Sarcomere Mutations in Cardiomyopathy With Left Ventricular Hypertrabeculation

Abstract

Background-Mutations in the genes encoding sarcomere proteins have been associated with both hypertrophic and dilated cardiomyopathy. Recently, mutations in myosin heavy chain (MYH7), cardiac actin (ACTC), and troponin T (TNNT2) were associated with left ventricular noncompaction, a form of cardiomyopathy characterized with hypertrabeculation that may also include reduced function of the left ventricle. Methods and Results-We used clinically available genetic testing on 3 cases referred for evaluation of left ventricular dysfunction and noncompaction of the left ventricle and found that all 3 individuals carried sarcomere mutations. The first patient presented with neonatal heart failure and was referred for left ventricular noncompaction cardiomyopathy. Genetic testing found 2 different mutations in MYBPC3 in trans. The first mutation, 3776delA, Q1259fs, rendered a frame shift at 1259 of cardiac myosin-binding protein C and the second mutation was L1200P. The frameshift mutation was also found in this mother who displayed mild echocardiographic features of cardiomyopathy, with only subtle increase in trabeculation and an absence of hypertrophy. A second pediatric patient presented with heart failure and was found to carry a de novo MYH7 R369Q mutation. The third case was an adult patient with dilated cardiomyopathy referred for ventricular hypertrabeculation. This patient had a family history of congestive heart failure, including pediatric onset cardiomyopathy where 3 individuals in the family were found to have the MYH7 mutation R1250W. Conclusion-Genetic testing should be considered for cardiomyopathy with hypertrabeculation. (Circ Cardiovasc Genet.2009;2:442-449.)

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

“…First, it showed prevention of a disease phenotype, but no rescue. Yet, we believe that prevention is the more realistic scenario in the patient group we would like to target with the gene therapy approach, namely infants with severe homozygous or compound heterozygous mutations who quickly develop a therapy-resistant form of systolic heart failure 14,[16][17][18][19][20] . Second, mouse models including our KI model clearly differ from human HCM in that they show a much milder phenotype, generally only at the homozygous state 8,40,41 .…”

“…Whereas the mean life expectancy of patients who survived into young adulthood does not markedly differ from that of the normal population 12 , sudden cardiac death is common in young adults with HCM, particularly athletes 13 , and some patients develop severe systolic dysfunction and heart failure. Less known is that neonatal forms of HCM rapidly evolve into systolic heart failure and death within the first year of life [14][15][16][17][18][19][20] . Some of these infants have homozygous or compound heterozygous frameshift MYBPC3 mutations 14,[16][17][18][19][20] , expected to result in low level or absence of mutant cMyBP-C.…”

“…Less known is that neonatal forms of HCM rapidly evolve into systolic heart failure and death within the first year of life [14][15][16][17][18][19][20] . Some of these infants have homozygous or compound heterozygous frameshift MYBPC3 mutations 14,[16][17][18][19][20] , expected to result in low level or absence of mutant cMyBP-C. Here we tested the easily generalizable idea to prevent the disease phenotype by adding full-length Mybpc3 by gene therapy in a Mybpc3-targeted knock-in (KI) mouse model 21,22 that genetically mimics the severe neonatal HCM cases 21,22 .…”

Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

“…In these adult cases, a more severe HCM phenotype is generally seen, characterized by an earlier age of onset around the second decade or during childhood (Table 2). 6,14,15,[20][21][22][23][24][25][26][27][28][29][30] In a recent study on sarcomeric protein gene variants in childhood-onset HCM, 6 out of 84 children (7%) had compound variants. 6 This suggests that a gene-dosage effect might be responsible for manifestations at a younger age.…”

Dilated Cardiomyopathy: A Disease of the Myocardium

“…29,30) Left ventricular noncompaction cardiomyopathy that is caused by a MYH7 missense mutation such as A1766T 31) is another disease that should be recognized as characteristic in dcM patients. 32,33) This disease is a myocardial disorder thought to occur as a result of arrested embryogenesis and is characterized by a spongy morphological appearance of the myocardium. 32,33) It is estimated that sarcomere gene mutations account for as much as 17% of left ventricular non-compaction (LVNc) cases, and may be present in dcM with hypertrabeculation.…”