Biochem Day 7: Consanguinity & Cytogenetics
Tetraploidy
- (also euploid) contain four of each chromosome (92 total) - very lethal, only a few cases of live births that are tetraploids have ever been reported
Triploidy
- (also euploid) contain three of each chromosome (69 total) - usually a result of two sperm fertilizing the same egg cell - very common at conception but most are spontaneously aborted - about 1 in 10,000 live births is a triploid, but death occurs very quickly due to numerous defects of the heart and the central nervous system
Turner syndrome
- 45, X - >99% of Tuner conceptions are spontaneously aborted - among survivors, ~57% have only one X chromosome - 14% are missing a part of one of the X chromosomes (partial MONOsomy) - 29% are mosaics (some cells are 45, X and other cells are 46 XX) - short stature - webbed neck - lymphedema of ankles and wrists (especially at birth) - broad chest with widely spaced nipples - sterility (gonadal dysgenesis)
Trisomy 21
- 47, XX +21/ 47 XY, +21 - the most common autosomal trisomy, causes Down syndrome - 1 in 800 live births - about 80% of cases of trisomy 21 are lost during pregnancy - the most common genetic cause of mental retardation - commonly called Down Syndrome
Trisomy 13
- 47, XX, +13 / 47, XY, +13 - 1 in 10,000 live births - >90% of conceptions with trisomy 13 are spontaneously aborted - among live births, >90% die within the first year of life - oral-facial clefts (midline deformities) - Microphthalmia (small eyes) - Polydactyly (extra fingers/toes) - congenital heart defects - other organ defects
trisomy 18
- 47, XX, +18 / 47, XY, +18 - Edwards syndrome - 1 in 6000 births - > 95% of conceptions with trisomy 18 spontaneously abort - among live births, >90% die within the first year of life
Klinefelter Syndrome
- 47, XXY - 1 in 800 males - sterility due to atrophy of the seminiferous tubules - feminized male - abnormally long arms and legs - small atrophic testes (only consistent finding) - lack of secondary sex characteristics for males (beard, deep voice, male pubic hair distribution) - Gynecomastia (breast development) - lower than average IQ (normally not mentally retarded) - ration of testosterone to estrogens determines degree of feminization
Consanguinity (incestuous relationships)
- Incestuous (consanguineous) mating is far more likely to produce a genetic disease than random mating --> in some areas of the world these matings are not unusual --> in the US these mating are not common - However, several well respected text books specifically mention the Appalachian Mountains, because of geographic isolation of the population, as regions where consanguineous mating is still found
what did the doctor at UK do?
- a doctor at the University of Kentucky heard of the legendary blue people, and began searching the mountains to see if he could find them - he had a particular interest in blood disorders, and was curious what may have made their skin turn blue - able to find some blue people and take blood samples - took the samples back to UK where he determined that the patients had a deficiency in NADH methemoglobin reductase - blue color of their skin was due to a larger than normal amount of methemoglobin in the blood
The Kentucky blue people and Methemoglobinemia
- a legendary example of consanguineous mating is the story of the Kentucky Blue People - the story takes place in a small community near Hazard, KY - very rare disease that is inherited as an autosomal recessive disorder - mutated enzyme: NADH- methemoglobin reductase (NADH diaphorase/diaphorase I) - heme component of hemoglobin becomes oxidized (Fe2+ to Fe3+) and cannot bind oxygen - NADH methemoglobin reductase normally reduces the iron in heme so it can return to its normal oxygen binding function
Lethal equivalents
- a term used to describe the potential death risk associated with each lethal allele or the group of lethal alleles if expressed in combination: --> each recessive lethal allele -- 50% lethal equivalent --> each lethal allele of a lethal allele group-- % contribution lethal equivalent
Lynch syndrome
- aka hereditary nonpolyposis colorectal cancer - defect in mismatch repair genes - is often called the American Founder Mutation - a startling conclusion: --> of the 32,000 Americans who carry the gene, 8,000 are Kentuckians
Lethal allele groups
- an individual may have several of the alleles of the lethal allele group, but not all of them and not expressed at the homozygous level - if mating is random among unrelated individuals, the chance of acquiring all of the lethal alleles in the group and potentially having homozygous levels of some of their expression is incredibly rare and lethality is rare
Summary points of the Kentucky Blue People and Methemoglobinemia
- blood of someone with methemoglobinemia is a characteristic bluish/brown color - stays that color when exposed to air - deoxyhemoglobin (dark red, appears blue in the veins) is immediately converted to hemoglobin when exposed to air (red) - babies are also much more prone to accumulating methemoglobin because the enzyme activity of their NADH methemoglobin reductase has not reached adult levels
