1. DR. ERNEST K. ADJEI FRCPath. DEPARTMENT OF PATHOLOGY SMS-KATH
GENETIC DISEASES I
DR. ERNEST K. ADJEI FRCPath.
DEPARTMENT OF PATHOLOGY
SMS-KATH

2. GENETIC DISEASES I
Human diseases can be classified under 3 main categories.
* Genetically determined
* Environmentally determined
* Interplay of both environmental and genetic factors
Definitions:
Hereditary disorders: Diseases which are transmitted through gametes of both parents to offspring. They run in families and hence are called familial disorders.
Congenital simply means born with the disease or the disease is present at birth. Eg. Spinal bifida, Autosomal Recessive PCKD.

3. Mutation. MUTATION: A permanent change in the genomic sequence of DNA.
Single gene mutations xterise mendelian disorders
Types of mutations:
*Point mutation: The substitution of a single nucleotide base by another base. Eg, in sickle cell disease where valine replaces glutamic acid at position 6.
-Missense point mutation: when a point mutation alters the meaning of the genetic code.
-Nonsense point mutation: when a point mutation changes the amino acid codon to a termination codon.
* Frame shift mutation: When there is insertion or deletion of one or two base pairs which alters the reading frame of DNA strand.
What about three pairs?

4. mutation
* Trinucleotide repeat mutations: It is as a result of sequential repeats of three nucleotides. This results in amplification of the nucleotides. Eg fragile X-syndrome.
Mendelian disorders (diseases of single gene defects)
These are diseases which follow the mendelian pattern of inheritance. There are three basic forms;
* Autosomal dominant
* Autosomal recessive
* X-linked disorders (sex linked disorders).

5. Mendelian disorders
Autosomal dominant disorders: Generally are manifested in the heterozygous state, at least one parent should have the condition. Both females and males are affected equally and both can transmit the disorder.
Other characteristics:
Some patients do not have affected parents. Mutation affected sperm or ovum. Siblings are not at any risk of the disease.
Clinical features can be modified by reduced penetrance to the extent that some individuals may inherit the mutant gene but are normal phenotypically. Eg Neurofibromatosis type 1.

6. Autosomal dominant disorders.
Most cases manifest clinical signs and symptoms during adulthood.
When an affected person marries a normal person, each of the children have 1 out of two chances of being affected.
A 50% reduction of normal gene product will lead to clinical expression of the disease.
Usually affects key structural proteins (nonenzymatic proteins). Eg collagen, Membrane receptors and transport proteins (eg LDL receptor gene mutation in familial hypercholesterolemia).
Eg of AD disorders: Adult polycystic kidney disease, familial hypercholesterolemia, Marfan syndrome, neurofibromatosis etc.

7. Autosomal recessive
AR disorders are the largest group of Mendelian disorders. They occur when mutation affects both alleles of a gene.
They have the following features:
Parents are usually not affected but are carriers of the defective gene.
Siblings have one chance in four of being affected.
Rare AR diseases usually manifest in consanguineous marriages.
Complete penetrance is common.
Unset is usually early (congenital or early childhood).

8. Autosomal recessive disorders
The expression of the defect usually tends to be more uniform than in AD.
AR disorders usually affect enzyme proteins.
Eg of AR disorders: Cystic fibrosis, Wilson disease, Sickle cell anemia etc.

9. X-linked disorders Most sex linked disorders are on the X chromosome.
They are usually recessive and have the following characteristics:
They are transmitted from mothers to sons
Heterozygous females rarely expresses the full phenotypic change (except in cases of inactivation of the normal X).
An affected male does not transmit the disorder to sons but all daughters are carriers.
Eg Hemophilias A and B, Duchenne muscular dystrophy, fragile X-syndrome etc.

10. Multifactorial disorders.
Polygenetic disorders are determined by minor additive effects of two or more genes with nongenetic (environmental) influences. Eg height, weight, hair colour etc.
The risk of the disease in siblings is conditioned by parents having severe form of the disease.
The rate of occurrence of the disorder is the same for all first degree relatives
The risk of identical twins being affected is higher than in non-identical.
Eg. Diabetes mellitus, hypertension, schizophrenia, bipolar disorders etc.

11. Group work and presentations.
Diseases caused by mutations in structural proteins. Eg. Marfan syndrome, Ehlers-Danlos syndrome.
Diseases caused by mutations in receptor proteins. Eg. Familial hypercholesterolemia.
Diseases caused by mutations of enzyme proteins. Eg. Phenylketonuria, galactosemia, lysosomal storage diseases, Glycogen storage diseases.
Diseases caused by mutations in proteins that regulate cell growth. Eg Neurofibromatosis 1 and 2.