Chapter 12 Flashcards
a-1 Antitrypsin deficiency (AATD)
Aka
a-1 proteinase inhibitor deficiency
-Deficiency in ATT is inherited in an autosomal-codominant pattern in which two different versions of the gene can be expressed together and contribute to the genetic trait,
-AATD is caused by mutations in the SERPINA1 gene, which codes for the protein product a-1 antitrypsin, a neutrophil elastase.
-This powerful enzyme is produced in the liver and secreted from white blood cells to fight infection.
-If not kept in check by a-1 antitrypsin, this enzyme can target normal lung tissue, specifically destruction of the alveoli.
-It has also been associated with the hypersecretion of mucus found with chronic bronchitis.
-deficiency leads to increased risk of both lung and liver disease, although through different pathogenic pathways.
-Persons with COPD and AATD are labeled as AATD-COPD, whereas those without AATD are desig- nated as AAT-replete COPD. The different nomenclature allows clinical questions that focus on detection in at-risk populations, diagnostic testing, and clinical evaluation with treatment as necessary
a-1 Antitrypsin Genotype
MM- Results in normal concentrations of AAT
MZ- Heterozygotes have a slightly increased risk of poor lung function.
SZ- A higher risk of lung problems among smokers but not usually associated with increased risk in nonsmokers
ZZ- Often associated with clinical disease and a plasma concentration of AAT that is less than 20% of normal
Hereditary hemochromatosis (HFE-HHC)
-associated with excessive absorption of dietary iron by the gastric mucosa.
-This excess iron accumulates in the skin, liver,pancreas, heart, joints, and testes.
-Accumulation in the skin causes the affected person to have a bronzelike skin discoloration. An older name for this disorder was “bronze diaberes.”
- Type 1 HFE-HHC is inherited as an autosomal-recessive trait; people who are either homozygous or compound heterozygous are at risk.
-Remember that heterozygous means having one copy of the mutant allele. Someone who has two different mutant alleles is said to be compound heterozygous.
-Fortunately, the penetrance for HFE-HHC is quite low, so not everyone who carries the genotype will show the phenotype. This makes the biochemical rather than the genetic testing of people who are at risk most useful. What matters most is whether the person is clinically affected.
Maturity-onset diabetes of the young (MODY)
-a single-gene problem that causes hyperglycemia, usually before the age of 30, and includes 1% to 2% of persons with diabetes
-MODY is transmitted in an autosomal-dominant panern, and mutations in six differenr genes cause the six major types of MODY.
-Because MODY is transmitted as an aurosomal-dominant trait, only one copy of the defective gene is needed for a person to have the disease.
-Rarely, people are homozygous (or compound heterozygous) for mutations in one of these genes and tend ro have more severe forms of the disease.
-Those who are homozygous for defects in the gene that codes for glucokinase can have severe diabetes mellitus (DM) as a newborn (severe neonatal DM).
-Those who are homozygous for mutations in the IPF] gene, which causes MODY 4, may not grow a pancreas at all (pancreatic agenesis).
gestational diabetes mellitus (GDM)
Self tolerance
the ability of immune system cells to recognize and not attack the cells of the body in which they reside.
Systemic lupus erythematosus (SLE)
-a classic autoimmune disorder caused by immune cells attacking self-cells all over the body.
-Symptoms appear in the skin, heart, lungs, kidneys, joints, and the nervous system.
-Affected people often have a “butterfly” rash over the cheeks of the face, a patchy skin rash, light sensitivity, arthritis, ulcers of the mucous membranes, pericarditis, pleuritis, or seizures.
human leukocyte antigens (HLAs)
-coded for by the major histocompatibility complex (MHC) genes located on chromosome 6
-Remember that the HLAs function as unique identifiers on the surface of almost all cells in the body. When an immune system cell recognizes an invader, the immune cell “examines” the HLA proteins on the invader’s surface to determine if it is a self-cell or a non-self-cell.
-If the proteins do not perfectly match me body’s HLAs, men the cell is identified as foreign, and me attack begins. There are about 40 different major HlAs and an unknown number of minor HLAs.
