My subject is genetic considerations in neuromuscular diseases. There are four topics that I would like to discuss. The first is the classification of neuromuscular diseases by their inheritance patterns. The second is problems and determination of genotype Variable expression is one diagnosis of carrier state is a second. The third topic is the value of prenatal diagnosis in neuro muscular diseases, and finally, the impact of genetic counseling. First, the classification of normal street diseases by inheritance patterns. The disease is inherited in the mandalorian character can be classified as autism or dominance, autism and recessive and excellent disorders. On the first slide, we can see that in autism all dominant inheritance an affected individual Need have only one gene of the given type, an affected individual unless the result of a new mutation has an affected parent and affected individuals, offspring is equally likely to be affected and to be normal. On the next slide are listed neuro muscular diseases with autism. All dominant inheritance. They include facial scapula, humerus, neuro muscular disease, hockey low fare and Jill muscular dystrophy. Central core disease, Neverland myopathy, my atomic dystrophy or my atomic atrophy. Most forms of My attorney. Congenital Parramatta, Tonia, congenital, all types of familial periodic paralysis, familiar hypertrophic pollen arthritis, amyloidosis of the Andreotti or Portuguese type. Most types of hereditary sensory, ridiculous neuropathy and acute intermittent porphyria. On the next slide, in cases of autism or recessive inheritance, we show that affected individual has the given gene in double dose relatives at risk are therefore generally siblings for the offspring of two carriers. The probability is one quarter for being affected and one half for being a carrier for rare, excessive, there is an increased probability of parental con Sanguinetti on the next slide are shown diseases with autism, a recessive inheritance. They include limb girdle, muscular dystrophy, Glycogen storage disease of two types, types five phosphorus deficiency and type seven possible fact. Aquinas deficiency, verdad, nick Hoffman's disease, Most types of cooking, bull, re Landers disease and rest and syndrome. On the next slide. In excellent recessive inheritance, an affected individual has no normal X. Consequently the great majority affected individuals are males, affected individuals in the same family are related through females. A female carrier, married to a normal male has an equal chance of producing and affected male, A normal male, a carrier female and a normal female with each pregnancy. The next slide lists neuromuscular diseases with excellent inheritance. They are Duchenne, muscular dystrophy, both of the severe type and of the mild or Becker type. The next object to be discussed. Our problems in determination of genotype, a common problem in genetic diseases is that due to variable expression of a single gene. This slide shows a family with my atomic dystrophy, a disease which is often different in members of the same family in this diagram of this family are plotted muscular weakness or stiffness, cataracts, characteristic fishies and mental slowness. We can see nearly all patterns of these four components in many neurological conditions in which the same gene has different manifestations in different members, we are uncertain as to the cause in my atomic district. He, however, we know one factor that affects the symptom pathology that is whether the affected parent is the mother or the father. Nearly all cases of my atomic dystrophy of infantile onset have the affected parent is the mother. We surmised that this means that the developing fetus is suffers in some way when the uterus which nourishes it. It is also my atomic dystrophin and type a second problem in the determination of genotype is that of carrier diagnosis and no place in neuro muscular diseases. Is this a more serious program a problem than in the diagnosis of carrier state and relatives of patients with Duchenne muscular dystrophy. The next slide shows a family shows criteria for carrier diagnosis and a woman relative of the Duchenne patient is definitely a carrier If more than one relative is affected. That is for example, in considering they are a mother or a sister of a patient, she, however, is only probably a carrier if there's only one affected son or brother and has a serie um CPK elevation on more than one occasion or a muscle biopsy is abnormal. The one there is often more history more relevant data in a pedigree in such a case than is evident. Uh ah an example is shown on the next slide. This woman is definitely a carrier because she has a brother, her brother as well as sons who are affected this individual. Here, her daughter may ask a position about the likelihood of producing affected sons. The conventional advice is that since she is the offspring of a woman who is definitely a carrier, That she has a 50 percent chance of being a carrier in this family. However, this woman has three sons whom we shall assume our normal because they are past the conventional age of onset for this disease. Now, if a woman who is definitely a carrier has one half chance that any male son is affected, the chance that such a woman would have three who are unaffected is one half Times 1/2 times