Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Biochemical hallmarks of tyrosine hydroxylase deficiency. 973 74

Tetrahydrobiopterin (BH4) is synthesized from guanosine triphosphate (GTP) by GTP cyclohydrolase I (GCH), 6-pyruvoyltetrahydropterin synthase (PTS), and sepiapterin reductase (SPD). GCH is the rate-limiting enzyme. BH4 is a cofactor for three pteridine-requiring monooxygenases that hydroxylate aromatic L-amino acids, i.e., tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and phenylalanine hydroxylase (PAH), as well as for nitric oxide synthase (NOS). The intracellular concentrations of BH4, which are mainly determined by GCH activity, may regulate the activity of TH (an enzyme-synthesizing catecholamines from tyrosine), TPH (an enzyme-synthesizing serotonin and melatonin from tryptophan), PAH (an enzyme required for complete degradation of phenylalanine to tyrosine, finally to CO2 + H2O), and also the activity of NOS (an enzyme forming NO from arginine), Dominantly inherited hereditary progressive dystonia (HPD), also termed DOPA-responsive dystonia (DRD) or Segawa's disease, is a dopamine deficiency in the nigrostriatal dopamine neurons, and is caused by mutations of one allele of the GCH gene. GCH activity and BH4 concentrations in HPD/DRD are estimated to be 2-20% of the normal value. By contrast, recessively inherited GCH deficiency is caused by mutations of both alleles of the GCH gene, and the GCH activity and BH4 concentrations are undetectable. The phenotypes of recessive GCH deficiency are severe and complex, such as hyperphenylalaninemia, muscle hypotonia, epilepsy, and fever episode, and may be caused by deficiencies of various neurotransmitters, including dopamine, norepinephrine, serotonin, and NO. The biosynthesis of dopamine, norepinephrine, epinephrine, serotonin, melatonin, and probably NO by individual pteridine-requiring enzymes may be differentially regulated by the intracellular concentration of BH4, which is mainly determined by GCH activity. Dopamine biosynthesis in different groups of dopamine neurons may be differentially regulated by TH activity, depending on intracellular BH4 concentrations and GCH activity. The nigrostriatal dopamine neurons may be most susceptible to a partial decrease in BH4, causing dopamine deficiency in the striatum and the HPD/DRD phenotype.
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PMID:Regulation of pteridine-requiring enzymes by the cofactor tetrahydrobiopterin. 1032 73

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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PMID:Tyrosine hydroxylase deficiency with severe clinical course: clinical and biochemical investigations and optimization of therapy. 1124 Oct 71

In individuals with a narrow or collapsible upper airway, sleep-related hypotonia of upper airway muscles leads to recurrent airway obstructions. Brainstem noradrenergic neurons reduce their activity during slow-wave sleep and become silent during rapid eye movement sleep; this may cause state-dependent changes in the motor output and reflexes. The loss of noradrenergic excitation is a major cause of sleep-related depression of activity in upper airway muscles innervated by the hypoglossal nerve. Our goal was to identify and compare the pontomedullary sources of catecholaminergic (CA) projections to the hypoglossal motor nucleus (Mo12) and the adjacent viscerosensory nucleus of the solitary tract (NTS). In 10 Sprague-Dawley rats, retrograde tracers, Fluoro-Gold or B sub-unit of cholera toxin, were microinjected (5-20nl) into the Mo12, NTS, or both nuclei. Tyrosine hydroxylase (TH) was used as a marker for CA neurons. Following tracer injections into the Mo12, retrogradely labeled and TH-positive neurons were found in the A1/C1 (18.5%), A5 (43.5%), A7 (15.0%), and sub-coeruleus (21.0%) regions, and locus coeruleus (1.7%). In contrast, following injections into the NTS, these proportions were: 48.0, 46.5, 0.2, 0.9, and 4.3%, respectively. The projections to both nuclei were bilateral, with a 3:2 ipsilateral predominance. In four animals with one tracer injected into the Mo12 and the other in NTS, TH-positive cells containing both tracers were found only in the A5 region. Thus, the pontomedullary sources of CA projections to the Mo12 and NTS differ, with only A1/C1 and A5 groups having significant projections to these two functionally distinct targets.
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PMID:Differential pontomedullary catecholaminergic projections to hypoglossal motor nucleus and viscerosensory nucleus of the solitary tract. 1713 70