Multiple sclerosis (MS)
- most common autoimmune disorder that involves the nervous system.
- the myelin coating of neurons is destroyed by inflammation (demyelination).
-Scattered regions of plaque found in the white matter of the central nervous system damage the myelin sheath until it becomes toO thin to allow the transmission of neural impulses from the brain to the spinal cord and periphery.
-The disease is characterized by episodes of exacerbation and remission and is the most common cause of neuro- logical disability in young people.
Rheumatoid arthritis (RA)
-a chronic and progressive autoimmune disorder that most frequently affects women and the elderly.
- considered the most common connective tissue disease
- It is two to three times more common in females.
-RA is characterized by synovitis (inflammation of the membrane that lines the joints) and production of autoantibodies. Rheumatoid factors, consisting mainly of IgA and IgM, attack tissue in the joints and cause inflammation.
Alzheimer disease (AD),
- the most common age- related cause of dementia.
-It is an irreversible disease that progresses from mild memory loss to complete incapacitation.
-Neurons lose their ability to connect, and eventually, brain cells die.
-Approximately 50% of cases of dementia are caused by AD
Age-related macular degeneration (AMD)
-most common cause of central vision loss among older people in affluent countries.
-AMD is caused by deteriora- tion of the retina that occurs with the accumulation of extracellular deposits of a protein called drusen.
-The macula, which is located in the center of the retina, controls our ability to clearly see what is central in our visual fields. That means that daiJy functions such as reading, recognizing familiar faces, and driving can be challenging if not impossible because images in the area we are trying to focus on will appear blurred.
-Two types of AMD exist. Atrophic or non-neouascularAMD, also called dry AMD, is caused by the break- down of light-sensitive cells in the macula. Although dry AMD accounts for about 85% of cases, it usually progresses slowly. Exudative or neouascularAMD is also called wet AMD, and it occurs when abnormal blood vessels grow underneath the macula and leak protein and blood. Although wet AMD accounts for only 10% of overall cases, those affected tend to have a rapid progression of the disease.
- About two-thirds of people with advanced AMD have the wet type. As with many of me adult-onset diseases we have discussed, AMD is complex. It is caused by a combination of variations in susceptibility genes and environmental factors.
age related hearing loss (ARHL)
Aka presbycusis
-a complex disorder with both genetic and environmental contribu- tions.
-The environmental contributions to age-related hearing impairment include ototoxic drugs (such as ami- noglycosides, aspirin, and loop diuretics), alcohol, tobacco intake, high-fat dietary intake, and exposure to chemicals.
Morphological Types of Presbycusis
-Sensory- Loss of hair cells and degeneration within the organ of Corti with
symmetrical high-frequency hearing loss
-Neural- Loss of neurons within the spiral ganglion and loss of nerve fibers, with diminished high-frequency hearing loss and problems discriminating speech
-Strial or metabolic- Atrophy of stria vascularis cells causing problems with K+recycling and, ultimately, hearing loss across all frequencies
-Cochlear conductive- Degenerative changes from stiffness in the cochlear duct, usually causing low-frequency hearing loss
-Mixed- Combination of all types; low-tone loss due to loss of cochlear neurons and decreased stria vascularis, and high-frequency tone loss due to loss of outer hair cells
-Intermediate presbycusis- Changes in cilia and mechano-electrical transduction channels
Summary pt 1.
Common adult-onset diseases are usually complex, involving conrribucions from both genes and the environment. Because environmental exposures increase over time, environmental contributions clearly become much bigger factors in disease onset as we age. The good news is that for many of these diseases, particularly those associated with aging, making lifestyle changes can have an impact on age at disease onset and overall disease severity. Maintaining a healthy weight, exercising, and eating well seem to have a significant impact on risk for many of the complex adult-onset disorders, including DM and age-related vision and hearing impair- ment. For others, such as the autoimmune disorders, making lifestyle changes has a less clear impact. For the rare, single-gene disorders, early diagnosis can lead to protective therapies, such as phlebotomy for people with hemochromatosis. As genetic/genomic knowledge progresses, options for both protective and therapeutic interventions for use by professionals and patients will also increase. However, much work remains to be done.