one Half, or 1 8. Thus, in calculating the likelihood of this woman being a carrier, which should take into account not only the fact that her mother was a definite carrier, but also the fact that she has ah if she were a carrier, she, she has not passed on this gene in three opportunities to do so. A third factor that might be considered is her CPK status. Known carriers have CPK elevations in only two 3rd of cases, and therefore this woman has a normal CBK. She has only 1 3rd chance on that basis alone for being a carrier. Thus, the statement about her risk for being a carrier should take into account the half chance based on her mother, the 1/8 chance based upon three out of three Children being sons being normal and the one third chance based upon her normal cPK. The analysis of the probability of carrier status. Taking into consideration multiple separate probabilities is called. Bayesian analysis. Ah If Beijing analysis considerations are included in the estimate of carriers state the true value is often seem to be lower than the figure commonly given such individuals when the the normal males in the family are not considered. The next subject to be considered is prenatal diagnosis in their muscular diseases. This lot reminds you that it's possible to withdraw amniotic fluid surrounding the fetus. This can be done from the 14th week of pregnancy onward, this fluid contains cells which are fetal in origin. Such cells can be cultured and used for examination of chromosomes or for examination of enzyme activity. The next slide shows three examples from neuromuscular Diseases utilizing three different methods of analysis. Graph sums disease is a neuro muscular disease in which the enzyme deficiency has been identified Furthermore, fibroblasts from patients are detective lee abnormal. In culture, it is therefore likely that Ressam's disease can be diagnosed in utero based upon the same abnormality in cultured amniotic cells. Ah In the cases of Duchenne muscular dystrophy, ah prenatal diagnosis is less successful. However, if the fetus of a woman who is a carrier is female, we can assure the mother that that the resulting child will not be symptomatic. It probably is worthwhile bringing up the possibility of prenatal diagnosis in such circumstances, We have found that many couples who can a benefit who from prenatal diagnosis art considering these days utilizing this procedure, despite their beliefs about abortion in general manifesting the suggesting that individuals who may not accept abortion on general grounds do wish to take advantage of selective abortion where the fetus can be proven to be defective. In the case of Duchenne muscular dystrophy. However, the diagnosis of a male fetus does not determine whether the child has Duchenne gene or not. The diagnosis of Duchenne in such a case Is only 50% likely. Some individuals who may be willing to abort a Now a known defective fetus may not be willing to abort a fetus when the likelihood of abnormality is only 50%. A third possible 3rd method for diagnosing prenatally is exemplified by a genetic linkage. This is a value in some families with maya tonic dystrophy. The next live presents the reason for this possibility my platonic dystrophy Locusts and the secreto Locusts are linked. To put it differently. This means that the position that the gene for my atomic dystrophy and the gene for what is called the secret er property are on the same chromosome. The diatonic dystrophy Locusts can have uh a Maya tonic dystrophy gene or normal normal gene in that position. The patient with monotonic dystrophy. We know has one my atomic district you gene and one normal gene at the homologous position on another chromosome. The secret er type determines whether an individual secretes A. B. H. Blood group substances in the body secretions such as saliva. The fact that the fetus secretes such substances into the ah amniotic fluid is the basis for prenatal diagnosis involving security types. My blood group is a and I'm a secret er And this means that I have blood group a not only on my red cells but also in present in my saliva. Individuals who are blood group. All secret what is called blood group, substance age in their body secretions and therefore it's possible by testing and individuals red cells and his saliva to determine not only his A. B. O. Blood group but also whether he's a secret er or not. The helios at the secretary Locusts are called big sc and little sc. An individual with one or two big assay genes secretes a. Bh substances into his saliva. Individuals who have only the little sc gene are the ones who failed to secrete these substances. The next slide presents the criteria for evaluating which couples may benefit from prenatal diagnosis of my atomic dystrophy. three criteria must be fulfilled. These are stated here and represented in the form of a pedigree which full of one type which fulfills the criteria below the first criteria is that the proposed notice must have one big sc gene and one little sc gene. Now in order to in this family. We have shown an affected man and his wife who wished to have prenatal diagnosis for their fetus. The the first step is to determine the HBO type of this man's red cells and to determine whether there is a B or H substance in his saliva. If he does not have these substances in his libel, then he is a non sequitur