kimia

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BIOCHEMISTRY

• PHENYLKETONURIA
• DONE BY
• PEER FATHIMA BARAKATHU
• INDIA

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Phenylketonuria  (PKU)

• 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.

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Phenylketonuria  (PKU)

• 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.

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Phenylketonuria  (PKU)

• Phenylalanine is a large, neutral amino acid .
  LNAAs compete for transport across
  the bloodbrain 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.

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• The normal metabolism of phenylalanine
• (pathways a and b)

BREAKDOWN
Dietry sources, particularly plant proteins
PHENYLALANINE HYDROXYLASE
PHENYLALANINE
TYROSINE
BODY PROTEINS
2008 Paul Billiet ODWS
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• The abnormal metabolism in phenylketonuric
  subjects
• (pathway c)

HYDROXYPHENYLACETIC ACID
PHENYLACETIC ACID
Agents, thought to be responsible for mental
retardation
2008 Paul Billiet ODWS
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LEVELS OF BLOOD PHENYLALANINE

• 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.

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SYMPTOMS

• Chronically, high levels of phenylalanine and
  some of its breakdown products can cause
  significant brain problems.
• There are other disorders of hyperphenylalaninemi
  a, but classic PKU is the most common cause of
  high levels of phenylalanine in the blood.

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SYMPTOMS

• Phenylalanine accumulates, causing rashes,
  seizures, hyperactivity, and mental retardation,
  if untreated.
• Prominent cheek and jaw bones widely spaced teeth
• Poor development of tooth enamel.

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SYMPTOMS

• 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.

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SYMPTOMS
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SYMPTOMS
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HEREDITY

• 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.

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HEREDITY

• 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.

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HEREDITY
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PREGNANCY (PKU)

• 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
  mothers blood phenylalanine is poorly controlled.

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INCIDENCE OF PKU

• The mean incidence of PKU varies widely in
  different human populations.
• The PKU disorder is as frequent in men as it is
  in women.

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INCIDENCE OF PKU
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INCIDENCE OF PKU

• 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 

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SCREENING TEST

• 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.

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SCREENING TEST

• 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 doesnt have extra
  phenylalanine, so bacteria cant grow.
• Babies with PKU have extra
• phenylalanine, so bacteria grow.

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Guthrie test for PKU

• Bacterial plate with newborn blood samples

http//www.childrenshospital.org/cfapps/research/d
ata_admin/Site2940/mainpageS2940P4sublevel15.html
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SCREENING TEST

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

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TREATMENT

• 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.

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TREATMENT

• 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.

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TREATMENT

• More frequent doctor visits.
• Required dietary restrictions that may impact day
  to day activities.
• Permanent monitoring of blood phenylalanine
  levels.

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• THANK YOU !!!