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

Figures

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  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.

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  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…

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  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…

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  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.