Sporadic late-onset nemaline myopathy (SLONM): Data from a case series and literature review of 144 patients

Sporadic Late-Onset Nemaline Myopathy (SLONM) is an acquired myopathy presenting in adulthood with progressive proximal and axial muscle weakness. A substantial proportion of cases are associated with monoclonal gammopathy of undetermined significance (MGUS), referred to as SLONM-MGUS, suggesting a potential immune-mediated pathogenesis. Although the presence of MGUS has clinical and therapeutic implications, its exact role in disease severity and progression remains unclear. We aimed to characterize clinical, pathological, and prognostic differences between SLONM-MGUS and SLONM without MGUS (SLONM-noMGUS). We conducted a systematic review of SLONM case series published over the past 25 years, supplemented by a single-center case series of five additional patients from our institution (Sant'Andrea Hospital, Rome). Eligible subjects included adult patients diagnosed with SLONM based on clinical features and muscle biopsy demonstrating nemaline rods. Data on demographics, laboratory parameters, histopathological findings, treatments and outcomes were extracted and compared between SLONM-MGUS and SLONM-noMGUS cohorts. Of the 144 patients analyzed, 47 % were classified as SLONM-MGUS. These patients exhibited more severe clinical manifestations, including increased respiratory involvement ( p = 0.006). Histopathologically, SLONM-MGUS revealed more prominent nemaline rods ( p = 0.032), often accompanied by cytoplasmic bodies and lobulated fibers, and frequently required repeat muscle biopsies for diagnosis ( p = 0.0285). Inflammatory infiltrates were less frequent in SLONM-MGUS ( p = 0.0176). Functional outcomes were significantly worse in this group, with reduced likelihood of full recovery ( p = 0.013) and higher rates of non-ambulatory status ( p = 0.01). Patients receiving dual or more treatment regimens, particularly those including IVIg and/or autologous stem cell transplantation (ASCT), had more favorable outcomes. These findings indicate that SLONM-MGUS represents a more severe phenotype of SLONM with distinct clinico-pathological features and poorer prognosis. Notably, combined treatment regimens, including IVIg and/or ASCT, were associated with improved outcomes, highlighting the importance of early recognition and aggressive therapeutic strategies in selected patients. • Patients with SLONM MGUS manifest a more severe clinical phenotype, with greater respiratory involvement and worse functional outcomes than SLONM without MGUS. • Diagnostic challenges include normal CK levels and the need for repeat muscle biopsies, highlighting the importance of clinical suspicion. • MGUS screening is critical for risk stratification and guiding therapeutic decisions in SLONM, as MGUS status significantly impacts disease severity and prognosis. • Early and aggressive combination therapy, including IVIg and ASCT, is associated with better outcomes in both SLONM-MGUS and SLONM-noMGUS patients.