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Ron A Wevers - One of the best experts on this subject based on the ideXlab platform.
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Tyrosine Hydroxylase Deficiency with severe clinical course
Molecular Genetics and Metabolism, 2009Co-Authors: Dimitrios I Zafeiriou, Michèl A.a.p. Willemsen, Marcel M. Verbeek, Euthymia Vargiami, A Ververi, Ron A WeversAbstract: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.
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long term course of l dopa responsive dystonia caused by Tyrosine Hydroxylase Deficiency
Neurology, 2004Co-Authors: A Schiller, Nenad Blau, Ron A Wevers, Gerry Steenbergen, Hans H JungAbstract:The authors report the long-term course of two siblings with L-dopa responsive dystonia (DRD) associated with a compound heterozygous mutation in the Tyrosine Hydroxylase (TH) gene. Both siblings manifested with lower-limb onset generalized DRD and had a sustained response to low-dose L-dopa therapy for over 35 years. Although the l-dopa therapy was delayed up to 20 years after disease onset, there were no cognitive or neurologic sequelae of the long-term catecholamine deficit.
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Tyrosine Hydroxylase Deficiency causes progressive encephalopathy and dopa nonresponsive dystonia
Annals of Neurology, 2003Co-Authors: G. F. Hoffmann, C. Bräutigam, G C H Steenbergenspanjers, Carlo Dionisivici, Birgit Assmann, Martin Haussler, Johannes B C De Klerk, Markus Naumann, Hans Michael Strassburg, Ron A WeversAbstract:Tyrosine Hydroxylase (TH) is the key enzyme in the biosynthesis of the catecholamines dopamine, epinephrine, and norepinephrine. Recessively inherited Deficiency of TH was recently identified and incorporated into recent concepts of genetic dystonias as the cause of recessive Dopa-responsive dystonia or Segawa's syndrome in analogy to dominantly inherited GTP cyclohydrolase I Deficiency. We report four patients with TH Deficiency and two with GTP cyclohydrolase I Deficiency. Patients with TH Deficiency suffer from progressive infantile encephalopathy dominated by motor retardation similar to a primary neuromuscular disorder, fluctuating extrapyramidal, and ocular and vegetative symptoms. Intellectual functions are mostly compromised. Prenatally disturbed brain development and postnatal growth failure were observed. Treatment with levodopa ameliorates but usually does not normalize symptoms. Compared with patients with dominantly inherited GTP cyclohydrolase I Deficiency, catecholaminergic neurotransmission is severely and constantly impaired in TH Deficiency. In most patients, this results not in predominating dystonia, a largely nondegenerative condition, but in a progressive often lethal neurometabolic disorder, which can be improved but not cured by L-dopa. Investigations of neurotransmitter defects by specific cerebrospinal fluid determinations should be included in the diagnostic evaluation of children with progressive infantile encephalopathy.
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Tyrosine Hydroxylase Deficiency clinical manifestations of catecholamine insufficiency in infancy
Movement Disorders, 2002Co-Authors: Padraic J Grattansmith, G C H Steenbergenspanjers, Ron A Wevers, Victor S C Fung, John W Earl, Bridget WilckenAbstract:Inborn errors of catecholamine biosynthesis are rare but of great interest as they are genetic disorders, and in some, treatment may completely reverse severe neurological abnormalities. They also provide insights into the action of the biogenic amines in the developing brain. We describe the clinical course of an infant with Tyrosine Hydroxylase (TOH) Deficiency over a 30-month period. The parents are consanguineous, and genetic analysis revealed the infant to be homozygous for the common G698A mutation in the TOH gene. TOH Deficiency can be seen as a model of pure catecholamine Deficiency. Experimental evidence, reports of other disorders of biogenic amines, and our experience with this infant suggest that the symptoms of catecholamine Deficiency in infancy can be broadly subdivided. Signs of dopamine Deficiency include tremor, hypersensitivity to levadopa (L-dopa) therapy, oculogyric crises, akinesia, rigidity, and dystonia. Manifestations of norepinephrine Deficiency include ptosis, miosis, profuse oropharyngeal secretions, and postural hypotension. Hypersensitivity to L-dopa was a particular management problem in this infant.
