disorders of phenylalanine metabolism
TRANSCRIPT
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• Enzyme defect: Deficiency of the hepatic
enzyme, phenylalanine hydroxylase.
• A variant of PKU-due to a defect in
dihydrobiopterin reductase (relatively less).
• This enzyme deficiency impairs the synthesis
of tetrahydrobiopterin required for the action
of phenylalanine hydroxylase.
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• There are 5 types of PKU described.
• Type I is the classical one.
• Type I is due to phenylalanine hydroxylase
deficiency.
• Types II & III are due to deficiency of
dihydrobiopterin reductase.
• Type IV & V are due to the deficiency of the
enzyme synthesizing biopterin.
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• Tetrahydrobioptrerin is the co-enzyme
required for serotonin & dopamine, the
decreased level of these neurotransmitters
may also result in the neurological symptoms.
• Phenylalanine hydroxylase gene is located in
chromosome 12 & dihyro biopterin reductase
gene in chromosome 4.
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• Phenylketonuria primarily causes the
accumulation of phenylalanine in tissues &
blood.
• It results in increased excretion in urine.
• Due to disturbances in the routine
metabolism, phenylalanine is diverted to
alternate pathways.
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• Resulting in the excessive production of
phenylpyruvate, phenylacetate, phenyllactate
& phenylglutamine.
• AII these metabolites are excreted in urine in
high concentration in PKU.
• Phenylacetate gives the urine a mousey
odour.
• Phenylpyruvate is a keto acid excreted in
urine in high amounts.
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Alternate pathways in PKU
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• Effects on central nervous system:
• Mental retardation, failure to walk or talk,
failure of growth & tremor are the
characteristic findings in PKU.
• lf untreated, the patients show very low lQ
(below50).
• The biochemical basis of mental retardation
in PKU is not well understood.
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• Accumulation of phenylalanine in brain
impairs the transport & metabolism of other
aromatic amino acids.
• The synthesis of serotonin (an excitatory
neurotransmitter) from tryptophan is
insufficient.
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• This is due to the competition of
phenylalanine & its metabolites with
tryptophan that impairs the synthesis of
serotonin.
• Defect in myelin formation.
• Effect on pigmentation:
• Melanin is the pigment synthesized from
tyrosine by tyrosinase.
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• Accumulation of phenylalanine competitively
inhibits tyrosinase & impairs melanin
formation.
• The result is hypopigmentation that causes
light skin colour, fair hair, blue eyes etc.
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• Normal level is 1 mg/dl.
• In PKU, the level is >20 mg/dl.
• Carried out by Guthrie fest, which is a bacterial
(Bacillus subtilis) bioassay for phenylalanine.
• Phenylpyruvate in urine can be detected by
ferric chloride test (a green colour is obtained).
• It is not specific, many other compounds give a
false positive test.
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• Dietary intake of phenylalanine should be
adjusted by measuring plasma levels.
• Early diagnosis (in the first couple of months
of baby's life) & treatment for 4-5 years can
prevent the damage to brain.
• The restriction to protein diet should be
continued for many more years in life.
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• In seriously affected PKU patients,
treatment includes administration of 5-
hydroxytryptophan & dopa to restore
the synthesis of serotonin &
catecholamines.
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• Enzyme defect: Tyrosine transaminase.
• This disorder-also known as Richner Hanhart
syndrome.
• There is a blockade in the routine degradative
pathway of tyrosine.
• Accumulation & excretion of tyrosine in urine.
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• Tyrosine & its metabolites namely p-
hydroxyphenylpyruvate, p-
hydroxyphenyllactate, p-hydroxy
phenylacetate, N-acetyltyrosine & tyramine
are excreted.
• Characterized by skin (dermatitis) & eye
lesions & rarely mental retardation.
• A diet low in protein is advised.
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• Enzyme defect: p-hydroxyphenylpyruvate
dioxygenase.
• Cause transient hypertyrosinemia in the new-
born.
• This condition respond to administration of
ascorbic acid & dietary protein restriction.
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• Enzyme defect: Homogentisate oxidase.
• Homogentisate accumulates in tissues &
blood & is excreted into urine.
• Homogentisate, on standing, gets oxidized to
the corresponding quinones, which
polymerize to give black or brown colour.
• The urine of alkaptonuric patients resembles
coke in colour.
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• Homogentisate gets oxidized by polyphenol
oxidase to benzoquinone acetate which
undergoes polymerization to produce a
pigment called alkapton.
• Alkapton is deposited in connective tissue,
bones & various organs (nose, ear etc.)
resulting in a condition known as ochronosis.
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• Many alkaptonuric patients suffer from
arthritis.
• This is due to the deposition of pigment
alkapton (in the joints), produced from
homogentisate.
• Diagnosis:
• Urine becomes black on standing when it
becomes alkaline.
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• Blackening is accelerated on exposure to
sunlight & oxygen.
• The urine when kept in a test tube will start
to blacken from the top layer.
• Ferric chloride test will be positive for urine.
• Benedict's test is strongly positive.
• Not a dangerous disorder & does not
require any specific treatment.
• Protein diet with low phenylalanine content.
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• Enzyme deficiency: Fumarylacetoacetate
hydroxylase or maleylacetoacetate
isomerase.
• Tyrosinosisis a rare & serious disorder.
• lt causes liver failure, rickets, renal tubular
dysfunction & polyneuropathy.
• Tyrosine, its metabolites & many other amino
acids are excreted in urine.
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• In acute tyrosinosis, the infant exhibits
diarrhea, vomiting, and 'cabbage-like' odor.
• Death may even occur due to liver failure
within one year.
• Treatment: Diets low in tyrosine,
phenylalanine and methionine are
recommended.
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• Albinism (Greek: albino-white) is an inborn
error, due to the lack of synthesis of the
pigment melanin.
• It is an autosomal recessive disorder with a
frequency of 1 in 20,000.
• Tyrosinase is completely absent, leading to
defective synthesis of melanin.
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• The ocular fundus is hypopigmented & iris may be
grey or red.
• There will be associated photophobia & decreased
visual acuity.
• The skin has low pigmentation & skin is sensitive to
UV rays (skin cancer).
• Hair is also white.
• Manifestations are less severe in tyrosinase positive
type, where the abnormality is in the uptake of
tyrosine by melanocytes.
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Albinism
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• Melanocyte deficiency secondary to a failure
of melanoblasts to colonize the skin.
• Failure of melanocytes to form melanosomes.
• Due to tyrosinase deficiency, melanin is not
produced in the melanosomes.
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• Failure of melanosomes to form melanin
owing to substrate deficiency.
• Failure of melanosomes to store melanin or
to transport melanin to keratinocytes.
• Excessive destruction of functional
melanosomes.
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• Textbook of Biochemistry-U Satyanarayana
• Textbook of Biochemistry-DM Vasudevan
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