What are the most frequent clinical profiles of genetic dilated cardiomyopathy and the most useful etiological investigations?

Having diagnosed left ventricular dilatation and dysfunction with angio-graphically normal coronary arteries and excluded secondary causes of dilated cardiomyopathy (hypertension, alcohol, arrhythmia, congenital heart disease, pericardial or systemic disease), the next step is to determine the pattern of inheritance from the family pedigree. In this regard, specific markers of cardiac dysfunction may provide genetic clues.

Male with an elevated serum creatine phosphokinase (muscle isoform). A dystrophin defect must be excluded. Dystrophin defects cause Duchenne and Becker muscular dystrophy, but there is a form in which cardiac involvement predominates in the presence of only mild or absent skeletal impairment. The first step, an extensive molecular screen of peripheral blood DNA, identifies defects in over 80% of cases. In the remaining 20%, molecular analysis should be followed by endomyocardial or skeletal muscle biopsy and electron microscopy. Identification of the defect must then be followed by screening of family members for incipient disease in younger brothers or maternal uncles and male cousins. Microsatellite studies can identify the female carriers (sisters, maternal aunts and female cousins, and obligate carrier daughters).

Male with an elevated serum creatine phosphokinase and documented clinical or molecular Becker muscular dystrophy. The disease should be considered as a cardiomyopathy in a Becker muscular dystrophy setting. Molecular analysis of the peripheral blood DNA gives the diagnosis.

Male or female with elevated serum creatine phosphokinase and suspected recessive inheritance.

Endomyocardial biopsy samples should be tested immunohistochemically for the expression of dystrophin-associated glycoproteins using commercial specific antibodies (sarcoglycan [oc, (3, y, 6], fi-dys-troglycan, merosin [laminin a2], and spectrin). If immunostains identify a defect in one of above glycoproteins, the relative gene can be analyzed. No dys-trophin-associated glycoprotein defect has been identified to date in several series of isolated dilated cardiomyopathy patients. However, the recent finding of a deletion affecting the first portion of the gene encoding D-sarcoglycan in the hereditary car-diomyopathic hamster is encouraging further studies in this direction.

Male or female with signs such as lactic acidosis, hypoacusis, palpebral ptosis, ragged red fiber myopathy, ophthalmoplegia, encephalopathy, retinitis pigmentosa, or other mitochondrial phenotype. The inheritance of these mitochondrial defects is matrilin-eal. However, it is unusual for the disease to present clinically as sporadic, especially in small families. In addition, the variable amount of mutated DNA in maternal relatives, and in different tissues from the same subject, complicates understanding of the clinical phenotype. Identical gene defects generate wide phenotypic heterogeneity. Ultrastructural analysis of endomyocardial biopsies from these patients always shows mitochondrial abnormalities: giant mitochondria, concentric crystae and intramitochondrial inclusions. Light microscopy abnormalities are nonspecific; however, histoenzymatic reactions for mitochondrial

Epidemiology and genetics oxidative enzymes (cytochrome c oxidase and NADH dehydrogenase) may show decreased enzyme activity if the defect involves mitochondrial genes encoding enzyme subunits or transfer RNAs. Decreased succinate dehydrogenase activity is extremely rare, and may derive from nuclear defects, since all succinate dehydrogenase subunits are encoded by nuclear genes.

It is important to underline that mitochondrial disorders can be due to defects in either mitochondrial or nuclear DNA. Thus, a Mendelian pattern of inheritance does not exclude mitochondrial disease. Little is known about nuclear DNA defects causing these diseases. In contrast, our information on mitochondrial DNA defects is steadily increasing, as is the number of mutations/defects associated with mitochondrial disease. Analysis of mitochondrial DNA defects is facilitated by the ability to screen the entire DNA, which has been entirely coded since 1981. There are also other aids in assessing the potential pathological role of any known or novel mutation: the coexistence of normal and defective DNA (het-eroplasmia), absence of the mutation in healthy control series, and defects in conserved regions, all of which make it more likely that the mutation plays a role in the disease. Once the defect has been identified, the only clinical implication is genetic counseling; there is no specific or effective therapy for mitochondrial cardiomyopathy.