Blue skin
- blue skin can be a sign of many things, not the least of which is heart or breathing problems (ex: COPD, asthma, etc.) - please do not think you treat anyone with blue skin with methylene blue
Methemoglobinemia vs. lack of oxygen
- can be distinguished from blue coloring due to lack of oxygen (a much more common cause of blue coloring of the skin) - blood that is simply low in oxygen will immediately turn red upon being exposed to air - blood from a person with methemoglobinemia will remain a bluish chocolate brown color
several causes of congenital methemoglobinemia
- deficiency of NADH methemoglobin reductase (Diaphorase I) (Autosomal recessive disease, seen in the Kentucky Blue People) - some types of abnormal hemoglobin (impaired production of NADH) - Glucose-6-phosphate dehydrogenase deficiency (G6PD) (impaired production of NADPH)
Aneuploidy
- deviation from the euploid number of chromosomes - ie: a loss or gain of specific chromosomes
cytogenetics and chromosome abnormalities
- egg cells of females are semi-permanently stuck in prophase of meiosis I until ovulation - as females age, non-disjunction at meiosis I becomes more frequent - you can visualize this as the chromosomes end up being "glued" together and have a harder time separating as a woman ages
Methemoglobinemia
- elevated levels of methemoglobin in the blood - also called chocolate cyanosis
What is the treatment for methemoglobinemia?
- for patients with methemoglobinemia due to a deficiency in NADH methemoglobin reductase, there is a very simple treatment - methylene blue can act as an electron donor that gives the methemoglobin an alternative way of being reduced to normal hemoglobin with Fe2+ - treatment is very effective and works quite rapidly - doctor went back to the Eastern Kentucky mountains armed with methylene blue - after dosing them with methylene blue, their skin, for the first time in their lives, turned a normal pink color
Methemoglobin
- hemoglobin in which the heme iron is oxidized from Fe2+ to Fe3+ - has no affinity for oxygen - stays in a deoxygenated state (deoxy-form) - giving blood a bluish chocolate brown color (methemoglobinemia is also called chocolate cyanosis)
Euploidy
- in humans, when a cell has a multiple of 23 chromosomes: --> haploid, 23 chromosomes --> diploid, 46 chromosomes --> triploid, 69 chromosomes --> tetraploid, 96 chromosomes
The blue people part 2
- in the blue people, the NADH methemoglobin reductase deficiency allows significant levels of methemoglobin to accumulate in blood - gives the skin a bluish hue - methemoglobin is actually brown in color, but appears blue through the skin - it is important to note, that NADH methemoglobin reductase is not completely devoid of activity in the blue people
the story of the blue people
- in the story of the blue people of Kentucky, a couple who settled near Hazard had seven children (Martin and Mary Fugate) - father was blue (homozygous) - mother was a carrier (heterozygous) - 7 children: 4 blue, 3 carriers
Down Syndrome symptoms
- mental retardation (IQ range 20-70) - short stature - characteristic facial features (flat profile, oblique palpebral fissures (upward slanting of the eyes), depressed nasal bridge, epicanthic fold (upper eyelid covering the inner corner of the eye), displastic ears (abnormal shape)) - congenital heart defects - frequent respiratory infections (abnormal immune system) -increased (10-20X) risk of leukemia - develop Alzheimer disease at ~40 years old - due to improved medical care, more than 80% of patients with Down syndrome survive beyond the age of 30
The rest of the aneuploidy
- mostly structural chromosome abnormalities, where chromosomes are "broken" and reattached in different ways
Consanguinity
- not necessarily incestuous but the gene pool is very small so there can be cross-over - more lethality than normal
47, XXX females
- occurs with the same frequency as Klinefelter syndrome - 1 in 800 - essentially normal females, and most are never diagnosed - there is an increased probability of psychiatric problems (specifically schizophrenia) in these women
47, XYY males
- occurs with the same frequency as Klinefelter syndrome - 1 in 800 - essentially normal males, but are usually very tall - often a mild degree of social problems, recently attributed to secondary effects of being much taller than average
Monosomy
- one copy of a specific chromosome is present - all autosomal monosomies are lethal - one sex chromosome monosomy is compatible with life (Turner Syndrome- X)
Trisomy 18-- Edward syndrome symptoms
- prominent occiput (back of the head) - small mouth and ears - small size for gestational period - congenital heart problems and other internal organ defects - clenched fists with overlapping fingers - rocker-bottom feet
what increases as the mother's age increases?