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l dopa responsive infantile hypokinetic rigid parkinsonism due to Tyrosine Hydroxylase Deficiency
Neurology, 2000Co-Authors: J F De Rijkvan Andel, B. Geurtz, F. J. M. Gabreëls, G C H Steenbergenspanjers, L P W J Van Den Heuvel, Jan A M Smeitink, Ron A WeversAbstract:Article abstract Tyrosine Hydroxylase Deficiency was confirmed biochemically and genetically in four unrelated Dutch patients. The patients have a hypokinetic-rigid parkinsonian syndrome with symptoms in early infancy (3 to 6 months of age). Only sporadic dystonic movements were seen. There was no diurnal fluctuation. All patients showed a rapid favorable response to low-dose l-dopa/carbidopa treatment. Motor performance improved but did not fully normalize. The patients have mild mental retardation.
G. F. Hoffmann - One of the best experts on this subject based on the ideXlab platform.
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neuromotor and cognitive outcomes of early treatment in Tyrosine Hydroxylase Deficiency type b
Neurology, 2017Co-Authors: Vincenzo Leuzzi, Mario Mastrangelo, Maria Teresa Giannini, Riccardo Carbonetti, G. F. HoffmannAbstract:Tyrosine Hydroxylase Deficiency (THD) is an autosomal recessive disorder resulting in severe dopamine depletion, with fewer than 70 patients diagnosed worldwide.1 Most of the reported cases of THD belong to 2 phenotypes: an infantile progressive hypokinetic-rigid syndrome with dystonia (type A) and a neonatal/early-onset severe encephalopathy (type B).1 Given the early onset, the extensive involvement of neurologic development, and the limited response to dopaminergic medications, prognosis for THD type B is poor.1–6 Twenty patients with THD type B have been described so far, with no data on long-term outcome.1,2 We report follow-up lasting 17 years with serial video recordings of the index case of THD type B.1,2,7 Acknowledgment: The authors thank Dr. Carlo Dionisi-Vici, Unit of Metabolism, Bambino Gesu Children's Hospital, Rome, for his contribution to the clinical management of the patient and Dr. Claudia Carducci, Department of Experimental Medicine, Sapienza University of Rome, who performed all the biochemical investigations.
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Tyrosine Hydroxylase Deficiency causes progressive encephalopathy and dopa nonresponsive dystonia
Annals of Neurology, 2003Co-Authors: G. F. Hoffmann, C. Bräutigam, G C H Steenbergenspanjers, Carlo Dionisivici, Birgit Assmann, Martin Haussler, Johannes B C De Klerk, Markus Naumann, Hans Michael Strassburg, Ron A WeversAbstract:Tyrosine Hydroxylase (TH) is the key enzyme in the biosynthesis of the catecholamines dopamine, epinephrine, and norepinephrine. Recessively inherited Deficiency of TH was recently identified and incorporated into recent concepts of genetic dystonias as the cause of recessive Dopa-responsive dystonia or Segawa's syndrome in analogy to dominantly inherited GTP cyclohydrolase I Deficiency. We report four patients with TH Deficiency and two with GTP cyclohydrolase I Deficiency. Patients with TH Deficiency suffer from progressive infantile encephalopathy dominated by motor retardation similar to a primary neuromuscular disorder, fluctuating extrapyramidal, and ocular and vegetative symptoms. Intellectual functions are mostly compromised. Prenatally disturbed brain development and postnatal growth failure were observed. Treatment with levodopa ameliorates but usually does not normalize symptoms. Compared with patients with dominantly inherited GTP cyclohydrolase I Deficiency, catecholaminergic neurotransmission is severely and constantly impaired in TH Deficiency. In most patients, this results not in predominating dystonia, a largely nondegenerative condition, but in a progressive often lethal neurometabolic disorder, which can be improved but not cured by L-dopa. Investigations of neurotransmitter defects by specific cerebrospinal fluid determinations should be included in the diagnostic evaluation of children with progressive infantile encephalopathy.
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Tyrosine Hydroxylase Deficiency with severe clinical course clinical and biochemical investigations and optimization of therapy
The Journal of Pediatrics, 2000Co-Authors: Carlo Dionisivici, Vincenzo Leuzzi, G. F. Hoffmann, Jan A M Smeitink, Helmut Hoffken, C Brautigam, Cristiano Rizzo, Gerry C H Steebergenspanjers, Ron A WeversAbstract:Tyrosine Hydroxylase Deficiency was diagnosed after determination of cerebrospinal fluid neurotransmitters and DNA analysis in a child with severe axial hypotonia and hypokinesia associated with dystonic and ballistic movements. L-dopa therapy was unsuccessful, whereas a combination with selegiline, a selective monoamine oxidase-beta inhibitor, with low-dose L-dopa markedly improved the severe clinical picture.
