G.P.264: Congenital myopathies with protein aggregates and inclusions: importance of extensive muscle biopsy analysis in the diagnostic workup

Abstract

The congenital myopathies with protein aggregates and inclusions are a subgroup of structural congenital myopathies characterized by aggregation of proteins in muscle. They include Nemaline Myopathy, Core Rod Myopathy, Cap Disease, Reducing body Myopathy, Cylindrical spirals Myopathy, and other entities presenting less distinct protein inclusions. This subgroup represents around 40 % of all biopsies with a structural congenital myopathy. We analysed 154 patients whose muscle was referred to our lab. Pathological diagnosis was achieved combining histochemical and ultrastructural analysis. Nemaline Myopathy was encountered in 103 (67%) patients, 14 (9%) patients had Core Rod myopathy, 12 (8%) Cap Disease, 16 (10%) Reducing Body Myopathy, 3 (2%) Cylindrical spirals Myopathy and 6 (4%) patients presented less distinct protein aggregates. Standard histoenzymology oriented the genetic analysis in around two third of our patients. In one third of cases extended immunohistochemical and ultrastructural studies were pivotal for the constitution of homogenous cohorts, and the orientation of molecular analysis. Genetic diagnosis was achieved in 76 (49%) patients through Sanger sequencing or next generation sequencing. NEB was mutated in 26 patients (34%), ACTA1 in 25 (33%), FHL1 in 14 (18%), TPM2 in 5 (7%) and TPM3 in 3 (4%), RYR1 in 2 (3%), and KLHL40 in 1 (1%). Our study demonstrates that detailed muscle biopsies analysis represents an essential tool in the diagnostic workup of congenital myopathies with protein aggregates and inclusions. Ultrastructural analysis turned to be fundamental in establishing the diagnosis in muscle biopsies from newborn and child patients. A combined clinic-histopathological and genetic approach will certainly help in the identification of the underlying molecular defect in patients without a genetic diagnosis. The congenital myopathies with protein aggregates and inclusions are a subgroup of structural congenital myopathies characterized by aggregation of proteins in muscle. They include Nemaline Myopathy, Core Rod Myopathy, Cap Disease, Reducing body Myopathy, Cylindrical spirals Myopathy, and other entities presenting less distinct protein inclusions. This subgroup represents around 40 % of all biopsies with a structural congenital myopathy. We analysed 154 patients whose muscle was referred to our lab. Pathological diagnosis was achieved combining histochemical and ultrastructural analysis. Nemaline Myopathy was encountered in 103 (67%) patients, 14 (9%) patients had Core Rod myopathy, 12 (8%) Cap Disease, 16 (10%) Reducing Body Myopathy, 3 (2%) Cylindrical spirals Myopathy and 6 (4%) patients presented less distinct protein aggregates. Standard histoenzymology oriented the genetic analysis in around two third of our patients. In one third of cases extended immunohistochemical and ultrastructural studies were pivotal for the constitution of homogenous cohorts, and the orientation of molecular analysis. Genetic diagnosis was achieved in 76 (49%) patients through Sanger sequencing or next generation sequencing. NEB was mutated in 26 patients (34%), ACTA1 in 25 (33%), FHL1 in 14 (18%), TPM2 in 5 (7%) and TPM3 in 3 (4%), RYR1 in 2 (3%), and KLHL40 in 1 (1%). Our study demonstrates that detailed muscle biopsies analysis represents an essential tool in the diagnostic workup of congenital myopathies with protein aggregates and inclusions. Ultrastructural analysis turned to be fundamental in establishing the diagnosis in muscle biopsies from newborn and child patients. A combined clinic-histopathological and genetic approach will certainly help in the identification of the underlying molecular defect in patients without a genetic diagnosis.