Kyphoscoliosis peptidase deficiency-induced myofibrillar degeneration, focal depletion of mitochondria, and protein aggregation: A true myofibrillar myopathy?

Figures

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  Figure 1.. Pedigrees, clinical features, and muscle MRI findings in two consanguineous families with homozygous KY variants. (A) Pedigrees of two unrelated families. The two affected members of family A harbor the homozygous missense variant c.727T > C residing in exon 9. Genetic analysis of the single affected member of family B resulted in the identification of the homozygous splice site variant c.710 + 1G > A in intron 8. Lateral tongue atrophy (B, in patient A/II/1), equinovarus deformity (E, in patient A/II/1), and generalized muscle wasting (C, in patient B/II/1) were present in all three affected individuals. In addition to neck and elbow contractures, all three patients showed signs of mild kyphoscoliosis and rigid spine (D, in patient B/II/1). Muscle MRI of the thighs in patient A/II/1 (T1-weighted TSE-sequences, transversal sections) depicted slight to moderate signal alterations in the proximal parts (F) of the vastus lateralis (1), vastus intermedius (2), semimembranosus (3), long head of biceps femoris (4), and adductor magnus (5) muscles. Note that the signal alterations were much more pronounced in the distal parts of the affected muscles (G).

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  Figure 2.. Myopathological findings, kyphoscoliosis peptidase modelling, and immunoblot analysis. (A) A H&E-stained section of a diagnostic muscle biopsy from the deltoideus muscle of patient A/II/1 showed a myodystrophic picture with a moderate to marked increase of endomysial connective tissue, rounding of muscle fibers, increased fiber size variability, a large number of internalized myonuclei, a few pyknotic clumps, degenerating fibers (asterisk), a few fibers with rimmed vacuoles (R), as well as multiple fibers containing eosinophilic sarcoplasmic inclusions (arrowheads). (B,D) Note the presence of multiple fibers with large core-like areas in the SDH-stained section. While kyphoscoliosis peptidase (C) and filamin-C (E) immunostaining showed a positive labelling of these sarcoplasmic inclusions (arrowheads), they only displayed a minimal or even absent enrichment of desmin (F, circles). (G-I) Electron microscopy revealed degenerative changes of the myofibrillar apparatus with lysis of myofibrils (asterisks), flag-like areas of Z-band steaming (z) and the absence of intermyofibrillar mitochondria, as well as the presence of lipofuscin deposits (hashtags). (J) Cartoon representation of…