• 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.

• 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.

• 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.

• 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.

• 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.

Alternate pathways in PKU

• 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.

• 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.

• 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.

• Accumulation of phenylalanine competitively

inhibits tyrosinase & impairs melanin

formation.

• The result is hypopigmentation that causes

light skin colour, fair hair, blue eyes etc.

• 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.

• 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.

• In seriously affected PKU patients,

treatment includes administration of 5-

hydroxytryptophan & dopa to restore

the synthesis of serotonin &

catecholamines.

• 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.

• 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.

• Enzyme defect: p-hydroxyphenylpyruvate

dioxygenase.

• Cause transient hypertyrosinemia in the new-

born.

• This condition respond to administration of

ascorbic acid & dietary protein restriction.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

Albinism

• 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.

• 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.

• Textbook of Biochemistry-U Satyanarayana

• Textbook of Biochemistry-DM Vasudevan