A novel autosomal dominant distal myopathy with early respiratory failure: Clinico‐pathologic characteristics and exclusion of linkage to candidate genetic loci

Abstract

We describe a novel autosomal dominant myopathy presenting in mid-adult life with tibialis anterior weakness. We carried out a detailed clinical assessment of 24 individuals spanning three generations, documenting pathologic features of the muscles in 7 of the 11 affected individuals, including an autopsy study on one case. The second generation of affected individuals presented at an earlier age, and the disease progressed more rapidly than in the first generation. Lung function tests revealed progressive global respiratory muscle weakness detectable from the time of presentation, with preferential diaphragmatic involvement in some cases. Hip girdle and shoulder girdle weakness appeared later in the disease course. We observed a striking correlation between the clinical and pathological features. Clinically unaffected muscles had minimal pathologic change. Fiber splitting, eosinophilic inclusions, and vacuoles with basophilic rims were seen in moderately affected muscles, and fat and fibrous connective tissue replaced muscle fibers in the severely involved muscles. The inclusions were Congophilic and reacted with antibodies to desmin, beta-amyloid, and phosphorylated tau protein. The disease was not linked to any of the known loci associated with distal myopathies, confirming that the disorder in this family is both genetically and phenotypically distinct.

Hereditary myopathy with early respiratory failure (HMERF): Still rare, but common enough

“…Disease onset was slightly later (mean 50.2 years) than previously described in HMERF. No other organ involvement (including heart) was found on autopsy in one patient [8].…”

“…Desmin was present only at their periphery, in the filamentous halo, and desmin staining was increased in the cytoplasm of CB containing fibers [7]. Chinnery et al [8] reported one family with 11 affected individuals over 2 generations with congophilic CBs and rimmed-vacuolar myopathy (RVM), variable respiratory dysfunction and predominant anterolateral lower leg muscle involvement. Disease onset was slightly later (mean 50.2 years) than previously described in HMERF.…”

“…On the whole, since the first description several names have been used to define this condition, such as the eponym "Edström myopathy" (OMIM database), or the clinicallyoriented "autosomal dominant myopathy with proximal weakness and early respiratory muscle involvement" [9] and "autosomal dominant distal myopathy with early respiratory failure" [8], as well as the more general and pathology-oriented "familial" [6] or "inherited cytoplasmic body myopathy [5].…”

Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin

“…Respiratory failure as an early symptom in ambulant patients with inherited primary muscle diseases is uncommon. However, early respiratory failure is a frequent complication in a group of myopathies with characteristic myofibrillar lesions and cytoplasmic bodies (Jerusalem et al, 1979;Patel et al, 1983;Winter et al, 1986;Chapon et al, 1989;Edström et al, 1990;Chinnery et al, 2001;Tasca et al, 2010). These myopathies have more recently been referred to as hereditary myopathy with early respiratory failure (HMERF; OMIM#603689).…”

Expanding importance of HMERF titinopathy: new mutations and clinical aspects

“…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].…”