Hereditary inclusion body myopathy (HIBM; OMIM 600737) is an adult-onset autosomal recessive myopathy that typically presents with distal muscle weakness, usually foot drop, in the second or third decade of life [1-3]. The disease progresses to require wheelchair confinement in two to three decades. The quadriceps muscles are relatively spared, at least clinically, even late in the disease. Muscle histology shows vacuolated fibers, variation of fiber size, increased connective tissue, and fibrofatty replacement of muscle fibers. Inflammation is typically absent.
HIBM is rare, but a Persian Jewish isolate [4] enabled investigators to map the condition to chromosome 9p12–13. The causative gene, GNE, was subsequently identified and a common mutation, M712T, was found among affected Persian Jews [5]. The GNE gene encodes the bifunctional enzyme, UDP-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase, catalyzing the rate-limiting steps in sialic acid synthesis [6,7]. The M712T mutation is located within the kinase domain of the GNE gene. Nearly 20 other GNE mutations have been described in HIBM patients of different ethnic backgrounds [8-12]; a condition allelic to HIBM, Distal Myopathy with Rimmed Vacuoles (DMRV), occurs in Japan [13-15]. HIBM-associated GNE mutations, whether in the epimerase or the kinase domain, result in reduced activity of both UDP-GlcNAc 2-epimerase and ManNAc kinase [16,17]. These decrements are considered responsible for reduced production of sialic acid, a negatively charged sugar that serves as the terminal carbohydrate on glycoconjugates [18]. Glycosylation of proteins is critical for proper folding of nascent proteins, resistance to proteases, intracellular trafficking, and cell-cell interactions [19,20].
The pathogenic mechanism of muscle fiber degeneration in HIBM remains unknown. However, evidence suggests that decreased availability of sialic acid causes hyposialylation of muscle glycoproteins, whether involving glycans in general [17,21], O-linked glycans [22], polysialic acid on neural cell adhesion molecules (PSA-NCAM) [23], or specific O-mannosylated glycosyl residues on α-dystroglycan [24]. These latter oligosaccharides govern interactions of α-dystroglycan with extracellular matrix proteins [25,26], and their deficiency is responsible for several congenital muscular dystrophies, including Walker-Warburg syndrome, Muscle-Eye-Brain disease, and Fukuyama's muscular dystrophy [27-29]. In HIBM, decreased sialylation of α-dystroglycan could impair interaction with other skeletal muscle proteins essential for function.
We reasoned that provision of sialic acid to HIBM patients could help normalize the sialylation status of muscle glycoproteins and provide clinical benefit. Because no approved source of free sialic acid is available, we delivered this charged sugar via intravenous immune globulin G (IVIG), a glycoprotein that contains 8 μmoles of sialic acid per gram [30]. Maintaining high levels of serum IgG could result in continuous breakdown of the glycoprotein by neuraminidase, providing sufficient quantities of free sialic acid to the blood, scavenger cells and eventually muscle tissue. Side effects included headaches, nausea and vomiting, particularly after the second day of the loading dose; these resolved within 48 hours. Improvements in quantitative muscle testing and the six-minute walk were recorded. Qualitative improvements in activities of daily living, muscle strength, and endurance were noted in all four treated patients.
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