Intravenous immune globulin in hereditary inclusion body myopathy: a pilot study

Abstract

Background: Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, adult onset, non-inflammatory neuromuscular disorder with no effective treatment. The causative gene, GNE, codes for UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, which catalyzes the first two reactions in the synthesis of sialic acid. Reduced sialylation of muscle glycoproteins, such as alpha-dystroglycan and neural cell adhesion molecule (NCAM), has been reported in HIBM.

Methods: We treated 4 HIBM patients with intravenous immune globulin (IVIG), in order to provide sialic acid, because IgG contains 8 micromol of sialic acid/g. IVIG was infused as a loading dose of 1 g/kg on two consecutive days followed by 3 doses of 400 mg/kg at weekly intervals.

Results: For all four patients, mean quadriceps strength improved from 19.0 kg at baseline to 23.2 kg (+22%) directly after IVIG loading to 25.6 kg (+35%) at the end of the study. Mean shoulder strength improved from 4.1 kg at baseline to 5.9 kg (+44%) directly after IVIG loading to 6.0 kg (+46%) at the end of the study. The composite improvement for 8 other muscle groups was 5% after the initial loading and 19% by the end of the study. Esophageal motility and lingual strength improved in the patients with abnormal barium swallows. Objective measures of functional improvement gave variable results, but the patients experienced improvements in daily activities that they considered clinically significant. Immunohistochemical staining and immunoblotting of muscle biopsies for alpha-dystroglycan and NCAM did not provide consistent evidence for increased sialylation after IVIG treatment. Side effects were limited to transient headaches and vomiting.

Conclusion: The mild benefits in muscle strength experienced by HIBM patients after IVIG treatment may be related to the provision of sialic acid supplied by IVIG. Other sources of sialic acid are being explored as treatment options for HIBM.

Figure 1

Serum IgG levels in patients during the course of treatment with IVIG. Arrows indicate loading doses (1 g/kg) and maintenance doses (0.4 g/kg).

Figure 2

Quadriceps and shoulder abduction testing in four patients with HIBM. On average, quadriceps strength increased 22% after IVIG loading and 35% at the end of the study. Shoulder abduction strength increased 44% after IVIG loading and 46% at the end of the study.

Figure 3

Expression of α-dystroglycan in quadriceps muscle from HIBM patients. A-F. Immunohistochemistry using antibodies to IIH6. No consistent difference in staining was apparent before (A,C,E) compared with after (B,D,F) IVIG treatment. The specimen shown in A was sampled from a deteriorating area. G. Immunoblots of muscle from a normal individual (N) and HIBM patients 1, 2, and 4, labeled with antibodies to α-dystroglycan. No consistent difference in IIH6 staining (reflecting the sialylation status of α-dystroglycan) was apparent before (Pre) compared with after (Post) IVIG treatment. β-Actin bands provide an indication of the level of protein loading.

Figure 4

Expression of sialylated NCAM in muscle of HIBM patients. A. Muscle from two control individuals exhibit NCAM mobility consistent with a higher molecular weight, indicative of sialylation. N₁ is normal and N₂ has sporadic IBM; note increased NCAM in this person's muscle. The muscle of patient 1 also has an increased amount of NCAM; patients 2 and 4 have moderate amounts of NCAM. The NCAM of the HIBM patients migrates with greater mobility than normal, indicating lack of sialylation. The amount of muscle NCAM decreased after (Post) compared with before (Pre) IVIG treatment in patients 1 and 2, but increased in patient 4. B. Sialidase treatment increased the mobility of control muscle (N₁ and N₂). The mobility of muscle NCAM was not altered by sialidase treatment in patient 2, but it was increased by sialidase treatment in patient 1.