Child with nonketonuric hypoglycemia, car-diomegaly and chronic muscle weakness. Carnitine deficiency should be suspected. Carnitine plays a key role in fatty acid metabolism. It is essential for the transfer of fatty acids into the mitochondria. The causes of carnitine deficiency can be classified as primary defects, due to mutations of the genes encoding carnitine transmembrane transport systems, and secondary defects, due to errors in mitochondrial fatty acid oxidation, with excess carnitine loss in the kidney. The disease can also present with arrhythmias and conduction defects, or with endocardial fibroelastosis. Despite the defect heterogeneity in carnitine cardiomyopathy, disease outcome essentially depends on making a correct diagnosis. Increasing serum carnitine concentrations by carnitine supplementation can over-come the carnitine transport defect across the cell membrane and achieve adequate intracellular carnitine levels.

Male child with dilated cardiomyopathy, short stature, and granulocytopenia. The suspicion of Barth syndrome (neutropenia, cardiomyopathy, muscle weakness, growth retardation) requires confirmation from the urinary 3-methylglutaconic acid level. Barth syndrome is a rare X-linked pediatric disease; the gene (TAZ) and its tafazzin product are known, and molecular diagnosis is available. Another X-linked tafazzin related cardiomyopathy is the ventricular compaction syndrome.

Cardiomyopathy and atrioventricular block. A series of known disorders must be ruled out:

– Hemochromatosis. Atrioventricular block may be the first clinical marker of the disease, with left ventricular dysfunction coming later, often at the end stage. The diagnosis requires measurement of the serum ferritin level and serum transferrin saturation. Investigations can be extended to include the known molecular defects of hereditary hemochromatosis, namely the Cys282Tyr, His63Asp, and Ser65Cys mutations in the HFE/HLA-H gene. In young patients, the disease is unlikely to be related to the HFE gene; for instance, only the Cys282Tyr mutation seems to be causally related to the disease. On the other hand, older patients are more likely to carry HFE gene defects. The paramount role played by correct and early diagnosis (hence early treatment) makes it mandatory to exclude this disease.

– X-linked emeriti defects. Patients characteristically present with Emery-Dreifuss disease. Diagnosis is simple: emerin is a nuclear membrane protein that can be identified by immunostaining endomyocardial biopsy sections with specific antibodies. The gene is known, and molecular diagnosis is readily available for family studies.

– Lamin A/C cardiomyopathy is a familial dilated cardiomyopathy with a variable course. Atrioventricular block may appear first, followed by the dilated cardiomyopathy phenotype. Two associated loci have been identified, one of which (lql) contains the LMNA gene for the nuclear envelope proteins lamin A and C. Mutations in the head and tail domains of the gene cause the autosomal form of Emery-Dreifuss muscular dystrophy. A recent study has identified five novel missense mutations in the rod domain of the lamin A/C gene, associated with progressive conduction system disease and familial dilated cardiomyopathy.

– Desmin storage disease. Atrioventricular block is the rule in desmin storage disease, with or without restrictive cardiomyopathy. The disorder is autosomal dominant, often associated with skeletal muscle involvement of variable extent and severity. Desmin accumulations in cardiac and skeletal muscle myocytes are easily diagnosed and characterized by electron and immunoelectron microscopy: the diagnostic marker is the granulofilamentous material immunoreacting with antidesmin antibodies. Light microscopy immunohistochemistry has a diagnostic role only in skeletal muscle biopsy, showing characteristic subsarcolemmal accumulations of desmin; it is nonspecific in endomyocardial biopsy. The disease gene is intriguing: since original linkage analysis had excluded desmin as the candidate, the defect was thought to be posttranscriptional, and other genes were proposed instead. In particular, a missense mutation in the a-B-crystallin gene (CRYAB) was identified in the affected members of one family with desmin storage disease. The role of a-B-crystallin in desmin accumulation has been ascribed to the interaction between the two proteins in the intermediate filament network assembly, which is negatively affected by the mutation. However, a heterozygous missense mutation has been reported in the desmin gene in one affected family, and compound heterozygosity for two other mutations in another family. A recent study has shown a further desmin gene defect in familial dilated cardiomyopathy without desmin accumulation. Since desmin is an essential intermediate filament linking Z bands, its gene represents an optimal candidate for dilated cardiomyopathy as well as for other types of cardiomyopathy.

Dilated cardiomyopathy. No specific marker is associated with cardiac dysfunction, and no clinical sign offers a guide to molecular genetic analysis.

Further reading

Keywords

familial dilated cardiomyopathy; diagnosis; etiology; genetics; biological marker; inheritance

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