Genetic Disorders &
Diseases
Types
&
Inheritance
Genetic Disorders & Diseases
MUTATIONS
(in the: Genome, Chromosome or Gene)
GENETIC DISORDER
in the form of
decrease or increase in the amount of genetic material
Or, abnormal genetic material

LEADING TO
Increase or decrease in the amount of gene products (proteins)
OR, Defective function of the protein
CLINICAL MANIFESTATIONS
of
GENETIC DISEASES
Types of Genetic Diseases
Some genetic disorders are entirely environmental and others are wholly genetic
1- Single Gene Disorders
2- Chromosomal Disorders
3- Multifactorial Disorders: used to describe the aetiology of the
disorders
4- Mitochondrial Disorders
5- Acquired Somatic Genetic Diseases
Chromosomal Disorders
•Result from defect in:
number (i.e. Numerical Disorders) of chromosomes
OR structure (i.e. Structural Disorders) of chromosomes
• Example: Trisomy 21 (Downs syndrome)
• These disorders are quite common and affect about 1/800 live born infants
• Account for almost half of all spontaneous first-trimester abortions
• Do not follow Mendelian pattern of inheritance
Chromosomal Disorders
Numerical
Structural
Increase or Decrease
in number of chromosomes
Change in the structure
of chromosomes
Euploidy
Aneuploidy
Euploidy
Increase in the total
set of chromosomes
e.g. 3N or 4N
-Triploidy (69 chromosomes)
found in cases of
spontaneous abortions
Aneuploidy
Increase or decrease in
one or more chromosomes.
e.g. 2N + 1, 2N - 1
-Trisomy (46+1) chromosomes
(Down Syndrome)
-Monosomy (46-1) chromosomes
(Turner Syndrome)
Non-Disjunction
Triploidy (69, XXY)
Mitochondrial Disorders
Effect generally energy metabolism.
Effect more those tissues which require constant supply of energy
e.g. muscles.
Show maternal inheritance:
Affected females transmit the disease to all their children (boys & girls)
 Affected males have normal children (boys & girls)
Males cannot transmit the disease as the cytoplasm is inherited only from
the mother & mitochondria are present in the cytoplasm
•
Multifactorial Disorders
• Interaction between environmental & genetic factors.
• Polygenic in nature, no single error in the genetic information.
• 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.
• Examples: Obesity, DM, Hypercholesterolemia, Hypertension
•Account for the majority of morbidity and mortality in developed
countries
Multifactorial
Disorders
Congenital
malformations
Common disorders
of adult life.
Single Gene Disorders
• Caused by mutation in only one gene
• Can lead to critical errors in the genetic information
(lead to inborn errors of metabolism)
• Follow Mendelian Inheritance
• Occur at a variable frequency in different population
• Over 7,000 single gene disorders have been identified.
• May be - Autosomal
- Sex-linked
⇒ Single Gene Disorders
Inborn Errors of Metabolism
Also called, Inherited metabolic diseases or congenital
metabolic diseases.

 They are a large group of genetic disorders, resulting in
metabolic defects due to a single gene mutation which
leads to
 Reduced or absent gene product or
 Production of a different protein with abnormal
function.
⇒ Single Gene Disorders
ENZYME
A
C
B
⇒ Single Gene Disorders
General Effects of Inborn Errors of Metabolism
 Accumulation of a substrate or its metabolic derivatives
that are harmful or may interfere with normal function of
cells.
 Accumulation
of
metabolic pathways
intermediates
from
alternative
 Decreased ability to synthesize essential compounds
 Defects in energy production
⇒ Single Gene Disorders
Inheritance of inborn errors of metabolism
 Most of the inborn errors of metabolism are inherited as
 Autosomal recessive or X-linked disorders in nuclear DNA
 Few are inherited as autosomal dominant.
 Some may involve mitochondrial functions as they are linked to mt-
DNA.
 The incidence of these diseases within different racial and ethnic
groups varies with predominance of certain inborn errors of
metabolism within particular groups.
 Some of these diseases occur in large numbers in communities in
which consanguinity is common.
⇒ Single Gene Disorders
⇒ Inheritance of inborn errors of metabolism
 Inborn errors of metabolism are important causes of illness in
children
 They may present as acute life-threatening illness in the
neonatal period or become apparent later in childhood
 Rarely, clinical presentation is delayed until adult life.
Inherited disorders may be detected in different stages
during life

Heterozygote carriers of a disease:
It may be found during screening (as such performed on family members of a patient with
muscular dystrophy).
 Before birth (intrauterine)
Some inherited disorders can be detected before birth (as cystic fibrosis).
 Neonatal (newborn) screening (in first days of life)
As for phenylketonuria
 In neonates (in first weeks of life)
Many disorders involving single gene defects become apparent clinically (give symptoms
& signs).
 Some disorders such as familial hypercholesterolemia may not be recognized until adult
life.
Before birth diagnosis of inherited metabolic diseases
 Prenatal diagnosis is important in detecting and preventing genetic diseases
 Prenatal screening of inherited metabolic disorders is done by demonstrating the
metabolic defects by chorionic villus biopsy (in first trimester) & cultured fetal
fibroblasts obtained by amniocentesis (in second trimester)
 Screening is indicated in:
- Women with previously affected infant
- Ethnic groups thought to have a high incidence of the carrier state
-------------------------------------------------------------------------N.B. prenatal screening for chromosomal abnormalities is also performed (e.g. serum α- fetoprotein
concentration for diagnosis of fetal neural tube defects & in Down’s syndrome)
Techniques For Prenatal Diagnosis
1. Ultrasonography:
It is safe and performed in the second trimester
2.



