileptic myoclonus. However, the episodic dystonia and oculogyric crisis manifested in these patients are frequently misdiagnosed as epilepsy, and multiple anti-epileptic drugs (AEDs) may be given. In the present short review, the pathogenesis and diagnosis of these neurotransmitter disorders are discussed, with the hope that correct diagnosis of pediatric neurotransmitter diseases can reduce the unnecessary AED treatment.

Biochemical and molecular characterization of tyrosine hydroxylase deficiency in Hong Kong Chinese

Tyrosine hydroxylase deficiency is a rare neurotransmitter disorder affecting the rate-limiting step in catecholamine biosynthesis. There are about 40 cases reported worldwide. Here, we report the biochemical and molecular findings of eight unrelated Chinese patients with tyrosine hydroxylase deficiency. We have identified eight novel mutations with 5 missense, 2 nonsense and 1 splicing mutations in the TH gene, namely p.R153X, p.R169X, p.G294R, p.G315S, p.A385V, p.I394T, p.G408R, and c.1163+5G>C. The mutations of the TH gene in Chinese are heterogeneous.

P306 Levodopa-induced dyskinesias in tyrosine hydroxylase deficiency

P306 Levodopa-induced dyskinesias in tyrosine hydroxylase deficiency

International Symposium on Pediatric Neurotransmitter Diseases

The second International Symposium on Pediatric Neurotransmitter Diseases (PNDs), entitled BMedical Management of Pediatric Neurotransmitter Diseases: A Multidisciplinary Approach^, was convened on July 18–19, 2008, in Washington, DC, USA. The meeting was sponsored conjointly by the National Institute of Neurological Disease and Stroke (NINDS), the Office of Rare Diseases (ORD), the Johns Hopkins School of Medicine and the PND Association. This second symposium followed almost six years to the day from the first International Symposium (May 18–19, 2002), the proceedings of which were presented in a supplement to Annals of Neurology (Volume 54 Issue S6, pages S1–S109 (2003)). There are currently five rare, inherited disorders that affect central neurotransmission and are housed under the umbrella of the PND Association. These are: succinic semialdehyde dehydrogenase (SSADH) deficiency (or g-hydroxybutyric aciduria), tyrosine hydroxylase (TH) deficiency, aromatic L-amino acid decarboxylase (AADC) deficiency, guanosine triphosphate cyclohydrolase I deficiency (GTP cyclohydrolase, or GTPCH deficiency), and sepiapterin reductase (SR) deficiency. Generally speaking, early presentation with an array of movement dysfunction is the rule in these disorders, and this umbrella is likely to expand as more disorders are recognized, and more parents join the ranks of the PND Association. The conference brought together scientists and clinicians to discuss current and potential treatments for PNDs, and to develop practical guidelines for multidisciplinary treatment of these disorders. The conference was attended by more than sixty medical professionals representing six countries, ten medical professionals from the National Institutes of Health, and more than thirty families whose child (or children) are affected with one of the PNDs. As it was with the first Symposium, the opening talks presented an overview of the phenotypes and metabolic features of the PNDs. The future prospects for gene therapy in this group of disorders was also discussed. As always, the exceptionally insightful comments of Prof. Segawa, who in 1971 first described autosomal-dominant GTP cyclohydrolase deficiency, provided thoughtful discussion for all in attendance. A goal of the second Symposium was to present a Bmultifaceted^ approach to treatment. The corresponding sessions highlighted traditional physiatry, sensory integration intervention and the potential for deep brain stimulation for amelioration of symptoms. These approaches generated lively discussion, and it is probable that these approaches will be discussed in future Symposia. The second Symposium afforded the opportunity for research updates by investigators funded through the PND Association, as well as other investigators who had important new data to present. An impressive update on neuroimaging in AADC deficiency was developed into one of the written contributions to the Symposium proceedings. One of the more rewarding J Inherit Metab Dis (2009) 32:319–320 DOI 10.1007/s10545-009-9961-1

