Nonaka Myopathy

A number sign (#) is used with this entry because of evidence that Nonaka myopathy (NM) is caused by homozygous or compound heterozygous mutation in the gene encoding UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE; 603824) on chromosome 9p13.

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 creatine phosphokinase (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.

Argov and Yarom (1984) described a 'rimmed vacuole myopathy' in Jews of Persian origin. The onset of this disorder usually occurred after the age of 20 years but before the middle of the fourth decade of life. Proximal and distal muscle weakness and wasting of the upper and lower limbs were progressive and resulted in severe incapacitation within 10 to 20 years. Despite this, there typically was sparing of the quadriceps muscles even in advanced stages of the disease, a feature unique to this form of inclusion body myopathy. It was not clear to the authors whether this disorder was primarily neurogenic or myopathic.

Massa et al. (1991) reported 2 unrelated patients with IBM2, each from a family of Iranian-Kurdish-Jewish origin. The picture was that of adult-onset, slowly progressive limb-girdle muscle weakness with a remarkable sparing of quadriceps muscles.

Zlotogora (1995) reported that rimmed vacuole myopathy had been identified in 19 subjects of Iranian Jewish extraction and 3 others, possibly of that origin. They cited the reports of Adam et al. (1981), Argov and Yarom (1984), and Sadeh et al. (1993). Muscular weakness usually appeared in the third decade as gait difficulties. Progression was gradual, and most patients became severely incapacitated a decade after onset. Ocular, pharyngeal, and cardiac muscles were not involved. The muscles of the shoulder girdle were severely affected in advanced cases, with relative sparing of the deltoid, biceps, and triceps. In the lower limbs, foot dorsiflexion was usually very weak at an early stage of the disease. When leg muscle weakness becomes widespread, the most characteristic finding becomes evident, namely sparing of the quadriceps. The quadriceps muscles stayed strong even in advanced stages of the disorder, and thus the patients were able to stand and walk until late in the course of the disease. Creatine kinase levels were normal or moderately elevated, and nerve conduction velocity was normal.

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.

Argov and Yarom (1984) found that muscle biopsies from affected patients showed a rimmed vacuole myopathy and that the degenerating muscle fibers contained abnormal accumulations of beta-amyloid protein (104760) and other pathologic markers found in brain specimens from neurodegenerative disorders such as Alzheimer disease (see 104300). However, there was no central nervous system disease in these patients.

Massa et al. (1991) reported that muscle biopsies of affected patients showed abundant lined vacuoles and characteristic cytoplasmic inclusions of 15- to 18-nm filaments. Many vacuolated muscle fibers showed immunoreactivity to neural cell adhesion molecule (NCAM1; 116930), a fetal muscle antigen. In muscle biopsies, Zlotogora (1995) found many muscle fibers containing clefts or round vacuoles rimmed by granular material that stained basophilic on hematoxylin and eosin.

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 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.

Ricci et al. (2006) found that NCAM1 was hyposialylated in IBM2 muscle, as suggested by its decreased molecular weight on Western blot analysis. NCAM1 was identified as a discrete band of 130 kD in affected muscle compared to a broad band of 150 to 200 kD in other myopathies. NCAM1 was almost undetectable in normal control muscles, since it is usually detectable in regenerating fibers. Ricci et al. (2006) suggested that this specific abnormality could be used for diagnosis.

In muscle biopsies from 5 patients with IBM2, Krause et al. (2007) found that the GNE protein was expressed at normal levels and showed normal localization, suggesting that the disorder results from impaired GNE function.

By gene expression profiling of muscle specimens from 10 patients with the Persian Jewish founder GNE mutation M712T (603824.0005) compared to controls, Eisenberg et al. (2008) found that a large proportion (56 of 300, 18.6%) of differentially expressed mRNAs of known function in this disorder encoded proteins implicated in various mitochondrial processes. Morphologic analysis of mitochondria using video-rate confocal microscopy showed a high degree of mitochondrial branching in patient cells, which may represent compensatory mechanisms. The results indicated that dysregulation of mitochondrial pathways, such as apoptosis, may be involved in the pathophysiology of the disorder. Eisenberg et al. (2008) suggested that these subtle changes may partially explain the slow evolution of the disorder.

Nomenclature

Huizing et al. (2014) noted the many names that have been used for this disorder and suggested that the disorder be called 'GNE myopathy.'

Diagnosis

Ricci et al. (2006) found that NCAM1 (116930) was hyposialylated in HIBM muscle, as suggested by its increased electrophoretic mobility on Western blot analysis. NCAM1 was identified as a discrete band of 130 kD in affected muscle compared to a broad band of 150 to 200 kD in other myopathies. In a follow-up report, Broccolini et al. (2010) demonstrated that Western blot analysis of muscle NCAM1 could be used for diagnosis of HIBM in patients with unusual phenotypes. Three of 84 patients with proximal or distal muscle weakness were found to have a 130-kD NCAM1 band, and all 3 patients were subsequently found to have homozygous or compound heterozygous mutations in the GNE gene. These 3 patients had features not typical for inclusion body myopathy, including lack of rimmed vacuoles on biopsy, severe early onset, and mild, very late onset with distal muscle weakness, respectively. The hyposialylated NCAM1 was expressed by abnormal nonregenerating muscle fibers.

