| #605820 | ||||||||||||||||||||||||||||||||||||
| NONAKA MYOPATHY; NM | ||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||
| NONAKA DISTAL MYOPATHY MYOPATHY, DISTAL, WITH RIMMED VACUOLES; DMRV | ||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||
| TEXT | ||||||||||||||||||||||||||||||||||||
| A number sign (#) is used with this entry because of evidence that Nonaka myopathy is caused by mutation in the gene encoding UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE; 603824). Autosomal recessive inclusion body myopathy type 2 (IBM2; 600737) is an allelic disorder with a similar phenotype. | ||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||
| Nonaka et al. (1981) described a form of muscular dystrophy with predilection for distal muscles, especially the anterior tibial muscles, and onset in early adulthood. The EMG demonstrated a myopathic pattern and CPK was mildly elevated. Rapid clinical progression was observed. Nonaka et al. (1981) thought the disorder in their families was autosomal recessive. They stated that the disorder appears to be common in Japan. Asaka et al. (2001) pointed out the unique distribution of muscular weakness and wasting in Nonaka distal myopathy. Although the hamstring and tibialis anterior muscles are affected severely by early adulthood, the quadriceps muscles are spared even in a late stage of the disorder. Pathologic Findings Nonaka et al. (1981) noted that a striking morphologic change on muscle biopsy was the presence of 'rimmed' vacuoles that had acid phosphatase-positive autophagocytic activity and contained numerous concentric lamellar bodies in various forms. There was almost no histologic sign of regeneration. Murakami et al. (1995) compared Congo red and immunohistochemical staining of 11 biopsies of distal myopathy with rimmed vacuoles to that of inclusion body myositis (IBM; 147421). All biopsies had characteristic tubulofilamentous inclusions in their nuclei on electron microscopy. Similarly, all specimens had deposits immunoreactive for beta-amyloid protein, ubiquitin, and tau protein. Most DMRV and IBM specimens had Congophilic amyloid material. Indeed, only the presence of inflammatory cell infiltrates in IBM cases distinguished them from DMRV. The authors suggested that the degenerative process involved in rimmed vacuole formation may share a common pathogenetic mechanism with that in Alzheimer disease (104300) brain. In 2 Japanese brothers with distal myopathy with rimmed vacuoles, confirmed by compound heterozygous mutations in the GNE gene, Yabe et al. (2003) reported the presence of inflammatory cells in affected muscle biopsies. Immunohistochemical characterization detected CD8 T cells, fewer CD4 T cells and macrophages, and no B cells. The authors noted that the inflammatory cells are an unusual finding in this disorder, and are usually seen in familial IBM. | ||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||
| Ikeuchi et al. (1997) found linkage to 9p1-q1 in Japanese families with autosomal recessive distal myopathy (Nonaka myopathy), suggesting that that disorder and autosomal recessive inclusion body myopathy (600737) are allelic disorders. By homozygosity and linkage disequilibrium mapping, Asaka et al. (2001) refined the assignment of the NM gene to a 1.5-Mb region between markers D9S2178 and D9S1791. Haplotype analysis indicated that a majority of NM chromosomes were derived from a single ancestral founder. They concluded that the cytogenetic location of the locus is 9p13. | ||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||
| Eisenberg et al. (2001) demonstrated mutations in the GNE gene (603824) in autosomal recessive inclusion body myopathy and urged that the GNE gene be studied in Nonaka myopathy. This was done by Kayashima et al. (2002). Sequence and haplotype analyses of the GNE gene in 2 sibs with Nonaka myopathy in a Japanese family revealed that both were compound heterozygotes for 2 missense mutations in that gene. Their normal parents and a normal older brother were all carriers for 1 or the other of the mutations. In 7 of 9 unrelated Japanese patients with Nonaka myopathy, Tomimitsu et al. (2002) identified a homozygous val572-to-leu (V572L; 603824.0013) mutation in the GNE gene. The eighth patient was a compound heterozygote for V572L and cys303-to-val (C303V; 603824.0014) mutations, and the ninth patient was homozygous for an ala631-to-val (A631V; 602824.0015) mutation. Tomimitsu et al. (2002) noted that patients with different mutations showed different clinical characteristics and that some showed overlap with the characteristics of IBM2. Tomimitsu et al. (2002) suggested that Nonaka myopathy and IBM2 may be the same entity rather than allelic disorders. Nishino et al. (2002) provided further evidence that IBM2 and Nonaka myopathy are allelic disorders. Among 33 Japanese patients and 1 patient of German and Irish ancestry with Nonaka myopathy, they identified homozygous or compound heterozygous mutations in the GNE gene in 27 unrelated patients. An unaffected father of 1 patient had a homozygous mutation that presumably caused disease in other patients. The V572L mutation (603824.0013) accounted for 61% of the abnormal alleles in the study, indicating a high frequency of carriers of this mutation in Japan. The authors noted that the patient of German and Irish ancestry had a compound mutation, although not the V572L mutation, indicating that the disorder is not restricted to Japan. Epimerase activity of GNE was significantly reduced in patient lymphocytes, suggesting that loss-of-function mutations are responsible for the disease. Hinderlich et al. (2003) commented on the difficulties in detecting GNE epimerase activity, but noted that they had found slightly reduced, although clearly active, levels of essential epimerase activity in lymphoblastoid cells derived from patients with hereditary inclusion body myopathy who had a met712-to-thr mutation in the kinase portion of the gene (M712T; 603824.0005). Kim et al. (2006) performed clinical and genetic analysis of 9 unrelated Korean patients suspected of having Nonaka myopathy and found that 8 of the 9 were homozygous or compound heterozygous for mutations in the GNE gene. | ||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||
| Malicdan et al. (2009) generated Gne-deficient mice expressing the human D176V-GNE mutation as a mouse model of distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy (DMRV-HIBM). They found that D176V-mutant mice treated orally with sialic acid showed increased survival, increased motor performance, and decreased number of rimmed vacuoles in skeletal muscle compared to untreated mice with the disorder. Prophylactic treatment prevented development of the myopathic phenotype. The findings indicated that hyposialylation is a key factor in the pathomechanism of DMRV-HIBM. | ||||||||||||||||||||||||||||||||||||
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