PHENYLKETONURIA
Diseases

Author: irene romeo
Date: 20/01/2012

Description

DEFINITION

Phenylketonuria (PKU) is an autosomal recessive disease in the catabolism of an amino acid, phenylalanine,caused by a deficiency in the activity of the enzyme phenylalanine hydroxylase, which follows the increase of plasmatic phenylalanine.

EPIDEMIOLOGY
It was one of the first human genetic defect to be discovered.
8-10 cases / 100000 people.
The recognition and early treatment of babies every year lead to save many resources, which
should be used in programs of social rehabilitation of children with mental retardation.
Moreover, the emotional trauma that the analysis manages to avoid to the parents of affected children is invaluable.

SYMPTOMS
Many amino acids are neurotransmitters or their precursors, or their antagonists, so the genetic defects against metabolism of amino acids can cause a defective development of the nervous system or mental retardation.
Children with phenylketonuria show no particular symptoms at birth. Over time, many develop the first symptoms such as rash, nausea, vomiting, irritability, eczema and urine odor characteristic "of
mouse ". Cause intellectual deficits (often severe) and other neurological disorders, such as seizures.
The toxicity of phenylalanine in the nervous system occurs gradually with tremors, hypertonus
muscle and tendon hyperreflexia. The lack of tyrosine does not allow it to be converted into quantities sufficient of DOPA and therefore in melanin, as a result people with this disease have often fair skin, blue eyes and blond hair, due to skin discoloration. In the long term, individuals develop a progressive mental retardation. Patients with PKU who succeed through proper diet to reach childbearing age, if a diet since the beginning of pregnancy, do not create significant problems to the fetus.In fact the fetus will born heterozygous for PKU, but healthy. Serious problems have unplanned pregnancies of women with PKU and, therefore, free diet. High levels of phenylalanine blood of the mother may have teratogenic effects on the fetus.
The fetus in the first two months risks heart problems and later microcephaly that can cause severe mental retardation. During childbirth there are no particular problems.
The excess of phenylalanine can compete with other amino acids for transport across the blood-brain barrier, causing a partial lack of other needed metabolites.

CASE STUDY
Genetic defect in the metabolism of amino acids.
A two year old child was taken to hospital. The mother told the child was vomiting frequently,
especially after meals.
The weight of the child and his physical development was below the norm. His hair, although they were blacks, showed white patches.
A urine sample treated with ferric chloride (FeCl3) took the green color characteristic of the presence of phenylpyruvate.
The results of quantitative analysis of urine samples of the child are shown in the following table:

Concentration (mM)

patient's urine essentially normal
phenylalanine 7.0 0.01
phenylpyruvic 4.8 0
fenillattato 10.3 0

a) which enzyme could be deficient?
b) Why appears phenylalanine in the urine in quantities
so high?
c) what is the source of the phenylpyruvic and fenillattate? Why
this way usually inactive becomes active when
increases the concentration of phenylalanine?
d) why the patient's hair show white spots?

PATHOGENESIS
The phenylalanine hydroxylase (or phenylalanine-4-monooxygenase) is part of a class of enzymes called oxidases mixed function, each of which catalyzes the hydroxylation of a substrate simultaneously, using atoms of a molecule of O2 and the other oxygen atom is instead reduced to water.
The phenylalanine hydroxylase requires the cofactor tetrahydrobiopterin ,that transports electrons from NADH to oxygen and, in the course of the reaction, is oxidized to dihydrobiopterin.

Reaction of phenylalanine hydroxylase:
When the phenylalanine hydroxylase is genetically defective, comes into play a minor route of phenylalanine metabolism, usually not used. In this way the phenylalanine is deaminated to phenylpyruvic acid through transamination reaction in which the amino group of the acceptor is pyruvate.

phenylalanine and phenylpyruvic accumulate in the blood and tissues and are excreted in the urine, hence the name of phenylketonuria.
Part of phenylpyruvic is reduced to phenillattate or undergoes decarboxylation to form phenylacetate.

DIAGNOSIS
The exams to identify the disease are relatively inexpensive.
• The phenylacetate confers a characteristic odor to the urine and may allow the diagnosis of PKU in newborns.
• Guthrie test:newborn screening for the detection of elevated levels of plasma phenylalanine. Is
carried out routinely.
It consists in placing a drop of blood on a disk filter paper, then put it in contact with a cultivation of the bacterium Bacillus subtilis to which is added ß-2-tienialanina, which inhibits bacterial growth.
In presence of phenylalanine, inhibition is opposed and the bacteria survive. Therefore a continuation of bacterial growth is a signal of high levels of phenylalanine, and the baby needs to undergo to further analysis.

THERAPY
When the disease is identified immediately after birth, you can minimize the damage with a strict diet control, that is, properly evaluating the amount of phenylalanine and tyrosine ingested by the infant. Moreover all foods rich in protein have to be eliminated.
You have also to take care not to ingest artificial sweeteners.

REFERENCES
1)David L. Nelson,Michael M. Cox,"I Principi di Biochimica di Lehninger",Zanichelli,2010
2)John Murtagh,"Professione: Medico Generale",McGraw-Hill,2006
3)Beppe Rocca,Gianfranco Pagano,Elisabetta Pisu,Eliana Ricci,"Dromos,dal Sintomo alla Diagnosi",
Roussel-Pharma,1994
4)Samir P.Desai,"Guida alla Medicina di Laboratorio",Menarini,2005
5)Wikipedia

AddThis Social Bookmark Button