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biochemical and molecular genetic characteristics of the severe form of Tyrosine Hydroxylase Deficiency
Clinical Chemistry, 1999Co-Authors: C Brautigam, G. F. Hoffmann, G C H Steenbergenspanjers, Jan A M Smeitink, Carlo Dionisivici, Lambert P Van Den Heuvel, Ron A WeversAbstract:Background: Tyrosine Hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of the catecholamines dopamine, norepinephrine, and epinephrine. Recently, mutations were identified in cases of autosomal recessive dopa-responsive dystonia and infantile parkinsonism. We describe a patient with severe symptoms and a new missense mutation in TH. Methods: Relevant metabolites in urine and cerebrospinal fluid were measured by HPLC with fluorometric and electrochemical detection. All exons of the TH gene were amplified by PCR and subjected to single-strand conformation polymorphism analysis. Amplimers displaying aberrant migration patterns were analyzed by DNA sequence analysis. Results: The patient presented with severe axial hypotonia, hypokinesia, reduced facial mimicry, ptosis, and oculogyric crises from infancy. The major metabolite of dopamine, homovanillic acid, was undetectable in the patient’s cerebrospinal fluid. A low dose of l-dopa produced substantial biochemical but limited clinical improvement. DNA sequencing revealed a homozygous 1076G→T missense mutation in exon 10 of the TH gene. The mutation was confirmed with restriction enzyme analysis. It was not present in 100 control alleles. Secondary structure prediction based on Chou-Fasman calculations showed an abnormal secondary structure of the mutant protein. Conclusions: We describe a new missense mutation (1076G→T, C359F) in the TH gene. The transversion is present in all known splice variants of the enzyme. It produces more severe clinical and biochemical manifestations than previously described in TH-deficient cases. Our findings extend the clinical and the biochemical phenotype of genetically demonstrated TH Deficiency.
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A review of biochemical and molecular genetic aspects of Tyrosine Hydroxylase Deficiency including a novel mutation (291delC)
Journal of Inherited Metabolic Disease, 1999Co-Authors: R. A. Wevers, B. Geurtz, J. F. Andel, C. Bräutigam, L. P. W. J. Heuvel, G. C. H. Steenbergen-spanjers, J. A. M. Smeitink, G. F. Hoffmann, F. J. M. GabreëlsAbstract:An overview is given of the current knowledge on the human Tyrosine Hydroxylase gene and on the biochemical aspects of diagnosing defects in this gene. Diagnostic biochemical findings are described in four cases of genetically confirmed Tyrosine Hydroxylase Deficiency. Decreased CSF levels of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), together with normal pterin and CSF Tyrosine and 5-hydroxyindoleacetic acid (5-HIAA) concentrations are the diagnostic hallmarks of Tyrosine Hydroxylase Deficiency. At the metabolite level the diagnosis can only be made reliably in CSF. Strict adherence to a standardized lumbar puncture protocol and adequate reference values are essential for diagnosis of this "new" treatable neurometabolic disorder. Measurements of HVA, vanillylmandelic acid (VMA) or catecholamines in urine are not relevant for diagnosing Tyrosine Hydroxylase Deficiency. The diagnosis should be considered in all children with unexplained hypokinesia and other extrapyramidal symptoms. Three of our patients are homozygous for a mutation in exon 6 (698G>A) of the Tyrosine Hydroxylase gene and one patient was compound heterozygous for the same mutation and a novel truncating mutation in exon 3 (291delC).
Jan A M Smeitink - One of the best experts on this subject based on the ideXlab platform.
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l dopa responsive infantile hypokinetic rigid parkinsonism due to Tyrosine Hydroxylase Deficiency
Neurology, 2000Co-Authors: J F De Rijkvan Andel, B. Geurtz, F. J. M. Gabreëls, G C H Steenbergenspanjers, L P W J Van Den Heuvel, Jan A M Smeitink, Ron A WeversAbstract:Article abstract Tyrosine Hydroxylase Deficiency was confirmed biochemically and genetically in four unrelated Dutch patients. The patients have a hypokinetic-rigid parkinsonian syndrome with symptoms in early infancy (3 to 6 months of age). Only sporadic dystonic movements were seen. There was no diurnal fluctuation. All patients showed a rapid favorable response to low-dose l-dopa/carbidopa treatment. Motor performance improved but did not fully normalize. The patients have mild mental retardation.
