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.
References
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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