The 2,054th Meeting of the Society

January 19, 1996

Powell Auditorium at the Cosmos Club

Pros and Cons of Genetic Studies

Lameh Fananapazir

Co-Chief, Inherited Cardiac Diseases
National Institutes of Health

About the Lecture

Advances in molecular biology have allowed the genetic abnormality to be defined in an increasing number of diseases. This, in turn, permits determination of who has or hasn’t inherited the genetic defect in an affected family. This leads to improved knowledge of the spectrum of the disease, of its natural history, and the diagnosis of the disease prior to the development of symptoms. Hence, therapies may be instituted early in childhood to prevent or modify the disease. There is also the promise of genetically engineered therapies. Exclusion of the disease allows family members to train for careers that would be contraindicated if at a later age they were to develop the disease. The diagnosis of the genetic abnormality may, however, have serious psychosocial consequences, such as guilt feelings for having passed on disease to their children and inability to obtain insurance among others. The problems may be aggravated if the disease is potentially lethal or severely disabling or for which there is no cure or good therapy at present. Therefore, our studies in hypertrophic cardiomyopathy, the most common cause of sudden death in otherwise healthy young individuals, such as athletes, are being performed side by side other studies to determine the risk benefit ratio of such studies.

About the Speaker

After receiving his M.D. degree from Edinborough University in Scotland, Lameh Fananapazir trained in electro-physiology at Duke Medical Center. He is currently Co-Chief of the Inherited Cardiac Diseases Section of the cardiology Branch at the National Heart and Blood Institute at NIH in Bethesda, Maryland.


President Coates called the 2054th meeting to order at 8:27 p.m. on January 19, 1996. In the absence of the Recording Secretary the minutes of the previous meeting were not read. The President introduced Mr. Lameh Fananapazir, Co-Chief of Inherited Cardiac Diseases at the National Institutes of Health, to discuss "Pros and Cons of Genetic Studies".

Mr. Fananapazir said that the promise of genetic engineering has been that by understanding the basis of genetic diseases we should be able to develop therapies for those diseases. The genetic disease he has been studying is hypertrophic cardiomyopathy. The disease can cause sudden death and is characterized by thickening of the heart muscle with consequent enlargement of the heart. The thickening of the heart muscle occurs in response to physiological stress such as strenuous exercise, or to pathology such as high blood pressure. The disease is the most common cause of non-traumatic, sudden death in atheletes, and the genetic defects responsible may have a prevalence in the population as high as 1 in 2000. Other consequences of the heart muscle thickening are restriction of blood flow into and out of the heart, interruption of the heart's own blood supply, the development of heart rhythm irregularities.

The first approach to treatment for this genetic disease is to attempt alleviating symptoms such as chest pain, headaches and black-outs. Next attempts are made to distinguish those patients who may be at risk for sudden death from those who are not. Finally, specific therapies can be attempted. Since this is a genetic disease, studies are conducted with as many members as possible of families identified as potentially carrying the defect because of a cluster of cases among family members. One such family that was studied had 270 members most living in Ohio. Chromosome and genetic analyses are performed to find the pieces of chromosomes that are shared by those with the disease and that are lacking in those without the disease.

Once a genetic defect has been located in the chromosomes, and its inheritance traced through the generations, it is seen that some family members are carrying the defect and passing it on to their children without themselves developing clinical symptoms of the disease. In some families the genetic defect was thus more prevalent than expected because it was so benign in its carriers. In other families a different mutation in the same gene had much more malignant results killing most of its adult carriers. In families with the more malignant mutations, family stress and even psychopathologies develop as a result of individuals having so many family members die suddenly. If there were a test that could tell whether someone carried the malignant mutation, would they want to have the test done and know the result?

So far six different genes have been found with mutations resulting in this disease. The principal gene identified carrying the mutations for this disease is the gene for beta myosin heavy chain; more than 30 different mutations resulting in the disease have been identified in this gene. The mutations are clustered in three regions of the myosin structure, at the site of interaction with the another muscle protein actin, at the site were energy is produced by hydrolysis of the compound ATP, or at the site were the myosin molecule swivels to interact with actin. Beacuse the defective myosins are weaker, the muscle fibrils they form are weaker, and the muscle fibers thicken to compensate for that weakness. The same protein occurs with the same defect in skeletal muscle, but because skeletal muscle fibrils are more readily replaced than heart muscle fibrils the heart fibrils are more prone to failure.

Before these genetic studies began it was thought that as many as 500 of the cases were sporadic, that is spontaneous mutations in the affected individuals. By making these family genetic studies and observing that not all carriers of the defect developed disease symptoms, it became evident that very few of the cases represented spontaneous mutations. It also became clear that some individuals could be at risk for sudden death without having symptoms of heart muscle thickening, that some deaths were due to instabilities or failures in nerve conduction. In one case, the disease appears to behave like SIDS, sudden infant deat syndrome. The disease has no gender or racial bias, but is variable in its expression. Members of the same family with the same mutation may experience different syptoms or even no symptoms as a result of interactions of the defective gene with different genes in different individuals.

Mr. Fananapazir kindly answered questions from the audience. The President thanked the speaker on behalf of the Society, announced the speaker for the next meeting, restated the parking policy, and adjourned the 2054th meeting at 9:23 p.m.

Attendance: 30
Temperature: not recorded
Weather: clear

Respectfully submitted,
John S. Garavelli
Recording Secretary

with the assistance of
Ron Hietala