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

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.

The distribution of desmin and titin in normal and dystrophic human muscle.

We have used monoclonal antibodies to desmin and titin, and a combination of immunofluorescence and immunogold labelling to study the disposition of these two proteins in normal human muscle fibres and in fibres at various stages of degeneration in dystrophic muscle. The normal pattern of desmin labelling, in particular the subsarcolemmal labelling, became disrupted at an early stage of fibre breakdown. There was a change from a transverse to a longitudinal orientation of the labelled intermediate filaments as the myofibrils sheared relative to one another. Thus, while it is probable that the desmin filaments are able to play a role in the mechanical integration of the myofibrils in healthy muscle, our results suggest that they cannot withstand the excessive forces generated by the hypercontraction and stretching of dystrophic muscle. However, small accumulations of desmin persisted between the damaged myofibrils until necrosis reached an advanced stage. In general, the degradation of titin appeared to occur before the degradation of desmin, and at the ultrastructural level, labelling with antibodies to epitopes from parts of the titin molecule close to the A-I-band junction was lost before labelling with an antibody to an epitope in the A-band. This suggests that different regions of the titin molecule break down at different stages in the breakdown of the fibre. We propose that lysis of titin in the I-band may underlie 'slippage', an abnormality often seen in dystrophic muscle, in which the A-band slips to one pole of the sarcomere such that it abuts onto the Z-line. Breakdown of the A-band section of titin may facilitate the disassembly of the A-filaments.

Inclusion body myositis: a case with associated collagen vascular disease responding to treatment.

Patients with inclusion body myositis demonstrate characteristic histological and electronmicroscopical abnormalities in muscle and are generally considered refractory to treatment. A patient with inclusion body myositis is described with evidence of associated autoimmune disease, who responded to steroids.

Phagocytosis of the A band following Z line, and I band loss. Its significance in skeletal muscle breakdown.

A band phagocytosis, following Z line and I band loss, is described in polymyositis, in epsilon amino caproic acid induced myopathy and in an experimental myositis of guinea pigs. It is far less prominent in Duchenne muscular dystrophy. This form of necrosis is always associated with lesions in the plasma membrane. It is argued that the ensuing ionic equilibration with the extracellular fluid allows activation of a calcium activated proteinase (CAP) which digests the Z line. Breakdown of the myofibrils into individual A bands promotes rapid phagocytosis of the myofibre contents and facilitates regeneration of the muscle.

Immunocytochemical localization of immunoglobulins in the inflammatory lesions of polymyositis.

Biopsy material from the muscles of 40 patients with either polymyositis or dermatomyositis was examined with the immunoperoxidase method to compare the distribution of immunoglobulin (Ig)-containing cells in the inflammatory infiltrates and elsewhere in the muscle tissue. Large numbers of IgG-positive and occasional IgM-positive cells were found in the infiltrates in 23 of these biopsies in contrast to the rather sparse representation of plasma cells. It is suggested that the Ig-containing cells may either represent local B-cell differentiation and proliferation or that the cells are involved in antibody-dependent cell-mediated tissue damage.

Studies of sarcolemmal integrity in myopathic muscle.

Studies of sarcolemmal integrity with extracellular Procion Yellow gave evidence of structural defects in a high percentage of muscle fibers in Duchenne dystrophy and in vitamin E-deficiency myopathy in the guinea pig. The dye entered fibers in these conditions more often than in controls. Myofibrillary clumping occurred in the region of major penetration of the dye. It seems likely that sarcolemmal defects occur in vivo in these conditions, allowing the entry of high concentrations of calcium into the sarcoplasm with consequent fiber damage. The biochemical basis of these sarcolemmal defects remains to be elucidated. Our procedure for biopsy of the vastus medialis muscle may prove useful in preparing a limb muscle for in vitro physiologic studies.

The pathology of type II skeletal muscle glycogenosis. A light and electron-microscopic study.

Muscle biopsies were obtained from three infants under the age of 12 mth, each of whom was diagnosed as having Pompe's disease. The biopsies revealed a severe vacuolar myopathy with accumulation of large amounts of PAS positive material within the muscle fibres, changes similar to those in adult cases of the disease. In addition large amounts of metachromatic material were found within the muscle fibres in all three cases and in two of them scattered, rather sparse perivascular lymphocytic infiltrates were seen in the interstitial tissue. Review of material previously obtained from two adult cases showed no accumulation of metachromatic material in the older case and only moderate amounts in the younger. However, dense interstitial lymphocytic infiltrates were seen in the former, some concentrated around small vessels. These observations suggest that the pathogenesis of the muscle disorder in acid maltase deficiency may not depend on abnormal glycogen storage only.

Stages in fibre breakdown in Duchenne muscular dystrophy. An electron-microscopic study.

A scheme is presented which divides the process of fibre breakdown in Duchenne muscular dystrophy into 5 sequential stages. In Stage 1 the fibre appears superficially normal although there are subtle changes in the relative volumes of the fibre components. In Stage 2 localised overcontraction of the myofibrils results in excessive stretching of the sarcomeres in other regions of the fibre. This continuing process results in the formation of contraction clumps in which the contractile filaments form an increasingly homogeneous mass. By the final stage the normal structural features of the fibre have completely disappeared and it is invaded by macrophages. It is suggested that the central process of myofibril clumping results from a localised inability of the sarcomeres to relax which implies a defect in the mitochondria, Z-line or sarcoplasmic reticulum. This is discussed in relation to other workers' findings of a decrease in the calcium-accumulating capacity of the sarcoplasmic reticulum in Duchenne muscular dystrophy.