Role of N-terminus of tyrosine hydroxylase in the biosynthesis of catecholamines

Tyrosine hydroxylase (TH) catalyzes the conversion of L: -tyrosine to L: -dopa, which is the initial and rate-limiting step in the biosynthesis of catecholamines [CA; dopamine (DA), noradrenaline, and adrenaline], and plays a central role in the neurotransmission and hormonal actions of CA. Thus, TH is related to various neuro-psychiatric diseases such as TH deficiency, Parkinson's disease (PD), and schizophrenia. Four isoforms of human TH (hTH1-hTH4) are produced from a single gene by alternative mRNA splicing in the N-terminal region, whereas two isoforms exist in monkeys and only a single protein exist in all non-primate mammals. A catalytic domain is located within the C-terminal two-thirds of molecule, whereas the part of the enzyme controlling enzyme activity is assigned to the N-terminal end as the regulatory domain. The catalytic activity of TH is end product inhibited by CA, and the phosphorylation of Ser residues (Ser(19), Ser(31), and especially Ser(40) of hTH1) in the N-terminus relieves the CA-mediated inhibition. Ota and Nakashima et al. have investigated the role of the N-terminus of TH enzyme in the regulation of both the catalytic activity and the intracellular stability by producing various mutants of the N-terminus of hTH1. The expression of the following three enzymes, TH, GTP cyclohydrolase I, which synthesizes the tetrahydrobiopterin cofactor of TH, and aromatic-L: -amino acid decarboxylase, which produces DA from L: -dopa, were induced in the monkey striatum using harmless adeno-associated virus vectors, resulting in a remarkable improvement in the symptoms affecting PD model monkeys Muramatsu (Hum Gene Ther 13:345-354, 2002). Increased knowledge concerning the amino acid sequences of the N-terminus of TH that control enzyme activity and stability will extend the spectrum of the gene-therapy approach for PD.

Tyrosine hydroxylase deficiency with severe clinical course

Tyrosine hydroxylase (TH) deficiency is a rare autosomal recessive disorder mapped to chromosome 11p15.5. Its clinical expression varies with presentations as dopa–responsive dystonia (recessive Segawa’s disease), dopa–responsive infantile parkinsonism, dopa–responsive spastic paraplegia, progressive infantile encephalopathy or dopa–non-responsive dystonia. We describe a 7-year-old boy with progressive infantile encephalopathy and non-responsiveness to dopamine. The patient demonstrated generalized hypotonia, pyramidal tract dysfunction and temperature instability after the second month of life. Dystonia, tremor and oculogyric crises complicated the clinical picture during the following months. Neurotransmitter analysis in CSF disclosed almost undetectable levels of HVA and MHPG, whereas serum prolactin was profoundly increased. Subsequent molecular analysis revealed homozygosity for a missense mutation (c.707T > C) in the TH gene. l-Dopa therapy in both high and low doses resulted in massive hyperkinesias, while substitution with selegiline exerted only a mild beneficial effect. Today, at the age of 7 years, the patient demonstrates severe developmental retardation with marked trunkal hypotonia, hypokinesia and occasionally dystonic and/or hyperkinetic crises. He is the third Greek patient with TH deficiency to be reported. Since all three patients carry the same pathogenetic mutation, a founder effect is suspected.

Oculogyric crisis in tyrosine hydroxylase deficiency

Oculogyric crisis in tyrosine hydroxylase deficiency

A novel missense mutation pattern of the GCH1 gene in dopa-responsive dystonia

Dopa-responsive dystonia (DRD) is an inherited metabolic disorder now classified as DYT5 with two different biochemical defects: autosomal dominant GTP cyclohydrolase 1 (GCH1) deficiency or autosomal recessive tyrosine hydroxylase deficiency. We report the case of a 10-years-old girl with progressive generalized dystonia and gait disorder who presented dramatic response to levodopa. The phenylalanine to tyrosine ratio was significantly higher after phenylalanine loading test. This condition had two different heterozygous mutations in the GCH1 gene: the previously reported P23L mutation and a new Q182E mutation. The characteristics of the DRD and the molecular genetic findings are discussed.