Tyrosine hydroxylase deficiency

Inspection of Table 6.2.2 shows that for tyrosine hydroxylase deficiency, only the concentration of HVA is decreased [2]. However, in cases of AADC deficiency, in... 

Brautigam C, Wevers RA, Jansen RJT, Smeitink JAM, et al (1998) Biochemical hallmarks of tyrosine hydroxylase deficiency. Clin Chem 44 1897-1904... 

Genetic disorders (not included above) tyrosine hydroxylase deficiency dopa-responsive dystonia dihydropteridine reductase deficiency aromatic L-amino acid decarboxylase deficiency Menkes disease monoamine oxidase deficiency. 

Patients with aromatic L-amino acid decarboxylase deficiency present with clinical and biochemical manifestations that overlap those of the tyrosine hydroxylase deficiency states described previously. However, this deficiency state is characterized by additional decreases in CSF and urinary levels of 5-HIAA. Also, levels of L-dopa in urine, plasma, and cerebrospinal fluid are increased, and not decreased as in the other deficiency states. Levels of 5-hydroxytryptophan are similarly increased. 

Tyrosine hydroxylase deficiency Brains kidney llpl5.5 191290... 

As the rate-limiting enzyme, tyrosine hydroxylase is regulated in a variety of ways. The most important mechanism involves feedback inhibition by the catecholamines, which compete with the enzyme for the pteridine cofactor. Catecholamines cannot cross the blood-brain barrier hence, in the brain they must be synthesized locally. In certain central nervous system diseases (eg, Parkinson s disease), there is a local deficiency of dopamine synthesis. L-Dopa, the precursor of dopamine, readily crosses the blood-brain barrier and so is an important agent in the treatment of Parkinson s disease. 

The remaining neurons of the LC seem to dampen NE deficiency by several mechanisms by increase in tyrosine hydroxylase mRNA expression and metabolic activity, and sprouting of axons into the hippocampus as evidenced by an increase in a2-adrenoreceptors (Szot et al., 2006) (Hoogendijk et al., 1999). However, an overall decrease in a2-adrenoreceptor density in the brain of AD patients has been described (Meana et al., 1992). Moreover, a reduced density of NE innervation into the hippocampus has been observed (Powers et al., 1988). 

Failure of the neuron to myelinate because of copper deficiency leads to abnormalities of the nervous system. This was first described in lambs and was referred to as "swaybacks. It is not known whether this is attributable to a diminished level of tyrosine hydroxylase, which is a copper-dependent enzyme. It is known, however, that epinephrine and norepinephrine are decreased in animals that are deficient in copper (II). In ruminants, copper is shown to be necessary for myelination of nerves and for the maintenance of normal skin pigmentation (33, 61),... 

Thousands of diseases related to deficient or defective enzymes occur, many of which are rare. For example, in phenylketonuria (which has an incidence of 1 in 10,000 births in whites and Asians), the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine, is deficient. Phenylalanine accumulates, and tyrosine becomes an essential amino acid that is required in the diet. Mental retardation is a result of metabolic derangement. A more common problem is lactase deficiency, which occurs in 69% to 90% of American Indians, blacks, and Asians, and in 10% of whites. Lactose is not digested normally and accumulates in the gut where it is metabolized by bacteria. Bloating, abdominal cramps, and watery diarrhea result. 

Deficiencies of tyrosine hydroxylase or of enzymes involved in production of tetrahydrobiopterin cofactor (e.g., dopa-responsive dystonia) usually result in presentation of severe neurological abnormalities in early childhood. Depending on the exact mutation, deficiencies of tyrosine hydroxylase can involve moderate to severe loss of enzyme activity, most accurately diagnosed by low cerebrospinal fluid levels of catecholamine metabolites, such as MHPG and HVA, but normal levels of In the autosomal... 

The answer is e. (Murray, pp 307-346. Scriver, pp 1667—1724. Sack, pp 121-138. Wilson, pp 287—3177) In humans, tyrosine can be formed by the hydroxylation of phenylalanine. This reaction is catalyzed by the enzyme phenylalanine hydroxylase. A deficiency of phenylalanine hydroxylase results in the disease called phenylketonuria [PKU(261600)]. In this disease it is usually the accumulation of phenylalanine and its metabolites rather than the lack of tyrosine that is the cause of the severe mental retardation ultimately seen. Once formed, tyrosine is the precursor of many important signal molecules. Catalyzed by tyrosine hydroxylase, tyrosine is hydroxylated to form L-dihydroxyphenylalanine (dopa), which in turn is decarboxylated to form dopamine in the presence of dopa decarboxylase. Then, norepinephrine and finally epinephrine are formed from dopamine. All of these are signal molecules to some degree. Dopa and inhibitors of dopa decarboxylase are used in the treatment of Parkinson s disease, a neurologic disorder. Norepinephrine is a transmitter at smooth-muscle junctions innervated by sympathetic nerve libers. Epinephrine and dopamine are catecholamine transmitters synthesized in sympathetic nerve terminals and in the adrenal gland. Tyrosine is also the precursor of thyroxine, the major thyroid hormone, and melanin, a skin pigment. 

A. The patient, despite being put on a low-Phe diet, exhibits neurologic problems resulting from an inability to synthesize catecholamine and indoleamine neurotransmitters. This is caused by a deficiency in dihydropteridine reductase (DHPR). DHPR regenerates tetrahydro-biopterin (BH ), which is oxidized to dihydrobiopterin by phenylalanine hydroxylase, as well as tyrosine hydroxylase and tryptophan hydroxylase (tryptophan 5-monooxygenase). If phenylalanine hydroxylase were deficient, a diet low in Phe would alleviate the effects. Since the urinary biopterin concentration is elevated, a deficiency in GTP cyclohydrolase I is eliminated because that is an enzyme in the biosynthetic pathway of BH. Phe hydroxylase, Tyr hydroxylase, and Tip hydroxylase activities are low because of a lack of BH. ... 

