Abstract
Nemaline myopathy (NM) is a rare congenital myopathy characterised by hypotonia, muscle weakness, and often skeletal muscle deformities with the presence of nemaline bodies (rods) in the muscle biopsy. The nebulin (NEB) gene is the most commonly mutated and is thought to account for approximately 50% of genetically diagnosed cases of NM. We undertook a detailed muscle morphological analysis of 14 NEB-mutated NM patients with different clinical forms to define muscle pathological patterns and correlate them with clinical course and genotype. Three groups were identified according to clinical severity. Group 1 (n = 5) comprises severe/lethal NM and biopsy in the first days of life. Group 2 (n = 4) includes intermediate NM and biopsy in infancy. Group 3 (n = 5) comprises typical/mild NM and biopsy in childhood or early adult life. Biopsies underwent histoenzymological, immunohistochemical and ultrastructural analysis. Fibre type distribution patterns, rod characteristics, distribution and localization were investigated. Contractile performance was studied in muscle fibre preparations isolated from seven muscle biopsies from each of the three groups. G1 showed significant myofibrillar dissociation and smallness with scattered globular rods in one third of fibres; there was no type 1 predominance. G2 presented milder sarcomeric dissociation, dispersed or clustered nemaline bodies, and type 1 predominance/uniformity. In contrast, G3 had well-delimited clusters of subsarcolemmal elongated rods and type 1 uniformity without sarcomeric alterations. In accordance with the clinical and morphological data, functional studies revealed markedly low forces in muscle bundles from G1 and a better contractile performance in muscle bundles from biopsies of patients from G2, and G3.In conclusion NEB-mutated NM patients present a wide spectrum of morphological features. It is difficult to establish firm genotype phenotype correlation. Interestingly, there was a correlation between clinical severity on the one hand and the degree of sarcomeric dissociation and contractility efficiency on the other. By contrast the percentage of fibres occupied by rods, as well as the quantity and the sub sarcolemmal position of rods, appears to inversely correlate with severity. Based on our observations, we propose myofibrillar dissociation and changes in contractility as an important cause of muscle weakness in NEB-mutated NM patients.
Highlights
Nemaline myopathy (NM) is a congenital muscle disorder associated with hypotonia, muscle weakness, and often skeletal muscle deformities with the presence of numerous nemaline bodies in muscle biopsy [1]
Summary Taken together, our results suggest that myofibrillar dissociation correlated with clinical severity
Muscle contractility experiments The maximal force generation capacity of the muscle fibre preparations was normalized to their cross-sectional area (Figure 5)
Summary
Nemaline myopathy (NM) is a congenital muscle disorder associated with hypotonia, muscle weakness, and often skeletal muscle deformities with the presence of numerous nemaline bodies (rods) in muscle biopsy [1]. To date at least nine genes have been implicated in NM (ACTA1, MIM#161800; NEB, MIM#256030; TPM2, MIM#609285; TPM3, MIM#609284; TNNT1, MIM#605355; KBTBD13, MIM#609273; CFL2, MIM#610687; KLHL40 MIM#615340; and KLHL41) encoding proteins of the thin filament of skeletal muscle sarcomere or the Kelch domain associated proteins [3,4,5,6,7,8,9,10,11]. ACTA1, TPM2 and TPM3 NM is inherited both as autosomal dominant or recessive trait, with de novo dominant mutations being common in all three genes. The other five genes present autosomal recessive mode of inheritance
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