Abstract
ObjectiveHereditary 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.MethodsAltogether 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.ResultsThree 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.ConclusionsOur 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.
Highlights
Hereditary myopathy with early respiratory failure (HMERF, OMIM #603689) is characterized by proximal and/or distal muscle weakness, and early and severe diaphragmatic insufficiency [1,2,3,4,5]
We describe here clinical features, pulmonary function tests, histopathological and muscle MRI findings of 19 HMERF patients from 12 families and diverse ethnic origins
Together with two novel mutations there are more than ten different TTN A-band mutations identified leading to typical muscle imaging and histology findings [4, 5, 11]
Summary
Hereditary myopathy with early respiratory failure (HMERF, OMIM #603689) is characterized by proximal and/or distal muscle weakness, and early and severe diaphragmatic insufficiency [1,2,3,4,5]. In HMERF, respiratory failure can be a presenting symptom in an ambulant adult patient, which is not a common feature in other genetic myopathies [5,6,7]. The reported mutations mainly show an autosomal dominant inheritance pattern, and are usually private mutations except for the most frequently identified mutation in HMERF patients, c.95134T>C p.C31712R, found in more than 20 families in Europe and Asia (Table 1) [11,12,13,14]
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