Expanding the 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.

Keywords: Hereditary myopathy; Respiratory failure; Titin; Titinopathy, mutations.

Fig. 1

Pedigree of the families. DNA was collected from individuals marked with an asterisk*. Filled symbols are affected and open symbols unaffected family members. Grey symbols are family members that are possibly affected

Fig. 2

Histological and muscle imaging findings. Patient a haematoxylin and eosin staining shows atrophic fibers and rimmed vacuolar pathology. b There are numerous mostly subsarcolemmal cytoplasmic bodies (CBs) present in the biopsy from patient L with Gomori trichrome staining but CBs can be present in only occasional fibers as seen in figure c (patient G). d Muscle MRI from Family I (III-4) with the novel mutation shows typical fatty degenerative changes in obturatorius, semitendinosus and anterior lower leg muscles. The same but more severe and diffuse involvement is present in her sister (III-5) (G). The mildest form of involvement is demonstrated in E (patient E) and more advanced fatty degeneration in F (patient B) and H (family F III-2). CT images in figure I (patient K) show the most typical changes in HMERF marked with arrows