Fig. 1

Muscle biopsy architectural characteristics in normal (a, b, and c) and dystrophic muscle (d, e, f, g, h, i, j, k, and l). Normal muscle biopsy from a 6 years old male patient suspected of congenital myopathy submitted to right vastus lateralis muscle biopsy that presented normal general architecture with very mild variation the same calibre with mild connective tissue in the perimisium (yellow arrows in a, b, and c) separating muscle fascicles, and almost imperceptible endomysium (white arrows in b and c) between muscle fibres that present nuclei (green arrows in b) disposed at the periphery of the fibres. Muscle biopsy with dystrophic pattern from a 22 years old male patient submitted to right tibialis anterior muscle biopsy for immunohistochemical confirmation of the pathogenicity of a homozygous VUS (variant of unknown significance) c.3235T > C p.(Cys1079Arg), in the exon 23 of the LAMA2 gene. The dystrophic pattern is characterized by abnormal architecture with endomysial fibrosis (white arrow in d) that results in fibrous replacement of the muscle tissue followed by muscle fat replacement (brown arrows in e, f, and i) with striking variation in fibre calibre with hypertrophy (yellow asterisks * in d, e, and j), atrophy (white asterisks * in d, e, f, and j); hypertrophic fibres may present fibre splitting (yellow arrow in d) and abnormally internalized nuclei (green arrow in d); the driver physiopathological events that result in the dystrophic pattern are necrosis (pale pink area of coagulative necrosis pointed by the white arrow in g, and pale green area pointed by the yellow arrow in k), phagocytosis (macrophages with abundant cytoplasm pointed by the yellow arrow in f, and g), and regeneration (muscle fibre with weak basophilic sarcoplasm and increased internalized nucleus pointed by the yellow arrow in h). Pathogenicity confirmation of the VUS in LAMA2 gene was demonstrated by irregular laminin-alpha2 imunohistochemical reaction (blue arrow in l), compared to the normal control (red arrow in the inset in l) (a. HE 100x, b. HE 200x, c. Modified Gomori trichrome 200x, d. HE 100x, e. HE 100x, f. HE 100x, g. HE 200x, h. HE 200x, i. Modified Gomori trichrome 25x, j. Modified Gomori trichrome 100x, k. Modified Gomori trichrome 200x, l. Immunohistochemistry anti-laminin-alpha-2 (anti-merosin) 200x, patient and control inset). VUS: variant of unknown significance)