Genetic Diseases and Chromosome Structure

• Genetic diseases are caused by alterations within chromosomes

Chromosome Structure

• A chromosome contains DNA, which is very tightly wound
• The DNA double helix can be observed many times
• Histones are proteins that DNA wraps around

Genes

• Genes are units of hereditary information found at a fixed position (locus) on a chromosome
• Genes direct the synthesis of proteins

Classification of Genetic Diseases

• Chromosomal disorders (cytogenic)
• Single-gene disorders (unifactorial or Mendelian disorder)
• Multifactorial disorders

Chromosomal Disorders

• Chromosomal disorders arise from numerical or structural abnormalities in chromosomes, affecting autosomes or sex chromosomes
• These disorders are a major cause of early abortions, congenital malformations, and mental retardation
• 1 in 200 newborn infants have some form of chromosomal abnormality and even more fetuses do not survive to term.
• Mitosis results in 2 identical diploid cells -Meosis results in 4 genetically different haploid cells

Numeric Abnormalities

• Euploid is the normal number of chromosomes for a species
• In humans, the euploid number is 46 (diploid = 2n) -Unfertilized eggs and sperm have 23 (haploid =1n)
• Euploid is the exact multiple of the haploid number
• Polyploid chromosome numbers are 3n and 4n, generally resulting in spontaneous abortion
• Aneuploid is any number that is not an exact multiple of n
• Aneuploidy involves abnormal numbers of chromosomes such as 45 or 47, when 46 is standard
• The chief causes of aneuploidy are nondisjunction, where a homologous pair of chromosomes fails to separate during the first meiotic division
• Failure of sister chromatids to separate during the second meiotic division also leads to aneuploidy
• Nondisjunction at meiosis results in gametes with an extra chromosome (n + 1) or one less chromosome (n - 1)
• Fertilization of such gametes results in trisomic (2n + 1) or monosomic (2n - 1) zygotes
• Mosaicism is the presence of two or more cell populations with different chromosome complements in the same individual
• Mosaicism affecting sex chromosomes is common
• Autosomal mosaicism commonly causes early fetal death and spontaneous abortion

Structural Abnormalities

• Structural abnormalities result from chromosome breakage followed by loss or rearrangement
• Cytogenetic mapping is used to diagnose structural abnormalities with short (p) and long (q) chromosome arms being divided into numbered regions to the centromere
• 2q34 indicates chromosome 2, long arm, region 3, band 4

Types of Structural Abnormalities

• Translocation involves the transfer of a chromosome part from one to another
• Balanced reciprocal translocation involves the exchange of chromosomal material between two chromosomes with no net loss or gain of genetic material
• Translocations are denoted by t, followed by chromosomes in numeric order (e.g., 46,XX,t(2;5)(q31;p14))
• This reciprocal translocation involves chomosome 2, long arm (q) region 3, band 1, and the short arm © of chromosome 5 region 1, band 4
• Balanced reciprocal translocation carriers are generally unharmed with a normal number of chromosomes
• Unbalanced gametes can form during gametogenesis, resulting in abnormal zygotes
• Centric fusion translocation (Robertsonian translocation) is a special translocation pattern involving two acrocentric chromosomes
• Breaks occur near centromeres affecting the short arms of chromosomes
• The segment transfer results in one very large and an extremely small chromosome
• The fragments are lost and the carrier has 45 chromosomes
• The short arms of acrocentric chromosomes have highly redundant genes causing this loss to be compatible while unbalanced gametes lead to abnormal offspring.
• Isochromosomes result when the centromere divides horizontally rather than vertically, one arm is lost, and the remaining arm is duplicated
• This results in a chromosome with either two short or two long arms only
• Deletion involves loss of chromosome portion:
• A single break may delete a terminal segment
• Two interstitial breaks result in loss of an intermediate segment after the segments are reunited
• Inversions occur with two interstitial breaks in a chromosome
• The segment reunites after complete turnaround
• A Ring chromosome:
• It is a variant of deletion
• Segments are lost from each end of the chromosome
• The arms unite to form a ring

