G.P.120 FHL1-related Reducing Body Myopathy and Emery–Dreifuss muscular dystrophy: A comparative histoenzymological, immunohistochemical and ultrastructural study

Abstract FHL1-related myopathies are rare disorders that recently emerged and include reducing body myopathy (RBM) a congenital disorder defined by the presence of cytoplasmic inclusions revealed by menadione-NBT staining, and Emery–Dreifuss muscular dystrophy (EDMD) characterized by early joint contractures, muscular dystrophy and cardiac involvement with arrhythmias. We report the muscle biopsy features in a series of 13 patients suffering from RBM (9) and EDMD (4) with mutations in FHL1 gene, emphasizing unusual morphological characteristics. A summary of the clinical examination was performed. Muscle specimens were processed for histoenzymological, immunohistochemical and ultrastructural analysis. Molecular analysis was accomplished by sequencing the coding regions of FHL1 gene. Muscle biopsies from RBM patients showed marked variation of fiber size, increased number of internal nuclei, fibro-fatty tissue proliferation and type I fiber predominance. A sectorial distribution of lesions was observed. Several fibers contained large inclusions strongly reacting with menadione-NBT. Desmin, alphaB-crystallin and myotilin immunoreactivity was observed surrounding RB but not within them. At the ultrastructural level, reducing bodies and cytoplasmic bodies were observed in all muscle biopsies. Furthermore a dense granular material was usually found in the subsarcolemmal region and between the myofibrils; surprisingly this was frequently seen around the myonuclei and associated to cytoplasmic bodies. By contrast, no reducing bodies were found in EDMD and the lesions were minimal. Molecular analysis revealed missense mutations in the 2nd FHL1 LIM domain for the RBM patients and ins/del or missense mutations affecting the 4th FHL1 LIM domain for EDMD patients. Our findings expand the morphological features of reducing body myopathy and further illustrate major morphological differences between patients carrying mutations in the 2nd or in the 4th LIM domain of FHL1.