Inborn Errors of Metabolism

Inborn Errors of
BCH 451
Dr. Amina ElGezeery
Continuous Assessment Tests (CAT)
• Two Tests --------------------------40 Marks
• Two Quiz --------------------------10 Marks
• Final----------------------------------50 Marks
• Dates for CAT:
– 1st CAT:Wed. …… 26 DhuAl-Qadah 1431
– 2nd CAT: Sat. ……… 7 Muharram 1432
Time: 10-11
Lecture Room: B8/R 686
Ref. Books :
• Inborn Metabolic Diseases .
• By :J. Fernandes , J. Saudubary , G. van den
Berghe .
• Harpers’s Biochemistry .
• By : Murray et all .
Inborn errors of metabolism (IEM) are
inherited disorders for a heterogeneous
group of more than 500 pathologies
originated from mutation of genes
resulting in deficiency or absence of a
protein, generally an enzyme, and loss
of its metabolic function.
So …
• IEM mainly affect the biochemical pathways in
body .
• They result from deficient activity of enzymes ,
cofactors or activators deficiencies or
defective transport of compounds .
• IRM are genetic disorders resulting from
mutation in a gene , mainly encoding enzyme ,
which produce a block in normal course of
metabolism .
• IRM are monogenic diseases .
Classification of Genetic
Single Gene Disorders ( monogenic ) .
Chromosomal Disorders .
Multifactorial Diorders .
Mitochondrial disorders .
Acquired Somatic Genetic Disorders
(eg.cancer ).
Single Gene Disorders
•Caused by mutation in or around a gene.
•Lead to critical errors in the genetic information.
•Exhibit characteristic pedigree pattern of inheritance
(Mendelian Inheritance) .
•Occur at a variable frequency ranging from 1/500 to
•Over 7,000single gene disorders have been identified .
•May be:
- Sex linked
Ex . For Single Gene Disorders
• Sickle cell anemia .
• Thalassemia .
• Familial hypercholesterolemia .
• Somatic human cell has 46 chromosomes i.e 23
pairs .
• 22 pairs are autosomes ( from No 1 to 22 ) .
• One pair is sex chromosomes : XY in males
XX in females .
Genes on sex chromosomes are said to be sex –
linked genes , X- linked and Y – linked .
Genes on autosomes are said to be autosomal
genes .
Human Chromosomes
• Autosomes =
chromosomes 1-22
• Sex chromosomes =
X and/or Y
• Autosomes carry
genes for all
• Sex genes carry
mostly genes for sex
Autosomal Inheritance
-This is the inheritance of the gene present on the
Autosomes ( chr. 1-22).
-Both sexes have equal chance of inheriting the disorder.
-Three types:* Autosomal dominant inheritance, if the
gene is dominant.
* Autosomal recessive inheritance, if the gene is
* Codominant inheritance , if the two alleles are equally
expressed in heterozygot .
Autosomal Dominant Inheritance
-Autosomal dominant inheritance, if the gene is
-The trait (characteristic, disease) appears in every
-The trait is transmitted by an affected person to half
the children.
-Unaffected persons do not transmit the trait to their
-The occurrence and transmission of the trait is not
affected by sex.
Examples of Autosomal dominant
- Familial hypercholesterolemia
- Adult polycystic kidney disease
- Dominant blindness
Autosomal Recessive Inheritance
-The trait (characteristic, disease) is recessive.
-The trait expresses itself only in homozygous
-Unaffected persons (heterozygotes) may have
affected childrens.
-The parents of the affected child may be
-Males and female are equally affected.
Punnetts quares howing autosomal recessive
Both Parents Heterozygous:
25% offspring affected “Homozygous”
50% Trait “Heterozygous normal but carrier”
25% Norml
Examples of Autosomal Recessive
Phenylketonuria .
Galactosemia .
Alkaptonuria .
Congenital deafness .
Sex –Linked Inheritance
-This is the inheritance of a gene present on the
sex chromosomes.
-The Inheritance Pattern is different from the
autosomal inheritance.
-Inheritance is different in the males and females.
Y –Linked Inheritance
-The gene is on the Y chromosomes.
-Shows Holandric inheritance. i.e. The gene is passed from
fathers to sons only.
-Daughters are not affected.
e.g. Hairy ears in India.
-Since male are Hemizygous, the condition
exhibits itself whether dominant or recessive.
X –Linked Inheritance
• - The gene is present on the X -chromosome.
-The inheritance follows specific pattern.
-Since males have one X chromosome, and are
hemizygous. ( heterozygot only )
-Females have 2 X chromosomes, they may be
homozygous or heterozygous.
-These disorders may be : recessive or
X –Linked Recessive Inheritance
-The incidence of the X-linked disorders is higher in
male than in female.
-The trait is passed from an affected man through all
his daughters to half their sons.
-The trait is never transmitted directly from father to
-An affected women has all affected sons and carrier
E.g. Glucose -6- phosphate dehydrogenase deficiency
Normal female, affected male
All daughters carriers “not affected,
pass the disease to 50% of their sons”.
X-Linked Dominant Disorders
• -The gene is on X Chromosome and is
-The trait occurs at the same frequency in
both males and females.
-Hemizygous male and heterozygous females
express the disease.
** Punnett square showing X –linked
dominant type of Inheritance:
Affected male and normal female:
All daughters affected, all sons
• What are the percentage of normal and
affected children in the following matting ?
• 1- Normal father X Affected (Heterozygous )
mother .
• 2- Normal father X Affected (homozygous )
mother .
Chromosomal Disorders
•Result from defect in the number (i.e. Numerical
disorders) or structure (i.e. Structural disorders)of
•The first chromosomal disorder was Trisomy 21 (Downs
syndrome)and was recognized in 1959.
•These disorders are quite common and affect about
7/1000 live born infants.
•Account for almost half of all spontaneous firsttrimester abortions.
•Do not follow a Pedigree pattern of inheritance.
Mitochondrial Disorders
* The defective gene is present on the
mitochondrial chromosomes.
* Effect generally energy metabolism.
* Effect those tissues more which require
constant supply of energy e.g muscles.
* Shows maternal inheritance:-affected mothers
transmit the disorder equally to all their children.
* affected fathers do not transmit the disease to
their children.
Multifactorial Disorders
• •Result from interaction between environmental and
genetic factors.
•Often polygenic in nature, no single error in the
genetic information.( sum of the effects of many genes
, each gene has a small effect )
•Environmental factors play a significant role in
precipitating the disorder in genetically susceptible
•Tend to cluster in families.
•Do not show characteristic pedigree pattern of
Examples of Multifactorial disorders
Diabetes Mellitus .
Coronary heart disease .
Cancer .
Cleft lip/ cleft palate .
 Cleft lip and palate
 Caused by a combination of
genetic predisposition and
environmental influences
 Pattern – more affected people
in family than expected from
incidence in population but
doesn’t fit dominant, recessive
or X-linked inheritance patterns