Early Clinical, Imaging, and Pathological Characteristics of SRPK3 / TTN ‐Digenic Myopathy

Figures

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  FIGURE 1. A. Pedigrees and variants segregation in patients with digenic SRPK3/TTN‐myopathy. Shaded symbols denote clinically affected individuals with their corresponding identifier next to the arrow, following standard pedigree conventions. S = SRPK3 disease‐causing variant, T = TTN disease‐causing variant, WT = wild type. B. Location of each of the disease‐causing variants identified in the cohort mapped to the inferred complete TTN metatranscript and bands (Refseq transcript NM_001267550.2) (top); and the SRPK3 gene scheme and protein domains (bottom).

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  FIGURE 2. Physical examination findings. A. P1 age 6 years, scapular winging, no spinal curve. B. P1 age 9 years, scapular winging and lordotic posture with mild lateral S‐shaped spinal curve, rigidity of lumbar and thoracic spine was noted. C. P3 age 9 years, mild scapular winging. D. P2 age 9 years, asymmetric scapular winging and early thoracic curve. E. P2 age 9 years, spinal rigidity noted with forward flexion. F. P2 age 19 years, following scoliosis correction surgery. G. P1 age 6 years, mild pectus excavatum, axial weakness (neck extension). H. P2 age 9 years, mild pectus excavatum, G‐tube in place. I. P3 age 9 years, normal‐appearing chest, axial hypotonia. J. P1 age 9 years, metacarpophalangeal joints hyperlaxity. K. P2 age 9 years, wrist hyperlaxity. L. P3 age 9 years, metacarpophalangeal and wrist joints hyperlaxity. M. P2 age 9 years, slender and tapering appearance of the fingers.

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  FIGURE 3. Muscle imaging. A. Anatomical reference. MRI axial T1‐weighted scans are indicated with red lines on a human reference figure: Pelvis (top row), thighs (middle row), and lower legs (bottom row). B‐C. correspond to P2, illustrating a progression in fibroadipose tissue replacement over a 10‐year period. D‐E. from P3 and P5 respectively, the semitendinosus muscle (red arrows) has a striking early selective involvement, a feature commonly seen in TTN‐related myopathies. F. Selective semitendinosus fibroadipose replacement (red arrows) in recessive biallelic titinopathy patient. G. Muscle ultrasound from P3 mirrors the MRI findings, showing greater involvement of the semitendinosus muscle (red *), which appears enclosed in a “fat pocket.” BF, biceps femoris; AM, adductor magnus; SM, semimembranosus; ST, semitendinosus.

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  FIGURE 4. Histology and ultrastructural findings. A‐B. Thigh muscle biopsy from P2 at age 7 months. A. H&E staining shows myopathic changes with significant variation in fiber size and increased centrally placed nuclei. B. Gömöri trichrome (GT) staining is notable for “rod‐like structures.” C‐D. Vastus medialis muscle biopsy from P2 at age 13 years C. COX‐SDH staining showing central cores. D. ATPase pH 4.3 stain shows type I fiber predominance. E‐H. vastus lateralis muscle biopsy from P6 at age 12 years. E. H&E stain shows marked fiber caliber variation, internal nuclei and slight increase of interstitial connective tissue. F. GT stain from the same patient. G. NADH staining shows central clearing and smaller regions of pallor suggestive of cores. H. Muscle fiber typing by immunofluorescence analysis of myosin heavy‐chain isoforms showing predominance of type 1 (blue) myofibers and rare type 2A myofibers (green). Type 2B (red) myofibers are only present in the control (inset). I‐K. Electron microscopy images from P6 confirm the presence of central cores with disrupted organization of myofibrils and foci of loss of myofilaments.