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

Pons, Roser; Serrano, Mercedes; Ormazábal, Aída; Toma, Claudio; García‐Cazorla, Àngels; Area‐Gómez, Estela; Ribasés, Marta; Kanavakis, Emmanuel; Drakaki, Kaliopi; Giannakopoulos, Aristotelis; Orfanou, I; Youroukos, Sotiris; Cormand, Bru; Artuch, Rafael

doi:10.1002/mds.23002

Cited by 23 publications

(14 citation statements)

References 24 publications

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“…Through the analysis of the 1388 CSF samples, 21 patients (7 males, 14 females) with genetic dopamine deficiencies were identified: 11 with tyrosine hydroxylase deficiencies, four with guanosine triphosphate cyclohydrolase deficiencies, three with l ‐amino‐acid decarboxylase deficiencies, and one each with a sepiapterin reductase deficiency, MAO‐A and MAO‐B deficiency, and NPO deficiency (Table ). After excluding these deficiencies ( n= 1367), when compared with our age‐related reference values, CSF HVA values were low in 15.4% (95% confidence interval [CI] 13.5–17.4) of patients, high in 4.6% (95% CI 3.6–5.9), and normal in 80.0% (95% CI 77.8–82.1).…”

Section: Resultsmentioning

confidence: 99%

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Homovanillic acid in cerebrospinal fluid of 1388 children with neurological disorders

Molero-Luís

Serrano

Ormazábal

et al. 2013

Develop Med Child Neuro

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METHOD We studied biogenic amines in 1388 cerebrospinal fluid (CSF) samples from children with neurological disorders (mean age 3y 10mo, SD 4y 5mo; 712 males, 676 females. Correlations among CSF homovanillic acid (HVA) values and other biochemical, clinical, neuroradiological, and electrophysiological parameters were analysed.RESULTS Twenty-one patients with primary dopaminergic deficiencies were identified. Of the whole sample, 20% showed altered HVA. We report neurological diseases with abnormal CSF HVA values such as pontocerebellar hypoplasia, perinatal asphyxia, central nervous system infections, mitochondrial disorders, and other genetic diseases. Overlapping HVA levels between primary and secondary dopamine deficiencies were observed. Prevalence of low CSF HVA levels was significantly higher in neonatal patients (v 2 =84.8, p<0.001). Abnormalities in white matter were associated with low CSF HVA (odds ratio 2.3, 95% confidence interval 1.5-3.5).INTERPRETATION HVA abnormalities are observed in various neurological diseases, but some are probably an unspecific finding. No clear limits for CSF HVA values pointing towards primary diseases can be stated. We report several neurological diseases showing HVA alterations. No neuroimaging traits were associated with low HVA values, except for white matter abnormalities. Dopamine and serotonin are neurotransmitters involved in several neurological and systemic functions. Their turnover in the central nervous system (CNS) can be assessed by biochemical analysis of several biogenic amines in cerebrospinal fluid (CSF) at are closely related to them.1-4 Homovanillic acid (HVA), which is the final product in dopamine catabolism, can be used as a marker of dopamine metabolism. Dopamine is synthesized from tyrosine by tyrosine hydroxylase (EC1.14.16.2), which converts tyrosine into L-3,4-dihydroxyphenylalanine (L-DOPA) with tetrahydrobiopterin as a cofactor. Aromatic L-amino-acid decarboxylase (EC4.1.1.28) transforms L-DOPA into dopamine using pyridoxal-5′-phosphate as a cofactor. Dopamine is catabolysed by monoamino oxidase (MAO, EC1.4.3.4) and catechol-O-methyltransferase (EC2.1.1.6), yielding HVA as the stable final product (Fig. S1, online supporting information). Acquired and genetic neurological diseases associated with dopaminergic dysfunction are known to cause movement disorders and neuropsychiatric disorders. There is scientific evidence suggesting that impaired HVA values could be a biomarker for dopamine dysfunction in several neurological diseases in children. 1,2,[5][6][7][8][9] In this study, we explored the prevalence of dopaminergic abnormalities in a large cohort of children with neurological disorders and correlated their HVA levels with clinical, radiological, and electrophysiological features. laboratory. The samples were collected from patients with several neurological disorders for which a diagnostic lumbar puncture was indicated. The samples originated from several hospitals in Spain, Portugal, Greece, Turkey, Argentina, and India. Three hundred...

