Genetic Diseases Lecture 10

Classification of Human Diseases

• Human diseases can be classified into three categories: genetically determined, environmentally determined, and genetically and environmentally determined diseases.

Classification of Genetic Diseases

• Genetic diseases can be classified into three categories: chromosomal disorders, single gene disorders, and multifactorial disorders.

Chromosomal Disorders (Cytogenic)

• Chromosomal disorders arise from chromosomal alterations, either numeric or structural abnormalities, affecting autosomes or sex chromosomes.
• They are a major category of genetic diseases, responsible for early abortions, congenital malformations, and mental retardation.

Numeric Abnormalities

• Euploid: the normal number of chromosomes for a species, which is 46 (diploid) in humans, with the exception of unfertilized egg and sperm, which is 23 (haploid).
• Polyploid: chromosome numbers such as 3n and 4n, which generally result in spontaneous abortion.
• Aneuploid: any number that is not an exact multiple of n, including mosaicism.
• Mosaicism: the presence of two or more populations of cells with different complements of chromosomes in the same individual, common in sex chromosomes, but rare in autosomal chromosomes due to early fetal death and spontaneous abortion.

Structural Abnormalities

• Result from chromosomal breakage followed by loss or rearrangement of the broken part.
• Diagnosed using cytogenetic mapping, which divides the short arm (p) and the long arm (q) of a chromosome into numbered regions and bands.
• Types of structural abnormalities:
  • Translocation: the transfer of a part of one chromosome to another chromosome, of two types:
    • Balanced reciprocal translocation: the exchange of chromosomal material between two chromosomes, with no net gain or loss of genetic material (e.g., 46,XX,t(2;5)(q31;p14)).
    • Centric fusion translocation (robertsonian): a special pattern of translocation involving two acrocentric chromosomes, typically resulting in one very large chromosome and one extremely small one, with the short fragments lost, and the carrier having 45 chromosomes.
  • Congenital malformations, such as horseshoe kidney, and cardiovascular abnormalities, which are the most common cause of death in childhood.
  • In adolescence, affected girls fail to develop normal secondary sex characteristics, with the genitalia remaining infantile, breast development minimal, and little pubic hair appearing.

Single Gene Disorders (Mendelian Disorder)

• Include uncommon conditions, such as storage diseases and inborn errors of metabolism, resulting from single-gene mutations of large effect.
• Follow the well-known Mendelian patterns of inheritance.
• Mutation: a permanent change in the DNA, which can be present in:
  • Somatic cells, which are not transmitted to the progeny, but are important in the causation of cancers and some congenital malformations.
  • Germ cells, which can transmit to the progeny and give rise to inherited diseases.
• The genes on each chromosome are arranged in pairs, with each gene occupying a specific location or locus, and can be:
  • Homozygous, where the two members of a gene pair are identical.
  • Heterozygous, where the two members of a gene pair are different, and the trait is expressed in the heterozygote (dominant) or only in the homozygote (recessive).

Transmission Patterns of Single-Gene Disorders

• Mutations involving single genes follow one of three patterns of inheritance:
  • Autosomal dominant.
  • Autosomal recessive.
  • X-linked.

Autosomal Dominant Disorders

• Manifested in the heterozygous state, where a single mutant allele from an affected parent is transmitted to an offspring, regardless of sex.
• Both males and females are affected, and both can transmit the condition.
• When an affected person marries an unaffected one, every child has one chance in two of having the disease.
• The gene products of autosomal dominant disorders usually are regulatory proteins of metabolism or key components of structural proteins, such as collagen.
• Examples: Marfan Syndrome, Ehlers-Danlos Syndromes.

Autosomal Recessive Disorders

• Manifested only when both members of the gene pair are mutated.
• Both parents may be unaffected but are carriers of the defective gene.
• If the mutant gene occurs with a low frequency in the population, there is a strong likelihood that the disorder is the product of a close relative marriage.
• Autosomal recessive disorders affect both sexes.
• The occurrence risk in each pregnancy is one in four for an affected child, two in four for a carrier child, and one in four for a normal (non-carrier, unaffected) homozygous child.
• The age of onset is frequently early in life.
• The symptomatology tends to be more uniform than with autosomal dominant disorders.
• The disorders are characteristically caused by deficiencies in enzymes, rather than abnormalities in structural proteins.
• Examples: phenylketonuria, lysosomal storage diseases, and Albinism.

X-Linked Disorders

• Sex-linked disorders are almost always associated with the X, or female, chromosome.
• No Y-linked diseases are as yet known.
• The inheritance pattern is predominantly recessive.
• Female heterozygotes rarely experience the effects of a defective gene.
• The common pattern of inheritance is one in which an unaffected mother carries one normal and one mutant allele on the X chromosome, transmitting the defective gene to her sons, and her daughters have a 50% chance of being carriers of the mutant gene.
• When the affected son procreates, he transmits the defective gene to all of his daughters, who become carriers of the mutant gene.
• Because the genes of the Y chromosome are unaffected, the affected male does not transmit the defect to any of his sons, who will not be carriers or transmit the disorder to their children.
• Example: hemophilia A, a haemorrhagic disorder in which blood does not clot normally, due to a lack of normal Factor VIII.