Phenylketonuria, also known as PKU, is a rare recessive genetic disease that is caused by a person’s body being unable to metabolize the amino acid phenylalanine that is found in our food. Most forms of PKU and hyperphenylalaninaemia (HPA) are caused by mutations in the PAH gene on chromosome 12q23.2. Untreated PKU is associated with an abnormal phenotype which includes growth failure, poor skin pigmentation, microcephaly, seizures, global developmental delay and severe intellectual impairment. PKU was first discovered in 1934 in Norway by Dr. Asbjörn Fölling, one of Norway’s first physicians to apply chemistry methods to the study of medicine. He calls it “imbecillitas phenylpyruvica” because of the serious mental retardation found in the
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Fölling to ascertain whether the strange musty odour of her children’s urine might be related to their intellectual impairment (1). The urine samples were tested for a number of substances including ketones. When ketones are present, urine usually develops a red-brown colour upon the addition of ferric chloride, whereas in this case the urine of the two children yielded a dark-green colour. Dr. Følling proceeded with a more detailed chemical analysis after confirming that the unusual result. The process involved organic extraction and purification of the responsible compound, and determination of its melting point. The basic elements were quantitated by combustion, and an empiric formula of C9H8O3 derived. Mild oxidation of the purified substance produced a compound which smelled of benzoic acid, leading Dr. Fölling to postulate that the compound was phenylpyruvic acid (3). Upon mixing of the unknown compound with phenylpyruvic acid, there was no change in the melting point. Therefore, confirming the mystery compound was indeed phenylpyruvic acid. In 1935, Dr Fölling published his findings and suggested the name imbecillitas phenylpyruvica is change to phenylketonuria because of the characteristic appearance of phenylketone, phenylpyruvic acid, in the urine.
Years later, in 1951, the first diet treatment for PKU is developed in the laboratory of Dr. Evelyn Hickmans in collaboration with Dr. Horst Bickel …show more content…
The para-hydroxylation of phenylalanine is not required for further transamination of the alanine side chain (4). This alternative pathway of transamination and decarboxylation leads to the formation of metabolites such as phenylpyruvate, phenyllactate, and o-hydroxyphenylacetate which are excreted in urine. The conversion of phenylalanine to tyrosine is via a pathway involving the para-hyroxylation of benzene by PAH, BH4, and molecular oxygen. First, it drives the endogenous production of the non-essential amino acid tyrosine. Second, the hydroxylation reaction is the rate limiting step for complete oxidation of phenylalanine to CO2 and H2O and contributes to the pool of glucose and 2-carbon metabolites (5). A number of rare, related disorders due to defects in the BH4 regeneration system can affect phenylalanine homeostasis. It also can affect the catecholamine and serotonin biosynthesis, a common cofactor to the phenylalanine, tyrosine and tryptophan hydroxylating enzymes
Fölling to ascertain whether the strange musty odour of her children’s urine might be related to their intellectual impairment (1). The urine samples were tested for a number of substances including ketones. When ketones are present, urine usually develops a red-brown colour upon the addition of ferric chloride, whereas in this case the urine of the two children yielded a dark-green colour. Dr. Følling proceeded with a more detailed chemical analysis after confirming that the unusual result. The process involved organic extraction and purification of the responsible compound, and determination of its melting point. The basic elements were quantitated by combustion, and an empiric formula of C9H8O3 derived. Mild oxidation of the purified substance produced a compound which smelled of benzoic acid, leading Dr. Fölling to postulate that the compound was phenylpyruvic acid (3). Upon mixing of the unknown compound with phenylpyruvic acid, there was no change in the melting point. Therefore, confirming the mystery compound was indeed phenylpyruvic acid. In 1935, Dr Fölling published his findings and suggested the name imbecillitas phenylpyruvica is change to phenylketonuria because of the characteristic appearance of phenylketone, phenylpyruvic acid, in the urine.
Years later, in 1951, the first diet treatment for PKU is developed in the laboratory of Dr. Evelyn Hickmans in collaboration with Dr. Horst Bickel …show more content…
The para-hydroxylation of phenylalanine is not required for further transamination of the alanine side chain (4). This alternative pathway of transamination and decarboxylation leads to the formation of metabolites such as phenylpyruvate, phenyllactate, and o-hydroxyphenylacetate which are excreted in urine. The conversion of phenylalanine to tyrosine is via a pathway involving the para-hyroxylation of benzene by PAH, BH4, and molecular oxygen. First, it drives the endogenous production of the non-essential amino acid tyrosine. Second, the hydroxylation reaction is the rate limiting step for complete oxidation of phenylalanine to CO2 and H2O and contributes to the pool of glucose and 2-carbon metabolites (5). A number of rare, related disorders due to defects in the BH4 regeneration system can affect phenylalanine homeostasis. It also can affect the catecholamine and serotonin biosynthesis, a common cofactor to the phenylalanine, tyrosine and tryptophan hydroxylating enzymes