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Section: Resultsmentioning

confidence: 99%

“…M, male; F, female; PNPO, pyridox(am)ine 5′‐phosphate oxidase; Rf values: reference values; TH, tyrosine hydroxylase; AADC, l ‐amino‐acid decarboxylase; MAO‐A/B, monoamino oxidase‐A, ‐B; GTPCH, guanosine triphosphate cyclohydrolase; SR, sepiapterin reductase. Data from some of the patients have been previously published …”

Section: Resultsmentioning

confidence: 99%

Homovanillic acid in cerebrospinal fluid of 1388 children with neurological disorders

Molero-Luís

Serrano

Ormazábal

et al. 2013

Develop Med Child Neuro

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“…The novel variant identified in exon12 p.Gly428Arg is not likely to be a benign polymorphism: it is not present in the sets of variants reported in publicly available databases (more than 12,000 chromosomes studied), it affects an amino acid highly conserved throughout different species down to invertebrates, and it is predicted in silico to have a deleterious effect on the TH protein function. TH pathogenic variants reported up to now are often private mutations confined to a single or a few pedigrees and, except for a common mutation (c.698GϾA, p.Arg233His) in the Dutch population, 39 and one reported in 3 Greek families (c.707TϾC, p.L236P), 40 no other founder effects have been described. Consequently, despite most THD being reported in Western Europe, the disease is expected to occur worldwide 2 and the novel mutation described here is the first pathogenic TH mutation in patients of African ancestry.…”

Section: Genetic Results For Thementioning

confidence: 99%

Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency

et al. 2012

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Objective: 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. Methods: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.Results: 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 CϾT) and a novel nonsynonymous substitution in exon 12 (c.1282GϾA, 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. Conclusion: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. Tyrosine hydroxylase deficiency (THD) is a rare autosomal recessive, dopa-responsive dystonia due to mutations in the TH gene.1 The phenotype of THD is thought to be a spectrum with overlap of clinical features between 2 main phenotypes 2 : one with onset of symptoms in the first year presenting as progressive hypokinetic-rigid syndrome, generalized dystonia, and good response to levodopa and the other with earlier onset presenting as a more complex encephalopathy, perinatal abnormalities, diurnal fluctuations, autonomic disturbances, and less response to levodopa.3-7 Here we present a new family with THD and a new phenotype of prominent levodopa-responsive myoclonus-dystonia (M-D) 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.METHODS Standard protocol approvals, registrations, and patient consents.

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“…Some of them have been already published as individual case reports [5,6,8,17]. Clinical, biochemical and molecular data of the whole series are described in Table 1.…”

Section: Patientsmentioning

confidence: 99%

“…This enzymatic conversion is a rate-limiting step in the biosynthesis of catecholamines. Around sixty patients with TH deficiency have been reported worldwide [1][2][3][4][5][6][7][8][9][10][11]. TH deficiency causes a neurological disease with predominant extrapyramidal signs and a variable response to L-DOPA.…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid synaptic proteins as useful biomarkers in tyrosine hydroxylase deficiency

Ortez

Duarte

Ormazábal

et al. 2015

Molecular Genetics and Metabolism

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Tyrosine hydroxylase (TH) deficiency is an inborn error of dopamine biosynthesis and a cause of early parkinsonism. Two clinical phenotypes have been described. Type "B": early onset severe encephalopathy; type "A": later onset, less severe and better response to L-dopa. We aimed to study the expression of several key dopaminergic and gabaergic synaptic proteins in the cerebrospinal fluid (CSF) of a series of patients with TH deficiency and their possible relation with the clinical phenotype and response to L-DOPA. Dopamine transporter (DAT), D2-receptor and vesicular monoamine transporter (VMAT2) were measured in the CSF of 10 subjects with TH deficiency by Western blot analysis. In 3 patients, data of pre-and post-treatment with L-DOPA were available, and in one of them, GABA vesicular transporter was determined. Results were compared to an age-matched control population. The concentration of D2-receptors in CSF was significantly higher in patients with TH deficiency than in controls. Similarly, DAT and vesicular monoamine transporter type 2 were up-regulated. Studies performed before L-DOPA, and on L-DOPA therapy showed a paradoxical response with D2 receptor expression increase as L-Dopa doses and homovanillic concentration gradually raised in a B phenotype patient. The opposite results were found in two patients with A phenotype. However, this is a very small sample, and further studies are needed to conclude robust differences between phenotypes. Synaptic proteins are detectable in the CSF and their quantification can be useful for understanding the pathophysiology of neurotransmitter defects and potentially to adjust and personalize treatments in the future.

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

Cited by 23 publications

References 24 publications

Homovanillic acid in cerebrospinal fluid of 1388 children with neurological disorders

Homovanillic acid in cerebrospinal fluid of 1388 children with neurological disorders

Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency

Cerebrospinal fluid synaptic proteins as useful biomarkers in tyrosine hydroxylase deficiency

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