Described defects in biogenic amine metabolism include deficiencies of tyrosine hydroxylase (TH) (EC 1.14.16.2) [1, 2], aromatic L-amino acid decarboxylase (AADC) (EC 4.1.1.28) [3], dopamine jff-hydroxylase (DjffH) (EC 1.14.17.1) [4, 5] and monoamine oxidase (MAO) (EC 1.4.3.4). MAO deficiency has been described as an isolated defect of MAO-A [6] and as a deficiency of either MAO-A or MAO-B, or both, in association with Norrie disease [7]. Inheritance in all of these disorders is thought to be autosomal recessive. 

L-amino acid decarboxylase. Thus, studies in monkeys and cats have shown that lesions in the nigro-striatal pathways deplete the activity of tyrosine hydroxylase [113-115, 286, 287], but the demonstration of this enzyme deficiency has yet to be made in human Parkinsonism where tyrosine levels are considered normal except in very advanced akinetic patients [288-291]. Nevertheless, high urinary excretion of tyramine [118, 292] and tryptamine [292, 293] in some Parkinsonian patients has led to the postulate that enzymatic defects of tyrosine hydroxylase [119] or tryptophan hydroxylase [293] may be involved. Although such defects could be attributed to low levels of the individual hydroxylases, it is equally plausible that deficiencies of the reduced pteridine co-factors could be rate-limiting [120, 293]. 

The most widely known metabolic disorders are those which result in impairment of the intermediary metabolism of nutrients such as proteins, carbohydrates and lipids. For example, phenylketonuria is due to a genetic deficiency of phenylalanine hydroxylase, an enzyme involved in the conversion of phenylalanine to tyrosine. As a result, when ingested in amounts normally encountered in the diet, phenylalanine accumulates in blood and cerebrospinal fluid along with its pyruvate, lactate and acetate derivatives. (See review by McBean and Stephenson. ) The toxic response takes the form of severe mental retardation, neural and dermal lesions and premature death. But phenylalanine is an essential dietary amino acid and cannot be rigorously excluded from the diet, even of sufferers from phenylketonuria, though fortunately they do respond to reduced dietary intakes. Clearly, phenylalanine hydroxylase deficiency narrows the gap between the required intake and that which elicits a toxic response because this pathway is more readily overloaded . 

A limited number of studies have been performed in which flies will respond to drugs added to food. The agents fed to flies include several biogenic amines such as octopamine (which can restore fertility in females sterile due to a genetic deficiency in octopamine Monastirioti et al. 1996) and those such as tyrosine, tyramine, L-DOPA, and dopamine (C. McClung and J. Hirsh, in prep.) that can affect in vivo responses to aerosolized cocaine and activity levels. In addition, cocaine-HCl can be fed to flies. It does not have same behavioral consequences as exposing flies to aerosolized cocaine-OH, most likely due to the ability of animals to adapt to relatively constant concentrations of cocaine, but can be shown to be effective due to its effects on responsiveness of dopamine receptors (R. Andretic and J. Hirsh, unpubl.). Finally, an inhibitor of tyrosine hydroxylase, 3,5 diio-do-L-tyrosine, can also be fed to flies (Neckameyer 1996). This enzyme performs the... 

Phenylketonuria usually is caused by a congenital deficiency of phenylalanine hydroxylase. Phenylketonuria (PKU) is among the more common aminoacidurias (-1 20,000 live births). The usual cause is a nearly complete deficiency of phenylalanine hydroxylase, which converts phenylalanine into tyrosine (Fig. 40-2 reaction 1). 

A much more serious genetic disease, first described by Foiling in 1934, is phenylketonuria. Here the disturbance in phenylalanine metabolism is due to an autosomal recessive deficiency in liver phenylalanine hydroxylase (Jervis, 1954) which normally converts significant amounts of phenylalanine to tyrosine. Phenylalanine can therefore only be metabolized to phenylpyruvate and other derivatives, a route which is inadequate to dispose of all the phenylalanine in the diet. The amino acid and phenylpyruvate therefore accummulate. The condition is characterized by serious mental retardation, for reasons which are unknown. By the early 1950s it was found that if the condition is diagnosed at birth and amounts of phenylalanine in the diet immediately and permamently reduced, mental retardation can be minimized. The defect is shown only in liver and is not detectable in amniotic fluid cells nor in fibroblasts. A very sensitive bacterial assay has therefore been developed for routine screening of phenylalanine levels in body fluids in newborn babies. 

Phenylketonuria (PKU) is a group of inherited disorders caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH) that catalyses the conversion of phenylalanine to tyrosine, the first step in the pathway for catabolism of this amino acid. As a result, the concentration of phenylalanine in the liver and the blood increases. This high concentration in the liver increases the rate of a side reaction in which phenylalanine is converted to phe-nylpyruvic acid and phenylethylamine, which accumulate in the blood and are excreted in the urine. 

BH4 is an obligatory cofactor for both tyrosine and tryptophan hydroxylase. Consequently, the inborn errors of BH4 metabolism are associated with impaired dopamine and serotonin turnover, which is reflected by decreased concentrations of HVA and 5HIAA in the CSF. Whilst such a pattern is particularly true for the autosomal recessive disorders of BH4 metabolism, an autosomal dominant disorder of BH4 metabolism, (autosomal dominant GTP cyclohydrolase deficiency) is not always associated with marked decreases in the CSF concentration of HVA and 5HIAA [1]. 

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