Familial Hypertrophic Cardiomyopathy
by Kenneth D. Dorsette
This is a case study involving three families, the Winchester, the Churchill and the Esposito family whom all suffer from Familial Hypertrophic Cardiomyopathy (FHC). FHC is a clinically and genetically heterogeneous autosomal dominant inherited heart disorder that causes a high incidence of sudden heart failure.
The symptoms of FHC include chest pains, lightheadedness (particularly during posture changes), palpitations, functional limitations and fatigue. Chest pains differ from individual to individual. They may be sharp or aching, have prolonged duration and may worsen after treatment with medication. Most patients are free of symptoms(or only have mild symptoms) before sudden death.
Familial Hypertrophic Cardiomyopathy is caused by a mutation in the gene encoding a part of the multi-subunit muscle protein myosin, called a myosin heavy chain. A myosin molecule is shaped like a rod with a bulge at one end, called the head. The other major muscle protein actin binds to the head. After actin binds to the head, ATP splits to provide the energy necessary for muscle contraction. A number of different mutations in the gene coding for the cardiac heavy myosin chain, a structural and functional protein of striated muscle, can cause FHC. The majority of FHC cases are caused by defective contractile proteins. The defective contractile proteins cause the heart to become stiff and poorly relaxed, requiring higher pressure than normal to expand the heart with the inflow of blood. The high pressure required for blood inflow cause asymmetrical thickening of the left ventrical wall and enlargement of the atria. The transitions between regions of the wall that are Hypertrophic and regions of normal thickness are often sharp and abrupt not infrequently creating right-angled contours of the ventricular wall. Usually the pattern of hypertrophy is diffuse and involves both the septum and the substantial portions of the anterolateral free wall, with the posterior segment of the free wall least affected by the Hypertrophic process. However, there is evidence that even siblings and "first-degree relatives," such as Aunts, Uncles, first cousins and grandparents with the genetically transmitted form of the disease show differences in pattern of left ventricular wall thickening. The differences in distribution and pattern of hypertrophy appear to be as substantial between members of the same family as between unrelated patients in different families.
Previous clinical studies show that there are at least four different gene locus for FHC: on chromosome 1q3, 7q35, 11p1-q1 and 15q2. Chromosome's 1q3 and 15q2 are of special interest because some families with loci's 15q2 express less severe cardiac hypertrophy than affected individuals of other families with loci's 1q3, who have a bad prognosis. In order to identify gene defects that cause FHC on chromosome's 15q2 and 1q3 several genes encoding for contractile proteins were mapped and screened for mutations. The gene for alpha tropomyosin was identified as the mutation on chromosome 15q2 and further genetic mapping suggested that troponin T was the mutation on chromosome 1q3. These findings established that FHC is caused in the majority of cases by defective contractile proteins. It is estimated that troponin T and alpha tropomyosin mutations account for 15% and 3%, respectively of all FHC cases. Other studies based on extensive echocariographic surveys of pedigrees showed that about 60% of families in which there was a patient with FHC had at least one other first-degree relative with clinical or morphological evidence of FHC. However, a genetic etiology for FHC could not be documented in about 40% of the families, even after systematic echocariographic pedigree surveys.
In the Winchester family, 34-year old Paul died from heart failure while playing basketball. When they analyzed his cardiac myosin heavy gene they found a mutation at amino acid 606, which changes valine (GUA) to methionine (AUG). The mutation in the Winchester family is a transition mutation because the G changes to an A and the A changes to a G. There are more members of the Winchester family affected with FHC than the Churchill and Esposito families because it has been present in that family for two generations and they live longer than the Esposito's and the Churchill's. The Churchill FHC mutation is at amino acid position 249 on the myosin heavy gene. In the Churchill family the mutation from arginine (AGA,AGG,CGA,CGC,CGG,or CGU) to glycine(GGA,GGC,GGG,or GGU) causes death in the early teens and late twenties. The Churchill's FHC mutation can be caused by either transition or transversion mutations. In the Esposito family the FHC mutation is also at amino acid position 249. In the Esposito family the mutation from arginine (AGA,AGG,CGA,CGC,CGG,or CGU) to cysteine (UGC or UGU). The mutation in the Esposito family can be caused by a transition, transversion or a frameshift mutation.
In the case study regarding the Churchill, Esposito and Winchester family it seems likely that the alpha tropomyosin mutation on chromosome 15q2 is the cause for the Winchester's FHC and the troponin T mutation on chromosome 1q3 is the cause for the Churchill's and Esposito's FHC. There is a need for more genetic research in this area because it is still unknown if some people die from hypertrophic cardiomyopathy based on genetics or whether they just do not take the proper care of their bodies.

Current Problems in Cardiology vol. 18 no. 11 1993 pg. 637-704 Barry J. Maron, MD Hypertrophic Cardiomyopathy

Current Problems in Cardiology vol. 21 no. 6 1996 pg. 385-444 John D. Symanski, MD Rick A. Nishimura, MD, FACC The Use of Pacemakers in the Treatment of Cardiomyopathies

Thierfelder, L., MacRae, C., Watkins, H., Tomfohrde, J., Williams, M., McKenna, W., Bohm, K., Noeske, G., Schlepper, M., Bowcook, A., Vosberg, H.P., Seidman, J.G. and Seidman, C. (1993). A familial hypertrophic cardiomyopathy locus maps to chromosome 15q2. Proc. Natl. Acad. Sci. 90, 6270-6274

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