- risk of down syndrome - risk of a significant chromosome abnormality
Turner syndrome symptoms
- short stature - webbed neck - lymphedema of ankles and wrists (especially at birth) - broad chest with widely spaced nipples - sterility (gonadal dysgenesis)
Sex chromosome aneuploidy
- tends to be less severe than autosomal aneuploidies - at least one X chromosome is required for survival
General message of chromosome abnormalities is...
- that the body tolerates extra genetic information better than it tolerates a loss of genetic information - however, most chromosomal abnormalities are incompatible with life
the story of the blue people part 2
- the descendants of the original couple, and their descendants had many different types of incestuous and consanguineous matings - lead to blue children "popping up" in the pedigree at various times and places - began in 1820, so the pedigree we have to work with is not complete - the blue people of Kentucky were quite reclusive, so we do not know the names or identities of every blue person, only a few are shown in the pedigree
Methylene blue side effects
- the fact that methylene blue happens to be "blue" is pure coincidence, and has nothing to do with its potential as an electron donor for "blue" hemoglobin - an interesting side effect is that people who take methylene blue have blue colored urine - some of the blue people who were given this treatment drew an obvious conclusion, that they were literally peeing the blue right out of their body
Trisomy
- three copies of a specific chromosome - trisomies of three autosomes (13, 18, 21) can potentially survive - sex chromosome trisomies are often compatible with life, and may even apparently normal
Recessive lethal alleles
- when recessive lethal alleles are present but the individual remains heterozygous for the loci, the phenotype is not rendered; lethal equivalent is only 50% - if mating is random among unrelated individuals, the chance of becoming homozygous is incredibly rare and lethality is rare
Types of aneuploid
1. monosomy 2. trisomy
there are two types of patterns associated with lethal alleles:
1. recessive lethal alleles 2. a group of alleles that are present and expressed in combination
Acquired methemoglobinemia
Due to oxidative stress cause by: - certain drugs/drug metabolites - certain antibiotics (i.e. trimethoprim--> involved in driving oxidation of hemoglobin) - caine anaesthetics - compounds containing nitrates
Consanguinity and its health consequences
It is estimated that a person carries an average of three to eight lethal equivalents (3 to 8) - most or all of these will be inherited from the parents - siblings share about half of these "mutations"/ lethal alleles - direct relatives are far more likely to share those mutations than the rest of the population
Lethal alleles
each individual "carries" a set of alleles that would result in death if: --> they were present and expressed: - in the required combination and/or - to the required level
Somatic cells are...
euploid (diploid, 46 chromosomes, 2 of each)
Gametes are...
euploid (haploid, 23 chromosomes, one of each)
how can a lethal equivalent be 100%?
if both alleles were present (homozygous)
blue-baby syndrome
infants under the age of 6 months are particularly prone to methemoglobinemia caused by: - elevated nitrate levels in drinking water (agricultural run off) - elevated nitrate levels in certain foods *this is because the enzymes used to protect against methemoglobinemia have not yet reached adult levels
What does NADH methemoglobin reductase (Diaphorase I) do?
it converts Fe3+ back to Fe2+
Monosomies and trisomies are cauesd by:
nondisjunction of chromosomes during meiosis (most common is during Meiosis I)
Hatfield-McCoy feud-- was it caused by genetics?
some descendants of the McCoy family have a disease called von Hippel-Lindau Syndrome - caused by a mutation in a tumor suppressor gene (an autosomal dominant condition) - one result of this condition is PheoChromoCytomas - ~20% of patients with vH-L syndrome have a tumor of the adrenal gland - can cause a predisposition to explosive temper due to excessive production of adrenaline
what would you see in increase in if someone has methemoglobinemia?
you would see an increase in 2,3-BPG in the blood (because taut form of Hb or deoxygenated form is very high in bloodstream)