Albero genealogico per un carattere AR PDF

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Albero genealogico per un carattere AR - Appunti in Inglese...

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After seeing the inheritance of an autsomal dominant character, we’re now going to focus on the inheritance of an autosomal recessive character.

By looking at the tree is possible to see immediately what are the difference with respect to the dominant traits, in particular the main difference is that in the tree nobody looks affected, in the ex. above we have two brothers affected and tipically in these diseases neither parents nor children, if it’s possible for the affected to have children, are affected, but we know that many people in this pedigree are actually healthy carriers, more than one. In this inheritance if we have more than one affected person in the pedigree we’ll get an horizontal pattern in the pedigree. Again male and female are equally likely to be affected. Once more was Mendel with his crosses of pea palnts to show us the actual probability of inheriting or not the particular allele. The first example of this kind of inheritance is SMA1 (Spinal Muscular Atrophy 1), it’s a lethal disorder due to disappereance of peripheral nerves because of structural defects of these nerves that leads to a compete paralysis. Normally these patients die in emergency room due to the involvment of respiratory muscles before the 2 years of age. Another example of this kind of inheritance is the OCA (oculo cutaneous albinism) the affected people are unable to synthesize melanin, as a result we have a very pale skin and it’s possible to spot blood vessel in the retina. These patients have some problems like strabism, but it’s not a lethal disease except for some regions of Africa where these people are hunted and killed.

In rare cases of marriages between albinoes the recurrence of disease is 100% (aa x aa=100% aa). Considering the biochemistry and genetics behind albinism we can see a metabolic pathway starting from phenylalanine which is in turn metabolized by Phe-hydroxylase in tyrosine, and, finally, tyrosine is transformed in melanin by tyrosinase which is the lacking, or not working, enzyme in OCA.

By looking at this pathway we can make a general consideration: in our biological system there are many metabolic pathways in which a substrate is metabolized and transformed into the next, so we have many steps and at each step we have an enzyme getting the job done, so ,generally speaking, in recessive disease there is a lacking of these enzymes. The problems could be the lack of substrate ahead, so melanin, or sometimes the problem is due to accumulation of substrate that cannot be metabolized. In OCA we don’t see an increase of tyrosine or phenylalanine, what is the cause of disease is the lack of melanin. Talking about the same metabolic pathway, this time switching to the left, we consider phenylalanine hydroxylase: this enzyme normally transform phenylalanine in tyrosine is lacking in PHENYLKETONURIA (PKU) (the name come from a metabollite present in urine which smell very badly), which was one of the most severe cause of mental retardation of genetic origin.

In the western world we have a massive system of neonatal screening and every newborn is tested for the disease. Phenylalanine is one of the 20 aa, but it’s one of the essential aa meaning that it cannot be synthesized de novo in a sufficient manner and have to be assumed through nutrition.

What happens in pku patients is that, for genetic mutation of phenylhydroxylase, phenylalanine ins’t able to be transformed in tyrosine, in this case what bothers more, on the contrary of albinism, is the accumulation of phenylalanine in blood (hyper-phenylaninemia). This specific aa and the mechanism are still not completely understood, but it’s extremely toxic fot the brain neurons, in particular is deleterious for newborns where the neurons are still forming and so an accumulation of this aa cause the destruction of billions of neurons. As we were saying there is a massive screening fot this disease and the test performed is the Guthrie test when the baby is 2 or 3 days old, the test is a microbiological test where we have a plate with different wells and strain of bacteria very selective for phenylalanine, a blood spot is added in the well, if the well becoma white this means that the bacteria are proliferating and so a lot of phenylalanine is present, so in this way is possible to identify affected newborns and what you do is stop the supply of phenylalanine in the diet allowing the brain to develop properly in adulthood, since only in formation of neurons the accumulation of phenylalanine is toxic. So this newly identified patients are put on a strict diet which is mantained until adulthood. There’s an exception when you have a female newborn, it is good practice to put this woman on a diet until she is fertile because after being put on a diet and develop normally you’re still unable to use phenylalanine and if the patient is pregnant the high levels of phe can cross the placenta and damage the fetus not because of a genetic disease but because of the environment. In particular babies tested positive are not allowed to have: meat, dairy products, dry beans, nuts, eggs and there also special milks. One of the main problem for this patients is, since being very young, follow the diet, because we are talking about children who can’t have single slice of bread or whatever because this would kill millions of neurons and also is complicated to teach to the parents the proper way of feeding. Test have been conducted on long term pku patients healed where the IQ of these patients ws compared to normal controls and is possible to see a slow, significant reduction of intellectual performance. Cystic Fibrosis (CF) is the most common potentially lethal genetic disease affecting caucasian children and many years ago was considered just a pediatric disease because everyone with cf passed away before the 20s, now we can have patients of 40-45 years hold who can survive thanks to lungs and liver transplantation, we have strong antibiotics and knowledge of the mechanisms, furthermore we have some drugs which can improve the conformation of the protein involved, which is an ion channel, sometimes the mutation turn the protein from an active state to an inactive state meamning

