Intravenous Immune Globulin to Treat Hereditary Inclusion Body Myopathy

Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive neuromuscular disorder with onset in early adulthood and progressive muscle weakness leading to death within 2-3 decades. The causative gene, GNE, codes for the bifunctional enzyme UDP N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase; mutations on both GNE alleles, in either or both the epimerase and kinase domains, can result in HIBM. Members of an Iranian-Jewish isolate are homozygous for a specific kinase domain mutation. The epimerase and kinase enzymes catalyze the first and second, rate-limiting steps in the synthesis of sialic acid, also called N-acetylneuraminic acid. This charged sugar provides the terminal carbohydrate on a variety of N-linked and O-linked glycoproteins that mediate cell-cell and protein-protein interactions. The cells of HIBM patients produce reduced amounts of free sialic acid, as evidenced by decreased sialylation of glycoproteins, including a critical muscle protein called alpha-dystroglycan (alpha-DG). This protein, decorated with O-mannosyl glycans containing a terminal sialic acid, is part of the dystrophin-glycoprotein complex responsible for linking the inside of muscle cells with the extracellular matrix. In HIBM, improper sialylation of alpha-DG, due to decreased sialic acid synthesis, is considered to impair the interactions of alpha-DG with its protein ligands, resulting in gradual deterioration of muscle cells. In this open-label pilot study, we propose to provide free sialic acid to muscle cells of HIBM patients by intravenous infusions of immune globulin (IvIg), a glycoprotein that contains 8 microlitermoles of sialic acid per gram and that has a proven safety profile as an FDA-approved drug. Four subjects will be treated - two homozygous for the Iranian Jewish kinase domain mutation, and two with at least one epimerase domain mutation. IvIg will be given as a loading dose of 1 gram per kilogram body weight on two consecutive days, followed each of the next 3 weeks by maintenance doses of 400 milligram per kilogram body weight. This should maintain the serum immune globulin level high enough to achieve continuous breakdown of large amounts of the glycoprotein, providing free sialic acid to the blood, scavenger cells and, we hope, muscle cells. Muscle biopsies and strength testing will be performed before and after the infusions. The primary clinical outcome parameter will be muscle strength, gauged mechanically by Quantitative Muscle Testing and manually by physical examination performed by a neurologist. Secondary outcome parameters will employ the 6-minute walk test, grip strength, tongue strength, swallowing duration, and the Human Activity Profile questionnaire. Staining of muscle beta-DG for sialic acid on O-mannosyl glycans will provide a histological outcome parameter. An improvement in muscle strength or alpha-DG sialylation will prompt a controlled trial of the efficacy of this treatment.