Chapter+3+Genetic+and+Congenital+Disorders+2024.docx

Chapter 3: Genetic and Congenital Disorders Background: Normal chromosome number is 46 (diploid) 23 from each parent (haploid) 22 of these are autosomes (body cells, 1 is the sex chromosome (gametes) The female has XX (one from each parent) The male has XY (the X is from the mother and the Y is from...

Chapter 3: Genetic and Congenital Disorders Background: Normal chromosome number is 46 (diploid) 23 from each parent (haploid) 22 of these are autosomes (body cells, 1 is the sex chromosome (gametes) The female has XX (one from each parent) The male has XY (the X is from the mother and the Y is from the father) The sex of the child is determined by the fathers since only males contribute the Y. In the absence of the Y chromosome the ‘default’ is female Chromosomal Disorders: Chromosomal abnormalities are the leading known cause of mental retardation and miscarriage (approximately 1 in 12) Most fetuses with chromosomal abnormality do not survive to term. The number of live births with chromosomal abnormality is about 1 in 150 births. Detect these with amniocentesis at 16 weeks pregnant) Sample of amniotic fluid is obtained, and a karyotype done. Each autosome pair is matched and examined. Another test is called CVS or chronic villa sampling which is done earlier in the pregnancy (8-10 weeks), is less invasive, and is results are returned much faster than amniocentesis. Miscellaneous information There are 60 identifiable syndromes that cause 50% of all first trimester spontaneous abortions (miscarriages) These are identified by the total number of chromosomes, followed by sex chromosomes, then description of the abnormality (47, XY, +21 is a male with Down Syndrome or Trisomy 21) Causes are usually: Abnormal chromosome structure Alterations in chromosome duplication Alterations in chromosome number (examples of sex chromosome abnormality) Turner syndrome is XO, 1 in 2500 live births It is estimated that almost all fetuses with 45, X/O karyotype are spontaneously aborted in first trimester Klinefelter Syndrome is XXY, most common genetic abnormality, 1 in 500 to 1 in 1000 live male births (cats can have this) Usually no obvious signs or symptoms, but will not be able to produce sperm Some want to change the name to XXY male Alterations in chromosome number in autosomes Polyploidy-cells with multiples of the normal number are called euploid. If it is more than diploid it is called Polyploidy IF the zygote has 3 copies it is triploidy Tetraploidy has been observed (92 chromosomes) but it is not compatible with life This accounts for 10% of all known miscarriages Aneuploidy If a somatic cell doesn’t have a multiple of 23 chromosomes Monosomy (1) is when there is only 1 copy This is always lethal with autosomes Trisomy (3) is when there are 3 copies of a single chromosome Down syndrome is the most common Aneuploidy with sex chromosomes is less serious Y chromosome has less genetic material An extra X chromosome is not as noticeable because the effect is diminished but a zygote without an X will not survive. Autosomal Aneuploidy examples Trisomy can occur for any chromosome but typically only see survival with chromosomes 13, 18, or 21. Trisomy 16 is most common trisomy among miscarried fetuses, and is never seen in live births It is rare but possible to see a partial trisomy 16 (long arm of chromosome) resulting in live neonate with severe complications and short life span. The best-known example of trisomy is Trisomy 21 or Down syndrome (1 in 800 live births) Children born with this condition are mentally retarded, distinctive facial features, low nasal bridge, epicanthal folds produce an ‘Asian’ appearance, protruding tongue, flat-low set ears, poor muscle tone, short stature, congenital heart defects seen in almost ½ of these children. They also have trouble with respiratory infections and are at increased risk for leukemia By age 40 most develop Alzheimer Disease 75% of fetuses with this condition spontaneously abort or are stillborn 20% die in the first 10 years, but average life expectancy is now 60 years. In 90-95% of the cases the nondisjunction of chromosomes is caused by the mother’s egg. Risk increases with advanced age of the mother. Sex Chromosome aneuploidies are fairly common 1 in 400 males 1 in 650 females Trisomy X occurs in 1 in 1000 