Hereditary inclusion body myopathy: a decade of progress

Abstract

Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, quadriceps sparing type commonly referred to as HIBM but also termed h-IBM or Inclusion Body Myopathy 2 (IBM2). The clinical manifestations begin with muscle weakness progressing over the next 10-20 years uniquely sparing the quadriceps until the most advanced stage of the disease. Histopathology of an HIBM muscle biopsy shows rimmed vacuoles on Gomori's trichrome stain, small fibers in groups and tubulofilaments without evidence of inflammation. In affected individuals distinct mutations have been identified in the GNE gene, which encodes the bifunctional enzyme uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase/N-acetyl-mannosamine (ManNAc) kinase (GNE/MNK). GNE/MNK catalyzes the first two committed steps in the biosynthesis of acetylneuraminic acid (Neu5Ac), an abundant and functionally important sugar. The generation of HIBM animal models has led to novel insights into both the disease and the role of GNE/MNK in pathophysiology. Recent advances in therapeutic approaches for HIBM, including administration of N-acetyl-mannosamine (ManNAc), a precursor of Neu5Ac will be discussed.

Fig. 1

T1 weighted magnetic resonance images of the thigh of an individual affected with HIBM. (A) Axial image showing fibrotic muscles of the posterior compartment or “hamstring” muscles (H) with comparatively less involvement of the quadriceps femoris (Q). (B) Coronal image showing similar findings.

Fig. 2

Sialic acid synthesis pathway. The biosynthesis of sialic acid (Neu5Ac) occurs in the cytosol, where glucose undergoes several modifications to become UDP-GlcNAc. The UDP-GlcNAC 2-epimerase activity of GNE/MNK then epimerises UDP-GlcNAc into ManNAc, after which its ManNAc kinase activity further converts this to ManNAc-6-P, which is then converted in several steps to the downstream product CMP-sialic acid. CMP-sialic acid is utilized by the Golgi complex to sialylate glycoconjugates. CMP-sialic acid can feedback-inhibit the UDP-GlcNAc 2-epimerase enzymatic activity in its allosteric site. For more details, see text.