Search

Neuromuscular disorders (NMD) with neonatal or perinatal onset are usually severe. The establishment of a definite diagnosis relies on the combination of clinical examination, enzymatic tests, muscle morphology analyses, and genetic investigations, and is essential to provide a vital prognosis, propose adequate genetic counseling, consider treatment options, and include the patients into clinical trials for innovative therapies. However, the recent and rapid advancements of panel, exome, and genome sequencing questions the utility of invasive muscle biopsies and the contribution of histological and ultrastructural studies of muscle sections to the diagnosis process. Here, we explored the relevance of muscle biopsies collected at the Institute of Myology in Paris over a period of more than 50 years (1970-2021) in light of the evolution of Sanger and next-generation sequencing (NGS) technologies. Altogether, 82% of the biopsies showed typical structural myofiber anomalies highly suggestive of specific NMD classes (congenital myopathies, metabolic myopathies, lower motor neuron (LMN) and neuromuscular junction (NMJ) disorders, muscular dystrophies, inflammatory myopathies), while the remaining 18% showed no or only non-specific histological abnormalities. The diagnosis success rate differed among the NMD classes and changed over time following the identification of major disease genes like SMN1 or DMD , shifting the focus to direct gene sequencing and reducing the necessity of muscle biopsies. Ultrastructural investigations were of particular importance for the diagnosis of congenital myopathies and less relevant for the other NMD categories. Typical myofiber lesions found in congenital myopathies as intranuclear rods in ACTA1-related nemaline myopathy are barely discernible under the light microscope and solely detectable by electron microscopy (EM). This shows that the higher resolution of EM is not only a feature complementing light microscopy, but also a powerful diagnostic method. From our experience, morphological muscle biopsy examinations were frequently accurate and either pointed to a group of myopathies or to single genes. In conclusion, this retrospective study describes a unique collection of neonatal muscle biopsies and illustrates that the thorough analysis of muscle sections was of major diagnostic relevance in the past and still plays an important role nowadays - either by directing purposeful gene sequencing or by complementing clinical findings and biochemical analysis methods. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]