P.236Myofibres with subsarcolemmal rims and/or central aggregates of mitochondria (SRCAM) are prevalent in congenital titinopathies

Abstract

With increasing use of massive parallel sequencing over recent years, congenital titinopathies due to recessively inherited truncating and/or splice-site pathogenic variants in TTN (which encodes titin) are emerging as a common cause of congenital myopathy (CM). The clinical phenotype is broad. Muscle biopsies show structural abnormalities including cores, central nuclei (CN) and fibre size disproportion. We report a novel structural abnormality prevalent in muscle biopsies from a cohort of patients with clinical and/or pathological features (cores and/or central nuclei and slow fibre predominance) of CM. Cases were classified genetically as "definite" (2 predicted pathogenic TTN variants), "probable" (1 predicted pathogenic and 1 missense variant) and ''possible'' (1 predicted pathogenic or 2 missense variants) titinopathy. The index case, a male with recessive splice-site TTN variants in trans, presented at birth, with profound hypotonia, respiratory weakness and cardiomegaly. CK was normal. EMG was myopathic. Quadriceps biopsy at 2 months showed mild CN and ill-defined cores. A novel observation concerned a striking sub-population of fibres, often smaller, with circumferential rims with/without central aggregates of oxidative staining. These were designated as myofibres with subsarcolemmal rims and/or central aggregates of mitochondria (SRCAM fibres). We subsequently identified SRCAM fibres in 35.7% of genetically definite or probable/possible TTN-CM cases (10/28 total; 4/9 definite, 2/3 probable and 4/16 possible). In stark contrast, SRCAM fibres were present in only 3.6% (2/56) of cases with pathogenic variants in other core/CN-CM genes (RYR1, SEPN1, MYH7, MYH2, DNM2, MTM1). They were most frequent in neonates. Analysis of additional cases and ultrastructural characterisation is ongoing. We recommend that patients with a clinicopathological picture compatible with CM and presence of SRCAM fibres in their muscle biopsy should be screened for TTN mutations.