Wevers, R. A. et al. A review of biochemical and molecular genetic aspects of tyrosine hydroxylase deficiency including a novel mutation (291delC). J. Inherit. Metab. Dis. 22, 364-373
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).
Available from: Chunquan Cai
- "Dopa-responsive dystonia (DRD), also known as Segawa’s syndrome, was first reported in 1976 . The clinical manifestations of DRD include postural or motor disturbances, generalized or focal dystonia, abnormal gait, and sometimes tremor or writing disturbance–. A significant therapeutic response to levodopa is a diagnostic hallmark of DRD. "
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ABSTRACT: Dopa-responsive dystonia (DRD) is a rare inherited dystonia that responds very well to levodopa treatment. Genetic mutations of GTP cyclohydrolase I (GCH1) or tyrosine hydroxylase (TH) are disease-causing mutations in DRD. To evaluate the genotype-phenotype correlations and diagnostic values of GCH1 and TH mutation screening in DRD patients, we carried out a combined study of familial and sporadic cases in Chinese Han subjects. We collected 23 subjects, 8 patients with DRD, 5 unaffected family members, and 10 sporadic cases. We used PCR to sequence all exons and splicing sites of the GCH1 and TH genes. Three novel heterozygous GCH1 mutations (Tyr75Cys, Ala98Val, and Ile135Thr) were identified in three DRD pedigrees. We failed to identify any GCH1 or TH mutation in two affected sisters. Three symptom-free male GCH1 mutation carriers were found in two DRD pedigrees. For those DRD siblings that shared the same GCH1 mutation, symptoms and age of onset varied. In 10 sporadic cases, only two heterozygous TH mutations (Ser19Cys and Gly397Arg) were found in two subjects with unknown pathogenicity. No GCH1 and TH mutation was found in 40 unrelated normal Han Chinese controls. GCH1 mutation is the main etiology of familial DRD. Three novel GCH1 mutations were identified in this study. Genetic heterogeneity and incomplete penetrance were quite common in DRD patients, especially in sporadic cases. Genetic screening may help establish the diagnosis of DRD; however, a negative GCH1 and TH mutation test would not exclude the diagnosis.
Available from: Rui A Carvalho
- "Tyrosine hydroxylase deficiency has been reported in humans and is characterized by generalized rigidity, hypokinesia, among other symptoms. Low cerebrospinal fluid levels of NA and dopamine metabolites, like HVA and 3-methoxy-4-hydroxy-phenylethylene glycol are observed in humans with tyrosine hydroxylase deficiency (Wevers et al., 1999, Carson and Robertson, 2002). The tyrosine hydroxylase knockout is unviable in mice as they die in the embryonic stage, presumably because catecholamine loss results in altered cardiac function (Zhou et al., 1995). "
Available from: André Mégarbané
- "These parameters (especially the HVA/5HIAA ratio in CSF), most probably reflecting the degree of residual tyrosine hydroxylase activity in the brain, may thus be used to predict L-dopa responsiveness and overall outcome. Measurements of phenylalanine and tyrosine in body fluids, and urinary concentrations of catecholamines, HVA and MHPG, are non-informative in patients with THD (Brautigam et al., 1998;Wevers et al., 1999;Hoffmann et al., 2003). The surprisingly often normal urinary dopamine excretion in THD is hypothetically attributed to residual tyrosine hydroxylase enzyme activity in peripheral non-neuronal tissues or alternative enzymes with the capacity to hydroxylate tyrosine, as discussed above. "
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ABSTRACT: 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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