80 Molecular pathomechanism of distal myopathy with rimmed vacuoles Acta Myologica • 2005; XXIV: p. 80-83 I. NISHINO,MAY CHRISTINE V. MALICDAN, K. MURAYAMA, I. NONAKA, Y.K. HAYASHI, S. NOGUCHI Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan Address for correspondence: Ichizo Nishino, M.D., Ph.D., Department of Neuromuscular Research, National Institute of Neuro- science, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan, Tel: +81-42-341-2711 ext 5111, Fax: +81-42-346-1742, E-mail: nishino@ncnp.go.jp Distal myopathy with rimmed vacuoles (DMRV) and hered- itary inclusion body myopathy (HIBM) are now known to be the same disease and are caused by mutations in the GNE gene that encodes a bifunctional protein with two enzymat- ic activities: UDP-GlcNAc2-epimerase (GNE) and ManNAc kinase (MNK). GNE catalyzes the rate-limiting step in the sialic acid biosynthesis and MNK catalyzes the next step. So far, we have found homozygous or compound heterozy- gous mutations in 55 unrelated Japanese DMRV patients. Among them, c.1714G>C (p.V572L) mutation is the most common, accounting for 57% of the mutant alleles. The same mutation was recently identified also in Korean DMRV patients, raising the possibility of the presence of a common founder. We have also found that cardiac involvement is not very rare and is found in 18% of patients, albeit degree of severity widely varies; in some patients, it can result in sudden death. The length of time when patients become non ambulatory is diverse. The severity of clinical symptoms also varies widely, as evi- denced by the presence of an asymptomatic homozygote harboring of p.D176V, the second most common muta- tion among Japanese patients. Patients’ fibroblasts and myotubes are hyposialylated and this hyposialylation can be recovered by adding GNE metabolite, ManNAc, or sialic acid per se, NeuAc. Accord- ingly, the sialylation status in the skeletal muscle tissue is also greatly altered especially in fibers with rimmed vacuoles, suggesting the tight association between hyposia- lylation and the formation of rimmed vacuoles. However, we still do not know why hyposialylation leads to the for- mation of rimmed vacuoles. To further elucidate the path- omechanism and to develop a therapy of DMRV, we need to produce mouse model mouse for this disease. Key words: DMRV, HIBM, rimmed vacuole, sialylation Clinical features Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive muscle disorder affecting young adults and was originally described by Non- aka et al. in 1981, and thus it is also called Nonaka myopathy [1-4]. This disease has been known to be clinicopathologically similar to hereditary inclusion body myopathy (HIBM), which was earlier described as “rimmed vacuole myopathy” sparing the quadri- ceps by Argov et al. in 1983 [5]. DMRV and HIBM were initially described in Japanese and Iranian Jews, respectively; at present, however, patients with these diseases are seen all over the world. In addition, as I will discuss later, DMRV and HIBM are now known to be the same disease [6]. DMRV/HIBM is characterized clinically by the preferential involvement of tibialis anterior muscle sparing the quadriceps muscles [1-5]. The age at onset ranges from 15 to 40 years with an average of 26 years. The initial symptom is usu- ally altered gait. Patients become wheelchair- bound between 26 and 57 years of age, on average 12 years after the onset of symptoms. Muscle biopsy is characterized by the presence of many rimmed vacuoles especially in atrophic fibers. Necrotic and regenerating fibers are rarely seen. The rimmed vacuoles occasionally contain con- gophilic amyloid material and deposits that are immunoreactive to β-amyoid and β-amyloid pre- cursor protein, ubiquitin and tau protein. The nucleus occasionally contains tubulofilamentous inclusions of 15-20 nm in diameter [2-4]. Genetic cause Both DMRV and HIBM had been mapped to chro- mosome 9 by two independent linkage analyses [7, 8]. In 2001, Israeli group identified that HIBM is associ- ated with mutations in the GNE gene which encodes a bifunctional enzyme, UDP-N-acetylglucosamine 2-