Journal article
Early Clinical, Imaging, and Pathological Characteristics of SRPK3/TTN-Digenic Myopathy
Annals of clinical and translational neurology
05/14/2026
DOI: 10.1002/acn3.70401
PMID: 42135902
Abstract
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.
Next generation sequencing and deep clinical phenotyping provide detailed genetic, clinical, imaging, and histopathological characterization of SRPK3/TTN-digenic myopathy.
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.
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.
Details
- Title: Subtitle
- Early Clinical, Imaging, and Pathological Characteristics of SRPK3/TTN-Digenic Myopathy
- Creators
- Rotem Orbach - National Institute of Neurological Disorders and StrokeSandra Donkervoort - National Institute of Neurological Disorders and StrokeCarola Hedberg-Oldfors - University of GothenburgGiovanni Baranello - Great Ormond Street HospitalDimah Saade - University of IowaPrecilla D'Souza - National Human Genome Research InstituteRuchee Patel - National Institute of Neurological Disorders and StrokeEva Michael - University of GothenburgA Reghan Foley - National Institute of Neurological Disorders and StrokeDiana Bharucha-Goebel - Nationwide Children's HospitalS Jin Haugland - National Institute of Neurological Disorders and StrokeMeghan McAnally - National Institute of Neurological Disorders and StrokeOmer Abdul Hamid - Nemours Children's ClinicKatherine Chao - Broad InstituteEllen F Macnamara - National Human Genome Research InstituteAlan H Beggs - Boston Children's HospitalAnna Sarkozy - Great Ormond Street HospitalJuliane Mueller - Great Ormond Street HospitalSteven A Moore - University of IowaRichard S Finkel - St. Jude Children's Research HospitalCynthia J Tifft - National Human Genome Research InstituteFrancesco Muntoni - Great Ormond Street HospitalAnders Oldfors - University of GothenburgCarsten G Bönnemann - National Institute of Neurological Disorders and Stroke
- Resource Type
- Journal article
- Publication Details
- Annals of clinical and translational neurology
- DOI
- 10.1002/acn3.70401
- PMID
- 42135902
- ISSN
- 2328-9503
- eISSN
- 2328-9503
- Publisher
- WILEY
- Grant note
- P50NS053672 / NIH HHS UM1 HG008900 / NHGRI NIH HHS 2021-02109 / Vetenskapsrådet R01 HG009141 / NHGRI NIH HHS NINDS NIH HHS
- Language
- English
- Electronic publication date
- 05/14/2026
- Academic Unit
- Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9985163702202771
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