The lecture has been given on Mar. 27th, 2011 by Dr. Jamal.

1. Inborn Errors of Metabolism
(IEM)
This is a group of genetically determined diseases, most of which are
inherited by A.R. mean. Several hundred diseases have so far been
identified and the number is increasing.
Nearly all forms of IEM are caused by absence of a single enzyme leading
to disturbance of a particular metabolic pathway. Accumulation of
compounds proximal to the enzymatic block in the metabolic pathway or
due to deficiency of products distal to it is the underlying causative factor
in the majority of cases.
A large proportion of IEM present soon after birth while others present
later with various manifestations.
Clinical situations and finding which should make IEM highly suspicious
include:
In neonate: lethargy, prolonged jaundice, convulsion, acidosis.
In infants and older children: delayed intellectual and motor mile stones,
unexplained odors during acute illness, corneal opacity, cataract or lens
dislocation, unexplained renal stones and unexplained episodes of vomiting,
acidosis and coma.
Classifications of IEM:
1. Errors in protein metabolism:

2. a. Errors in plasma protein synthesis: e.g. Afibrinogenemia,
hemophilia, agamaglobulinemia…etc
b. Errors in Hb synthesis as hemoglobinopathies.
c. Errors in amino acid metabolism or transport defects as
PKU, Alkaptunurea, Homocystinurea, maple syrup urine
disease, Hartnup disease, Fanconi syndrome, Cystinurea and
cystinosis.
2. Errors in carbohydrate metabolism; Congenital lactose intolerance,
Galactosemia, Glycogen storage diseases, D.M.&
Mucopolysaccharidosis.
3. Errors in lipid metabolism; Lipidosis ( Gauchers, Neimann-pick and
Tay-Sachs disease), Abetalipoproteinemia& hyperlipidemia.
4. Errors in pigment metabolism; Albinism, porphyria, Meth-
hemoglobinemia, primary hemochromatosis, Dubin-johnson and
Gilbert disease.
5. Unknown biochemical errors as ontogenesis imperfect, Marfan
syndrome, Achondroplasia and Ehlers-Danlos syndrome.
Examples of IEM:
Phen
ylketonurea

3. An A.R. disorder which occurs at a rate of 1 in 10.000, caused by a defect
in the enzyme phenyl alanine hydroxylase which is responsible for
converting phenylalanine to tyrosine
Phenyl alanine hydroxylase
Phenyle alanine Tyrosine
Melanin
Affected children look normal at birth, then they become blonde and have
blue eyes due to melanin deficiency .they also suffer progressive
deterioration becoming intellectually retarded, hyperactive, have
convulsion and may show skin eczema.
They also suffer anorexia vomiting, excessive sweating with a peculiar odor
of sweat and urine.
Diagnosis is made by urine ferric chloride test and then by serum phenyl-
alanine level.
Treatment is by special formula which is low in phenylalanine, this should
be started from neonatal period and continued for several years.
Homozygous affected females should go back to this treatment during
every pregnancy to avoid prenatal affection of the fetus.
Ga
lactosemia:

4. An A.R. disorder caused by absence of the enzyme Galactose-1-phosphate
–uridyl- transferase which is responsible for converting galactose to
glucose, as a result of this galactose accumulates in the blood & different
body tissues causing permanent damage in some of them.
Clinically affected children show symptoms as soon as galactose (from milk
lactose) is consumed, they will show feeding difficulty, vomiting, prolonged
jaundice, hepatomegaly, hypoglycemia and convulsion.
Mental retardation, cataract, and renal manifestations (albuminurea and
aminoaciduria) may occur after neonatal period in untreated patients.
Diagnosis can easily be made at the bedside of the patient by having +ve
clinitest (indicate presence of a reducing substance) and –ve clinistix
(specific for glucose), further confirmation requires estimation of the
involved enzyme in RBC.
Treatment consists of absolute withdrawal of milk and its products for
several years.
Glycogen
storage diseases “GSD”:
A group of A.R. disorders, caused by deficiency of various enzymes and
have various clinical manifestations.
 Type 1 GSD (Von-Geirkes disease): the commonest form of the
group, caused by glucose-6-phoshpatase deficiency. Clinically this
type is characterized by frequent attacks of hypoglycemia, doll-face,

5. short stature, massive hepatomegaly, hyperurecemia, ketonurea and
bleeding tendency.
Diagnosis is confirmed by liver biopsy which shows increased fat
and glycogen while absence of the involved enzyme.
Treatment is by frequent feeding during infancy.
 Type IIa (pompes disease) characterized by progressive
cardiomegaly and congestive H.F.
Type IIb characterized by skeletal muscle dystrophy without heart
affection.
 Type III (cori) characterized by involvement of liver, skeletal muscle
and RBC.

Mucopol
ysaccharidosis (MPS)
A group of hereditary conditions, characterized by storage of acid-
mucopolysaccharides in different body tissues.
The known types of MPS are:
1- Hurler syndrome.
2- Hunter syndrome.
3- Sanfillipo disease.
4- Morquio disease.
5- Sly syndrome.

6. 6- Maroteaux-Lamy.
The main characteristics of MPS in general include:
• Specific enzyme deficiency in each type e.g.: a-L-iduronidase in
Hurler and iduronosulfate sulfatase in Hunter type.
• Skeletal deformity (dysostosis multiplex) occurs in all type.
• Affection of multiple organs and body systems in most.
• All are A.R. except type II (hunter) which is XLR.
• Intellectual sub normality (in all except in Morquio and Maroteaux
Lamy).
• Diagnosis depends on :
1. Clinical manifestations.
2. Urinary excretion of mucopolysaccharides.
3. Finding of the specific enzyme deficiency.
• No treatment is yet available for any of them.
B.M. or cord blood transplant or specific enzyme replacement may in
future be a successful treatment for them.
Lipidosis (lipid storage diseases):
A rare group of inherited (A.R.) diseases, characterized by, deposition of
lipid in various tissues & body organs.

7. The 3 main types of which are:
1. Gauchers disease: caused by deficiency of the enzyme Beta-
glucosidase.
• Infantile type is characteristically rapidly progressive,
hepatosplenomegaly and mental retardation.
• Juvenile type spares the brain while only causes
hepatosplenomegaly.
• The adult type is less severe and causes anemia, thrombocytopenia
and involvement of long bones.
Diagnosis is by finding Gauchers cell in the bone marrow.
Treatment is symptomatic. Death is nearly always the rule in all forms.
2. Neimann-Pick disease (NPD): caused by deficiency of sphingomylinase
enzyme, which results in accumulation of sphingomylin in various
tissues and organs.
Affected patients have mental retardation, anemia, hepatosplenomegaly,
lymphadenopathy and a cherry-red spot is seen in the region of macula in
1/3 of cases.
Diagnosis is made by finding NP cells in the bone marrow or blood.
Miliary T.B. –like picture can be seen on chest X-ray.
No treatment is available and the condition is almost fatal.
3. Tay-sachs disease (Amaurotic family idiocy) caused by hexosaminidase
deficiency and is far more common in Jewish.

8. There is cerebral but no-visceral involvement. Macula cherry-red spot is
seen in some.