疾患詳細

疾患詳細





#605820
Nonaka myopathy (NM)
(Nonaka distal myopathy)
(Myopathy, distal, with rimmed vacuoles (DMRV)

埜中ミオパチー
(埜中遠位ミオパチー)
(ミオパチー, 遠位, 縁取り空胞を伴う)
(封入体ミオパチー, 常染色体劣性)
(封入体ミオパチー, 四頭筋を除く)
(GNE ミオパチー)
(封入体ミオパチー2, 常染色体劣性, 以前の)
指定難病30 遠位型ミオパチー

責任遺伝子:603824 UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) <9p13.3>
遺伝形式:常染色体劣性

(症状)
(GARD)
 <80%-99%>
 Fatty replacement of skeletal muscle (骨格筋の脂肪置換) [HP:0012548]
 Foot dorsiflexor weakness (足背筋力低下) [HP:0009027] [156070]
 Mildly elevated creatine kinase (軽度CK上昇) [HP:0008180] [2045]
 Muscle fiber inclusion bodies (筋線維封入体) [HP:0100299]
 Rimmed vacuoles (縁取り空胞) [HP:0003805]
 Tibialis muscle weakness (脛骨筋筋力低下) [HP:0008963] [0270]
 
 <30%-79%>
 Absent Achilles reflex (アキレス腱反射欠損) [HP:0003438] [0242]
 EMG: myopathic abnormalities (筋電図: ミオパチー変化) [HP:0003458]
 EMG: myotonic discharges (筋電図: ミオトニア放電) [HP:0100284] 
 EMG: positive sharp waves (筋電図: 棘波陽性) [HP:0030007]
 Hip flexor weakness (股関節屈曲筋筋力低下) [HP:0012515] [0270]
 Hypothyroidism (甲状腺機能低下症) [HP:0000821] [2121]
 Increased variability in muscle fiber diameter (筋線維直径多様性の増加) [HP:0003557]
 Limited shoulder movement (肩運動制限) [HP:0006467] [15100]
 Limited wrist extension (手関節伸展制限) [HP:0006251] [15100]
 Shoulder girdle muscle weakness (肩帯筋筋力低下) [HP:0003547] [0270]
 Steppage gait (鶏歩) [HP:0003376] [028]
 
 <5%-29%>
 Abnormality of the right hemidiaphragm (右側横隔膜異常) [HP:0040047] [1202]
 Facial palsy (顔面神経麻痺) [HP:0010628] [02603]
 Lower limb amyotrophy (下肢萎縮) [HP:0007210] [0270]
 Scapular winging (翼状肩甲骨) [HP:0003691] [11031]
 Shoulder girdle muscle atrophy (肩帯筋萎縮) [HP:0003724] [0270]
 
 <1%-4%>
 Cardiomyopathy (心筋症) [HP:0001638] [0273]
 Weakness of long finger extensor muscles (長指伸展筋筋力低下) [HP:0009077] [0270]
 
 
 Adult onset (成人発症) [HP:0003581]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Deposits immunoreactive to beta-amyloid protein (βアミロイド蛋白へ免疫反応する沈着物) [HP:0003791] [2010]
 Distal amyotrophy (遠位筋萎縮) [HP:0003693] [0270]
 Distal muscle weakness (遠位筋力低下) [HP:0002460] [0270]
 Elevated serum creatine kinase (血清クレアチニンキナーゼ上昇) [HP:0003236] [2045]
 Gait disturbance (歩行障害) [HP:0001288] [028]

(UR-DBMS)
【神経】筋ジストロフィー (遠位筋, 特に前脛骨筋, 早期成人で発症)
 ミオパチーパターンの筋電図
 軽度の CK 高値
 '縁のある' 小胞 (筋生検)
 膝腱筋病変
 前脛骨筋病変
 四頭筋は除く
 EMG はミオパチー変化
 生検で管線維性核または細胞質封入体
 沈着物はβアミロイドタンパクと免疫反応する
 コンゴ染色性アミロイド物質
 炎症反応なし
 歩行異常
 CK 高値
【その他】早期成人期発症 (平均26歳)
 発症後平均12年で車椅子生活
 常染色体性劣性封入体ミオパチー-2 (IBM2, 600737)

