Phenylketonuria

Phenylpyruvic acid can cause mental retardation m infants who are deficient m the enzymes necessary to convert l phenylalanine to l tyrosine This disorder is called phenylketonuria, or PKU disease PKU disease can be detected by a simple test rou tmely administered to newborns It cannot be cured but is controlled by restricting the dietary intake of l phenylalanine In practice this means avoiding foods such as meat that are rich m l phenylalanine... 

Pish protein concentrate and soy protein concentrate have been used to prepare a low phenylalanine, high tyrosine peptide for use with phenylketonuria patients (150). The process includes pepsin hydrolysis at pH 1.5 ptonase hydrolysis at pH 6.5 to Hberate aromatic amino acids gel filtration on Sephadex G-15 to remove aromatic amino acids incubation with papain and ethyl esters of L-tyrosine and L-tryptophan, ie, plastein synthesis and ultrafiltration (qv). The plastein has a bland taste and odor and does not contain free amino acids. Yields of 69.3 and 60.9% from PPG and soy protein concentrate, respectively, have been attained. 

In the case of hyperphenylalaninaemia, which occurs ia phenylketonuria because of a congenital absence of phenylalanine hydroxylase, the observed phenylalanine inhibition of proteia synthesis may result from competition between T.-phenylalanine and L-methionine for methionyl-/RNA. Patients sufferiag from maple symp urine disease, an inborn lack of branched chain oxo acid decarboxylase, are mentally retarded unless the condition is treated early enough. It is possible that the high level of branched-chain amino acids inhibits uptake of L-tryptophan and L-tyrosiae iato the brain. Brain iajury of mice within ten days after thek bkth was reported as a result of hypodermic kijections of monosodium glutamate (MSG) (0.5—4 g/kg). However, the FDA concluded that MSG is a safe kigredient, because mice are bom with underdeveloped brains regardless of MSG kijections (106). 

Folic acid deficiency Hyperthermia Phenylketonuria Rheumatic disease Virilizing tumors Drugs and chemicals Androgenic chemicals Angiotensin-converting enzyme inhibitors Captopril, enalapril Antibiotics... 

Recently, multidimensional GC has been employed in enantioselective analysis by placing a chiral stationary phase such as a cyclodextrin in the second column. Typically, switching valves are used to heart-cut the appropriate portion of the separation from a non-chiral column into a chiral column. Heil et al. used a dual column system consisting of a non-chiral pre-column (30 m X 0.25 mm X 0.38 p.m, PS-268) and a chiral (30 m X 0.32 mm X 0.64 p.m, heptakis(2,3-di-(9-methyl-6-(9-tert-butyldimethylsilyl)-(3-cyclodextrin) (TBDM-CD) analytical column to separate derivatized urinary organic acids that are indicative of metabolic diseases such as short bowel syndrome, phenylketonuria, tyrosinaemia, and others. They used a FID following the pre-column and an ion trap mass-selective detector following the... 

The drug is contraindicated in die presence of an allergy to die drug, pregnancy (Category C), lactation, and phenylketonuria (oral form only). Linezolid is used cautiously in patients with bone marrow depression, hepatic dysfunction, renal impairment, hypertension, and hyperthyroidism. 

More complex detective work is required to analyze large biomolecules and drugs. However, fragmentation generally follows predictable patterns, and one compound can be identified by comparing its mass spectrum with those of other known compounds with similar structures. In Fig. 2, we see the spectrum of a sample of blood from a newborn infant. The blood is being analyzed to determine whether the child has phenylketonuria. The presence of the compound phenylalanine is a positive indication of the condition. Some... 

FIGURE 2 The two phenylalanine peaks include the radioactive tracer (the right-hand peak) and the phenylalanine in the blood (the peak 5mu to the left). The presence of the latter peak shows that the babv from whom the blood was drawn has phenylketonuria. 

Patients who use the lozenge for smoking cessation should use one lozenge every 1-2 hours for the first 2— weeks, decreasing the interval to every 2-4 hours thereafter. Adverse effects that are common with the nicotine lozenge include heartburn, hiccups, and nausea (Shiffman et al. 2002). Because the product contains phenylalanine, the lozenge should not be used for smoking cessation by individuals with phenylketonuria. 

The detection of restriction fi agment length polymorphisms (RFLPs) facilitates prenatal detection of hereditary disorders such as sickle cell trait, beta-thalassemia, infant phenylketonuria, and Huntington s disease. Detection of RFLPs involves cleavage of double-stranded DNA by restriction endonucleases, which can detect subtle alterations in DNA that affect their recognized sites. Chapter 40 provides further details concerning the use of PCR and restriction enzymes for diagnosis. 

Figure 30-13. Alternative pathways of phenylalanine catabolism in phenylketonuria. The reactions also occur in normal liver tissue but are of minor significance.

Metabolic disorders of phenylalanine catabolism include phenylketonuria (PKU) and several hyper-phenylalaninemias. 

There are important methodologic considerations which apply to the use of cultured amniotic fluid cells for the detection of biochemical disorders. The first is that the enzymes which can be sampled are those which are usually present in fibroblasts or fibroblast-like cells. Therefore, conditions such as phenylketonuria and glycogen storage disease type I, which are associated with deficiencies of enzymes present only in liver and kidney, are not amenable to this approach. The same also pertains to enzyme deficiencies affecting other specific tissues. 

Fig. 25.8 (a) Normal metabolism, in which phenylalanine is converted by phenylalanine 4-mono-oxygenase to tyrosine, (b) Phenylketonuria, in which there is a transamination reaction between phenylalanine and a-ketoglutaric acid. Phenylalanine 4-mono-oxygenase is absent in about 1 in every 10000 human beings because of a recessive mutant gene. 

Because of the high incidence of lactose intolerance in the general population, lactose is not recommended as a sweetener for pediatric populations [70]. Aspartame, a phenylalanine derivative, is incorporated in many chewable tablets and sugar-free dosage forms. Aspartame-containing products should be avoided in children with autosomal recessive phenylketonuria [54]. 

RFLPs are often a reflection of individual genetic diversity and are not related to a clinical phenotype, but occasionally they can be diagnostic of an inherited disease. This technique is relatively new yet, it has been applied to the prenatal detection of sickle cell anemia, thalassemia, phenylketonuria, a,-antitrypsin deficiency, Huntington s chorea, Duchenne muscular dystrophy, hemophilia A and B, cystic fibrosis, and several other, diseases. 

Other leukodystrophies are associated with the lysosomal and peroxisomal disorders in which specific lipids or other substances accumulate due to a deficiency in a catabolic enzyme - for example Krabbe s disease, meta-chromatic leukodystrophy (MLD) and adrenoleuko-dystrophy (ALD) [1,2]. (These are discussed in detail in Ch. 40.) Similarly, disorders of amino acid metabolism can lead to hypomyelination - for example phenylketonuria and Canavan s disease (spongy degeneration) [1, 2, 25] (Ch. 40). The composition of myelin in the genetically... 

Phenylketonuria AR Phenylalanine hydroxylase White matter is up to 40% deficient in myelin hypomyelination may be caused by inhibition of amino acid transport and/or protein synthesis by the high level of phenylalanine that accumulates 1, Ch. 40... 

Phenylketonuria usually is caused by a congenital deficiency of phenylalanine hydroxylase 672... 

Rarely, phenylketonuria results from a defect in the metabolism of biopterin, a cofactor for the phenylalanine hydroxylase pathway 673... 

Phenylketonuria Usually defect of Normal at birth. Mental retardation in untreated Diet low in phenylalanine... 

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