Cardiomyopathy, Dilated, 1aa, With Or Without Left Ventricular Noncompaction

A number sign (#) is used with this entry because of evidence that cardiomyopathy of the dilated (CMD1AA) or hypertrophic (CMH23) type, with or without left ventricular noncompaction (LVNC), can be caused by heterozygous mutation in the gene encoding alpha-actinin-2 (ACTN2; 102573) on chromosome 1q43.

For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200).

For a general phenotypic description and a discussion of genetic heterogeneity of hypertrophic cardiomyopathy, see CMH1 (192600).

Clinical Features

Mohapatra et al. (2003) reported a 7-year-old girl who died of dilated cardiomyopathy only a few weeks after the onset of symptoms. At autopsy, marked dilation of both ventricles, myocyte hypertrophy, and interstitial fibrosis were noted; there were no viral genomic sequences on PCR analysis of cardiac tissue or histologic evidence of myocarditis. Her father had died of acute-onset idiopathic CMD at 42 years of age.

Theis et al. (2006) reported 3 sporadic patients with hypertrophic cardiomyopathy who were diagnosed in the second to fourth decades of life and who had maximum left ventricular wall thicknesses ranging from 16 to 20 mm; all 3 had a sigmoid septal shape and underwent myectomy. Pathology reports available from 2 of the patients noted marked myocyte hypertrophy, focal myocyte disarray, and endocardial and interstitial fibrosis. There was no family history of CMH or sudden cardiac death.

Chiu et al. (2010) studied a large 3-generation Australian family with clinically heterogeneous CMH. The proband was diagnosed after experiencing cardiac arrest during pregnancy, at which time she was found to have mild apical hypertrophy and an abnormal electrocardiogram (ECG) indicating left ventricular hypertrophy (LVH). She underwent placement of an implantable cardioverter-defibrillator (ICD) and subsequently progressed to severe heart failure. Screening of family members revealed that her father, who was being treated for atrial fibrillation, also had biventricular concentric hypertrophy. A brother had moderate asymmetric septal LVH and nonsustained ventricular arrhythmias, and received an ICD. A sister, who had apical hypertrophy with evidence of apical trabeculations as well as mild right ventricular hypertrophy, also received an ICD, which delivered shocks in response to ventricular tachycardia twice in the following 3 years. Another brother died suddenly at age 36 years; autopsy revealed asymmetric septal hypertrophy and histopathologic features consistent with CMH, including myocyte hypertrophy, myofiber disarray, and interstitial fibrosis. An echocardiogram the previous year had shown an asymmetric septal wall with a thickness of 16 mm. Their paternal uncle had mild LVH with borderline LVH changes on ECG as well as evidence of left ventricular wall thinning at age 74 years. His daughter had previously been diagnosed with arrhythmogenic cardiomyopathy and received an ICD.

Bagnall et al. (2014) studied 4 affected members over 2 generations of an Australian family with marked cardiac phenotype heterogeneity, including CMD, LVNC, ventricular fibrillation, and sudden unexplained death. The 35-year-old female proband presented at age 22 with syncope and a family history of sudden death. ECG was unremarkable, but echocardiogram and MRI showed prominent left ventricular apical trabeculations, consistent with LVNC. Electrophysiologic study did not uncover any inducible arrhythmias, and QTc was measured at 440 ms. An ICD was implanted, which had not discharged during follow-up. Her sister had died suddenly during sleep at 25 years of age, and autopsy failed to identify a cause of death. Their deceased father had a history of dyspnea, left bundle branch block, maximum left ventricular wall and posterior wall thickness of 12 mm, and left ventricular dilation with a reduced ejection fraction of 27%. A 33-year-old female cousin experienced cardiac arrest; postresuscitation MRI showed no evidence of myocardial fibrosis or cardiomyopathy. She underwent placement of an ICD for ventricular fibrillation, and the device subsequently delivered 2 appropriate shocks.