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Tyrosine Hydroxylase Deficiency with severe clinical course clinical and biochemical investigations and optimization of therapy
The Journal of Pediatrics, 2000Co-Authors: Carlo Dionisivici, Vincenzo Leuzzi, G. F. Hoffmann, Jan A M Smeitink, Helmut Hoffken, C Brautigam, Cristiano Rizzo, Gerry C H Steebergenspanjers, Ron A WeversAbstract:Tyrosine Hydroxylase Deficiency was diagnosed after determination of cerebrospinal fluid neurotransmitters and DNA analysis in a child with severe axial hypotonia and hypokinesia associated with dystonic and ballistic movements. L-dopa therapy was unsuccessful, whereas a combination with selegiline, a selective monoamine oxidase-beta inhibitor, with low-dose L-dopa markedly improved the severe clinical picture.
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biochemical and molecular genetic characteristics of the severe form of Tyrosine Hydroxylase Deficiency
Clinical Chemistry, 1999Co-Authors: C Brautigam, G. F. Hoffmann, G C H Steenbergenspanjers, Jan A M Smeitink, Carlo Dionisivici, Lambert P Van Den Heuvel, Ron A WeversAbstract:Background: Tyrosine Hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of the catecholamines dopamine, norepinephrine, and epinephrine. Recently, mutations were identified in cases of autosomal recessive dopa-responsive dystonia and infantile parkinsonism. We describe a patient with severe symptoms and a new missense mutation in TH. Methods: Relevant metabolites in urine and cerebrospinal fluid were measured by HPLC with fluorometric and electrochemical detection. All exons of the TH gene were amplified by PCR and subjected to single-strand conformation polymorphism analysis. Amplimers displaying aberrant migration patterns were analyzed by DNA sequence analysis. Results: The patient presented with severe axial hypotonia, hypokinesia, reduced facial mimicry, ptosis, and oculogyric crises from infancy. The major metabolite of dopamine, homovanillic acid, was undetectable in the patient’s cerebrospinal fluid. A low dose of l-dopa produced substantial biochemical but limited clinical improvement. DNA sequencing revealed a homozygous 1076G→T missense mutation in exon 10 of the TH gene. The mutation was confirmed with restriction enzyme analysis. It was not present in 100 control alleles. Secondary structure prediction based on Chou-Fasman calculations showed an abnormal secondary structure of the mutant protein. Conclusions: We describe a new missense mutation (1076G→T, C359F) in the TH gene. The transversion is present in all known splice variants of the enzyme. It produces more severe clinical and biochemical manifestations than previously described in TH-deficient cases. Our findings extend the clinical and the biochemical phenotype of genetically demonstrated TH Deficiency.
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biochemical hallmarks of Tyrosine Hydroxylase Deficiency
Clinical Chemistry, 1998Co-Authors: C. Bräutigam, F. J. M. Gabreëls, Jan A M Smeitink, Ron A Wevers, Riet J T Jansen, Johanneke F De Rijkvan Andel, G. F. HoffmannAbstract:We report the biochemical hallmarks of Tyrosine Hydroxylase Deficiency with emphasis on reliable diagnostic strategies of four new cases of an inborn error of Tyrosine Hydroxylase (TH). Three of our patients from different parts of the Netherlands were found homozygous for a mutation in exon 6 (G698A) of the TH gene, and one patient was found compound heterozygous for the same mutation and an additional mutation in exon 3. The first clinical symptoms of hypokinesia, rigidity of arms and legs and axial hypotonia, developed between 3 and 7 months of age. Cerebrospinal fluid investigations revealed a characteristic metabolite constellation in every case: low homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethyleneglycol concentrations in the presence of normal reference range 5-hydroxyindolacetic acid concentrations. Strict adherence to a standardized lumbar puncture protocol and adequate age-related reference values are essential for diagnosis of this "new" treatable neurometabolic disorder. Urinary measurements of HVA, vanillylmandelic acid, and catecholamines can lead to false-negative conclusions. All patients showed a remarkable clinical improvement on a low dose of L-dihydroxyphenylalanine/ (S)-2-(3,4-dihydroxybenzyl)-2-hydrazinpropionic acid. During treatment, cerebrospinal fluid HVA, and 3-methoxy-4-hydroxy-phenylethyleneglycol increased substantially.