Amniocentesis:
Procedure risk : It has 0.5-1% of risk during procedure
Performed in second trimester
Widely available
3.



Chorionic villus sampling
Procedure risk : 1-2 %
Performed in first trimester
Specialized technique
4.



Cordocentesis
Procedure risk: 1%
Performed in second trimester
Specialized technique
⇒Techniques For Prenatal Diagnosis continued
5.




Fetal tissue biobsy
Procedure risk > 3%
Performed in second trimester
Very specialized technique
Limited application
General Criteria For Prenatal Diagnosis
Criteria of the disorder to be diagnosed prenatally:
1.
2.
3.
4.
5.
High risk
Severe disorder
Treatment not available
Reliable prenatal test available
Accepted to parents
Before birth diagnosis of inherited metabolic diseases
(cont.)
1- Prenatal Diagnosis (chrorinic villus biopsy)
 At earlier stage of pregnancy than amniocentesis: (from 10th week of
pregnancy, first trimester)

Biopsy can be used for karytyping and gene probe diagnosis.

It takes ~ 10 days

It has been applied particularly for
 Hemoglobinpathies (e.g. sickle cell disease, etc)
 cystic fibrosis
 Duchene's muscular dystrophy.
Before birth diagnosis of inherited metabolic diseases
(cont.)
2-
Prenatal Diagnosis (amniocentesis)
 Carried out at about 15th week of pregnancy (second
trimester) from amniotic fluid for cytogenic reasons
(e.g. detect chromosomal disorders as Down’s syndrome)
 Diagnosis is usually made on the basis of enzyme studies
carried out on fibroblasts cultured from the amniotic fluid.
Screening of Newborns
 Programmes for screening all newborns for certain metabolic disorders are
performed with the following criteria:
1- The disease should not be clinically apparent at the time of screening
2- The disease should have a relatively high incidence in the population
screened.
3- The disease should be treatable & so results of screening test must be
obtained before irreversible damage is likely to have occurred.
4- Screening test should be simple (qualitative) & reliable.

Examples of screening programmes:
Phenylketonuria
Congenital hypothyroidism
Galactossemia
⇒Screening of Newborns
 A positive
screening qualitative test result should be confirmed by
quantitative analysis
 In a second positive test, the individual might be required to be reassessed
after a period of time in some cases.
In Neonates & Infants
 Clinical features are often nonspecific and include failure to thrive, feeding
difficulties, vomiting, hypotonia and fits, etc…
 There may be symptom-free period after birth
 It is very important to establish whether there is a relationship between onset
of disease and changes in feeding patterns (e.g. galactosemia after
introduction of milk).
 So what about role lab investigations in diagnosis??
Laboratory investigations for neonates & infants
1- Basic investigations:

Carried as a part of normal care of a risk infant

Nonspecific as determination of plasma glucose & blood gases

May show results consistent with inherited metabolic disease.
2- Metabolic tests:

Provide an additional evidence

The measurement of specific metabolites

Determination of enzyme activity (of the enzyme responsible for the
inherited metabolic disorder).

May be a part neonatal screening i.e. for phenylketonuria in first days of
life
3- Sequencing of the specific gene (molecular genetic techniques):

Using PCR and gene sequencer, etc….(Molecular Genetics)

Karytyping may help in some cases: (chromosomal study, cytogenetics)
Examples of Genetic
Diseases
A.Single-gene Disorders
- Adenosine deaminase deficiency
- Alpha-1-antitypsin deficiency
- Cystic fibrosis
- Duchenne muscular dystrophy
- Familial hypercholesterolemia
- Hemophilia A and B
- G-6-PD deficiency
- Phenylketonuria
- Sickle cell anaemia
- Thalassaemia
C. Multifactorial Disorders
(i) Congenital malformation
- Cleft lip and cleft palate
- Congenital heart disease
- Neural tube defects
(ii) Adult onset disease
- Cancer (some)
- Coronary artery disease
- Diabetes mellitus
Examples of Multifactorial disorder
Disorder
Incidence
Cleft lip/ Cleft palate
1/250 – 1/600
Congenital heart disease
Neural tube defects
1/125 – 1/250
1/100 – 1/500
Coronary heart disease
1/15 – Variable
Diabetes mellitus
1/10 – 1/20
Cancer
variable
D.Mitochondrial Disorders
Lebers hereditary optic neuropathy
E. Acquired somatic genetic disorders
Some forms of cancer