Early Clinical, Imaging, and Pathological Characteristics of SRPK3 / TTN ‐Digenic Myopathy
Year: 2026
Type: article
Study design: Case Report
Abstract: OBJECTIVE: SRPK3/TTN-digenic myopathy was recently established as a skeletal muscle myopathy caused by digenic inheritance. This study characterizes the early clinical presentation of SRPK3/TTN-digenic myopathy in one previously reported and seven newly identified pediatric patients. METHODS: Next generation sequencing and deep clinical phenotyping provide detailed genetic, clinical, imaging, and histopathological characterization of SRPK3/TTN-digenic myopathy. RESULTS: From the cohort of eight male patients (5-19 years at last evaluation), five presented prenatally with reduced fetal movements. At the time of birth, five had hypotonia, two had contractures, and two had respiratory distress. All patients demonstrated motor delay and muscle weakness within the first 15 months of life. Independent ambulation was achieved in six patients (ages 1.5-4 years); three could run. Variable respiratory compromise was documented as early as 5 years of age, with one patient requiring non-invasive nocturnal ventilation support. Cardiac evaluation was normal in all except one patient who had left ventricular non-compaction cardiomyopathy. Muscle MRI demonstrated mild, slowly progressive fibroadipose replacement of muscle with striking early selective involvement of the semitendinosus muscle. Histopathologic and ultrastructural features mimicked TTN-related myopathy (titinopathy), showing abnormal fiber size variation, increased internally placed nuclei, type 1 fiber predominance, and cores/minicores. INTERPRETATION: This work highlights the early clinical manifestations of SRPK3/TTN-digenic myopathy and demonstrates early muscle imaging patterns and histopathological features that are indistinct from those observed in monogenic biallelic titinopathy cases. These features could help with the potentially challenging interpretation of digenic SRPK3 and TTN variants to allow for a confident clinical diagnosis of this novel congenital myopathy.
DOI: 10.1002/acn3.70401
Authors: Rotem Orbach, Sandra Donkervoort, Carola Hedberg‐Oldfors, Giovanni Baranello, Dimah Saade, Precilla D'Souza, Ruchee Patel, Eva Michael, A. Reghan Foley, Diana Bharucha‐Goebel, S. Jin Haugland, Meghan McAnally, Omer Abdul Hamid, Katherine Chao, Ellen F. Macnamara, Alan H. Beggs, Anna Sarkozy, Juliane Mueller, Steven A. Moore, Richard S. Finkel, Cynthia J. Tifft, Francesco Muntoni, Anders Oldfors, Carsten G. Bönnemann
Institutions: National Institutes of Health, National Institute of Neurological Disorders and Stroke, University of Gothenburg, Great Ormond Street Hospital, National Institute for Health and Care Research, UCL Biomedical Research Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, University of Iowa, National Human Genome Research Institute, Nationwide Children's Hospital, Nemours Children's Clinic, Broad Institute, Boston Children's Hospital, Harvard University, Manton Center for Orphan Disease Research, St. Jude Children's Research Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
OpenAlex ID: W7161284592