G C H Steenbergenspanjers - One of the best experts on this subject based on the ideXlab platform.
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Tyrosine Hydroxylase Deficiency causes progressive encephalopathy and dopa nonresponsive dystonia
Annals of Neurology, 2003Co-Authors: G. F. Hoffmann, C. Bräutigam, G C H Steenbergenspanjers, Carlo Dionisivici, Birgit Assmann, Martin Haussler, Johannes B C De Klerk, Markus Naumann, Hans Michael Strassburg, Ron A WeversAbstract:Tyrosine Hydroxylase (TH) is the key enzyme in the biosynthesis of the catecholamines dopamine, epinephrine, and norepinephrine. Recessively inherited Deficiency of TH was recently identified and incorporated into recent concepts of genetic dystonias as the cause of recessive Dopa-responsive dystonia or Segawa's syndrome in analogy to dominantly inherited GTP cyclohydrolase I Deficiency. We report four patients with TH Deficiency and two with GTP cyclohydrolase I Deficiency. Patients with TH Deficiency suffer from progressive infantile encephalopathy dominated by motor retardation similar to a primary neuromuscular disorder, fluctuating extrapyramidal, and ocular and vegetative symptoms. Intellectual functions are mostly compromised. Prenatally disturbed brain development and postnatal growth failure were observed. Treatment with levodopa ameliorates but usually does not normalize symptoms. Compared with patients with dominantly inherited GTP cyclohydrolase I Deficiency, catecholaminergic neurotransmission is severely and constantly impaired in TH Deficiency. In most patients, this results not in predominating dystonia, a largely nondegenerative condition, but in a progressive often lethal neurometabolic disorder, which can be improved but not cured by L-dopa. Investigations of neurotransmitter defects by specific cerebrospinal fluid determinations should be included in the diagnostic evaluation of children with progressive infantile encephalopathy.
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Tyrosine Hydroxylase Deficiency clinical manifestations of catecholamine insufficiency in infancy
Movement Disorders, 2002Co-Authors: Padraic J Grattansmith, G C H Steenbergenspanjers, Ron A Wevers, Victor S C Fung, John W Earl, Bridget WilckenAbstract:Inborn errors of catecholamine biosynthesis are rare but of great interest as they are genetic disorders, and in some, treatment may completely reverse severe neurological abnormalities. They also provide insights into the action of the biogenic amines in the developing brain. We describe the clinical course of an infant with Tyrosine Hydroxylase (TOH) Deficiency over a 30-month period. The parents are consanguineous, and genetic analysis revealed the infant to be homozygous for the common G698A mutation in the TOH gene. TOH Deficiency can be seen as a model of pure catecholamine Deficiency. Experimental evidence, reports of other disorders of biogenic amines, and our experience with this infant suggest that the symptoms of catecholamine Deficiency in infancy can be broadly subdivided. Signs of dopamine Deficiency include tremor, hypersensitivity to levadopa (L-dopa) therapy, oculogyric crises, akinesia, rigidity, and dystonia. Manifestations of norepinephrine Deficiency include ptosis, miosis, profuse oropharyngeal secretions, and postural hypotension. Hypersensitivity to L-dopa was a particular management problem in this infant.
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l dopa responsive infantile hypokinetic rigid parkinsonism due to Tyrosine Hydroxylase Deficiency
Neurology, 2000Co-Authors: J F De Rijkvan Andel, B. Geurtz, F. J. M. Gabreëls, G C H Steenbergenspanjers, L P W J Van Den Heuvel, Jan A M Smeitink, Ron A WeversAbstract:Article abstract Tyrosine Hydroxylase Deficiency was confirmed biochemically and genetically in four unrelated Dutch patients. The patients have a hypokinetic-rigid parkinsonian syndrome with symptoms in early infancy (3 to 6 months of age). Only sporadic dystonic movements were seen. There was no diurnal fluctuation. All patients showed a rapid favorable response to low-dose l-dopa/carbidopa treatment. Motor performance improved but did not fully normalize. The patients have mild mental retardation.
