Download Inborn Errors of Metabolism BCH 451

Inborn Errors of
Metabolism
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: …… Sat. 10-4-1433
– 2nd CAT: ……… Sat.29-5-1433
Time: 11-12
Lecture Room:
Ref. Books :
• Inborn Metabolic Diseases .
J. Fernandes , J. Saudubary , G. van den Berghe .
• Genetic in Medicine.
Nussbaum R L , Mclnnes R and Willard H .
Course Outline
1- Definition and classification of genetic disorders
2-Mode of inheritance
3- Gene structure , genetic code and gene mutation
4- Major histocompatibility genes
5- Disorders of carbohydrate metabolism
6- Disorders of amino acids and urea cycle enzymes
7- Disorders of lipoprotein metabolism
8- Lipid storage diseases
9- Disorders of purine and pyrimidine metabolism
4
Inborn errors of metabolism
Inborn errors of metabolism (IEM) or
inherited metabolic diseases 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.
• Inborn errors of metabolism ( IEM) or metabolic
disorders 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 .
• IEM mainly affect the biochemical pathways in
body .
• They result from deficient activity of enzymes ,
cofactors , activators or defective transport of
compounds .
Classification of Genetic
Diseases
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Single Gene Disorders ( monogenic ) .
Chromosomal Disorders .
Multifactorial Diorders .
Mitochondrial disorders .
Acquired Somatic Genetic Disorders
(eg.cancer ).
Definitions
• Chromosome is the carrier of the genetic element .
• Gene is ( the genetic element ) a sequence of
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•
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chromosomal DNA that is required for the production
of functional product (mRNA , polypeptide chain , rRNA
, tRNA)
Alleles are different forms, or variants, of a gene.
Genotype is the particular set of alleles for all the
genes carried by an individual.
Wild type is the normal, non mutant allele.
Phenotype is the observable expression of the
genotype .
Human Chromosomes
• Chromosomes are double chromatide during cell
division BUT it’s a single chromatide in the rest
of cell cycle .
So Genes are present in pairs
• If the two alleles are simillar→ Homozygous
• If the two alleles are different → Heterozygous
• 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
functions
• Sex genes carry
mostly genes for sex
determination
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
1/200,000.
•Over 7,000 single gene disorders have been identified .
•May be:
-Autosomal
- Sex linked
Ex . For Single Gene Disorders
• Sickle cell anemia .
• Thalassemia .
• Familial hypercholesterolemia .
Mode of inheritance of single gene disorders
Sex Linked
Autosomal
Dominant
Recessive
X- Linked
Y- Linked
Codominant
Dominant
Recessive
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 gives its
phenotype in heterozygous state.
Autosomal recessive inheritance, if the gene gives its
phenotype in homozygous state only .
Codominant inheritance , if the two alleles are equally
expressed in heterozygot .
Autosomal Dominant Inheritance
-The trait ( character , disease) occurs in heterozygous .
-The trait (character, disease) appears in every
generation.
-The trait is transmitted by an affected parent to half
the children.
- The occurrence and transmission of the trait is not
affected by sex.
- Both males and females affected, and can pass on the
trait with equal probability
Examples of Autosomal dominant
disorders
- Familial hypercholesterolemia
- Adult polycystic kidney disease
- Dominant blindness
Autosomal Recessive Inheritance
-The trait expresses itself only in homozygous
state
-Unaffected persons (heterozygotes) may have
affected childrens.
-The parents of the affected child may be
consanguineous.
-Males and female are equally affected.
- Not found in multiple generations
Punnetts quare showing autosomal recessive
inheritance
(1) Both Parents Heterozygous:
25% offspring affected “Homozygous”
50% Trait “Heterozygous normal but carrier”
25% Norml
Examples of Autosomal Recessive
Diorders
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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.
Y-Linked Inheritance
• Traits on the Y
chromosome are only
found in males, never in
females.
• The father’s traits are
passed to all sons.
• Dominance is irrelevant:
there is only 1 copy of
each Y-linked gene
(hemizygous).
X –Linked Inheritance
• The gene is present on the X -chromosome.
• Each son has a 50% chance of receiving the mutant gene
from the mother
• Daughters also have a 50% chance, but will also inherit a
normal X from the father .
• Variable phenotype in carrier daughters, because of
random X inactivation
• 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 dominant.
X –Linked Recessive Inheritance
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
sons.
-An affected women has all affected sons and carrier
daughters
- Ex . Glucose 6-phosphate dehydrogenase deficiency .
Albinism (Ocular).
Lesch–Nyhansyndrome.
Hemophilia A.
Hemophilia B.
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 dominant.
• Affected females are about twice as common as affected
males ( homo. And heterozygotes), but affected females
typically have milder (although variable) expression of
the phenotype.
• Hemizygous male and heterozygous females express the
disease.
Punnett square showing X –linked
dominant type of Inheritance:
(1) Affected male
and normal female:
All daughters affected, all sons
normal.
• What are the percentage of normal and
affected children in the following matting ?
1- Normal father and Affected (Homozygous )
mother with recessive autosomal disease .
2- affected father with dominant X-linked
disorder and normal mother.
3- Affected father with Y-linked disease and a
normal mother .
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.
Mitochondrial DNA
• In the human mitochondria the chromosomes are
present as 10 circular double helices of DNA.
• They are self replicative.
• Contain: 16,596bp, genes for 22tRNAsand 2 types of
ribosomal RNA required for mitochondrial protein
synthesis.