newborn females No obvious physical abnormalities but can have menstrual irregularities, could be sterile, or some form of mental retardation Single X is more problematic (45 chromosomes) Turner Syndrome children are always female (no Y chromosome) They are sterile and don’t produce ovaries Are short of stature, have webbing of neck, widely spaced nipples, aorta is narrow, feet are swollen (edematous) at birth, have sparce body hair, and have reduced carrying angle at the elbow (cubitus vulgaris) Most are meiotic error by father Occurs in 1 in 3000 newborn females 15-20% spontaneous abortions are due to this karyotype making it one of the most common single chromosomal aberrations. Highly lethal during gestation, only 0.5% of 45, X conceptions survive to term Many live born 45, X are mosaics (different genetics in different cells) and may have combinations with XX, XXX, or XY in Turner Syndrome. Klinefelter Syndrome (1 in 1000 male births) Male appearance, sterile, female like breasts (gynecomastia), small testes, high pitched voice, slight mental impairment 2/3 of cases are nondisjunction of X chromosomes in mother (frequency increases with age of the mother) Possible to see XXXY and XXXXY, and with the increase there is more mental retardation and physical impairment. Jacobs syndrome, also known as 47, XYY syndrome Males, taller than average, may have slightly less than normal IQ Behavioral issues (impulse control), may have learning disability and need therapy in school for speech, etc. Study found inmates often had this condition leading to the incorrect theory that these males were more aggressive Broken Chromosomes Cri du chat syndrome (cry of the cat) Low birth weight, smaller head, mental retardation, heart defects, caused by deletion of short arm of chromosome 5 Cries like a cat meow Autosomal Dominant disorders There are over 8,000 single gene disorders and over half are autosomal dominant disorders Most well-known autosomal dominant disease is Huntington Disease Huntington Disease Dementia and chorea (uncontrollable movement of limbs) Degeneration of basal ganglia (putamen and caudate nuclei) and cerebral cortex (frontal lobe) Delayed age of onset is a key feature of this disease (usually older than 40) A person who has a parent with this disease has a 50% chance of developing the disease Defect is on the short arm of chromosome 4 (excessive repetition of CAG [40-70 instead of 9-34]. 5 per 100,000 and occurs in all races Age of onset of symptoms is related to length of repeat sequences Discovered a genetic marker (G8) on chromosome 4 paved the way for presymptomatic diagnosis of the disease The hope is someday this will allow for recombinant DNA to prevent or control the disorder Would you want to know if you had reason to suspect this was in your family and you might have inherited it? Marfan Syndrome Long, thin body, spider fingers, pigeon chest deformation, mitral valve prolapse, life span of 30-40 years usually due to heart issues, specifically rupture of the aorta, the gene is FBN1 Neurofibromatosis Neurogenic tumors that arise from Schwann cells and other elements from peripheral nerves Defect of tumor suppressor protein that regulates growth Type 1 (NF1) or von Recklinghausen disease (gene on chromosome 17) Type 2 (NF2) bilateral acoustic NF (gene on chromosome 22) Achondroplasia A genetic condition affecting a protein in the body called the fibroblast growth factor receptor. In achondroplasia, this protein begins to function abnormally, slowing down the growth of bone in the cartilage of the growth plate. This leads to shorter bones, abnormally shaped bones and shorter stature; adult height in people with achondroplasia is between 42 and 56 inches. Shortened arms and legs, with the upper arms and thighs more affected than the forearms and lower legs Large head size with a prominent forehead and a flattened nasal bridge Crowded or misaligned teeth Curved lower spine, a condition also called lordosis (or sway-back) which may lead to kyphosis or the development of a small hump near the shoulders that usually goes away after the child begins walking Extra space between the middle and ring fingers (also called a trident hand) Poor muscle tone and loose joints Frequent middle ear infections that may lead to hearing loss Delayed developmental milestones — for instance, walking may occur