Novel α-Actin Gene Mutation p.(Ala21Val) Causing Familial Hypertrophic Cardiomyopathy, Myocardial Noncompaction, and Transmural Crypts. Clinical-Pathologic Correlation

Abstract

Background: Mutations of α-actin gene (ACTC1) have been phenotypically related to various cardiac anomalies, including hypertrophic cardiomyopathy and dilated cardiomyopathy and left ventricular (LV) myocardial noncompaction. A novel ACTC mutation is reported as cosegregating for familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts.

Methods and results: In an Italian family of 7 subjects, 4 aged 10 (II-1), 14 (II-2), 43 (I-4) and 46 years (I-5), presenting abnormal ECG changes, dyspnea and palpitation (II-2, I-4, and I-5), and recurrent cerebral ischemic attack (I-5), underwent 2-dimensional echo, cardiac magnetic resonance, Holter monitoring, and next-generation sequencing gene analysis. Patients II-2 and I-5 with ventricular tachycardia underwent a cardiac invasive study, including coronary with LV angiography and endomyocardial biopsy. In all the affected members, ECG showed right bundle branch block and left anterior hemiblock with age-related prolongation of QRS duration. Two-dimensional echo and cardiac magnetic resonance documented LV myocardial noncompaction in all and in I-4, I-5, and II-2 a progressive LV hypertrophy up to 22-mm maximal wall thickness. Coronary arteries were normal. LV angiography showed transmural crypts progressing to spongeous myocardial transformation with LV dilatation and dysfunction in the oldest subject. At histology and electron microscopy detachment of myocardiocytes were associated with cell and myofibrillar disarray and degradation of intercalated discs causing disanchorage of myofilaments to cell membrane. Next-generation sequencing showed in affected members an unreported p.(Ala21Val) mutation of ACTC.

Conclusions: Novel p.(Ala21Val) mutation of ACTC1 causes myofibrillar and intercalated disc alteration leading to familial hypertrophic cardiomyopathy and LV myocardial noncompaction with transmural crypts.

Keywords: familial hypertrophic cardiomyopathy; gene mutation; myocardial noncompaction.

Figure 1

Pedigree of reported family. Squares and circles indicate male and female family members, respectively. Arrow indicates proband. Solid symbols are affected individuals. Ages refer to age of diagnosis. HCM indicates hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction; ys, years.

Figure 2

Magnetic resonance, histological, and ultrastructural characteristics of patient III‐2 with α‐actin gene mutation p.(Ala21Val). Cine steady‐state free precession image acquired on vertical long axis (A) midventricular short‐axis (B) and horizontal long‐axis (C) views show diffuse and symmetric mild left ventricular hypertrophy, mostly distributed at basal anterior wall (maximal wall thickness, 12 mm) and apical lateral wall, trabeculated noncompacted myocardium involving anterior and lateral walls, and deep transmural crypts located at basal inferior LV wall (arrowheads). No areas of gadolinium enhancement have been detected on late gadolinium‐enhanced inversion recovery imaging (D). E and F, Represents diastolic and systolic frames of LV angiography showing diffuse transmural crypts with preserved LV function. G and H, LV endomyocardial biopsy showing hypertrophy with disarray of myocardiocytes with cell separated by unendothelialized large and deep spaces (c=channels). At high magnification (H) detail of 2 myocardiocytes in a region close to their intercalated disc. The organization of sarcomeric filaments appears variously disordered, possibly attributed to the mutated nonsarcomeric actin, which normally contributes to the physiological interactions between sarcomeric actin and anchorage system of Z‐disc associated to the intercalated disc. Bar represents 10 μm. LV indicates left ventricular.

Figure 3

Magnetic resonance, histological, and ultrastructural characteristics of patient II‐5 with α‐actin gene mutation p.(Ala21Val). Cine steady‐state free precession images acquired on 3‐chamber (A), short‐axis (B), and 4‐chamber (C) views show deep myocardial crypts (arrowheads) penetrating almost the entire thickness of myocardium, involving almost all segments, hypertrophy of basal septum (maximal wall thickness, 22 mm), and highly trabeculated midapical anterolateral wall as commonly observed in noncompaction myocardium. Late gadolinium‐enhanced inversion recovery short‐axis image (D) shows diffuse enhancement of anterolateral wall consistent with diffuse interstitial fibrosis. E and F, LV angiography showing LV dilation and dysfunction associated with spongeous conformation of LV myocardium. G, LV endomyocardial biopsy showing severe hypertrophy with disarray of cardiomyocytes separated by large unendothelialized channels (c=channels). H, TEM at low magnification of the final niche of the abnormal invaginations among myocardiocytes, which characterize the “spongy” zone of the myocardium. The compact zone is clearly defined by the presence of junctional complexes of the intercalated disc. Myocardiocytes (lower part of the picture) can show large areas of myofibrillolysis. Bar represents 10 μm. LV indicates left ventricular; TEM, transmission electron microscopy.

Figure 4

Location of Ala²¹ in the tridimensional structure of the actin–myosin binding module. Docking of S1 myosin domain (yellow) onto actin showing that S1 interacts with 2 actin molecules (green and red). Ala²¹ (colored in cyan and highlighted by arrows) is part of the actin core domain and is nearby the binding site with ATP.