PHENYLKETONURIA

DONE BY : PEER FATHIMA

BARAKATHU INDIA

Phenylketonuria (PKU) is an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional. This enzyme is necessary to metabolize the amino acid phenylalanine (Phe) to the amino acid tyrosine. When PAH activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which can be detected in the urine.

The enzyme phenylalanine hydroxylase ( in the presence of co-factor Tetrahydrobiopterin BH4) normally converts the amino acid phenylalanine into the amino acid tyrosine. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be metabolized into phenylketones through the minor route, a transaminase pathway with glutamate. Metabolites include phenylacetate, phenylpyruvate and phenethylamine. Elevated levels of phenylalanine in the blood and detection of phenylketones in the urine is diagnostic, however most patients are diagnosed via newborn screening.

Phenylalanine is a large, neutral amino acid . LNAAs compete for transport across the blood–brain barrier via the large neutral amino acid transporter . If phenylalanine is in excess in the blood, it will saturate the transporter. Excessive levels of phenylalanine tend to decrease the levels of other LNAAs in the brain. However, as these amino acids are necessary for protein and neurotransmitter synthesis, Phe buildup hinders the development of the brain, causing intellectual disability.

PHENYLALANINE HYDROXYLASEPHENYLALANINE

Dietry sources, particularly plant proteins

BODY PROTEINS

BREAKDOWN

(b)

(a)

The normal metabolism of phenylalanine (pathways a and b)

TYROSINE

© 2008 Paul Billiet ODWS

HYDROXYPHENYLACETIC ACID

PHENYLACETIC ACID*

(c)

(c)

The abnormal metabolism in phenylketonuric subjects (pathway c)

*Agents, thought to be responsible for mental retardation

PHENYLALANINE*

Dietry sources, particularly plant proteins

BODY PROTEINS

(b)

(a)

PHENYLALANINE HYDROXYLASE

© 2008 Paul Billiet ODWS

A normal blood phenylalanine level is about 1mg/dl.

In cases of PKU, levels may range from 6-80mg/dl, but are usually greater than 30mg/dl.

Chronically, high levels of phenylalanine and some of its breakdown products can

cause significant brain problems. There are other disorders of

hyperphenylalaninemia, but classic PKU is the most common cause of high levels

of phenylalanine in the blood.

Phenylalanine accumulates, causing rashes, seizures, hyperactivity, and mental retardation, if untreated.

Prominent cheek and jaw bones widely spaced teeth

Poor development of tooth enamel.

It is important to remember that some phenylalanine is needed to maintain

normal body function.

Insufficient phenylalanine intake may cause mental and physical

sluggishness, loss of appetite, anemia, rashes, and diarrhea.

A single mutant recessive allele of the Phenylalanine Hydroxylase (PAH) gene Location : Long arm of Chromosome 12 -locus 22.

PAH only allow a tolerance of 20 mg/kg/day. Missense mutations and deletions. Dietary excess of plant proteins which

results in the exhaustion of a protein cofactor Tetrahydrobiopterin BH4 needed by the enzyme.

Two people who conceive a child must both be the carriers of the defective gene in order for their child to have the disorder.

The “carrier” for PKU does not have the symptoms.

It is recommended that women with PKU who are of child bearing age, closely adhere to the low-phenylalanine levels before conception and throughout pregnancy. The risk of miscarriage, mental retardation, microcephaly, and congenital heart disease in the child is high if the mother’s blood phenylalanine is poorly controlled.

The mean incidence of PKU varies widely in different human populations.

The PKU disorder is as frequent in men as it is in women.

Country Incidence of PKU: India 1 in 18,300 China 1 in 18,000 Finland 1 in 100,000 Ireland 1 in 4,500 Japan 1 in 120,000 Korea 1 in 41,000 Norway 1 in 13,000 Turkey 1 in 2,600 United States1 in 15,000 

Usually a few drops of blood are obtained by a small prick on the heel, placed on a card and then sent for measurement.

Newborn screening allows early identification and early implementation of treatment.

All babies are screened for PKU by heel-prick test.

Blood tested for excess phenylalanine. Blood placed on agar plate with bacteria

that need phenylalanine to grow. Healthy babies’ blood doesn’t have

extra phenylalanine, so bacteria can’t grow.

Babies with PKU have extraphenylalanine, so bacteria grow.

Bacterial plate with newborn blood samples

Negative controls: no bacterial growth

Positive blood test results: bacterial halo = PKU

Negative blood test results: no bacterial growth = healthy babies

Positive controls : increasing phenylalanine concentrations give bacterial halos

http://www.childrenshospital.org/cfapps/research/data_admin/Site2940/mainpageS2940P4sublevel15.html

Ferric chloride + urine of new born baby Green colour in the presence of ketone bodies.

No cure. A strictly controlled phenylalanine free diet up to the age of about 14 years old. Phenylalanine is itself an essential amino acid

small doses must be supplied. After 14 years, the growth and development of

the brain is not affected by high levels of phenylalanine in the body.

Individuals with PKU must be alert for food sweetened with aspartame - artificial sweetener made from amino acids phenylalanine and aspartic acid.

If PKU goes untreated or undetected, severe brain problems occur such as seizures and mental retardation.

More frequent doctor visits. Required dietary restrictions that may

impact day to day activities. Permanent monitoring of blood

phenylalanine levels.

THANK YOU !!!