Hereditary myopathy with early respiratory failure: occurrence in various populations

Palmio, Johanna; Evilä, Anni; Chapon, Françoise; Tasca, Giorgio; Xiang, Fengqing; Brådvik, Björn; Eymard, B.; Echaniz‐Laguna, Andoni; Laporte, Jocelyn; Kärppä, Mikko; Mahjneh, Ibrahim; Quinlivan, R.; Laforêt, Pascal; Damian, Maxwell S.; Berardo, Andrés; Taratuto, Ana Lía; Bueri, J. A.; Tommiska, Johanna; Raivio, Taneli; Tuerk, Matthias; Gölitz, Philipp; Chevessier, Frédéric; Sewry, C.; Norwood, Fiona; Hedberg, Carola; Schröder, Rolf; Edström, Lars; Oldfors, Anders; Hackman, Peter; Udd, Bjarne

doi:10.1136/jnnp-2013-304965

Cited by 69 publications

(102 citation statements)

References 24 publications

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“…However, HMERF-causing TTN mutations have now been identified in 30 families of different origins, implying that HMERF is neither restricted to Northern Europe nor as exceptional as previously thought [Pfeffer et al, 2012;Izumi et al, 2013;Toro et al, 2013;Palmio et al, 2014;Pfeffer et al, 2014c]. In the last years, eight mutations causing HMERF have been identified [Ohlsson et al, 2012;Pfeffer et al, 2012;Izumi et al, 2013;Toro et al, 2013;Palmio et al, 2014;Pfeffer et al, 2014a;Pfeffer et al, 2014d]. All of them are localized in TTN exon 344 (coding exon 343), encoding the 119th Fn3 domain in the A-band, which establishes this exon as the primary target for molecular diagnosis of HMERF.…”

Section: Skeletal Muscle Diseases Associated With Ttn Mutationsmentioning

confidence: 96%

A Rising Titan:TTNReview and Mutation Update

2014

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The 364 exon TTN gene encodes titin (TTN), the largest known protein, which plays key structural, developmental, mechanical, and regulatory roles in cardiac and skeletal muscles. Prior to next-generation sequencing (NGS), routine analysis of the whole TTN gene was impossible due to its giant size and complexity. Thus, only a few TTN mutations had been reported and the general incidence and spectrum of titinopathies was significantly underestimated. In the last months, due to the widespread use of NGS, TTN is emerging as a major gene in human-inherited disease. So far, 127 TTN disease-causing mutations have been reported in patients with at least 10 different conditions, including isolated cardiomyopathies, purely skeletal muscle phenotypes, or infantile diseases affecting both types of striated muscles. However, the identification of TTN variants in virtually every individual from control populations, as well as the multiplicity of TTN isoforms and reference sequences used, stress the difficulties in assessing the relevance, inheritance, and correlation with the phenotype of TTN sequence changes. In this review, we provide the first comprehensive update of the TTN mutations reported and discuss their distribution, molecular mechanisms, associated phenotypes, transmission pattern, and phenotype-genotype correlations, alongside with their implications for basic research and for human health.

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Section: Skeletal Muscle Diseases Associated With Ttn Mutationsmentioning

confidence: 96%

A Rising Titan:TTNReview and Mutation Update

2014

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“…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.…”

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confidence: 99%

A new titinopathy

et al. 2015

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Objective: To identify the genetic defects present in 3 families with muscular dystrophy, contractures, and calpain 3 deficiency.Methods: We performed targeted exome sequencing on one patient presenting a deficiency in calpain 3 on Western blot but for which mutations in the gene had been excluded. The identification of a homozygous truncating mutation in the M-line part of titin prompted us to sequence this region in 2 additional patients presenting similar clinical and biochemical characteristics.Results: The 3 patients shared similar features: coexistence of limb-girdle weakness and earlyonset diffuse joint contractures without cardiomyopathy. The biopsies showed rimmed vacuoles, a dystrophic pattern, and secondary reduction in calpain 3. We identified a novel homozygous mutation in the exon Mex3 of the TTN gene in the first patient. At protein level, this mutation introduces a stop codon at the level of Mex3. Interestingly, we identified truncating mutations in both alleles in the same region of the TTN gene in patients from 2 additional families. Molecular protein analyses confirm loss of the C-ter part of titin. Conclusions:

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“…Hereditary myopathy with early respiratory failure (HMERF): HMERF (OMIM #603689) is caused by mutations in the 119 th fibronectin 3 domain of the giant sarcomeric gene titin (TTN) [74][75][76] and meets diagnostic criteria for MFM on muscle pathology [75,76], as well as having similarities with other subtypes of MFM in clinical presentation and MRI abnormalities [77,78]. The condition is common compared with other subtypes of MFM in the United Kingdom, probably owing to a founder effect [75], although another study of MFM patients in the United States found a similar prevalence [79], suggesting that the disease is internationally distributed and likely to be common in other populations as well.…”

Section: Inherited Muscle Diseasesmentioning

confidence: 99%

Diagnosis of muscle diseases presenting with early respiratory failure

et al. 2014

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Here we describe a clinical approach and differential diagnosis for chronic muscle diseases which include early respiratory failure as a prominent feature in their presentation (i.e. respiratory failure whilst still ambulant). These patients typically present to neurology or respiratory medicine out-patient clinics and a distinct differential diagnosis of neuromuscular aetiologies should be considered. Amyotrophic lateral sclerosis and myasthenia gravis are the important non-muscle diseases to consider, but once these have been excluded there remains a challenging differential diagnosis of muscle conditions, which will be the focus of this review. The key points in the diagnosis of these disorders are being aware of relevant symptoms, which are initially caused by nocturnal hypoventilation or diaphragmatic weakness; and identifying other features which direct further investigation. Important muscle diseases to identify, because their diagnosis has disease-specific management implications, include adult-onset Pompe disease, inflammatory myopathy, and sporadic adult-onset nemaline myopathy. Cases which are due to metabolic myopathy or muscular dystrophy are important to diagnose because of their implications for genetic counselling. Myopathy from sarcoidosis and colchicine each has a single reported case with this presentation, but should be considered because they are treatable. Disorders which have recently had their genetic aetiologies identified include hereditary myopathy with early respiratory failure (due to TTN mutations), the FHL1-related syndromes, and myofibrillar myopathy due to BAG3 mutation. Recently described syndromes include oculopharyngodistal muscular dystrophy that awaits genetic characterisation.

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Hereditary myopathy with early respiratory failure: occurrence in various populations

Cited by 69 publications

References 24 publications

A Rising Titan:TTNReview and Mutation Update

A Rising Titan:TTNReview and Mutation Update

A new titinopathy

Diagnosis of muscle diseases presenting with early respiratory failure

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