Fig. 2: Spectrum of histopathological lesions.

Skeletal muscle biopsies from patients CIII.7 (a), AIII.2 (b-d, g), EII.4 (f, h-j) and DII.2 (e, k). Muscle biopsy from the most severe patient (a) showed mildly increased endomysial connective tissue, a subpopulation of very small fibers and abundant fibers with apparently normal diameter and centrally located nuclei (arrowheads). In milder patients, dystrophic features were absent and the pattern was more typical of a congenital myopathy, including FSV (b,c), internalized nuclei, often central, (c, black arrowheads), whorled fibers (c, white arrowheads) and type 1 fiber predominance (b). Intense oxidative rims beneath the sarcolemma, compatible with mitochondrial proliferation or mislocalization, were found in one patient in NADH-TR (e) and also in SDH and COX stains (not shown). There were multiple areas lacking oxidative activity (pink arrows in d) and showing mitochondrial depletion and sarcomere disorganization on EM (minicores) (g, k). Modified Gomori trichrome revealed purple stained lesions (f) which corresponded to electron-dense nemaline rods (h, j) on EM. Subsarcolemmal myofibrillar disorganization along with cytoplasmic bodies and/or subsarcolemmal rods were also observed (i). Transversal frozen sections, HE (a,c), ATPase pH 9.4 (b), NADH-TR (d,e), modified Gomori trichrome (f); electron microscopy (EM) (g-k). Scale bars= 25 µm (a,b), 50 µm (c,d), 25 µm (e,f), 10 µm (g), 1 µm (h), 2 µm (i,k), 500 nm (j).