General description (for patients): Heart disease has many causes. In mild forms it is associated with fatigue in adults and failure to thrive in infants and young children. As the heart becomes weaker, breathing difficulties and swelling of the ankles may be noted. Sometimes the heart beats irregularly, and the lips and nailbeds may turn blue. In the most advanced stages, the heart beat may cease completely, often without warning. Besides ageing, infections, malnutrition and certain toxins, there are a large number of gene mutations that are responsible for heart disease.
The proper functioning of heart muscle requires the normal interaction of many proteins whose synthesis is under the direction of specific genes. Among the most essential of these is a group called myosin-binding proteins known as MYBPC3. Mutations in one or more of these are responsible for symptoms of heart failure in some parents and others with a single mutation. Infants who have the mutation in both MYBPC3 genes have far more serious disease. These young children have severe heart disease, considerable breathing difficulties from birth, often eat poorly and fail to gain weight, and without a heart transplant succumb to their disease within a few weeks or months. There is no other known treatment.
Clinical description: Hypertrophic cardiomyopathy (HCM) is often responsible for sudden cardiac death among young, otherwise healthy adults. Among the most important causes are mutations in one of at least nine genes encoding sarcomere proteins; more than 500 mutations have been reported. Mutations in the gene MYBPC3 coding for the C protein in particular are one of the most frequent causes of genetic heart disease in adults. A unique change in the MYBPC3 gene has been identified among the Amish, which is likely the cause of sudden death in some young people. The Amish mutation in MYBPC3 is unique and the first reported to consistently lead to infant mortality in the homozygous state. Signs and symptoms of congestive cardiac failure including respiratory distress, lethargy, irritability, poor feeding, and failure to thrive are often present from birth. Echocardiography usually reveals LVH and frequently a VSD with bidirectional shunting. The usual treatment of diuretics, ionotropics, and beta-blockers do little to prevent the progressive heart failure. Histology shows myocardial fiber disarray with branching myocytes of various sizes and foci of whorled cells containing bizarre-shaped nuclei. Adult heterozygotes are also at significant risk for heart disease, including sudden death before the 5th decade as a result of asystole. Males complain of exertional fatigue and may be unable to perform hard labor. They may complain of palpitations and extra-systoles, and sometimes feel faint or may actually collapse temporarily. Females become symptomatic most notably in the later stages of pregnancy during the 4th decade. Diuretics and beta-blockers may relieve these symptoms but many women discontinue them following delivery and often deny significant symptoms thereafter. Echocardiography in symptomatic adults usually reveals hypertrophy of ventricular walls, especially the left, without dilation and outflow obstruction.
GENETICS: The MYBPC3 Amish mutation resides on chromosome 11, in the region 11p11.2. A splice site change (3330+2T>G) is present in intron 30, homozygous in affected infants and in a single allele in heterozygous adults. The gene is autosomal recessive in affected infants but can also be considered autosomal dominant in symptomatic heterozygous adults. Another mutation in MYBPC3 with a G insertion at 791 in exon 25 has been found in three DG Mennonite families in Manitoba and Belize. Heterozygous adults in the third and fourth decades of life were at risk of sudden cardiac death. No homozygous infants have been reported in these families.
TREATMENT: The only known treatment for infants with two copies of the mutation is a heart transplant. Adult carriers should be monitored by a cardiologist. Many will never develop clinical heart disease, but for those who have heart disease, appropriate medications for heart failure and implants for arrhythmias can be life-saving.
PROGNOSIS: The only surviving homozygotes have had orthotropic heart transplants. Heterozygous adults may experience asystole and sudden death, or chronic low-grade heart failure unless appropriately treated. Arrhythmias and repeated syncopal episodes may benefit from pacemaker and defibrillator implantation. Importantly, the majority of adults never have cardiac symptoms and live otherwise healthy lives.
SPECIALISTS AND SPECIALTY CENTERS: Survival of homozygous infants requires immediate attention by a cardiologist and ultimately a major medical center skilled in pediatric heart transplantations. Heterozygous adults should be monitored by a cardiologist, with appropriate pharmaceutical and medical intervention as indicated.
ANCILLARY TREATMENTS AND SUPPORT SERVICES: Families in which the gene is known to segregate should be appropriately counseled regarding the risk of homozygosity in future children. It may also be advisable that all potential heterozygous adults, as determined by the family pedigree, be genotyped and, if found to be carriers, have a full cardiac evaluation, including echocardiography. Lifestyle and nutrition are important in those at risk of heart disease and should be modified as recommended by a cardiologist.
Zahka, K., Kalidas, K., Cross, H., Keller, B.B., Galambos, C., Gurtz, K., Patton, M.A., and Crosby, A.H.: Homozygous mutation of MYBPC3 associated with severe infantile hypertrophic cardiomyopathy at high frequency amongst the Amish. Heart 94: 1326-1330, 2008. PubMed ID: 18467358
Xin, B., Puffenberger, E., Tumbush, J, Bockoven, J.R., and Wang, H.: Homozygosity for a novel splice site mutation in the cardiac myosin-binding protein C gene causes severe neonatal hypertrophic cardiomyopathy. Am. J. Med. Genet. 143A: 2662-2667, 2007. PubMed ID: 17937428
Orton, N.C., Innes, A.M., Chudley, A.E., and Bech-Hansen, N.T.: Unique disease heritage of the Dutch-German Mennonite population. Am. J. Med. Genet. 146A: 1072-1087, 2008. PubMed ID: 18348259
Niimura, H., Bachinski, L.L., Sangwatanaroj, S., Watkins, H., Chudley, A.E., McKenna, W., Kristinsson, A., Roberts, R., Sole, M., Maron, B.J., Seidman, J.G., Seidman, C.E.: Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. New Eng. J. Med. 338: 1248-1257, 1998. PubMed ID: 9562578