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)

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

Tetrahydrobiopterin (BH4) deficiencies are a heterogeneous group of disorders caused by a defect in two of the three enzymes involved in its biosynthesis or in the two recycling enzymes. Except for the deficiency of dehydratase, an enzyme catalyzing a reaction in the recycling pathway, all other variants of BH4 deficiency are characterized by developmental delay, progressive neurological deterioration, hypokinesis, drooling, swallowing difficulty, truncal hypotonia, increased limb tone, myoclonus and brisk deep tendon reflexes. A deficiency of guanosine triphosphate cyclohydrolase I (GTPCH), the first enzyme in the biosynthetic pathway of BH4, is described in a 14-month-old male infant with hyperphenylalaninemia, developmental delay, hypertonia of the extremities, seizures, feeding difficulties, and vomiting. Urinary pteridine screening revealed very low levels of neopterin and biopterin which was highly suggestive of GTPCH deficiency. Low cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid concentrations, together with no detectable neopterin and decreased concentrations of biopterin and folate, agreed with the diagnosis of GTPCH deficiency. Subsequently measured neopterin and biopterin synthesis in cytokine-stimulated skin fibroblasts confirmed GTPCH deficiency, albeit indirectly. The patient showed marked improvement on a low-protein low-phenylalanine diet with neurotransmitter precursor administration. The favorable outcome in this patient clearly shows that not only newborns with elevated phenylalanine levels but also older children with neurological signs and symptoms should be screened for a BH4 deficiency in order to have maximum benefit of the treatment.
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PMID:Guanosine triphosphate cyclohydrolase I deficiency: a rare cause of hyperphenylalaninemia. 1077 Jun 63

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