between 18 to 24 months of age instead of around 12 months Neurological impairment is caused by compression created as children grow faster than their bones. Arrested bone growth at the base of the skull and the spine can cause the spinal cord and brain stem to become compressed. Brainstem compression can ultimately lead to death if it is left untreated, so parents and physicians of children with achondroplasia should watch for these symptoms. Autosomal recessive disorders Rare in population but there are a lot of carriers Marriage between related individuals is likely a reason for these recessive disorders Inbreeding-produce offspring from marriage between related individuals Question to ponder: Is it illegal for 1st cousins to marry in Arkansas? Phenylketonuria or PKU-inborn error of metabolism characterized by the inability of the body to convert phenylalanine to tyrosine, caused by phenylalanine hydroxylase deficiency causing an accumulation of phenylalanine in serum. High levels of phenylalanine prevent neutral amino acid entry into the brain which contributes to neuropathologic process of PKU. Abnormalities occur in the brain include defective myelination, disturbance in cortical layers, and degeneration of gray and white matter. This can cause mild to severe behavioral disturbances, self-abusive tendencies, and seizures. Due to lack of tyrosine children have blonde hair and blue eyes and fair skin. Treatment is restricting phenylalanine in diet with supplements to ensure adequate nutrients (energy, proteins included) Cystic fibrosis Most common lethal recessive disease in Caucasian children 1 in 3500 births in white children, 1 in 12,000 nonwhite children Defect is on the long arm of chromosome 7 (Ever seen the movie “Five Feet Apart”?) Defect in chloride ion transport causes salt imbalance that causes really thick secretions of nasty mucus. Pancreas (exocrine gland) becomes obstructed, lungs clog, bacterial infections occur regularly Clubbing of fingers, hypoxia, cyanosis, barrel chest, kyphosis, and pectus carinatum are signs Chronic rhinitis is common Death usually by age 30 due to pulmonary disorders Gene therapy is promising for the future Sickle Cell Disease Caused by one mistake in amino acid sequence (glutamic acid is changed to valine) Causes RBC to become ‘sickle’ shaped RBC’s have a shorter lifespan (less than 120 days-possible to go as low as 20 days) Can transport oxygen normally, but low erythrocyte count causes low hemoglobin Major problem is obstruction of small blood vessels leading to thrombus formation and tissue necrosis Sickle cell crisis larger BV are involved and can cause significant organ damage Heterozygotes have sickle cell trait Carrier population very high in Africa, linked to malaria. Lysosomal storage disorders (Tay Sach) Best known lysosomal storage disorder (most are Jewish ancestry) Neurons become swollen and balloon, Microglial cells proliferate, number of neurons diminish, motor cells in anterior gray horn change causing hypotonia, hyporeflexia, and overall weakness. Infants start getting symptoms between 3 and 6 months old, loss of milestones, excessive startle reflex, seizures, muscular rigidity, blindness become prominent by age 1, head size may increase. Death usually occurs between age 2 and 5. X linked Diseases Fragile X syndrome is the second most common cause of mental retardation after Down Syndrome Puzzling pattern of inheritance. Males who inherit do not necessary express it but can pass it on to offspring who do express it. Typically, a male who inherits a disease gene of the X chromosome expresses it since he has only 1 X chromosome. Another uncommon feature is about 1/3 of female carriers are affected, but not as severely as males. Hemophilia Hemophilia A is classic hemophilia (90% of patients have this one) Deficit in clotting factor VIII About 70% have the severe form X linked in most cases, rarely a spontaneous mutation Signs and symptoms include: Prolonged hemorrhage after minor tissue injury Persistent oozing after minor injuries and hematomas are common (bruising) Spontaneous hemorrhage into joints (hemarthrosis) may occur causing crippling and painful deformities due to recurrent inflammation Blood in urine (hematuria) or feces due to bleeding in kidneys or GI Diagnostic tests include PTT, APTT, and coagulation time Partial thromboplastin time (PTT) and activated partial thromboplastin time (aPTT) are used to test for the same functions; however, in aPTT, an activator is added that speeds up the clotting time and results in a narrower reference range. The aPTT is considered a more sensitive version of the PTT and is used to monitor the patient’s response to heparin therapy. The reference range of the aPTT is 30-40 seconds.  