General Features of Chromosomal Disorders:

• Chromosomal disorders can be associated with an absence of a chromosome (deletion, monosomy)
• Chromosomal disorders can be associated with excess chromosomes (trisomy), abnormal rearrangements (translocations)
• Loss of chromosomal material usually produces more severe defects than gain of chromosomal material
• Excess chromosomal material may arise from a complete chromosome (trisomy) or part of a chromosome (Robertsonian translocation)
• Imbalances of sex chromosomes are tolerated better compared to similar autosomal imbalances
• Sex chromosome disorders may not be detected at birth
• Infertility is a mainfistation that can arise from sex chromosome disorders can be diagnosed in adolescence

Cytogenetic Disorders Involving Autosomes

• Trisomy 21 (Down Syndrome) is the most common chromosomal disorder
• About 95% of affected individuals have trisomy 21, resulting in a chromosome count of 47
• Those with trisomy 21 have parents with a normal karyotype
• Maternal age strongly influences the incidence of Down syndrome It occurs mostly in women older than 45 years
• Meiotic nondisjunction of chromosome 21 usually occurs in the ovum
• Down syndrome clinical features:
• Epicanthic folds and flat facial profile
• Mental retardation
• Congenital malformations
• Cardiac malformations
• Serious infections
• Increased risk of developing acute leukemias
• Premature development of Alzheimer's disease

Cytogenetic Disorders Involving Sex Chromosomes

• Abnormal sex chromosome karyotypes, from 45,X to 49,XXXXY, are compatible with life due to limited genetic information on the Y chromosome
• Males can have two or even three Y chromosomes and are phenotypically normal
• Extra Y chromosomes are well-tolerated, because information on the Y chromosome is mainly related to male differentiation
• The very presence of Y dictates a male phenotype, regardless the number of X chromosomes.
• Klinefelter Syndrome is male hypogonadism with at least two X chromosomes and one or more Y chromosomes
• The majority of patients have 47, XXY
• This karyotype is from nondisjunction of sex chromosomes during meiosis
• Advanced maternal age and a history of parent irradiation can contribute to meiotic error
• 15% of Klinefelter patients show mosaic patterns
• Clinical manifestations of Klinefelter syndrome:
• Only expressed as hypogonadism
• Gigantism
• Reduced facial, body, and pubic hair
• Gynecomastia (breast development)
• Markedly reduced testes size (testicular atrophy)
• Sterility occurs due to impaired spermatogenesis
• Mild mental retardation
• Turner Syndrome is primary hypogonadism in phenotypic females. It is also monosomy of the X chromosome, resulting in a 45, X karyotype
• Key Traits:
• Significant growth retardation leads to short stature
• Swelling of the neck due to distended lymphatic channels (in infancy)
• Low posterior hairline
• Wide chest with widely spaced nipples
• High-arched palate
• Problems in lymph system (lymphedema in hands and feet)
• Congenital malformations like horseshoe kidney
• Cardiovascular abnormalities (common cause of childhood deaths)
• In affected girls normal secondary sex characteristics are not developed upon reaching adolescence; genitalia remains infantile with minimal breast development, along with little pubic hair

Single Gene Disorders

• Single gene disorders include many uncommon disorders such as storage diseases and inborn errors of metabolism
• Single gene disorders follow Mendelian inheritance patterns
• A mutation is a permanent change in the DNA
• Mutation refers to disturbances in the nucleotide sequence arrangement
• A mutant gene may be present on somatic cells (not transmitted to progeny, but linked to cancers and congenital malformations, or germ cells which transmit to successive generation.