we cannot let the chloride pass through and some drugs now, acting like chaperones, can open up the protein. We said that is the most common AR disease in caucasian 1:2500 newborns, but around 1 out of 25 people are CF carriers (i have a small a), fortunately is very unlikely that I marry someone with another small a (unless we are cousins). The defective protein in this disease is CTFR. Two Aas have 1/4 probability to have an affected child (as all other AR diseases, 25% of risk). CF is a multi-system disorder that produces a variety of symptoms including: - persistent cough with thick mucous - wheezing and shortness of breath - frequent chest infections, which may include pneumonia - bowel distubances, such as intestinal obstruction - weight loss - infertility in men and decreased fertility in women - another interesting thing is that the salt of these patients tend to be salty and many years ago pediatricians used to lick the patients to test for CF, now we perform sweat test to measure the concentration of salt. Furthermore even the ancient egyptians, more than 5000 years ago, knew, as written in a document, CF because they said those who have a salty sweat will die very young, and this is very interesting because this tells us that genetic diseases tend to stay with us for a very long time and as the Hardy-Weinberg law tells the frequency of alleles tend to stay the same. The sex linked traits aren’t mendelian because he didn’t analyzed them, only the autosomal ones, so in this perspective sex inheritance isn’t mendelian. Sex is the opposite of cloning, production without sex means homogeneity. When we talk about sex inheritance we think only about the X chromosome because the Y one is just involved in production of sperm, so there’s no genetic disease on the Y.

The two most important situation in X linked diseases are: 1) both parents phenotypically normal, but the mother is a carrier, in this case the risk is 25% of having an affected child, but in this case, if you know that there is an X disorder running in the family, it’s a nice procedure to get the fetal sex and if you know your fetus is a male you have 50% chances of disease if the mother is a carrier. Let’s imagine that the boy in the left figure is born with a light disorder, not a severe one, for ex. emophylia a. In the clotting system we have a system of 12 step, in this case number 8 isn’t working so you cannot get the blood to clot. Suppose that this boy grows and here we arrive at pattern number 2. 2) In pattern 2 the man is affected, if the man ask for genetic counseling and ask for the risk of having affected children, we have no risk of affected children if the father is affected, but every daughter is an obligate carrier, which is important because on the contrary of AR traits, in X linked recessive trait, a carrier could be not completely normal becasue of X inactivation (lyonization). Since female are mosaics for X some cells express paternal X other maternal, so female are a mix and it’s impossible to predict the phenotype, for ex. if you’re a carrier of Duchenne muscular distrophy normally 50% of your cells are out, but it could happen that 80% of muscualr cells express the disease chromosome, so you may not be walking so well, ecc. Let’s say that a female carrier is almost always a healthy carrier. Examples of XR-linked disease - DALTONISM: very frequent in the population, so it could happen that I am color blind, so the only X is mutated, and my wife is a carrier, so we could have a daughter who is affected because she’s homozygous. - HEMOPHILIA A: clotting factor 8 deficiency, typical location of bleedin is big joints (knees, elbows) and this is called “emartro” and this can lead to chornic and painful arthrosis. For emophilia we have no cure, you should assume recombinant factor 8, good nutrition, good ental hygiene, avoid injury and meds that promote bleeding. These patients can have intracranial hemorrage, prolonged nosebleeding, briuse easily and gastrointestinal hemorrage. As we told we have lacking of this factor and this happens in the liver, according to the type of mutation the liver can synthesize enough amont of factor 8 so you have hemophilia but it’s asymptomatic. Otherwise the most severe situation is when your liver doesn’t produce any factor 8 in the blood and this is tragic because you can bleed to death when you’re born, second as a young boy you can suffer from spontaneous brain hemorrhage. The most critical point is that when you treat these boys with factor 8 their body may not recognize factor

8 because they don’t have any of it, so the body recognizes it as an antigen and make antibodies anti-factor 8, so the therapy is useless, fortunately this is only a small part of hemophilia patients. Nowadays emophlic patients are treated with recombinant factor 8, back in the days the factor 8 was given by transfusions and a lot of men died in Europe because of defective blood in transfusions such HIV, Hepatits, ecc. - DUCHENNE and BECKER: different types of distrophy, same gene but different mutation; Duchenne present frameshift, Becker present inframe mutation, so distrophy is synthesized even though it’s not completely normal. The less severe form is Becker. Duchenne have an incidence of 1:3000 males ,so it’s not so rare, we have muscular weakness between 3-6 years, they develop heart disease which lead to death, they are on a wheelchair by the age of 10-12, they need tracheostomy, curiously the calves show hypertrophy, posturing problems, but the most important clinical sign is the Gowers sign, it consists in asking the boy to lay down on his belly and then to raise up, they find difficulties and have to climb on their own legs. One diagnostic test is the Immunohistochemistry (IHC) on muscular biopsy which use monoclonal antibodies to recognize dystrophin. Dystrophin is a structural glycoprotein which protects the muscular fibers. If we compare the biopsy, in an healthy male we see the cells surrounded by dystrophin, in a DMD male we see no dystrophin.

In a female carrier, due to X inactivation, I’d expect to see a mix of the figure above, some fibers are okay meaning that the cells express the right X, but maybe next to these we have a completely black hole because of an inactive

X. Another diagnostic test we can use is performed by measuring the levels in the blood of an enzyme called creatina fosfo kinasi (cpk), which is a muscular enzyme, if we measure the cpk levels in a normal person we expect to find low levels of enzyme because most of it should be within the muscle, in affected patients we found high levels of enzyme in the blood. Female are mosaics for the X gene they can express either the paternal or the maternal allele in eache specific cell, so if a female is a carrier of a disease it’s not automatic that you’re healthy because ther could be an unbalanced X inactivation. This unbalanced inactivation could justify clinical sign in female who is a heterozygous carrier, is called ‘manifesting carrier’....