Expanding importance of HMERF titinopathy: new mutations and clinical aspects

Abstract

Objective Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and considered quite rare. Respiratory insufficiency is an early symptom. A collection of families and patients with muscle disease suggestive of HMERF was clinically and genetically studied. Methods Altogether 12 new families with 19 affected patients and diverse nationalities were studied. Most of the patients were investigated using targeted next-generation sequencing; Sanger sequencing was applied in some of the patients and available family members. Histological data and muscle MRI findings were evaluated. Results Three families had several family members studied while the rest were single patients. Most patients had distal and proximal muscle weakness together with respiratory insufficiency. Five heterozygous TTN A-band mutations were identified of which two were novel. Also with the novel mutations the muscle pathology and imaging findings were compatible with the previous reports of HMERF. Conclusions Our collection of 12 new families expands mutational spectrum with two new mutations identified. HMERF is not that rare and can be found worldwide, but maybe underdiagnosed. Diagnostic process seems to be complex as this study shows with mostly single patients without clear dominant family history.

Expanding the Clinico-Genetic Spectrum of Myofibrillar Myopathy: Experience From a Chinese Neuromuscular Center

“…The recurrent c.95185T>C mutation patient 15 carries was first reported in one German HMERF family presenting with both proximal and distal weakness ( 23 ). Contracture of Achilles tendon and rigid spine has been reported in some HMERF cases ( 21 ), severe joint abnormalities are nevertheless not the predominant feature of HMERF. The early and severe involvement of spine in patient 15 is reminiscent of an Emery–Dreifuss muscular dystrophy phenotype, which has been reported in recessive titinopathy cases ( 44 ).…”

Characterization of Chinese patients with myofibrillar myopathy from a single center: expanding the clinico-genetic spectrum

“…So far, the mutations associated with the HMERF phenotype are all located in exon 344 of TTN, which is in the 119th fibronectin 3 region of the A-band part of titin. The c. 95134T>C missense mutation of patient 14 was first associated with HMERF in three Scandinavian families [3] and later in various ethnic groups including the Chinese population [4][5][6][7][8][9][10]. It is noteworthy that over 100 reported cases of HMERF, peripheral nerves were considered spared [31].…”

Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?

“…Mutations in the last exons can result in a dominant form, the Tibial Muscular Dystrophy, a late onset distal myopathy [20]. Missense mutations in a specific exon (exon 344) have been associated with an adult onset hereditary myopathy with early respiratory failure (HMERF) [21,22].…”

“…The different forms of titinopathies show specific progression-related patterns of muscular involvement [18,19,21,56]. In the RYR1-related dominant central core myopathies, MRI studies show a selective involvement of vasti, sartorius and adductor magnus in the thigh and of soleus, gastrocnemii, and peroneal group in the leg with relative sparing of rectus femoris, gracilis, adductor longus and tibialis anterior [57].…”