Low-phenylalanine diet

Changes in IQ scores after discontinuation of low-phenylalanine diet in patients with phenylketonuria. 

An inability to degrade amino acids causes many genetic diseases in humans. These diseases include phenylketonuria (PKU), which results from an inability to convert phenylalanine to tyrosine. The phenylalanine is instead transaminated to phenylpyruvic acid, which is excreted in the urine, although not fast enough to prevent harm. PKU was formerly a major cause of severe mental retardation. Now, however, public health laboratories screen the urine of every newborn child in the United States for the presence of phenylpyru-vate, and place children with the genetic disease on a synthetic low-phenylalanine diet to prevent neurological damage. 

Phenylketonurics appear normal at birth, but are severely defective by age 1 if untreated. The therapy for phenylketonuria is a low phenylalanine diet. The aim is to provide just enough phenylalanine to meet the needs for... 

Errors in amino acid metabolism served as sources of some of the first insights into the correlation between pathology and biochemistry. Although there are many hereditary errors of amino acid metabolism, phenylketonuria is the best known. This condition is the result of the accumulation of high levels of phenylalanine in the body fluids. By unknown mechanisms, this accumulation results in mental retardation unless the afflicted are placed on low phenylalanine diets immediately after birth. 

Individuals with the rare, genetic disease PKU cannot properly metabolize phenylalanine. These individuals are placed on special low-phenylalanine diets to control their blood phenylalanine concentrations, and need to be aware that aspartame is a source of phenylalanine. 

Hepatic cytosolic tyrosine aminotransferase (tyrosine transaminase) deficiency produces tyrosinemia type II, an autosomal recessive trait marked by hypertyrosine-mia and tyrosinuria. Clinical manifestations may include corneal erosions and plaques, inflammation (from intracellular crystallization of tyrosine), and mental retardation. Low-tyrosine and low-phenylalanine diets are beneficial. 

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. 

The proportion of nitrogen excreted as ammonia (in the form) helps with acid-base balance, especially with increased ketone-body excretion, normal blood concentrations of phenylalanine can be maintained by feeding a low-phenylalanine diet. 

Finally, a group of mild phenylketonuric patients with autosomal recessive mutations in the gene encoding PAH but with normal BH4 metabohsm respond to treatment with oral BH4 as an alternative to a low-phenylalanine diet. " " Recent investigations on the mechanism of this BH4-responsive PKU revealed a multifactorial basis, including a chemical chaperon effect of BH4 that prevents degradation of mutant PAH proteins and protection from... 

When diketopiperazines are administered to humans intravenously, they are not assimilated and are excreted unchanged in the urine. However, oral administration of compound 148 results in the breakdown of the compound, presumably in the digestive tract, and it therefore cannot be detected in the urine. " In contrast, people with phenylketonuria, who are fed on a low phenylalanine diet, excrete large amounts of the diketopiperazine 149. Although this compound is found in small amounts in the urine of normal hiunans, the excessive excretion of this diketopiperazine has been shown not to be due to a metabolic defect. Instead the compound originates in the diet itself and is not metabolized in the human digestive tract. ... 

Other types of tyrosinemia are related to specific enzyme defects (see Fig. 39.17). Tyrosinemia II is caused by a genetic deficiency of tyrosine aminotransferase (TAT) and may lead to lesions of the eye and skin as well as neurologic problems. Patients are treated with a low-tyrosine, low-phenylalanine diet. 

The first evidences related to gene, nutrient, and disease interaction are emerged from single gene mutation originated metabolic diseases like phenylketonuria. Phenylketonuria is an inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase and characterized by mental retardation and is treatable by a low phenylalanine diet [71]. 

The diketopiperazine of histidylproline (CXIX) has been found in greatly increased amounts in the urines of patients with phenylketonuria who were being fed a low phenylalanine diet. Perry et al. (1965) identified the urinary product by its infrared spectroscopic, chromatographic, electrophoretic, and other chemical properties, e.g., products of hydrolysis. The markedly increased amounts of the product in the urine of phenylketonurics receiving a low phenylalanine diet apparently resulted from ingestion of the diketopiperazine of histidylproline in the low phenylalanine diet itself. 

Smith I, Erdohazi M, Macarthney FJ, Pincott JR, Wolff OH, Brenton DP, Biddle SA, Fairweather DV, Dobbing J. Fetal damage despite low-phenylalanine diet after conception in a phenylke-tonuric woman. Lancet 1979 1 17-19. 

WMA) in all lobes (arrows) - female (MM) aged 27 years on low-phenylalanine diet from 3 to 8 years of age, blood phenylalanine concentration at MRl was 1,571 pmol/1, DQ 32... 

Fig. 9.6 Regression of hyperintense lesions in white matter (WMA) of all lobes arrows) during low-phenylalanine diet. Magnetic resonance imaging of the head (T2-weighted images, FLAIR, and FSE). Same patient...

Smith I, et al. Effect of stopping low-phenylalanine diet on intellectual progress of children with phenylketonuria. Br Med J. 1978 2(6139) 723-6. 

The LNAA diet differs from the standard low-phenylalanine diet. Whereas the low-phenylalanine diet depends on approximately 80 % of daily protein requirements being supplied from medical foods, the LNAA diet consists of approximately 70-80 % protein from whole protein foods with 20-30 % of protein requirements from LNAA. Calculations should be based on a daily protein intake of 0.8 g protein/kg/day. When prescribing the diet, first, calculate the total daily protein requirement, and then subtract the 70-80 % of total protein from food sources. The remaining 20-30 % of protein equivalents should be supplied as LNAA (Box 11.3). 

The dose of LNAA in the diet depends on current blood phenylalanine concentrations, age, and tolerance to whole protein foods. Reported doses range from 0.25 g LNAA to 0.5 g LNAA/kg body weight/day [25, 26, 29]. Van Spronsen and colleagues [32] showed the LNAA content of the diet in standard low-phenylalanine diet, LNAA supplementation alone, and the combination of both LNAA and low-phenylalanine diet. LNAA intake consumption with LNAA supplementation is higher than on a conventional low-phenylalanine diet [32]. The most beneficial effect on clinical ontcomes occurs when individuals with PKU consume increased dietary LNAA [26]. Although the LNAA diet was intended to be used in place of standard low-phenylalanine diet, LNAA may also be added to a standard low-phenylalanine diet using other medical foods [32]. 

Classic PKU Classic PKU is an autosomal recessive disease due to deficiency of phenylalanine hydroxylase and is treated with a low phenylalanine diet. Since phenylalanine is present in most food, dietary management is not easy, especially for a growing child. However, conscientious compliance is rewarded with a lifetime of normal achievement (Fig. 48.2). 

Phenyllactic and phenylpyruvic acids have an inhibitory effect on dopa decarboxylase and glutamic decarboxylase activity, but phenylalanine does not. Phenyl-acetic acid in equimolar concentrations had only half the inhibitory power of the two other metabolites. These findings might explain why low-phenylalanine diets restore pigmentation to normal in phenylke-tonuric individuals. 

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