Digenic SRPK3-TTN related myopathy: early clinical characteristics and muscle imaging findings

Topic:

Other

Poster Number: P336

Author(s):

Rotem Orbach, MD, National Institute of Neurological Disorders and Stroke (NINDS)/NIH, Sandra Donkervoort, MS, CGC, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Dimah Saade, MD, University of Iowa, Precilla D'Souza, NP, NHGRI/NIH, Jin Haugland, NINDS/NIH, A. Reghan Foley, MD, MD(Res), National Institute of Neurological Disease and Stroke, Diana Bharucha-Goebel, MD, Children's National Hospital and NINDS/NIH, Meghan McAnally, MD, MPH, Neuromuscular and Neurogenetic Disorders of Childhood Section, NIH, Abigail Potticary, BS, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, Katherine Chao, Broad Institute of MIT and Harvard, Ellen Macnamara, NHGRI/NIH, Richard S Finkel, MD, St. Jude Children’s Research Hospital, Alan Beggs, PhD, Boston Children's Hospital, Cynthia Tifft, MD, PhD, NHGRI/NIH, Carsten G Bönnemann, National Institute of Neurological Disorders and Stroke

SRPK3-TTN-related myopathy was recently established as a neuromuscular disorder inherited through digenic transmission. Here, we present clinical findings from four new cases (age range: 3-19 years; all males) diagnosed with SRPK3-TTN-related myopathy with a truncating TTN-variant and a concomitant pathogenic variant in the X-chromosomal SRPK3. All four newly identified patients presented before birth with reduced fetal movements. At birth, three patients had contractures and hypotonia, and one had respiratory involvement. Motor developmental delay and muscle weakness were evident in all patients during their first year of life. Independent ambulation was achieved between 1.5-4 years (P1-P3) while P4 has not attained independent ambulation yet (3.8 years). P1 was diagnosed with respiratory insufficiency (forced vital capacity: 57% of predicted at age 9 years and 29% at age 19 years). None of the patients showed cardiac involvement up to their last evaluation. Muscle MRI (available for P1, P2, and P3) demonstrated progressive fibro-adipose tissue replacement over a 10-year period (P1), variability in disease severity among patients (P1 vs. P2 and P3), and notably early, selective involvement of the semitendinosus muscle (P1, P2, and P3) – a distinctive imaging hallmark of titinopathy. P1 had two muscle biopsies, both with myopathic changes, marked by significant variation in fiber size, increased centrally placed nuclei, and predominance of type-1 fibers. The first biopsy (age 7 months) suggested rod-like structures on Gömöri-Trichrome staining, not confirmed on electron microscopy, and the subsequent biopsy (age 13 years) was consistent with central core myopathy. This work highlights early clinical manifestations of SRPK3-TTN-related myopathy and highlights muscle imaging patterns that resemble those observed in monogenic titinopathy cases. These features should help with the potentially challenging variant interpretation in digenic SRPK3-TTN disease and allow for a confident diagnosis of this novel di-genic condition.