After determining the pattern of inheritance from the family pedigree whether autosomal dominant, recessive, X-linked, or mitochondrial the
next steps are the following:
Male with elevated serum creatinine phosphokinase (muscle isoform). Exclude a dystrophin defect. Dystrophin is a large rod-like protein linking intracellular actin with extracellular matrix proteins via a transmembrane protein complex. Dystrophin defects cause Duchenne and Becker muscular dystrophy. If the patient is a heart transplantation candidate, and undergoes endomyocardial biopsy to exclude disorders contraindicating transplantation, then perform dystrophin immunohistochemistry on the biopsy samples. An abnormal dystrophin immunostain is an indication for biochemical and molecular diagnostics: Western blotting, using the same antibodies as for immunohistochemistry, shows banding pattern abnormalities, and can indicate further investigation of underlying gene defects by peripheral blood DNA analysis.
Male with elevated creatine phosphokinase and documented pathological or molecular diagnosis of Becker muscular dystrophy. Assume cardiomyopathy in a Becker muscular dystrophy setting. Endocardial biopsy is unnecessary. Molecular analysis can be performed on peripheral blood DNA.
Male or female with elevated serum creatine phosphokinase and suspected recessive inheritance.
Perform immunohistochemistry of dystrophin-associated glycoprotein expression on endomyocardial biopsy samples using commercially available specif- ic antibodies. If immunostaining identifies a glycoprotein defect, analyze the gene concerned.
Male or female with signs such as lactacidemia, hypoacusis, palpebral ptosis, ragged red fiber myopathy, ophthalmoplegia, encephalopathy, retinitis pigmentosa, or another mitochondrial-related phenotype. Suspect mitochondrial disease. The endomyocardial biopsy ultrastructure always shows mitochondrial abnormalities: giant mitochondria, concentric crystae, and intramitochondr-ial inclusions. Light microscopy abnormalities are nonspecific.
Child with nonketonuric hypoglycemia, car-diomegaly, and chronic muscle weakness. Suspect carnitine deficiency. Carnitine plays a key role in fatty acid metabolism. It is essential for amino acid transfer into the mitochondria. Despite the defect heterogeneity in carnitine cardiomyopathy, outcome essentially depends on diagnosis: increasing serum carnitine concentrations by carnitine supplementation overcomes the carnitine transport defect across the cell membrane and achieves adequate intracellular carnitine levels.
Male child with dilated cardiomyopathy, short stature, and granulocytopenia. Suspect Barth syndrome. Check urine for 3-methylglutaconic acid. Barth syndrome is a rare X-linked disease that presents in childhood. The gene and its product are known. Molecular diagnostics are available.
Cardiomyopathy with associated atrioventricular block. Exclude conditions such as hemochromatosis (serum ferritin and serum transferrin saturation),
X-linked emerin defects (immunostaining endomyocardial biopsy), and idiopathic cardiomyopathy (molecular diagnostics).
Most patients with familial or nonfamilial dilated cardiomyopathy have no creatinine phosphokinase elevation, no atrioventricular block, and no extracardiac clues to a molecular diagnosis. Linkage analysis has identified several disease loci, and three disease genes in recent years. Actin and desmin gene defects have been recently described in a few unrelated families. Although molecular screening of candidate genes and/or linkage analysis represent ideal diagnostic tools, management still has to rely, not on molecular genetics, but on clinical examination, assessment of the familial setting, identification of predinical signs and asymptomatic patients, prevention of life-threat-ening ventricular arrhythmias, and counseling.
Arbustini E, Diegoli M, Fasani R, et al. Mitochondrial DNA mutations and mitochondrial abnormalities in dilated cardiomyopathy. Am J Pathol. 1998;153:1501-1510.
Arbustini E, Morbini P, Pilotto A, Gavazzi A, Tavazzi L. Familial dilated cardiomyopathy: from clinical presentation to molecular genetics. Eur Heart J. 2000;21:1825-1832.
Cox GF, Souri M, Aoyama T, et al. Reversal of severe hypertrophic cardiomyopathy and excellent neuropsychologic outcome in very-long-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr. 1998; 133:247-253. D’Adamo P, Fassone L, Gedeon A, et al. The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies. Am J Hum Genet. 1997;61:862-867.
familial dilated cardiomyopathy; cardiomyopathy; diagnosis; inheritance; genetics
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