A new congenital multicore titinopathy associated with fast myosin heavy chain deficiency

Figure 1. Clinical presentation and MRI features. (A–F) P1’s clinical features. (A) Mildly elongated face with bilateral ptosis and low‐set ears. (B) High‐arched palate. (C) Deficit in arm elevation (45°). (D) Scapular winging. (E) Distal joint hyperlaxity. (F) Prominent hyperkeratosis pilaris. (G–J) P2’s clinical features. (G) Mild ptosis without other facial dysmorphisms. (H) High‐arched palate. (I) Pelvic muscle proximal weakness; the patient cannot squat. Note the extremely thin muscle bulk. (J) Thin muscle bulk, mild scapular winging. (K and L) Three‐dimensional volume rendering reconstruction of MRI sequences in P1 (K1‐11) and P2 (L12‐22) with anterior, lateral and posterior views. These views allow a global analysis of the patients’ phenotype. Selection of 11 slices among the 350 mm thick, contiguous axial slices from head to toe; DIXON T2 (IDEAL T2) in‐phase images. P1 is older and the disease is more advanced with more fat infiltration and atrophy compared with P2. The distribution of involved muscles is similar but less pronounced in P2. Only one muscle is more fatty ‐infiltrated in P2. The upper part of the semi‐tendinous muscle is as white as subcutaneous fat in P1 (K‐7). The…

Figure 2. Skeletal muscle histology, genetic, transcripts and proteins analyses. (A–G) P1 deltoid muscle biopsy. (A) Hematoxylineosin staining. Presence of marked fiber size variation, nuclear internalization, and increased endomysial connective tissue. (B) Gömöri trichrome staining. Altered distribution of the mitochondrial network. (C) NADH. Multiple small areas of reduced oxidative activity alternating with areas of intense activity, conferring a blurred lobulated aspect to the fibers. Intense areas of oxidative staining are evident in some fibers. (D) ATPase pH 4.63. Absence of differentiation between type 1 and type 2 fibers. Only one color is detected. (E–G) Immunofluorescence analysis with antibodies against myosin alpha and beta‐slow heavy chain (E), fast 2A and 2X heavy chain (F), and merge. Presence of few scattered green fibers, demonstrating the almost complete absence of type 2 fibers that express fast myosin heavy chain isoforms. The merged image confirms this observation (G). Magnification 16×. (H) Deltoid muscle biopsy from the mother. NADH. Normal oxidative reaction. (I) Deltoid muscle biopsy from the father. NADH. Normal oxidative reaction. (J–L) Ultrastructural studies.…