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

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.