A: About a baby with PKU (AM-01)

Original Question

 

Answer (a)

 

Phenylalanine, per se, can follow three metabolic pathways:

 

a)     incorporation to the process of synthesis of proteins

b)     hydroxylation  to tyrosine

c)      conversion to phenyl pyruvate and derivatives like phenyl lactic and phenyl acetic.

 

The incorporation of Phenylalanine to proteins depends on the requirements in the synthesis of proteins.

 

Normally, conversion of phenylalanine to phenyl pyruvate and derivatives occurs in small quantities, since most of the phenylalanine is used in the other two metabolic processes.

 

The hydroxylation of Phenylalanine to Tyrosine is catalyzed by the enzyme Phenylalanine Hydroxylase, as represented in this graphic from the NLM:

                                         

This reaction is impaired in PKU (Phenylketonuria), due to the lack of Phenyl alanine hydroxylase or to the lack of Tetrahydrobiopteryn reductase, an enzyme necessary for supplying the reduced cofactor (TH4) required for this reaction.

 

As a consequence, Phenylalanine accumulates and it is drained to the formation of Phenylpyruvate, in a transamination reaction.  Pyruvate can be reduced to Phenyllactate or decarboxylated to Phenylacetate, in a same way that Pyruvate can be reduced to Lactate or, by decarboxylation,  form the  Acetyl group of Acetyl CoA).

 

1) Phenylalanine + alpha-ketoglutarate <——–> Phenylpyruvate + glutamate

 

2) Phenyl lactate <———— Phenylpyruvate ———————–> Phenylacetate

                          (reduction)                            (decarboxylation)

 

These compounds, which are normally produced in very small amounts, accumulate in PKU and are eliminated by urine in increased quantities, where they can be detected.

 

The name Phenylketonuria corresponds to the finding of notable quantities of phenyl pyruvate and derived metabolites in urine of the patients and the detection of the metabolites was an important tool of diagnosis of this disease before the Guthrie test made available a screening test for newborns and the detection of phenylalanine in blood gave an appropriate diagnosis tool.

 

Note: questions very similar to the former one can be found frequently in different tests. The Step 1 Content description and General information 2008 (FSMB/NBME) includes a sample question in which the compound released in urine is phenylacetic. Copyrights issues do not allow me to show the question here, but you can find it as the question number 126 in the referred document. Observe that in these kind of questions the patient usually, for some circumstance, have escaped to mandatory screening for PKU)

 

 

The following site contains useful information and several links to other sites about Phenylketonuria:

 

 

http://ghr.nlm.nih.gov/condition=phenylketonuria