‫ميحرلا نمحرلا هللا مسب‬

Inborn error of
metabolism

By Yusuf Salih
Hassan Mohammed
 Topic of presentation

1. Review of metabolism
2. Definition and classification of inborn error of
metabolism
3. Phenylketonuria
4. Galactosemia
5. Glycogen storage disease
 What is metabolism ?
• It’s a set of life sustaining chemical reaction
that aim to :
1. Convert food to energy to run different
cellular process
2. Convert food to building block essential
for other metabolism like lipid , protein ,
fat , CHO
3. Eliminate waste product outside body
which if stay inside can be harmful
 What is metabolism ?
• Metabolism usually consist of several step
• Each step usually require enzyme
• Metabolism can be divide into 2 part :
1. Anabolism : synthesis of compound like
synthesis of protein from several amino acid
Anabolism consume energy
2. Catabolism : is break down of compound
Catabolism release energy
 Inborn error of metabolism ?
• Its group of genetic ( inherited) disorder that
result in abnormality in metabolism inside
body
• There is hundreds of inborn error of
metabolism
And there is variable way for clasification
 Inborn error of metabolism

Disorder of fatty acid Disorder of organic acid :

metabolism : • Alkaptonuria
Disorder of amino- • Mcad defiency • 2 hydroxyglutaric aciduria
acid metabolism : • others • Others
• Phenylketonuria
• homocystinuria
• Tyrosinemia
• others Disorder of urea cycle :
• Carbamoyle phosphate
• synthetase deficiency
• Others
Disorder of porphyrine
metabolism :
Disorder of • Acute porphyria
carbohydrate: • Others
• Galactosemia
• Glycogen storage
disease
 Phenylketonuria
• The amino-acid is phenylalanine
• Phenylalanine is one of the 20 essential
amino-acid that should present in food, and
the body cant synthesis it
• Incidence is 1 / 10,000 person
Normal metabolism of phenylalanine:

Phenylalanine hydroxylase
Phenylalanine Tyrosine
Tetrahydrobipterine

Non
enzymatic

Transaminase
Thyroid

melanin T3 andT4
Dopamin
Epinphrine
Norepinphrine
 Metabolism of phenylalanine
• Source of phenylalanine
Food only
• Source of tyrosine :
1. Food
2. From conversion of phenylalanine
 What is phenylketonuria ?

• Inborn error of metabolism in which the body

cant convert phenylalanine into tyrosine
• The cause is autosomal recessive gene
• Type :
1. Classic PKU : the defect in enzyme itself
(p.a.hydroxylase )
2. Non classical PKU : the defect in the cofactor
of the enzyme ( tetrahydrobiopterine )
 Clinical manifestation
1- On brain :
the elevated free Phenylalanine can cross BBB and
directly damage the brain cell lead to sever mental
retardation
As it has neurotoxic effect it can damage any area of brain
so lead to motor deficit , convulsion
Free elevated level suppress the transaminase enzyme ,
this lead to decrease level of neurotransmitter
so cause of mental retardation in PKU is :
• Direct damage to brain cell
• Indirect effect by decreasing neurotransmitter level
2- On skin :
As phenylalanine suppress the transaminase so it
will lead to melanin deficiency
This lead to albinism
3- Specific odor :
When phenylalanine break down to ketoacid
This has to route :
1.Urine : thus called phenylketonuria
2.Saliva : give specific bad odor in mouth
 Child with albinism

N.B :
Not all patient with PKU will have albinism
This depend on the suppression of transaminase enzyme
 Investigation
1. Plasma level of phenylalanine :
Normal level is 1-2 mg / dl
If above 6 mg/dl then further investigation needed
If above 20 mg / dl this usually confirm PKU
2. level of dihydrobiopterin reductase in erythrocytes and
by analyzing biopterin metabolites in urine
3. Other investigation :
Enzyme analysis of P.A hydroxylase
 Treatment

