Phenylalanine hydroxylase mental retardation, cause

T Given that many amino acids are either neurotransmitters or precursors or antagonists of neutrotransmitters, genetic defects of amino acid metabolism can cause defective neural development and mental retardation. In most such diseases specific intermediates accumulate. For example, a genetic defect in phenylalanine hydroxylase, the first enzyme in the catabolic pathway for phenylalanine (Fig. 18-23), is responsible for the disease phenylketonuria (PKU), the most common cause of elevated levels of phenylalanine (hyperphenylalaninemia). 

Inborn errors of metabolism are inherited metabolic disorders caused by the absence of an enzyme in a metabolic pathway. Alkaptonuria is caused by the lack of homogentisate oxidase and is harmless, whereas phenylketonuria, which is due to a lack of phenylalanine hydroxylase, can cause severe mental retardation. 

Some diseases are caused by enzyme deficiencies. The congenital disease phenylketonuria is caused by the deficiency of the enzyme phenylalanine hydroxylase, resulting in a build-up of compounds that cause brain damage and mental retardation. This damage can be lessened and prevented by a diet containing a low amount of the amino acid phenylalanine. The complaint is caused by a genetic mutation. 

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. 

Phenylketonuria, caused by a deficiency of phenylalanine hydroxylase, is one of the most common genetic diseases associated with amino acid metabolism. If this condition is not identified and treated immediately after birth, mental retardation and other forms of irreversible brain damage occur. This damage results mostly from the accumulation of phenylalanine. (The actual mechanism of the damage is not understood.) When it is present in excess, phenylalanine undergoes transamination to form phenylpyruvate, which is also converted to phenyllactate and phenyl-acetate. Large amounts of these molecules are excreted in the urine. Phenylacetate gives the urine its characteristic musty odor. Phenylketonuria is treated with a low-phenylalanine diet. 

Figure 1.2 Consequences of a metabolic block in pheylalanine-tyrosine Defective phenylalanine hydroxylase can lead to the accumulation of phenylalanine, which can cause damage to brain cells and mental retardation in phenylketonuric babies. Another metabolic blockage caused by a defective enzyme can lead to alcaptonuria.

Phenylketonuria is an inherited disorder caused by the deficient function of the enzyme phenylalanine hydroxylase this results in increased phenylalanine levels, which damage the developing brain and result in mental retardation. The aim of dietary management is to maintain a normal plasma phenylalanine level by restricting the routine... 

Elevated levels of phenylalanine have been shown to inhibit transport of other amino acids besides tyrosine. This might result in an imbalance of amino acids in the brain that could disrupt protein synthesis or control of the synthesis of neurotransmitters. Several enzymes, including tyrosine hydroxylase, tryptophan, and pyruvate kinase, are inhibited in vitro by phenylalanine. Irrespective of such phenomena in a patient who died with PKU, catecholamine concentration and serotonin levels were much lower than those in control brains from patients suffering mental retardation from other causes, a finding consistent with such a possible role in vivo (Ikeda et al., 1967). 

A disease in which hypomyelination occurs in specific forebrain tracts, but neurons and their axons are spared, is the autosomal recessive disorder PKU (Malamud, 1996 Dyer et al., 1996). As already mentioned, PKU is caused by a rise in blood phenylalanine (Phe) levels, due to a deficiency in the enzyme phenylalanine hydroxylase (PHA) (Scriver et al., 1995), which is expressed primarily in liver and not in brain, and catalyzes the conversion of Phe to tyrosine (Lee et al. 2003a and Lee et al. 2005). Blood Phe levels normally are about 121 mmol however, in untreated individuals (and mice) with PKU, levels may increase to 1,200 p. or more. For the past several decades, newborns diagnosed with PKU are placed on a low Phe diet for life. The low Phe diet decreases Phe levels in blood and brain, thereby allowing myelination to proceed (Thompson et al., 1993 Pietz et al., 1995). Individuals with PKU that are continuously treated from birth avoid the severe mental retardation that occurs in untreated individuals (Levy et al., 1994). 

Phenylalanine (P) is an essential AA that participates in protein synthesis. It is converted to tyrosine via hydroxylation (see Section 15.6.7). Phenylalanine is both glncogenic and ketogenic." Phenylketonuria (PKU) is a rare disease (generally diagnosed at birth) caused by an inborn error in the abihty to metabolize P (lacking the enzyme phenylalanine hydroxylase). In affected people, if the diet is not controlled by severe restriction of P intake, PKU can lead to serious irreversible neurological disorders, such as mental retardation. 

A genetic disease is the result of a defective enzyme caused by a mutation in its genetic code. For example, phenylketonuria (PKU) results when DNA cannot direct the synthesis of the enzyme phenylalanine hydroxylase, required for the conversion of phenylalanine to tyrosine. In an attempt to break down the phenylalanine, other enzymes in the cells convert it to phenylpyruvate. If phenylalanine and phenylpyruvate accumulate in the blood of an infant, it can lead to severe brain damage and mental retardation. If PKU is detected in a newborn baby, a diet is prescribed that eliminates all the foods that contain phenylalanine. Preventing the buildup of the phenylpyruvate ensures normal growth and development. 

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