• They also have genes for 13 polypeptides, involved in
cellular oxidative phosphorylation.
• Both strands of DNA are transcribed and translated.
Mitochondrial DNA cont….
• The mitochondrion divides by simple division during
cytokinesis , the mitochondria are randomly
distributed to the 2 daughter cells .
• When the cell containing a mixture of normal and
mutated mtDNA divides , its daughter cells may contain
only normal mtDNA , only mutant mtDNA or a mixture
of both.
• The phenotypic expression of a mutation in mtDNA
depends on the relative proportions of normal and
mutant mtDNA , so the variability of expression is a
feature of mitochondrial disorders .
Mitochondrial DNA cont….
• The unique feature of mtDNA is its maternal
inheritance because the ovum is well supplied
with mitochondria , but the sperm contains
few , and even those few do not persist in
offspring .
• So the mother transmits her mtDNA to all her
offspring .
Mitochondrial Genes
• Mitochondria are only
inherited from the mother.
• If a female has a mitochondrial
trait, all of her offspring inherit
it.
• If a male has a mitochondrial
trait, none of his offspring
inherit it.
• Note that only 1 allele is
present in each individual, so
dominance is not an issue.
• Ex. Lebers hereditary optic
neuropathy .
Multifactorial inheritance
• Inheritance controlled by many genes with
small additive effects (polygenic) plus the
effects of the environment
• Clinical clue: One organ system affected
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
individuals.
•Tend to cluster in families.
•Do not show characteristic pedigree pattern of
inheritance.
• Are not inherited in Mendelian fashion
Examples of Multifactorial disorders
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Diabetes Mellitus .
Coronary heart disease .
Cancer .
Cleft lip/ cleft palate .
Risk factors for coronary artery disease
Uncontrollable
(but identifiable)
Family history (genetics)
Age
Male sex
Potentially controllable or
treatable
Fatty diet
Hypertension
Smoking
High serum cholesterol
Low serum HDL
High serum LDL
Stress
Insufficient exercise
Obesity
Diabetes
Multifactorial Disorders
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
Chromosomal Disorders
•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.
Chromosomal Abnormalities
I - Numerical abnormalities ;change in
chromsome number :
1- Aneupliody ; increase or decrease in one
or more of chr. 2n+1 or 2n-1 …
2-Polypliody : increase in a whole set of chr.
3n ,4n,…..
II - Structural abnormalities ; change in
chromosome structure .
Aneuploidy
• The variation in chromosome number not
involved the whole set .
• Most commonly involve increase or decrease in
one chromosome .
• May be in autosomes or sex chr .
• The main cause is non disjunction during
gametogenesis .
• Trisomy : increase in one chr. (47 chr.)
• Monosmy : decrease in one chr. (45 chr.)
• Tetrasomy : increase in two chr.(48 chr)
Aneuploidy
• Trisomy: results from fertilization
between one normal gamete & one
gamete that contains an extra
chromosome.
• In Humans: Autosomal Trisomy
usually results in spontaneous
abortion.
• The only autosomal trisomies seen in
live births are trisomy 13, 18 and 21.
• Trisomosy 21 (Down Syndrome) is
the only autosomal trisomy that
allows survival until adult hood.
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23
47
Causes of Aneuploidy
• The main cause of aneuploidy is non-disjunction .
•
Non-disjunction ( ND ) : is the failure of a pair of
chromosomes to separate ( or associate ) during cell
division resulting in unequal distribution of the
chromosomes between the two daughter cells .
• The most common cause of aneuploidy is ND in meiosis
in females .
Common Sex Chromosome
Anuploidy
• Turner Syndrome
(female)
45,XO
• Trisomy X
47, XXX
(female)
• Klinefelter Syndrome
47,XXY
(male)
• Extra “Y” chromosome
47,XYY
(male)
Polyploidy
• Presence of additional set of chromosomes ; 3n ,4n
, 5n …
• Origin
– Failure of the spindle mechanism after the
chromosomes have been duplicated which result in 2n
gamete .
– Multiple sperm fertilize an egg
• Polyploidy is present in certain cells of the body,
some liver cells , and frequently seen in the
chromosomes of tumor tissues .
Triploidy
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Complete extra set of chromosomes ,3n; 69 chromosomes .
Most common form of human polyploidy .
Mostly miscarriages, 15-18% of spontaneuos abortions
Approximately 75% have two sets of paternal
chromosomes, probably due to polyspermy , fertilization by
two sperms .
• Two types:
- Digynic ; the extra chromosomal set is maternal.
- Diandric ; the extra set is paternal .
• Fetal wastage skeleton more than cephalic, 2% survive to
be recognized
• Genital and CNS abnormalities
Types of Structural Chromosomal
abnormalities
• Structural abnormalities either :
* Balanced (usually normal phenotype) :
- Translocations
- Inversions
* Unbalanced (abnormal phenotype) :
– Deletions
– Duplications
– Insertions
– Rings
– Isochromosomes
Crossing Over
• Crossing over is the exchange of genetic
material between homologous chromosomes
leading to increased genetic variations .
• During miosis , the pair of homologous
chromosomes should be paired exactly so that
each gene should face the homologous gene
in the other chromosome , so the exchanged
material is equal .
Unequal Crossing Over
Deletions
Isochromosome
Ring chromosome
Duplications
Robertsonian translocation
Inversions