and no benefit can be derived from this approach. If we establish that he is a secret er then the next problem is to determine whether he is a hetero zygote as required in this case. This is done by analyzing his parents. His mother turns out to be a non sequitur and the only genotype for a non sequitur is uh the homos august little sc ST. Thus uh this family feels uh therefore this subject must have a little sc gene because his mother had no other to give him. And hence the first criteria is satisfied by this family. The second criterion is that the phase of linkage must be known. This means that we must be able to decide whether the chromosome bearing the muscular dystrophy gene in this family carries the big sc gene or the little scg. The man's mother is we, as we is the one with must be dystrophy and she has only little sc jeans. Thus it's clear that in her case it was the the diatonic dystrophy gene is on chromosome with a little S. E. Jean the third and therefore we can assume that in most in all probability the my atomic dystrophy gene in her son is also carried on his cross and was on with a little scg. And thus the phase of linkage is established. The third criterion is that the the pra positive spouse must not be big sc sc. The reason for that requirement is that if the spouse had only big sc jeans, then she could have transmitted only little big sc genes to the fetus. And no matter whether the fetus got the chromosome with Moscow dystrophy on it or not, the security status would be positive. This is a fortunate circumstance because this woman is a non sequitur. Now in this family, if the fetus is a a non sequitur as determined by a. B. H. Assessment of the amniotic fluid, then probably the child did inherit the monotonic dystrophy gene uh from the father. If on the other hand, the child has is a secret er ah then the chromosome from the father ah contributing the security type was the one without the district Eugene. And most of my atomic dystrophy gene was presumably not inherited. Now, the reason for saying probably rather than definitely is that any two genes on the same chromosome have a certain any too low signed. Some chromosome have a certain risk of recombination. Now, from studies of segregation of diatonic dystrophy and secretive type in families. We know that there is a 11% chance that the recombination will occur between the two lo sai between any given parent and child. Therefore the probability to be attached to this prediction is not 100%,, but 100 Percent -11% or 89%. Now suppose that the wife in this case was secreted positive, then we would have to decide whether she had too big, too big sc jeans or only one. We would determine that by looking at her parents. If as in this case one parent was little sc, little sc, we would know that this woman was a hetero saga. If this were the case, we could offer prenatal diagnosis in the sense that if the fetus was non sequitur then the child must would probably have inherited the monotonic dystrophy gene from the affected father. However, if the fetus was secret, er we would be unable to determine whether this is the biggest, see jeanne had come from the father or from the mother and in this case we would have no information to relate to the couple. It's important to make clear clear to the family in such a in this last example that certain outcomes of the test will not inform them as to the likely this trophic status of the fetus. The next slide shows that my atomic dystrophy is linked not only to the secreto Locusts but also to the Lutheran locus. The Lutheran locust determines what Lutheran antigen is on the red cell surface Lutheran A. Or Lutheran B. Now, at the present time, it's not possible to determine the Lutheran status of the fetus because there is no generally available method for acquiring for obtaining fetal red cells. Nevertheless, the linkage of my atomic dystrophy to Lutheran maybe a value in detecting ah who has inherited the dystrophy gene after birth, but before the onset of symptoms here, for example, one of your patients has a with monotonic dystrophy has a son. Uh considering becoming a concert pianist, it may be constructive to determine whether he has inherited the dystrophy gene. And in such a case, the if the secret information is not uh if this critter genotype do not permit this, the Lutheran Jenna types may notice however, that the Lutheran linkage to my atomic dystrophy is looser. That is Recombination occurs 24% of the time, Rather than merely 11% of the top. And therefore, the prediction made on the basis of the inheritance of Lutheran Is not accurate 100% of the time, but 100% -24% or 76% of the time. Now, how many couples? One of whom has monotonic dystrophy can be offered prenatal diagnosis in this way, from the incidents of various genotype for security, We can predict that 37.5% of us individuals should uh permit i prediction as to the inheritance of multi dystrophy in the fetus. However, the practical. Um In practice, this figure is lower because of the lack of availability of affected relatives, which permit a decision as to the phase of linkage in the affected parent. And last Only 10-20% of couples of this type are likely to be helped by this kind of analysis. The principles underlying prenatal diagnosis or presymptomatic post natal diagnosis by genetic linkage are important to understand