title: Muscle histopathology in nebulin-related nemaline myopathy: ultrastrastructural findings correlated to disease severity and genotype.
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.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Malfatti
authors.forename: Vilma-Lotta
authors.initials: VL
authors.lastname: Lehtokari
authors.forename: Johann
authors.initials: J
authors.lastname: Böhm
authors.forename: Josine M
authors.initials: JM
authors.lastname: De Winter
authors.forename: Ursula
authors.initials: U
authors.lastname: Schäffer
authors.forename: Brigitte
authors.initials: B
authors.lastname: Estournet
authors.forename: Susana
authors.initials: S
authors.lastname: Quijano-Roy
authors.forename: Soledad
authors.initials: S
authors.lastname: Monges
authors.forename: Fabiana
authors.initials: F
authors.lastname: Lubieniecki
authors.forename: Remi
authors.initials: R
authors.lastname: Bellance
authors.forename: Mai Thao
authors.initials: MT
authors.lastname: Viou
authors.forename: Angéline
authors.initials: A
authors.lastname: Madelaine
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.forename: Ana Lía
authors.initials: AL
authors.lastname: Taratuto
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Katarina
authors.initials: K
authors.lastname: Pelin
authors.forename: Michel
authors.initials: M
authors.lastname: Fardeau
authors.forename: Coen A C
authors.initials: CA
authors.lastname: Ottenheijm
authors.forename: Carina
authors.initials: C
authors.lastname: Wallgren-Pettersson
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
authors.affiliation: Unité de Morphologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France. nb.romero@institut-myologie.org.
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008854:Microscopy, Electron; D009119:Muscle Contraction / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics*; D018908:Muscle Weakness / Q000209:etiology; D009132:Muscles / Q000473:pathology* / Q000648:ultrastructure*; D017696:Myopathies, Nemaline / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D009218:Myosins / Q000378:metabolism; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D009124:Muscle Proteins; C035620:nebulin; D018995:Myosin Heavy Chains; D009218:Myosins
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