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biochemical and molecular genetic characteristics of the severe form of Tyrosine Hydroxylase Deficiency
Clinical Chemistry, 1999Co-Authors: C Brautigam, G. F. Hoffmann, G C H Steenbergenspanjers, Jan A M Smeitink, Carlo Dionisivici, Lambert P Van Den Heuvel, Ron A WeversAbstract:Background: Tyrosine Hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of the catecholamines dopamine, norepinephrine, and epinephrine. Recently, mutations were identified in cases of autosomal recessive dopa-responsive dystonia and infantile parkinsonism. We describe a patient with severe symptoms and a new missense mutation in TH. Methods: Relevant metabolites in urine and cerebrospinal fluid were measured by HPLC with fluorometric and electrochemical detection. All exons of the TH gene were amplified by PCR and subjected to single-strand conformation polymorphism analysis. Amplimers displaying aberrant migration patterns were analyzed by DNA sequence analysis. Results: The patient presented with severe axial hypotonia, hypokinesia, reduced facial mimicry, ptosis, and oculogyric crises from infancy. The major metabolite of dopamine, homovanillic acid, was undetectable in the patient’s cerebrospinal fluid. A low dose of l-dopa produced substantial biochemical but limited clinical improvement. DNA sequencing revealed a homozygous 1076G→T missense mutation in exon 10 of the TH gene. The mutation was confirmed with restriction enzyme analysis. It was not present in 100 control alleles. Secondary structure prediction based on Chou-Fasman calculations showed an abnormal secondary structure of the mutant protein. Conclusions: We describe a new missense mutation (1076G→T, C359F) in the TH gene. The transversion is present in all known splice variants of the enzyme. It produces more severe clinical and biochemical manifestations than previously described in TH-deficient cases. Our findings extend the clinical and the biochemical phenotype of genetically demonstrated TH Deficiency.
Michèl A.a.p. Willemsen - One of the best experts on this subject based on the ideXlab platform.
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effects of carrying a pathogenic variant in the Tyrosine Hydroxylase gene on motivated action and valuation a pilot study in family members with Tyrosine Hydroxylase Deficiency
Donders Series ; 359, 2019Co-Authors: Jennifer C Swart, Michèl A.a.p. Willemsen, Monja I Frobose, Tessa Wassenberg, H Den E M Ouden, Roshan CoolsAbstract:Catecholamines (particularly dopamine) have long been implicated in motivation, learning and behavioural activation. Benign variants in dopamine-regulating genes have widely been linked to these processes as well, yet the cognitive effects of carrying pathogenic variants in the gene coding for Tyrosine Hydroxylase, which transforms Tyrosine into dopamine’s direct precursor L-Dopa, have never been studied. Here, we assessed for the first time whether carriers of Tyrosine Hydroxylase Deficiency (THD) show altered motivated action due to putative reductions in dopamine synthesis. To this end, we employed a motivational Go/NoGo learning task, which is sensitive to manipulations in dopamine function and compared 16 family members of THD patients with 20 education- and age-matched controls. In the first learning phase of this task, subjects learnt to make Go or NoGo responses to cues that predict reward vs. punishment. In the second transfer phase, the subjects were presented with pairs of cues and chose the one they preferred, in the absence of reinforcement. Cue valence strongly biased Go/NoGo responding in the learning phase, such that subjects made more Go responses to reward than punishment cues. The groups did not significantly differ in this motivational bias. However, the THD carriers exhibited a shift in preference from NoGo-to-Win to Go-to- Avoid cues relative to matched controls during the transfer phase. These results suggest that subjective valuation is altered in THD carriers, potentially due to catecholamine-dependent changes in reward expectations, whereas task performance was unaffected. This pilot study provides a first insight into the cognitive consequences of carrying pathogenic TH variants, focusing on alterations in the reward valuation system and motivational biases in action.
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Tyrosine Hydroxylase Deficiency: a treatable disorder of brain catecholamine biosynthesis
Brain, 2010Co-Authors: Michèl A.a.p. Willemsen, Marcel M. Verbeek, Erik-jan Kamsteeg, Johanneke F. De Rijk-van Andel, Alec Aeby, Nenad Blau, Alberto Burlina, Maria Anna Donati, B. Geurtz, Padraic J. Grattan-smithAbstract: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.
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Tyrosine Hydroxylase Deficiency with severe clinical course
Molecular Genetics and Metabolism, 2009Co-Authors: Dimitrios I Zafeiriou, Michèl A.a.p. Willemsen, Marcel M. Verbeek, Euthymia Vargiami, A Ververi, Ron A WeversAbstract: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.
