Genetic disorders phenylketonuria

Phenylalanine (Phe or F) (2-amino-3-phenyl-propanoic acid) is a neutral, aromatic amino acid with the formula HOOCCH(NH2)CH2C6H5. It is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. Tyr and Phe play a significant role not only in protein structure but also as important precursors for thyroid and adrenocortical hormones as well as in the synthesis of neurotransmitters such as dopamine and noradrenaline. The genetic disorder phenylketonuria (PKU) is the inability to metabolize Phe. This is caused by a deficiency of phenylalanine hydroxylase with the result that there is an accumulation of Phe in body fluids. Individuals with this disorder are known as phenylketonurics and must abstain from consumption of Phe. A nonfood source of Phe is the artificial sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester), which is metabolized by the body into several by-products including Phe. The side chain of Phe is immune from side reactions, but during catalytic hydrogenations the aromatic ring can be saturated and converted into a hexahydrophenylalanine residue. ... 

Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. Millions of babies are tested each year in the United States. All states currently test infants for phenylketonuria (a genetic disorder that causes mental retardation if left untreated) and congenital hypothyroidism (a disorder of the thyroid gland). Most states also test for other genetic disorders. 

Today aspartame is used in more than 6,000 food products. Aspartame is 160 times as sweet as sucrose based on mass equivalents. Approximately 16,000 tons are consumed annually on a global basis, with approximately 8,000 tons used in the United States and 2,500 tons in Europe. In the body aspartame is metabolized into its three components aspartic acid, phenylalanine, and methanol (Figure 11.1). Aspartic acid is a nonessential amino acid and phenylalanine is an essential amino acid. The condition called phenylketonuria (PKU) is a genetic disorder that occurs when a person lacks the enzyme phenylalanine hydroxylase and cannot process phenylalanine. This results in high phenylalanine blood levels that are metabolized into products one of these is phenylpyruvate, which contains a ketone group and... 

A number of genetic disorders are associated with phenylalanine and tyrosine metabolism. The best known is the classic phenylketonuria, discovered in 1934 by Foiling. It is characterized by the virtual absence of phenylalanine hydroxylase from the organism. As a result, phenylalanine is converted to a large extent to phenylpyruvate, phenyllactate, and phenylacetate (Figure 20.22). Their levels and that of phenylalanine in the bloodstream are elevated. Hyper-phenylalaninemia may also result from the absence of dihydrobiopterin reductase or any enzyme required for dihydrobiopterin biosynthesis from GTP. Although the etiologies of such disorders differ from that of classic phenylke-... 

Dire consequences may result if one or more of these amino acids is either absent or overabundant. For instance, a genetic disorder called phenylketonuria (PKU) is caused by the body s inability to get rid of extra phenylalanine, an amino acid abbreviated Phe. PKU is an autosomal recessive disorder, meaning that the only way to get the disease is if both of your parents carry a version of a gene linked with this disease. If only one parent has the gene linked to PKU, his or her children cannot develop the disease. Children who have... 

Phenylketonuria A genetic disorder in which the body cannot break down the amino acid phenylalanine abbreviated PKU. 

PHENYLKETONURIA A genetic disorder in which a person s body is unable to metabolize the amino acid phenylalanine. 

Nevertheless, all of this amazing functionality displayed by natural proteins seems to be based on a simple fact a complex and completely defined primary structure. In living cells, protein biosynthesis is carried out with an absolute control of the amino acid sequence, from the first amino acid to the last with a complete absence of randomness. In fact, the need for this absolute control is dramatically clear in some genetic disorders in which the lack or a substitution of a single amino acid in the whole protein leads to a complete loss of the original function, which can have dramatic consequences in some cases such as falciform anemia (sickle cell anemia), phenylketonuria, and cystic fibrosis [7]. 

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... 

As discussed above, in the case of phenylketonuria, early intervention can make the difference between mental retardation and a near normal life course for a newborn. Congenital adrenal hyperplasia and maple syrup urine disease are two examples of neonatal hereditary disorders where early diagnosis and medical intervention can make the difference between life and death for the newborn. In addition, in a number of genetic diseases, early diagnosis and treatment can help ameliorate symptoms these include fragile X syndrome, homocystinuria, sickle cell anemia, cystic fibrosis, and many /1-thalassemias. 

Brumm VL, Bilder D, Waisbren SE. Psychiatric symptoms and disorders in phenylketonuria. Mol Genet Metab. 2010 99 Suppl l S59-63. 

Inborn errors of metabolism are inherited physiologicai defects which interfere with the normal utilization of nutrients by the body. For example, phenylketonuria (PKU) may cause mental retardation due to the accumulation of phe-nylpyruvic acid, which is derived from the incomplete metabolism of the amino acid phenylalanine. Sometimes, permanent damage from these disorders may be prevented by restricting the dietary content of the nutrients which give rise to the harmful products of metabolism. In other cases. It may be necessary to provide extra amounts of certain nutrients to people who have a genetic defect which leads to poor utilization of these nutrients. 

Note In victims of the genetically transmitted disorder called phenylketonuria (PKU), the hydroxylase enzyme system described here does not function properly. Instead, phenylalanine in the brain is converted into 2-phenyl-2-oxopropanoic (phenyl-pyruvic) acid, the reverse of the process shown in Problem 57 of Chapter 21. The buildup of this compound in the brain can lead to severe retardation thus people with PKU (which can be diagnosed at birth) must be restricted to diets low in phenylalanine. 

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 . 

---