1. Genetic Disorders & Diseases
Types
&
Inheritance

2. 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

3. 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

4. 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

5. Chromosomal Disorders in number of chromosomes Change in the structure
Numerical
Structural
Increase or Decrease
in number of chromosomes
Change in the structure
of chromosomes
Euploidy
Aneuploidy

6. Aneuploidy Euploidy Increase in the total Increase or decrease in
set of chromosomes
e.g. 3N or 4N
Increase or decrease in
one or more chromosomes.
e.g. 2N + 1, 2N - 1
-Triploidy (69 chromosomes)
found in cases of
spontaneous abortions
-Trisomy (46+1) chromosomes
(Down Syndrome)
-Monosomy (46-1) chromosomes
(Turner Syndrome)

7. Non-Disjunction

8. Triploidy (69, XXY)

9. 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

10. 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

11. Multifactorial Disorders
Congenital
malformations
Common disorders
of adult life.

12. 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

13. Inborn Errors of Metabolism
⇒ 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.

14. ⇒ Single Gene Disorders
ENZYME
A B C

15. ⇒ 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 intermediates from alternative metabolic pathways
Decreased ability to synthesize essential compounds
Defects in energy production

16. Inheritance of inborn errors of metabolism
⇒ 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.

17. ⇒ Inheritance of inborn errors of metabolism
⇒ 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.

18. 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.

19. 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)

20. Techniques For Prenatal Diagnosis
Ultrasonography:
It is safe and performed in the second trimester
Amniocentesis:
Procedure risk : It has 0.5-1% of risk during procedure
Performed in second trimester
Widely available
Chorionic villus sampling
Procedure risk : 1-2 %
Performed in first trimester
Specialized technique
Cordocentesis
Procedure risk: 1%

21. ⇒Techniques For Prenatal Diagnosis continued
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:
High risk
Severe disorder
Treatment not available
Reliable prenatal test available
Accepted to parents

22. 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.

23. 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.

24. 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

25. ⇒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.

26. 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??

27. 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)

28. Examples of Genetic
Diseases

29. 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

30. 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

31. Examples of Multifactorial disorder
Incidence
Cleft lip/ Cleft palate
1/250 – 1/600
Congenital heart disease
1/125 – 1/250
Neural tube defects
1/100 – 1/500
Coronary heart disease
1/15 – Variable
Diabetes mellitus
1/10 – 1/20
Cancer
variable

32. Mitochondrial Disorders
Lebers hereditary optic neuropathy

33. E. Acquired somatic genetic disorders
Some forms of cancer