Titin mutation segregates with hereditary myopathy with early respiratory failure

Abstract

In 2001, we described an autosomal dominant myopathy characterized by neuromuscular ventilatory failure in ambulant patients. Here we describe the underlying genetic basis for the disorder, and we define the neuromuscular, respiratory and radiological phenotype in a study of 31 mutation carriers followed for up to 31 years. A combination of genome-wide linkage and whole exome sequencing revealed the likely causal genetic variant in the titin (TTN) gene (g.274375T>C; p.Cys30071Arg) within a shared haplotype of 2.93 Mbp on chromosome 2. This segregated with the phenotype in 21 individuals from the original family, nine subjects in a second family with the same highly selective pattern of muscle involvement on magnetic resonance imaging and a third familial case with a similar phenotype. Comparing the mutation carriers revealed novel features not apparent in our original report. The clinical presentation included predominant distal, proximal or respiratory muscle weakness. The age of onset was highly variable, from early adulthood, and including a mild phenotype in advanced age. Muscle weakness was earlier onset and more severe in the lower extremities in nearly all patients. Seven patients also had axial muscle weakness. Respiratory function studies demonstrated a gradual deterioration over time, reflecting the progressive nature of this condition. Cardiomyopathy was not present in any of our patients despite up to 31 years of follow-up. Magnetic resonance muscle imaging was performed in 21 affected patients and revealed characteristic abnormalities with semitendinosus involvement in 20 of 21 patients studied, including 3 patients who were presymptomatic. Diagnostic muscle histopathology most frequently revealed eosinophilic inclusions (inclusion bodies) and rimmed vacuoles, but was non-specific in a minority of patients. These findings have important clinical implications. This disease should be considered in patients with adult-onset proximal or distal myopathy and early respiratory failure, even in the presence of non-specific muscle pathology. Muscle magnetic resonance imaging findings are characteristic and should be considered as an initial investigation, and if positive should prompt screening for mutations in TTN. With 363 exons, screening TTN presented a major challenge until recently. However, whole exome sequencing provides a reliable cost-effective approach, providing the gene of interest is adequately captured.

Recessive truncating titin gene, TTN , mutations presenting as centronuclear myopathy

“…11,[26][27][28][29][30][31] Based on these reasons, we hypothesized that the TTN mutations present in our 5 patients with CNM were likely to be causative for the disease. Although occasional fibers with internal nuclei have been reported in other muscle diseases with TTN mutations, 19 patients had a noteworthy cardiac phenotype, although the ages at last examination only ranged from 5 to 19 years. In addition, ophthalmoplegia, a common finding in the previously defined CNM cases, was not present.…”

“…[10][11][12] Encompassing 363 exons, TTN includes several regions subject to extensive differential splicing, producing a number of different isoforms in cardiac and skeletal muscles. 10,13,14 TTN mutations have previously been implicated in various cardiac and skeletal muscle diseases including adult-onset tibial muscular dystrophy, [15][16][17] limb-girdle muscular dystrophy 2J, 15,18 hereditary myopathy with early respiratory failure, 19,20 and earlyonset myopathy with fatal cardiomyopathy. 21 Heterozygous truncating mutations in TTN have also been shown to be a common cause of dilated cardiomyopathy, accounting for ;25% of cases in one large series.…”

“…11,21 Binding of calpain 3 to the M-line region of titin is required for its stabilization, as mutations in this region of titin cause a decrease in the amount of calpain 3 in the muscle. 19,21,36 figure 2C). Altogether, these results suggested that all patient muscles analyzed had truncated titin proteins lacking a significant portion of their Cterminal regions.…”

A new titinopathy

“…The Mex6 (exon 363) TMDmutation homozygous LGMD2J is childhood onset and shows a secondary calpain deficiency, but the clinical presentation is different, without contractures. [24][25][26][27] Overall, the presentation described here is unique among titinopathies.…”

Pathologies musculaires liées à la titine

“…Originellement considérée comme très rare et restreinte aux pays scandinaves, cette titinopathie est en fait relativement fréquente et surtout universelle. Des études récentes ont identifié des mutations de TTN à l'origine de HMERF dans au moins 30 familles d'origines différentes [6][7][8][9][10][11][12]. Certaines mutations retrouvées dans des cas d'HMERF paraissent plus fréquentes en Espagne ou en Grande-Bretagne.…”