Girolami et al. (2014) reported a large 4-generation Italian family with atypical CMH and early-onset atrial fibrillation (AF). Of 18 family members who were clinically assessed, 11 had evidence of cardiomyopathic involvement, comprising variable combinations of 3 distinctive features: asymmetric LVH consistent with CMH, early-onset supraventricular arrhythmias and atrioventricular (AV) block, and regional LVNC. The proband was an 82-year-old man with mild, asymmetric LVH localized to the base and midseptum, marked biatrial dilatation, and a restrictive LV filling pattern with preserved systolic function. He had been diagnosed with nonobstructive hypertrophic cardiomyopathy (HCM) almost 3 decades earlier. He had onset of paroxysmal AF at age 30 that evolved into permanent AF with advanced AV block, requiring VVI pacing at the age of 68. Despite early onset of disease manifestations and adverse cardiac remodeling, consistent with restrictive evolution of HCM, he remained fully active with only mild functional limitation (functional class New York Heart Association class II); no significant ventricular arrhythmias were noted on repeated 24-hour ECG Holter monitoring. Prior screening was negative for mutation in the 8 most prevalent CMH-associated sarcomere genes. His brother and 2 nephews exhibited similar echocardiographic and clinical features, characterized by nonobstructive HCM with restrictive evolution, AV block, and biatrial dilation. A 4-year-old great-nephew presented at birth with esophageal atresia and tracheal fistula, ostium secundum atrial septal defect (ASD), and supraventricular tachycardia. Although there was no evidence of LVH or noncompaction, ventricular septal biopsy taken during surgery to repair the ASD revealed cardiomyocyte hypertrophy and 'typical features' of CMH. Seven other affected family members showed milder forms of cardiac disease, including mild apical LVH, regional LVNC, left atrial dilation with frequent premature atrial contractions or AF, and first-degree AV block.

Mapping

In affected members of a large 3-generation Australian family with clinically heterogeneous CMH who were negative for mutation in 10 known CMH-associated genes, Chiu et al. (2010) performed genomewide linkage analysis and obtained a maximum lod score of 2.82 on chromosome 1 at marker D2S2850 (theta = 0). Recombination events defined a 5.7-Mb critical region flanked by markers D1S2800 and D1S2670.

Molecular Genetics

In a 7-year-old girl who died of dilated cardiomyopathy and was negative for mutation in 8 known cardiomyopathy genes, Mohapatra et al. (2003) identified heterozygosity for a missense mutation at a conserved residue in the ACTN2 gene (102573.0001). The mutation was not found in the mother or in 200 controls; DNA was unavailable from the deceased father.

In a cohort of 239 patients with hypertrophic cardiomyopathy who were negative for mutation in the 8 most common CMH-associated myofilament genes, Theis et al. (2006) analyzed 5 candidate Z-disc genes and identified 14 mutations in 13 patients, including 3 different heterozygous missense mutations in the ACTN2 gene in 3 sporadic patients (102573.0002-102573.0004). The authors observed that 11 (85%) of the 13 patients with Z-disc-associated CMH had a sigmoidal septal contour, in contrast to the reverse septal curvature seen with myofilament-associated CMH.

In affected members of a large 3-generation Australian family with clinically heterogeneous CMH mapping to chromosome 1, Chiu et al. (2010) identified heterozygosity for a missense mutation in the ACTN2 gene (A119T; 102573.0005) that was not present in unaffected family members or in 260 controls. Screening of an additional 297 CMH probands identified 3 heterozygous missense mutations that segregated with disease in the respective families (see, e.g., 102573.0003 and 102573.0006). Chiu et al. (2010) noted that in contrast to previously reported patients with ACTN2 mutations (Theis et al., 2006), none of these patients displayed sigmoidal morphology; rather, they exhibited a generally mild hypertrophy with a diverse distribution, involving the septum in some individuals, whereas others showed apical, concentric, or right ventricular hypertrophy, with progression to a dilated phenotype and severe heart failure in some cases.

In 4 affected members over 2 generations of an Australian family with marked cardiac phenotype heterogeneity, including CMD, LVNC, ventricular fibrillation, and sudden death, Bagnall et al. (2014) identified heterozygosity for the same A119T substitution in the ACTN2 gene that had previously been detected in an apparently unrelated Australian family with clinically heterogeneous CMH by Chiu et al. (2010). Haplotype analysis was consistent with a common ancestor for the 2 Australian families. Genotyping of 31 additional patients with LVNC revealed no mutations.

In a large 4-generation Italian family with clinically heterogeneous cardiomyopathic disease comprising variable combinations of asymmetric LVH consistent with CMH, early-onset supraventricular arrhythmias and AV block, and regional LVNC, Girolami et al. (2014) performed next-generation sequencing and identified heterozygosity for a missense mutation in ACTN2 (M228T; 102573.0007). The mutation, which segregated fully with disease in the family, was not found in 570 control alleles. The authors noted that although the features in this Italian family were similar to those of the ACTN2-related CMH that was described in an Australian family by Chiu et al. (2010), the Italian family had a relatively favorable long-term clinical course, whereas the Australian family had a high prevalence of progressive heart failure and sudden cardiac death.