• Diet free of phenylalanine

Usually in protein rich food like egg , fish , milk ,
cheese …..
For neonate & infant special formula for feeding
usually required
After that when he start to eat , he should avoid
the diet that contain phenylalanine
• Treatment with modifid preparation of
tetrahydrobiopterin has shown good
responses in some individuals with PKU
 Special condition
• If the patient was female and she become
pregnant she should have a very strict control of
phenylalanine level and avoid ( maternal PKU
syndrome )
The phenylalanine can cross the placenta and cause
sever brain damage , congenital heart disease and
microcephaly
 Prognosis
• Prognosis is excellent if the condition
diagnosed and phenylalanine containing diet
avoid
most of them will have normal life with normal
intelligence
 galactocemia
• Galactosemia is an autosomal recessive
disease caused by defciency of galactose-1-
phosphate uridyltransferase .
• is a condition in which the body is unable to
use the simple sugar galactose which is mostly
in milk. and turning it into energy.
• Galactosemia occurs in about 1 in 50,000
births, mainly Caucasians.
 types
• There are three main types of galactosemia:
• Classic (type I) commenst
• Galactokinase deficiency (type II)
• Galactose epimerase deficiency (type III)
 Sign and symptoms
• jaundice
• vomiting
• diarrhea
• poor weight gain
• irritability
• seizures
• cataract ,renal tubular disease
• For girls, it can cause their ovaries to stop
working.
 diagnosis
• Galactose frequently is present in the urine
and can be detected by a positive reaction for reducing
substances without a reaction with glucose oxidase on
urine strip

• Te diagnosis is made by showing extreme reduction in

erythrocyte galactose-1-phosphate
uridyltransferase activity

• . DNA testing for the mutations in

galactose-1-phosphate uridyltransferase confrms the
diagnosis and may be useful in predicting prognosis.
 Treatment
• 1-The Treatment for Galactosemia is the removal of
galactose from your diet. All lactose products must be
totally avoided. Milk and milk products contain the most
amount of lactose; however it is also present in other foods
such as legumes, organ meats and processed meats.
• 2-Infants will need to be fed with food that is lactose free
such as soy formula, meat-base formula, or Nutramigen (a
protein hydrolysate formula)
• 3-There is no definite cure for Galactosemia, the condition is
life long and it can only be controlled. Doctors advise a
calcium supplement for patients with Galactosemia as Milk
is an important source of calcium for a growing child
 Glycogen storage diseases
• Glycogen storage (GSDs) are a group of inherited
genetic disorders that cause glycogen to be
improperly stored in the body. Children with
glycogen storage diseases have a buildup of
abnormal amounts or types of glycogen in their
tissues many cause hepatomegaly and
hypoglycemia
• A glycogen storage disorder occurs in about one
in 20,000 to 25,000 babies. The most common
types of GSD are types I, II, III, and IV, with type I
being the most common
 classification
• Glycogen storage diseases fall into the following four
categories:
1. Diseases that predominantly affect the liver and have a
direct influence on blood glucose (types I, VI, and VIII)
2. Diseases that predominantly involve muscles and affect
the ability to do anaerobic work (types V and VII)
3. Diseases that can affect the liver and muscles and directly
influence blood glucose and muscle metabolism (type III)
4. Diseases that affect various tissues but have no direct
effect on blood glucose or on the ability to do anaerobic
work (types II and IV).
 symptoms
• Glycogen storage disease symptoms in
pediatric patients depend on its type. The
following is a list of common glycogen storage
disease symptoms:
• Low blood sugar
• Enlarged liver
• Slow growth
• Muscle cramp
 Dx and tx
• Dx
• For all forms, a diagnosis can normally be confrmed by
DNA mutation testing in white blood cells
• Biopsy of the affected organs
• Blood tests and urine tests
• MRI scan
• Tx:
• Frequent high carbohydrate meals during the day.
• Cornstarch
• allopurinol and human granulocyte colony stimulating factor
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