because we can confidently predict that they will become of increasing usefulness in the future. This is because of the rapid increase in the knowledge of the number of genetic markers and because of the rapidly expanding knowledge of the location of markers in relationship to known disease entities. The final topic I would like to discuss is the impact of genetic counseling. The data that I'd like to draw upon deals with Duchenne muscular dystrophy. It's based upon A study of 109 families with Duchenne muscular dystrophy, studied in Toronto at the hospital for sick Children by Elaine Hutton and Margaret Thompson. And I use their data with their permission thanks to their generosity. It will be available in published form in the Canadian Medical Association journal in the near future. The question that it is to be asked is do patients really use uh recurrence risk risk recurrence information, recurrence risk information in planning their families. Their study shows that they do. Indeed. The first question to be asked is do they take into account the carrier status risk when deciding how on their family plans for further Children. This table classify on this table. The female relatives of known Duchenne muscular dystrophy cases are classified as too high risk, moderate risk or low risk. For each class. We show whether these individuals have decided not to have further Children. On the basis of the risk figures they have been given. We see that individuals given a high risk figure were deterred In intent by 80 and 81% of the cases. This is backed up by the fact that in 55% of the cases the woman or her spouse were sterilized, individuals given low risk of the Cases were deterred in only five of cases And were sterilized in only 13% of cases. Thus, there was a good correlation between the risk that was provided to the female relatives and the deterrent effect of this information. The next question to ask is does the risk provided affect not only intent but also reproductive performance. In order to add to asked to answer this question, we need to look to not only not simply asked the woman what she and her husband plan to do, but actually count their lives born offspring substitutes subsequent to the diagnosis of carrier status. The next slide presents these results here again, the female relatives are classified into the high risk, moderate risk or low risk categories and in this column we find, we can tabulate. The number of females apparently deterred by this risk, on the basis of not having had any live born offspring subsequent to being informed of what their risk was. Those in the high risk category Were deterred in 67 percent of the cases, those in the lowest category, Where you've heard in only 24% of the cases. Thus, we see that informing female relatives of the risk figures appears to have impact not only on their announced intent to have Children, but on their actual performance. Now, if a if a clinic is effective in there educational efforts, one might expect that there would be a decline in the number of families in the number of new cases of Duchenne dystrophy in subsequent years, in which there was a positive family history. This has been the experience in the Toronto group has shown him the next lot. In this column, we list the year of ascertainment of the new case, The number of the next call, the number of cases ascertained In the 3rd column, the number of cases with positive family history and in the final column, the number of cases in which the mother was aware of the positive family history at the time of conception of the new case. In the earliest year, recorded In 42% of cases, the mother was aware of the positive family history, where is in the most recent two years recorded This figure had dropped to only 7-9 and thus the prediction about effectiveness of genetic counseling is reflected in a drop in the percentage of cases in which the mother was aware of the positive family history at the time of conception. Thus, the message is clear, at least when dealing with clear cut with extremely serious conditions. People are influenced in their reproductive plans by risk figures. Hence it's the responsibility of physicians to make these figures just as accurate as they can. How where can you look for information to provide this accurate information to your patients? One source is the book by victor mcusic entitled dandelion inheritance in man. This book lists For over 2000 human conditions their inheritance patterns with a statement as to how well known how well established this inheritance pattern is and a brief description of the condition and the authoritative literature citations. A second useful reference is the book entitled The principles of genetic counseling, edited by written by Edmund A Murphy and Gary a Chase. This book explains the principles of genetics underlying the calculation of recurrence risk and in particular details the problems associated with carrier diagnosis for excellent conditions like Duchenne muscular dystrophy and takes into account the Bayesian analysis that I alluded to briefly. Hey, a third valuable resource is the uh birth defects uh International Directory of Genetic services uh published by the National Foundation. Thus, if you have difficulty determining the best information for your family's yourself. There is help available in your region.