P338 Clinical, morphological, and proteomic features of patients suspected of X-linked myopathy with excessive autophagy (XMEA)
Résumé
XMEA is a slowly progressive disease that affects male patients and is defined by proximal limb muscle weakness. It is caused by hemizygous mutations in the VMA21 gene encoding a protein which assembles lysosomes’ proton pumps. We have studied eight patients from six new unrelated French families clinically suspected of XMEA. The clinical charts were reviewed, and extensive histological, immunohistochemical and electron microscopy analysis of the muscle biopsies were performed. Sanger sequencing or next generation panel of VMA21 gene was done. Proteomic profiling was carried out on muscle protein extracts derived from three of these patients. The patients presented typical clinical and pathological features of XMEA with onset during childhood or adulthood, proximal limb weakness and mildly elevated CK. Four patients had cardiac alterations and three of them have restrictive respiratory insufficiency. Muscle biopsy of patients showed numerous cytoplasmic vacuoles, segmented fibers, internalized nuclei and significant variability in fiber size. Vacuoles stained positive for sarcolemmal proteins, LAMP2, LC3, p62 and complement C5b-9. Ultrastructural evaluation revealed basal lamina duplication, subsarcolemmal and cytoplasmic vacuoles and extensive autophagosome extrusion. Proteomic results indicated complement activation and impaired proteolysis in addition to mitochondrial and cytoskeletal vulnerability. Molecular investigation disclosed two pathogenic variants in VMA21 (c.164-7T>G, n=5; c.163+4A>G, n=1) and a novel variant in the 3′UTR (c*124A>G, n=1). No mutation was found for one of the patients.
In conclusion, we reported a novel mutation and a new clinical aspect with the presence of cardiac abnormalities. Although all muscle biopsies mimic XMEA, we failed to identify VMA21 mutation in one patient suggesting the involvement of additional genes in this unique histopathology. Proteomic findings provide insights into the underlying pathophysiology.