Noradrenergic (NE) excitatory drive maintains activity of hypoglossal (XII) motoneurons during wakefulness. In predisposed persons, sleep-related decrements of NE cell activity may contribute to hypotonia of upper airway muscles innervated by XII motoneurons. The goal of this study was to determine whether NE neurons of the pontine A7 group, an anatomically identified source of NE projections to the XII nucleus, provide significant, endogenous NE excitatory drive to XII motoneurons. In anesthetized rats, we microinjected clonidine (0.75 mM, 20-40 nl), an alpha(2)-adrenergic receptor agonist that inhibits pontine NE cells, aiming at the A7 region. Nine injections were placed within 0.4 mm from the A7 group identified using tyrosine hydroxylase immunohistochemistry: they reduced XII nerve activity by 31.3+/-2.8% (standard error) and decreased the central respiratory rate by 6%. Another 21 injections, including eight placed near NE cells of the sub-coeruleus region, were made at distances over 0.5 mm from the A7 group and they did not alter either XII nerve activity or respiratory rate. In control experiments, clonidine injections into the A7 group preceded by injections of an alpha(2)-receptor antagonist, RS-79948, did not change XII nerve activity. Four experiments with unilateral clonidine injections into the A7 region and with Fos immunohistochemistry used as a marker of cell activity revealed that the percentage of Fos-positive A7 cells was significantly reduced on the injected side. There was also a significant positive correlation between Fos expression in A7 cells and XII nerve activity. Thus, decrements of NE excitatory drive from the A7 group may significantly reduce XII nerve activity. In obstructive sleep apnea patients, in whom the muscles innervated by XII motoneurons act as upper airway dilators, this may contribute to sleep-related respiratory disorders.
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PMID:Inhibition of pontine noradrenergic A7 cells reduces hypoglossal nerve activity in rats. 1883 13

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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PMID:Tyrosine hydroxylase deficiency with severe clinical course. 1928 9

Aminergic neurotransmitter disorders occurring in childhood include metabolic disorders of pteridine and tyrosine hydroxylase (TH). Pteridine metabolic disorders cause a deficiency of serotonin (5-HT) and dopamine (DA) and TH disorder causes a deficiency of noradrenaline (NA) and DA in the terminals of each aminergic neuron. The activities of TH or DA in the terminals are marked in early childhood, and then they show an exponential age-dependent decrement and achieve stationary or minimal levels in the twenties. As observed in Segawa disease, TH or DA activities in these disorders follow this age-related decrease with levels around 20% of normal, and patients develop symptoms age-dependently, with onset in childhood, progression by the late teens, and a stationary period after the twenties, but this does not cause morphological changes. These phenomena may occur with other neurotransmitters. So replacement therapies are effective irrespective of the clinical course. However, early-onset cases in infancy or early childhood showing a marked decrement of 5-HT or NA activities show postural hypotonia and failed locomotion. These cause failure in atonia restriction in the REM stage and induce dysfunction of the pedunculopontine nucleus, and, consequently induce dysfunction or failure in the development of DA neurons in the sutbstantia nigra and ventrotegmental area. These relate to failure in the development of higher cortical functions. Thus, assessing of ages at onset and activities of antigravity muscles and locomotion in infancy is cardinal for the treatment the neurotransmitter disorders occurring in infancy and early childhood. PARK2 with deficiency of DA in the substantia nigra leads to dystonia in the teens and Parkinson disease after 20 years, although these respond to 1-Dopa favorably but induce D2 receptor upregulation and intractable dyskinesia. A decrease of DA in the perikaryon leads to symptoms after 10 years and causes dysfunction of the target structures.
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PMID:[Neurotransmitter disorders in children--special reference to Segawa disease]. 2194 41

Tyrosine hydroxylase (TH) deficiency is a rare autosomal recessive and often treatable neurometabolic disorder with variable phenotypes. More than 20 pathological mutations have been identified in patients with TH deficiency. We report the case of a 10-month-old male patient who presented with developmental delay, hypotonia and oculogyric crises to the Salmaniya Medical Complex in Manama, Bahrain. At a later stage, he developed orofacial dyskinaesia and tremors with hyper-reflexia and clonus. A magnetic resonance imaging scan of the brain showed mild atrophy with widened ventricles and genetic testing revealed a novel homozygous mutation (c.938G>T; p.Arg313Leu) in exon 9 of the TH gene. The patient showed a remarkable response to treatment using combined levodopa-carbidopa. In this case, the orofacial dyskinaesia may be a specific clinical association unique to this novel mutation, which is the first to be described in Bahrain and the Middle East.
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PMID:A new tyrosine hydroxylase genotype with orofacial dyskinaesia. 2509 78

Inborn errors of monoamine neurotransmitter biosynthesis and degradation belong to the rare inborn errors of metabolism. They are caused by monogenic variants in the genes encoding the proteins involved in (1) neurotransmitter biosynthesis (like tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC)), (2) in tetrahydrobiopterin (BH4) cofactor biosynthesis (GTP cyclohydrolase 1 (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SPR)) and recycling (pterin-4a-carbinolamine dehydratase (PCD), dihydropteridine reductase (DHPR)), or (3) in co-chaperones (DNAJC12). Clinically, they present early during childhood with a lack of monoamine neurotransmitters, especially dopamine and its products norepinephrine and epinephrine. Classical symptoms include autonomous dysregulations, hypotonia, movement disorders, and developmental delay. Therapy is predominantly based on supplementation of missing cofactors or neurotransmitter precursors. However, diagnosis is difficult and is predominantly based on quantitative detection of neurotransmitters, cofactors, and precursors in cerebrospinal fluid (CSF), urine, and blood. This review aims at summarizing the diverse analytical tools routinely used for diagnosis to determine quantitatively the amounts of neurotransmitters and cofactors in the different types of samples used to identify patients suffering from these rare diseases.
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PMID:Analysis of Catecholamines and Pterins in Inborn Errors of Monoamine Neurotransmitter Metabolism-From Past to Future. 3140 45