Differential diagnosis of vacuolar myopathies in the NGS era

Prominent alterations of autophagy are a common denominator of many late-onset, familial and sporadic non-inflammatory muscle diseases. We studied 33 adult patients with a histological diagnosis of vacuolar myopathy. Genetic testing including whole exome sequencing (WES) was performed in index patients and relatives and established a genetic diagnosis in 18 patients. Pathogenic mutations were found in genes often linked to vacuolar myopathy (GNE, ZASP, MYOT, DES, TRIM32, GAA), but also in genes not regularly associated with prominent autophagic vacuoles (FKRP, DYSF, CAV3, COL6A2, GYG1, SMCHD1). We identified several characteristic histopathological features helpful to distinguish different causes of vacuolar myopathies. Histopathology validated the pathogenicity of the novel mutations Phe55Ter and Arg216Ter in GYG1 and of the hemizygous Leu156Pro mutation in TRIM32 and helped to expand the phenotype of Ala93Thr-caveolinophathy and of LGMD2I due to FKRP mutation. In a patient with a family history of muscle weakness, the vacuolar myopathy was related to chloroquine intake. In 12 patients no relevant gene defects were detected even by extensive genetic testing including WES. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In many cases, the question still remains open whether the cause is hereditary, sporadic or degenerative.