Sporadic late-onset nemaline myopathy: clinico-pathological characteristics and review of 76 cases.

BACKGROUND: Sporadic late-onset nemaline myopathy (SLONM) is a rare, late-onset muscle disorder, characterized by the presence of nemaline rods in muscle fibers. Phenotypic characterization in a large cohort and a comprehensive overview of SLONM are lacking. METHODS: We studied the clinico-pathological features, treatment and outcome in a large cohort of 76 patients with SLONM, comprising 10 new patients and 66 cases derived from a literature meta-analysis (PubMed, 1966-2016), and compared these with 15 reported HIV-associated nemaline myopathy (HIV-NM) cases. In 6 SLONM patients, we performed a targeted next-generation sequencing (NGS) panel comprising 283 myopathy genes. RESULTS: SLONM patients had a mean age at onset of 52 years. The predominant phenotype consisted of weakness and atrophy of proximal upper limbs in 84%, of proximal lower limbs in 80% and both in 67%. Other common symptoms included axial weakness in 68%, as well as dyspnea in 55% and dysphagia in 47% of the patients. In 53% a monoclonal gammopathy of unknown significance (MGUS) was detected in serum. The mean percentage of muscle fibers containing rods was 28% (range 1-63%). In 2 cases ultrastructural analysis was necessary to detect the rods. The most successful treatment in SLONM patients (all with MGUS) was autologous peripheral blood stem cell therapy. A targeted NGS gene panel in 6 SLONM patients (without MGUS) did not reveal causative pathogenic variants. In a comparison of SLONM patients with and without MGUS, the former comprised significantly more males, had more rapid disease progression, and more vacuolar changes in muscle fibers. Interestingly, the muscle biopsy of 2 SLONM patients with MGUS revealed intranuclear rods, whereas this feature was not seen in any of the biopsies from patients without paraproteinemia. Compared to the overall SLONM cohort, significantly more HIV-NM patients were male, with a lower age at onset (mean 34 years). In addition, immunosuppression was more frequently applied with more favorable outcome, and muscle biopsies revealed a significantly higher degree of inflammation and necrosis in this cohort. Similar to SLONM, MGUS was present in half of the HIV-NM patients. CONCLUSIONS: SLONM presents a challenging, but important differential diagnosis to other neuromuscular diseases of adult onset. Investigations for MGUS and HIV should be performed, as they require distinct but often effective therapeutic approaches. Even though SLONM and HIV-NM show some differences, there exists a large clinico-pathological overlap between the 2 entities.

Novel FHL1 mutation in a family with reducing body myopathy.

INTRODUCTION: Reducing body myopathy is a rare X-linked myopathy. It is characterized by intracytoplasmic inclusions that stain with menadione-nitroblue tetrazolium. It is caused by mutations in the FHL1 gene, which encodes the four-and-a-half LIM domain 1 protein (FHL1). METHODS: We performed a clinical, muscle MRI, and histopathological characterization and immunoblot and genetic analysis of the FHL1 protein in a family with 4 individuals affected by reducing body myopathy. RESULTS: We identified a novel missense mutation in FHL1 (c.449G>C; p.C150S). The patients presented with asymmetric proximal weakness and scoliosis. Both of the boys had a more severe course with earlier onset, contractures, and death due to heart failure at 14 and 18 years of age, respectively. MRI revealed fatty infiltration of posteromedial thigh and paraspinal muscles. Histopathological findings showed FHL1-immunoreactive inclusions. Immunoblot analysis revealed a 50% reduction of FHL1 protein. CONCLUSION: In this study we highlighted diagnostic clues in this myopathy and compared our data with the literature.