European journal of neurology · 2026
Over-Representation of TTN Truncating Variants in a Finnish Cohort of Patients With Axial Myopathy.
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Di Feo Maria Francesca, Capece Giuliana, Savarese Marco, Udd Bjarne, Jokela Manu, Palmio Johanna
Аннотация
BACKGROUND: Axial myopathies present with late onset selective paravertebral weakness causing bent spine/camptocormia or dropped head, and the genetic basis remains currently only partially understood. Truncating variants in TTN (TTNtv) are found in about 1% of the general population and, when biallelic, cause recessive titinopathies. Also, TTNtv located in cardiac exons are known to confer an increased risk of cardiomyopathy, with incomplete penetrance.
METHODS: We retrospectively analyzed 55 Finnish adults with late-onset axial myopathy evaluated at the Tampere Neuromuscular Center (2015-2025). Clinical, imaging, and histopathological data were collected, and genetic testing was performed using the MYOcap targeted next-generation sequencing panel.
RESULTS: Heterozygous TTNtv were identified in 9 of 55 patients (16%), representing a significant enrichment compared with the general population (odds ratio = 14.1; p ≈5 × 10-8). The variants were ultra-rare, distributed across different exons expressed in skeletal muscle, and five were absent from gnomAD. Mean age at onset was 60 ± 11 years; six patients were female, and five reported a positive family history. Camptocormia was the main presentation, with muscle MRI showing a consistent fatty-fibrous replacement of paravertebral muscles in all cases. Muscle biopsies revealed either myopathic or myofibrillar changes without a uniform pattern.
CONCLUSIONS: Heterozygous TTNtv are significantly enriched in patients with late-onset axial myopathy, suggesting a potential contribution to this phenotype. These findings broaden the clinical spectrum of titin-related diseases and support inclusion of TTN in genetic testing for idiopathic axial myopathies.
METHODS: We retrospectively analyzed 55 Finnish adults with late-onset axial myopathy evaluated at the Tampere Neuromuscular Center (2015-2025). Clinical, imaging, and histopathological data were collected, and genetic testing was performed using the MYOcap targeted next-generation sequencing panel.
RESULTS: Heterozygous TTNtv were identified in 9 of 55 patients (16%), representing a significant enrichment compared with the general population (odds ratio = 14.1; p ≈5 × 10-8). The variants were ultra-rare, distributed across different exons expressed in skeletal muscle, and five were absent from gnomAD. Mean age at onset was 60 ± 11 years; six patients were female, and five reported a positive family history. Camptocormia was the main presentation, with muscle MRI showing a consistent fatty-fibrous replacement of paravertebral muscles in all cases. Muscle biopsies revealed either myopathic or myofibrillar changes without a uniform pattern.
CONCLUSIONS: Heterozygous TTNtv are significantly enriched in patients with late-onset axial myopathy, suggesting a potential contribution to this phenotype. These findings broaden the clinical spectrum of titin-related diseases and support inclusion of TTN in genetic testing for idiopathic axial myopathies.