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  1. GNE myopathy is a rare muscle disease caused by mutations in GNE, the gene that encodes the rate-limiting enzyme of the biosynthetic pathway of sialic acid.

  2. Uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase (GNE) catalyzes the first 2 committed steps in sialic acid synthesis and is encoded by the GNE gene.

  3. GNE myopathy patients have nonallosteric, biallelic, predominantly missense mutations in GNE. GNE myopathy has historically also been named hereditary inclusion body myopathy (HIBM), distal myopathy with rimmed vacuoles (DMRV), Nonaka myopathy, inclusion body myopathy type 2 (IBM2), and quadriceps-sparing myopathy (QSM).

  4. GNE myopathy presents in early adulthood with lower extremity distal muscle weakness. The disease is characterized by a slow progression of muscle weakness and atrophy, from distal to proximal, initially in the lower extremities, with relative sparing of the quadriceps, and subsequently in the upper extremities. The disease leads to marked disability, wheelchair use, and dependent care.

  5. The diagnosis of GNE myopathy is currently based upon clinical features, muscle pathology, and, ultimately, the presence of GNE gene mutations. Histopathology of muscle biopsies typically shows rimmed vacuoles and characteristic filamentous inclusions, but may be negative. Diagnosis is usually delayed or missed, likely because of the rare nature of the disease and the lack of inexpensive and noninvasive diagnostic tests.

  6. Impaired sialylation of (muscle) glycans likely underlies the disease pathology. However, the exact pathophysiology of GNE myopathy remains unknown.

  7. No approved therapies are currently available for GNE myopathy. Clinical trials are being conducted, including trials that increase sialic acid levels through exogenous means or through GNE gene therapy. Exogenous therapies include oral administration of the sialic acid precursor N-acetylmannosamine (ManNAc) or sialic acid (Neu5Ac) itself and intravenous administration of immunoglobulin (IVIG), a highly sialylated compound.

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