CONGENITAL MYOPATHIES 1 – NEMALINE: P.28 Distinctive pathological features of inherited and sporadic late-onset nemaline myopathies

Abstract

Inherited nemaline myopathies (iNM) are a genetically heterogeneous group of disorders characterized by accumulation of Z-disc derived nemaline rods in muscle fibres and presenting from infancy to adulthood. Nemaline rods are also a pathological feature of sporadic late onset nemaline myopathy (SLONM), an acquired myopathy sometimes associated with monoclonal gammopathies or HIV infection. We sought to identify pathological parameters distinguishing these two myopathies. This distinction has significant implications, as SLONM may respond to pharmacological therapy. We randomly selected 9 patients with iNM and 10 with non-HIV SLONM. Their median ages were 11 and 64 years, respectively. The causative genes in iNM were ACTA1 (3 patients), NEB (1 patient) or unknown (5 patients, aged 2-11). Six SLONM patients had monoclonal gammopathies. Muscle fibre sizes and the proportion of fibres harbouring nemaline rods were determined using unbiased sampling methods. The proportion of fibres harbouring nemaline rods was higher in iNM (median 53%, range: 39-99%) than in SLONM (median 11%, range: 1.2-47%). In SLONM, fibres containing nemaline rods had a smaller diameter than fibres devoid of rods (median ratio 0.60), while the opposite was observed in iNM (median ratio 1.12). Atrophic fibres filled with rods occurred in 8/10 SLONM patients and, less conspicuously, in 1/9 iNM patients. In 6/10 SLONM patients, nemaline rods were spread diffusely within the individual fibres, while rods occurred in clusters in 8/9 iNM patients. Necrotic fibres were present in 7/10 SLONM patients, but only in 1/9 iNM patients. In summary, SLONM can be distinguished from iNM on the basis of clinical and pathological features. The pathological differences are particularly relevant when the underlying genetic defect cannot be found in adult patients with iNM, and can guide identification of patients amenable to treatment.