What are the genetic transmission patterns of familial dilated cardiomyopathy?

Dilated cardiomyopathy is a heart muscle disease characterized by dilatation and impaired contraction of the left ventricle or both ventricles. It may be idiopathic, familial/genetic, viral, and/or immune, alcoholic/toxic, or associated with preexisting cardiovascular disease to a degree unexplained by the abnormal loading conditions or extent of ischemic damage. The etiopathogenesis is unknown in half the cases. The importance of genetic factors was long underestimated. In 1981, a retrospective Mayo Clinic study estimated the proportion of familial cases to be 2%. Since then, however, several prospective studies have shown that at least 25% of cases are genetically transmitted.

The overall reported prevalence of familial dilated cardiomyopathy, including X- and non-X-linked disease, ranges from 2% to 56%. The discrepancies result from the differences in settings and family study approaches. However, the true frequency probably remains underestimate, as familial and nonfamilial cases can still not be differentiated on the basis of any clinical or histopathological feature, but only from the family history. Underestimation is also caused by the variable penetrance of the gene defects and/or the absence of early disease markers.

Familial dilated cardiomyopathy is a heterogeneous disorder as suggested by its different, predominantly

It can be classified as follows:

Autosomal dominant pure familial dilated cardiomyopathy features ventricular dilatation and impaired systolic ventricular function during second or third decade of life, with the gradual development of heart failure and ventricular arrhythmias. The disease loci with an autosomal dominant transmission have been mapped to chromosomes 9, lq32, and 10q21-23. The phenotypic features support the theory that dilated cardiomyopathy is caused by mutations in cytoskeletal proteins such as vinculin, anchirin, and actin.

Autosomal dominant dilated cardiomyopathy associated with atrioventricular conduction defects typically onsets with second- or third-degree atrioventricular block requiring permanent pacing. In this early phase ventricular dysfunction is often mild. Two loci have been identified in this subset: 3p22-25 and lpl-lql, the latter containing the gene for the nuclear envelope proteins lamin A and C. Mutations in the head and tail domains of this gene cause the autosomal form of Emery-Dreifuss muscular dystrophy.

Autosomal dominant dilated cardiomyopathy associated with myopathy presents with subclinical skeletal muscle disease and marked variability of expression. The phenotype shows no clinical difference between affected males and females; the degree of skeletal muscle involvement varies; and conduction defects may be present, together with frequent ventricular arrhythmia, and levels of serum creatine kinase skeletal muscle isoenzymes (CK-MM) ranging from overtly abnormal to normal even in the same subjects, depending on the disease stage. Skeletal muscle biopsy shows dystrophic changes, with normal dystrophin.

Autosomal recessive dilated cardiomyopathy appears in young people in whom its course is characterized by a rapid progression to death or transplantation.

X-linked dilated cardiomyopathy due to dystrophin gene deletion/mutations. Dystrophin is a cytoskeletal protein that plays an important role in membrane stability, transduction of the contractile force, and membrane organization in skeletal and cardiac myocytes. It is a large rod-like protein linking intracellular actin with extracellular matrix proteins via a transmembrane protein complex. Mutations or deletions in the dystrophin gene cause two X-linked disorders: Duchenne and Becker muscular dystrophy. X-linked dilated cardiomyopathy causes rapidly progressive severe heart failure in young males, with no clinical signs of skeletal myopathy, but usually an increase in CK-MM. Inheritance is X-linked with no male-to-male transmission. Onset in the female carrier is delayed and progression slower.

Matrilineal mitochondrial dilated cardiomyopathy.

It has long been suspected that a defect in mitochondrial DNA could be responsible for dilated cardiomyopathy, in particular in families with suspected matrilineal transmission. Mitochondrial DNA differs from genomic DNA in having no introns, no DNA-folding (histonic) proteins, and no effective systems of DNA repair. Its mutation frequency is also over 10-fold that of nuclear DNA. The presence of cells with normal or mutated mitochondrial DNA and/or the coexistence within the same cell of normal and mutated mitochondrial DNA may explain the variability of cardiac involvement and penetrance. Cardiomyopathy is a frequent development in several mitochondrial syndromes, such as mitochondrial myopathy, encephal-omyopathy, lactic acidosis, and stroke-like symptoms (and sometimes seizures) (MELAS), myoclonus epilepsy with ragged red fibers (MERRF), Kearns syndrome (mitochondrial cytopathy), and maternally inherited myopathy and cardiomyopathy (MIMyCA). Multiple mitochondrial DNA deletion has been described in a family with dilated cardiomyopathy, but its causal role is disputed. Point mutations may be relevant, but further research is needed.

Right ventricular cardiomyopathy, which can mimic dilated cardiomyopathy, has arrhythmogenic right ventricular dysplasia as its predominant feature, with localized or widespread fibrofatty infiltration of the right ventricular myocardium, dilatation, dysfunction and arrhythmia, and left bundle branch block.

Keywords

genetics; familial dilated cardiomyopathy; transmission; etiopathogeny; epidemiology

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