Phenylketonuria
Lecture 2
• Norwegian doctor Asbjørn Følling discovered
PKU in 1934.
• Only 1 in about 15,000 babies are born with
PKU, which means PKU is very rare.
• Caused by deficiency of phenylalanine
hydroxylase
• Accumulation of phenylalanine and deficiency
of Tyrosine
Classical PKU
• Phe is high in tissue, plasma and urine
• Phenyllactate, phenylacetate and phenylpyruvate give
characteristic musty (mousy odor) to urine.
CNS symptoms (appear after the age of 1 yr, IQ below 50)
• Mental retardation
• failure to walk or talk,
• Seizures
• Hyperactivity
• Tremor
• Microcephaly
• failure to grow
Hypopigmentation
• Fair hair
• Light skin color
• Blue eyes
(The hydroxylation of tyrosine by tyrosinase
(first step in the formation of the pigment
melanin, is competitively inhibited by the high
levels of phenylalanine present in PKU)
Neonatal screening and diagnosis
• Early diagnosis is mandatory as it is treatable
disease
• In infants levels are normal as mother clears
elevated levels by placenta
• Levels rise after 24-48 hours of the exposure
to diet.
• After positive screening test you have to do
quantitive test for phenylalanine levels
Test
• Ferric chloride + urine of new born baby
Green colour in the presence of ketone bodies
© 2008 Paul Billiet ODWS
• Phenylketonuria, also known as PKU, is a
genetic disorder that affects a person’s ability
to process an important part of protein called
phenylalanine or phe.
• from the food we eat, and it helps our bodies
grow, learn, and feel healthy
• Soon after birth, babies born in the United
States are checked for PKU and other medical
conditions. This is called newborn screening.
• If children and adults with PKU eat too much
phe, it will actually hurt them.
• Children and adults with PKU have to eat such
small amounts of phe so cannot eat meats,
dairy, eggs, beans or nuts.
• Someone with PKU cannot eat pizza, birthday
cake, regular bread, yogurt, cheese, ice cream,
• chocolate, hot dogs, hamburgers, or turkey.
• Children and adults with PKU eat fruits,
vegetables, and special foods very low in
protein.
• Some cereals and crackers are okay in small
amounts.
• Phe must be calculated using a gram scale,
measuring cups or by counting how many
pieces, all day, every day.
Treatment
• The earlier treatment is started, the more completely
neurologic damage can be prevented (within first 7-10
days.
• over zealous treatment that results in blood
phenylalanine levels below normal is avoided because
this can lead to poor growth and neurologic symptoms.
• tyrosine cannot be synthesized from phenylalanine
and, therefore, it becomes an essential amino acid and
so must be supplied in the diet.
• Discontinuance of the phenyalanine-restricted diet
before 8 years of age is associated with poor
performance on IQ tests. Adult PKU patients show
deterioration of IQ scores after discontinuation of the
diet
• Individuals with PKU are advised to avoid
aspartame, an artificial sweetener that contains
phenylalanine.
Maternal PKU
• If women with PKU who are not on a low-phenyl alanine diet become pregnant, the offspring are
affected with “maternal PKU syndrome.”
• High blood phenylalanine levels in the mother
cause microcephaly, mental retardation, and
congenital heart abnormalities in the fetus—
phenlyalanine is a teratogen.
• Some of these developmental responses to
high phenylalanine occur during the first
months of pregnancy. Thus, dietary control of
blood phenylalanine must begin prior to
conception, and must be maintained
throughout the pregnancy
Cystic fibrosis
• This is the most common lethal genetic disease in
Caucasians of Northern European ancestry, and has a
prevalence of about 1:3,000 births.
• This autosomal recessive disorder is caused by
mutations on to the gene for the CF transmembrane
conductance regulator (CFTR) protein chromosome 7
that functions as a chloride channel on epithelium.
• Defective CFTR results in decreased secretion of
chloride and increased reabsorption of
sodium and water.
•
1:25 are carriers
• deletion of three nucleotides from the coding region of
a gene, resulting in the loss of phenylalanine at the
508th position (ΔF508) in the protein encoded by that
gene.
• This ΔF508 mutation prevents normal folding of the CF
transmembrane conductance regulator (CFTR) protein,
leading to its destruction by the proteasome
• The name cystic fibrosis refers to the
characteristic scarring (fibrosis) and cyst formation
within the pancreas, first recognized in the 1930s.
• Defective CFTR results in decreased secretion of
chloride and increased reabsorption of sodium
and water.
• In the pancreas, the decreased hydration results
in thickened secretions such that pancreatic
enzymes are not able to reach the intestine,
leading to pancreatic insufficiency.
• Treatment includes replacement of these
enzymes and supplementation with fat-soluble
vitamins
• CF also causes chronic lung infections with
progressive pulmonary disease.
Prenatal diagnosis and carrier
detection of cystic fibrosis
• Sweat test
• Concentration greater than 45 mmol/l for
sodium is suggestive of cystic fibrosis. Usually
it is 100 mmol/L
PCR
• a PCR test can distinguish between
homozygous normal, heterozygous (carriers),
and homozygous mutant (affected)
individuals.