Objective 1 – Characterize Chromosome Disorders

Chromosome Disorders

Defect due to an abnormality in chromosome number or structure

Structure of the genes in chromosome disorders may be normal, but the genes may be present in multiple copies or be situated on a different chromosome

Leading known cause of mental retardation and miscarriage

A major chromosome aberration occurs in at least 1 in 12 conceptions

Estimated at 50% of 1^st Trimester spontaneous abortions have major chromosome aberrations

1 in 150 births have a diagnosable chromosome abnormality

POLYPLOIDY

Euploid Cells

Cells with a multiple of normal number of chromosomes
Haploid and Diploid Cells are both euploid cells

Polyploidy

When a euploid cell has more than the diploid number of chromosomes

Liver, bronchial and epithelial tissues are normally polyploid

A zygote having three copies of each chromosome rather than the usual two has a form of polyploidy called triploidy

When euploid cells have 92 chromosomes the condition is called tetraploidy

Both triploidy and tetraploidy are incompatible with life

ANEUPLOIDY

A somatic cell that does not contain a multiple of 23 chromosomes

Trisomy – a cell containing three copies of one chromosome

Monosomy – the presence of only one copy of a given chromosome in a diploid cell

Disjunction – the normal separation and migration of chromosomes during cell division

Nondisjunction – failure of disjunction in a meiotic division resulting in one daughter cell receiving both homologous chromosomes and the other receiving neither. Primary cause of aneuploidy.

ABNORMALITIES OF CHROMOSOME STRUCTURE

Deviations in normal structure of chromosomes result from the chromosome material breaking and reassembling in an abnormal arrangement
Structural abnormalities include deletion, duplication, inversion, or translocation
Deletion

Loss of a portion of a chromosome
Can be at the end of a chromosome or in the middle
Most common example is Cri-du-chat syndrome

Term means “cry of the cat”
Describes the characteristic cry of the child
Other sx – low birth weight, severe mental retardation, microcephaly, heart defects, and typical facial expression (see page 47)
Caused by a deletion of part of the short arm of Chromosome

Duplication

Presence of a repeated gene or gene sequence
Have less serious consequences than deletion

Inversion

The reversal of gene order
No loss or gain of genetic material occurs, so inversions are balanced
Often have no apparent physical effect
Can cause serious problems in offspring of individuals carrying the inversion due to duplications or deletions transmitted to the offspring

Translocation

The transfer of part of one chromosome to a nonhomologous chromosome
Occurs when two chromosomes break and the segments are rejoined in an abnormal arrangement

Objective 2 – Cite Examples of Chromosome Disorders

DOWN SYNDROME

Best known example of aneuploidy in an autosome is trisomy of the 21^st chromosome which causes Down syndrome
Occurs 1 in 1000 births
May result when nondisjunction of chromosome 21 occurs at meiosis, producing one gamete with an extra chromosome 21 and one gamete with no chromosome 21. Union of the extra chromosome female gamete with a normal sperm produces a 47 chromosome zygote, or trisomy 21
Principle features on page 44-45
Risk of having a child with Down syndrome increases greatly with maternal age, risk greater after age 35 and still greater after age 45

TURNER SYNDROME

sex chromosome aneuploidy disorder
Occurs in the female
Most common karyotype showing female phenotype is 45, X
See pages 44-45 for characteristics

KLINEFELTER SYNDROME

Sex chromosome aneuploidy disorder
Occurs in the male
Most common karyotype showing female phenotype is 47, XXY
See pages 44-45 for characteristics

Objective 3 – Characterize and Cite Examples of Single-gene Disorders

SINGLE GENE DISORDERS

An inherited gene may be present on one or both chromosomes of a pair
The pedigree patters of inherited traits are dependent on whether the gene is located on an autosomal chromosome, any chromosome other than a sex chromosome, or the X chromosome and whether the gene is dominant or recessive
These factors allow four basic patterns of inheritance for single gene traits, whether normal or abnormal: autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive
Autosomal dominant

abnormal allele is dominant and the normal allele is recessive.
Principles are:

1. affected persons have an affected parent
2. affected persons mating with normal persons have affected and unaffected offspring in equal proportion
3. males and females are equally affected

Autosomal recessive

Abnormal allele is recessive
Principles are:

The trait usually appears in siblings only, not in parents
Males and females are equally affected
For parents of one affected child, the recurrence risk is one in four for every subsequent birth
Both parents of an affected child carry the recessive allele
The parents of the affected child my be cosanguineous or blood relatives

X-linked dominant

Traits expressed in the male (father)
Disorders are rare
Affected male transmits the gene to all of his daughter and none to his sons
Affected female my transmit the gene to offspring of either sex

X-linked recessive

Males are predominantly affected
Affected males cannot transmit the gene to sons but transmit the gene to all daughters
Sons of female carriers have a 59% risk of being affected
Daughters of female carriers have a 50% risk of being carriers

SINGLE GENE DISORDERS

Huntington Disease

One of the best-known autosomal dominant diseases
Neurologic disorder that exhibits progressive dementia and increasingly uncontrollable movements of the limbs
Symptoms are not usually seen until after age 40
Those who develop the disease often have had children before they are aware they have the disease

Neurofibromatosis or Recklinghausen disease

An example of variable expressivity
Can vary from a few harmless “café au lait” spots on the skin to numerous malignant neurofibromas, scoliosis, seizures, gliomas, neuromas, hypertension and mental retardation

Cystic fibrosis

Autosomal recessive disease
Defective transport of chloride ion leads to a salt imbalance that results in secretions of abnormally thick, dehydrated mucous
Digestive organs especially the pancreas become obstructed with mucous, resulting in malnutrition
Lung airways tend to become clogged with mucous, making them highly susceptible to bacterial infections
Death from lung disease or heart failure occurs before 30 years in about one-half of those with cystic fibrosis

Duchenne muscular dystrophy

Most common and severe of all X-linked recessive disorders
Characterized by progressive muscle degeneration
Unable to walk by age 10 or 12
Also affects the heart and respiratory muscles, and death because of respiratory or cardiac failure may occur before age 20

Objective 4 – Characterize Multifactorial Inheritance and Cite Examples

MULTIFACTORIAL INHERITANCE

Not all traits are produced by single genes
Some traits are the result of several genes acting together – polygenic
When environmental factors also influence the expression of the trait, the term multifactorial inheritance is used
Both genes and environment contribute to variation in traits
Multifactorial disorders tend to cluster in families
A certain threshold of liability must be crossed before multifactorial disease is expressed
An example of a threshold trait is pyloric stenosis

Disorder characterized by narrowing or obstruction of the pylorus
Chronic vomiting, constipation, weight loss and electrolyte imbalance can result
More common in males
More common in males because the threshold of liability is much lower in males than in females

Other multifactorial diseases include cleft lip and/or cleft palate, neural tube defects, club feet, and some congenital heart diseases
Hypertensive heart disease and diabetes mellitus likely can be grouped in the category of multifactorial disorders
Refer to page 59 for Criteria used to define multifactorial diseases