The reference range of the PTT is 60-70 seconds. Coagulation time- how long it takes for a blood clot to form. The results are given in the number of seconds: 70 to 120 seconds is the usual amount of time for blood to clot without heparin. 180 to 240 seconds is the usual amount of time for blood to clot with heparin. PT and platelet tests are normal for these patients Treatment with replacement factor VIII New therapies using recombinant DNA are being developed Hemophilia B (Christmas disease) has a deficit of factor IX Hemophilia C (Rosenthal’s hemophilia) has a deficit of factor XI Duchenne muscular Dystrophy Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. It is the most common hereditary neuromuscular disease and does not exhibit a predilection for any race or ethnic group. Mutations in the dystrophin gene lead to progressive muscle fiber degeneration and weakness. usually recognized between three and six years of age. DMD is characterized by weakness and wasting (atrophy) of the muscles of the pelvic area followed by the involvement of the shoulder muscles. The first line of treatment is corticosteroids, which have been shown in clinical trials to decrease the rate of declining strength in people with DMD. A neurologist will manage this treatment and help minimize medications’ side effects. Red Green Color Blindness Most red-green colorblind people inherit it from their parents. Men get the condition far more often than women do because of differences in how parents pass their genes to their kids.  Basically, genes travel from parent to child on chromosomes. In humans, chromosomes called “X” and “Y” determine whether we are born male or female. Males have one X chromosome and one Y chromosome (XY), while females have two X chromosomes (XX).  Red-green color blindness travels exclusively in the X chromosome. Red-green color deficiencies come in four varieties based on how much of each color people perceive:  Red-blind (protanopia) – Red can’t be seen.   Green-blind (deuteranopia) – Green can’t be seen. Red-weak (protanomaly) – Some red is visible; green and blue are normal.  Green-weak (deuteranomaly) – Some green is visible; red and blue are normal.  Multifactorial inheritance disorders Multiple genes and possibly environmental factors Cleft lip or palate-more frequent in females, is caused by multiple gene-environment interactions (maternal smoking and genetic variation of tumor growth factor-alpha gene) reduces the amount of neural crest mesenchyme that migrates into the area that will develop into the face of the embryo. It can also be part of a syndrome determined by a chromosome defect (trisomy 13). Mitochondrial DNA disorders Mitochondrial DNA subjected to mutations at a higher rate than nuclear DNA and no repair mechanism exists MDNA has 37 genes which encode 2 types of rRNA, 22 types of tRNA, and 13 polypeptides that participate in oxidative phosphorylation (74 polypeptides are in nuclear DNA) Diseases are rare and many affect neuromuscular system Leigh Disease-proximal muscle weakness, sensory neuropathy, developmental delay, ataxia (poor muscle control), seizures, dementia, visual impairment due to retinal degeneration Myoclonic epilepsy-monoclonic seizures, cerebellar ataxia, mitochondrial myopathy (muscle weakness and fatigue) Leber hereditary optic neuropathy-painless, subacute, bilateral visual loss, with central blind spots (scotomas) and abnormal color vision MELAS-Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like syndrome, with seizures but may manifest as only diabetes mellitus MEPRF-Myoclonic Epilepsy, Ragged Red Fibers in muscle, ataxia, sensorineural deafness Deafness-progressive sensorineural deafness, often associated with aminoglycoside antibiotics Chronic progressive external ophthalmoplegia-progressive weakness of extraocular muscles Kearns-Sayre Syndrome-progressive weakness of the extraocular muscles of early onset with heart block, retinal pigmentation That’s enough!!