Mapping

Mitrani-Rosenbaum et al. (1996) performed linkage analyses in 9 Persian Jewish families selected for study because at least 1 member was previously diagnosed with hereditary IBM. Clinical studies provided evidence for autosomal recessive inheritance. A genomewide analysis demonstrated linkage to 9p1-q1 (D9S166); maximum lod score of 5.32 at theta = 0.0. Ikeuchi et al. (1997) found linkage to 9p1-q1 in Japanese families with autosomal recessive distal myopathy (Nonaka myopathy), suggesting that NM and HIBM are allelic. Christodoulou et al. (1998) performed linkage analysis in 10 families, 6 of Iranian-Jewish origin and 4 from other ethnic groups, with autosomal recessive quadriceps-sparing inclusion body myopathy. They confirmed linkage to chromosome 9p1, with a maximum lod score of 11.33 at a recombination fraction of 0.001 between the disease and locus D9S1859.

Ikeuchi et al. (1997) found linkage to 9p1-q1 in Japanese families with autosomal recessive distal myopathy with rimmed vacuoles and suggested that this disorder may be allelic to the autosomal recessive HIBM identified in Persian Jewish families.

Eisenberg et al. (1999, 2001) localized the locus for inclusion body myopathy in Middle Eastern Jews to 9p13-p12 within a genomic interval of about 700 kb. Haplotype analysis of the chromosomal region in 104 affected people from 47 Middle Eastern families indicated 1 unique ancestral founder chromosome. By contrast, single non-Jewish families from India, U.S., and the Bahamas, with quadriceps-sparing myopathy and linkage to the same 9p13-p12 region, showed 3 distinct haplotypes.

By homozygosity and linkage disequilibrium mapping, Asaka et al. (2001) refined the assignment of the NM locus 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

After excluding other potential candidate genes that mapped to the 9p13-p12 region, Eisenberg et al. (2001) identified mutations in the GNE gene in affected members of families with hereditary inclusion body myopathy; all patients of Middle Eastern descent shared a single homozygous missense mutation (M712T; 603824.0005), whereas affected individuals of families of other ethnic origins were compound heterozygous for distinct mutations.

By sequence and haplotype analyses of the GNE gene in 2 sibs with Nonaka myopathy in a Japanese family, Kayashima et al. (2002) found that both were compound heterozygous for 2 missense mutations (603284.0012-603284.0013). Their normal parents and a normal older brother were all carriers for one or the other of the mutations.

In 2 second cousins from an Italian family with hereditary inclusion body myopathy, Broccolini et al. (2002) identified compound heterozygous mutations in the GNE gene: a novel mutation (met171 to val; 603824.0016) and M712T (603824.0005). The authors noted that this was the first report of the M712T mutation in patients of non-Middle Eastern descent. In an American patient with inclusion body myopathy, Vasconcelos et al. (2002) identified compound heterozygous mutations in the GNE gene (603824.0015; 603824.0017).

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 compound heterozygous 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 hereditary inclusion body myopathy. Tomimitsu et al. (2002) suggested that Nonaka myopathy and hereditary inclusion body myopathy may be the same entity rather than allelic disorders.

Among 33 Japanese patients and 1 patient of German and Irish ancestry with Nonaka myopathy, Nishino et al. (2002) 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 the M712T mutation in the kinase portion of the gene. Nishino et al. (2002) noted that Nonaka myopathy and hereditary inclusion body myopathy may be the same disorder.

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.

Population Genetics

This disorder, affecting mainly leg muscles but with an unusual distribution that spares the quadriceps, was first described in Japanese patients by Nonaka et al. (1981) and later in Jews of Persian descent by Argov and Yarom (1984).

Argov et al. (2003) identified homozygosity for the GNE M712T mutation (603824.0005) in 129 Middle Eastern patients from 55 families with this disorder. Eleven patients had atypical features: 5 had involvement of the quadriceps muscle, 2 patients did not have distal weakness, 3 patients had facial weakness, and 1 patient had perivascular inflammation. There were 5 unaffected individuals with the homozygous mutation from 5 different families, including 2 who were 50 and 68 years old. The families included Middle Eastern Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin. Argov et al. (2003) offered a detailed historical perspective of the different cultures, and concluded that this founder mutation is approximately 1,300 years old and is not limited to those of Jewish descent.

Animal Model

Malicdan et al. (2007) generated Gne-deficient mice expressing the human D176V-GNE mutation as a mouse model of DMRV-HIBM. Complete knockout of the Gne gene was embryonic lethal. Mice with the D176V mutation showed marked hyposialylation in serum, muscle, and other organs. Reduction in motor performance in these mice could only be seen from 30 weeks of age. By 32 weeks, myofibers developed beta-amyloid deposition, which preceded rimmed vacuole formation at 42 weeks. The findings also suggested that hyposialylation plays an important role in the pathomechanism of DMRV-HIBM. Malicdan et al. (2009) 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.

History

Sivakumar et al. (1995) analyzed the sequence of exons 16 and 17 of amyloid precursor protein in 8 individuals with familial inclusion body myopathy, including 5 patients from Caucasian families segregating IBM in autosomal dominant fashion and 3 individuals who had apparent autosomal recessive inheritance, one of whom was of Iranian-Jewish ancestry. No mutations were demonstrated in these exons.