Mutation Info

• A mutation can affect one member of an autosomal gene pair or both
• Genes in chromosome pairs are arranged in strict order and occupying a location or locus
• These gene pairs are called alleles
• Two members of a gene pair are two alleles with one inherited from the mother and another from the father.
• If the members of a gene pair are identical then the person is homozygous,
• If the members are heterozygus then the person is heterozygous
• If a trait is expressed in a heterozygote, it is dominant or if it is only expressed in a homozygote, it is recessive
• Single-gene mutations follow one of three inheritance patterns
• Autosomal dominant
• Autosomal recessive
• X-linked

Autosomal Dominant Disorders

• Autosomal dominant disorders manifest in the heterozygous state where a single mutant allele originates from an affected parent
• Both males and females are affected and transmit the condition
• When an affected person marries an unaffected person, a child has one out of two chances of inheriting the disease (50%)
• Certain disorders present delayed age of onsets where effects are delayed until later in life
• Gene products of autosomal dominant disorders are usually:
  • Regulatory proteins of metabolism
  • Key components of structural proteins such as collagen
• An example of autosomal dominant diseases is Marfan Syndrome Symptoms Include:
  • It is caused by a mutation in a gene encoding fibrillin which is required for the structural integrity of tissues
  • Affected tissues are the skeleton (tall stature, long fingers), eyes, and cardiovascular system
  • The mutation in a gene that encodes collagen results in the collagen defects Clinical features include:
  • Fragile
  • Hyperextensible skin
  • Hypermobile joints
  • Poor wound healing

Autosomal Recessive Disorders

• Autosomal recessive disorders are only manifested when both gene pairs are mutated, both parents are carriers of the defective gene
• These disorders affect both sexes
• There is a 25% chance for a child to be affected if both parents are carriers
• There is a 50% chance for a child to only be a carrier, unnaffected
• There is a 25% chance that offspring will be not be a carrier or affected
• Age of onset is frequently early in life with uniform symptomatology compared to autosomal dominant
• Autosomal recessive are caused by deficiencies in enzymes, almost including all inborn metabolism errors
• Enzyme disorders include:
  • Impaired metabolic pathways that may result in an accumulation of phenylketonuria, caused by a lack of phenylalanine hydroxylase Clinical features include:
  • Mental retardation
  • Seizures
  • Decreased skin pigmentation
  • Restricted phenylalanine intake in the diet
• Another enzyme disorder is the accumulation of cellular constituents e.g., characterized as a inherited lack of lysosomal enzyme so the catabolism of the substrate remains incomplete. Results in partially degraded insoluble metabolites.
• Albinism is an autosomal recessive disease characterized by a lack of pigmentation of the skin, hair, and eyes
• Homozygous recessive individuals generate no pigments
• Cannot create brown pigment melanin through albinism
• Is caused by lack of one or another enzyme along the melanin-producing pathway It can be caused by an inability of that enzyme to enter pigment cells and convert tyrosine to melanin

X-Linked Disorders

• Sex-linked disorders are almost always associated with the X or female chromosome with one or more Y chromosomes
• There are no known Y linked diseases
• The inheritance is predominantly recessive where a male who only has one X chromsome is more likely to inherit it, while females who have two X chromosomes need both to be affeced for the diseases traits to be apparent, if only one gene is affected, the female would be classified as just a carrier of the mutation
• Unaffected mothers cary one mutant allele on the X chromosome (abnormal gene), and have 50% chance of transmitting to her sons(affected)
• All the carrier affects the daughters(carriers of gene and possible mutation)

Genetic Traits

• Multifactorial inheritance involves genetic and environmental factors to influence the expression of a phenotypic characteristic
• Multifactorial inheritance can be seen in traits relating to height, weight, and hair color and diseases related to hypertension, diabetes mellitus, schizophrenia and congenital heart disease
• Physiologic traits as well as pathologic traits may result from multiple gene interactions and environmental, non-genetic influences
• Results may vary even amongst monozygotic twins due to environmental influences related to nutrition