Autosomal-Dominant Transmission

Autosomal-dominant transmission accounts for most cases of familial DCM, which may present either as heart failure or as a conduction abnormality. Ten genetic loci have been mapped for cardiomyopathy without conduction system disease. Seven of these genes are known: actin (chromosome 15q14), desmin (chromosome 2q35), δ-sarcoglycan (chromosome 5q33), β-sarcoglycan (chromosome 4q12), cardiac troponin T (chromosome 1q3), β-myosin heavy chain (β-MHC, chromosome 14q11), and α-tropomyosin (chromosome 15q22); see Table 21-1. Mutations in the α-tropomyosin gene are associated with familial HCMs. Actin, a sarcomeric protein, leads to DCM if the mutation affects its binding to dystrophin (at the sarcolemma level) or to HCM if the mutation affects the myosin-binding region. Mutations of the β-MHC and of cardiac troponin T genes are thought to produce DCM by causing reduced force generation by the sarcomere. In particular, the β-MHC mutation disrupts interactions between actin and myosin or with a hinge area within myosin that transmits movement. Mutations in cardiac troponin T decrease the power of contraction by reducing the ionic interactions between cardiac troponins T and C. The α-tropomyosin mutation interferes with the integrity of the thin filaments. Other mutations are involved either with the stability of the sarcomere or the sarcolemma, or with signal transduction.

Cardiomyopathy with conduction system disease is associated with five mapped loci and one identified gene, lamin A/C, on chromosome 1q21, which encodes a nuclear envelope intermediate filament protein. This mutation also causes Emery-Dreifuss muscular dystrophy.

X-Linked Transmission

Characterized by elevated amounts of serum creatine kinase muscle isoforms, the disease-causing gene of X-linked transmission leads to a severe reduction or absence of dystrophin, a cytoskeletal protein, in the heart. This gene is responsible for Duchenne’s and Becker’s muscular dystrophies as well. The mutations cluster in the 5′ portion of the gene affecting the N-terminal actin-binding region of the dystrophin protein.

Mitochondrial Inheritance (Barth’s Syndrome)

Seen most often in male infants, mitochondrial inheritance also follows an X-linked genetic transmission but is considered a separate category because it is characterized by abnormal mitochondrial function, neutropenia, and 3-methylglutaconic aciduria. The responsible gene was found to encode the protein tafazzin. Although the role of tafazzin is unknown, its mutation results in many clinical disorders, including DCM, hypertrophic DCM, endocardiac fibroelastosis, and left ventricular (LV) noncompaction, with or without Barth’s syndrome features. There are also reports linking abnormalities of energy production and mitochondrial DNA mutations to cardiomyopathies. In at least two families, HCMs that have evolved to severe DCMs have been linked to transfer RNA–lysine defects.