(要約) GNE-関連ミオパチー
(縁取りのある空胞を伴う遠位ミオパチー (DMRV), 遺伝性封入体ミオパチー 2 (HIBM), 埜中ミオパチー
●GNE-関連ミオパチー (封入体ミオパチー2として知られる) は, 緩徐進行性遠位筋筋力低下が特徴である
 →10歳代後半から早期成人に, 前脛骨筋筋力低下に二次的な歩行障害や垂足で始まる
 その後, 手や大腿筋を含むが, 進行例であっても四頭筋は除くことが多い
 患者は通常発症後20年くらいで車椅子生活となる
 四頭筋を除くことが不完全な場合は, 移動能喪失が早期に生じる傾向がある
●診断:臨床および組織病理学的基準による
 孤発例が多いがめ, 親戚に患者がいることは診断に必須ではない
 筋組織病理学は, 縁取りのある奇異方と特徴的線維性封入体を示す
○GNE (二頭酵素である UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase をコード) が責任遺伝子である (60-80%)
 中東のユダヤ人では p.Met712Thr がほぼ100%
●治療:対症療法
●遺伝:常染色体劣性
●診断基準
・原発性筋疾患で, 通常下肢の筋力低下で始まる
・近位下肢筋の著明な筋力低下にもかかわらず四頭筋は除く
・10歳代後半または早期成人発症
・軽度の血清CK値増加:正常の2〜4倍
・筋生検:縁取りのある空胞 (HE染色で塩基性顆粒物質, 修正Gomori trichrome染色で紫赤色)
●頻度:> 200例
 イラン系ユダヤ人 (p.Met712Thr ホモ接合創始者変異) 160例

<指定難病30 遠位型ミオパチー>
1. 概要
 遠位筋が好んで侵される遺伝性筋疾患の総称。世界的には少なくとも9つの異なる疾患が含まれるとされているが, これまでのところ, 本邦では
「縁取り空胞を伴う遠位型ミオパチー (Nonaka myopathy)」(常染色体劣性),
「三好型 ミオパチー (Miyoshi myopathy 1, 2, 3)」(常染色体劣性),
「眼咽頭遠位型ミオパチー (Oculopharyngodistal myopathy); Satoyoshi」(AD(日本)/AR(トルコ))
の 3 疾患しか見出されていない。
 何れも本邦において発見された疾患である。
2. 原因
 「縁取り空胞を伴う遠位型ミオパチー」は, シアル酸生合成経路の律速酵素をコードする GNE 遺伝子のミスセンス変異によりシアル酸合成能が低下することで発症する。→ Sialuriaがアレリック疾患
 「三好型ミオパチー」は筋鞘膜修復に関係する蛋白質ジスフェルリン Dysferlin (DYSF)の欠損症である。
 「眼咽頭遠位型ミオパチー」の一部の患者は, 実際には, 臨床病理学的に類似する眼咽頭型筋ジストロフィーに罹患しているが, 大半の患者では原因不明である。
3. 症状
 「縁取り空胞を伴う遠位型ミオパチー」は, 10 代後半~30 代後半にかけて発症し, 前脛骨筋を特に強く侵すが, 進行すると近位筋も侵される。病理学的に縁取り空胞の出現を特徴とする。
 「三好型ミオパチー」は 10 代後半~30 代後半に発症し, 主に下腿後面筋群が侵されるが進行すると近位筋も侵される。病理学的 には筋線維の壊死・再生変化が特徴であり, 血清 CK 値が高度に上昇する。
 「眼咽頭遠位型ミオパチー」は 通常成人期~老年期にかけて発症し, 眼瞼下垂, 眼球運動障害, 嚥下障害に加えて, 特に前脛骨筋を侵すミオパチーを呈する。筋病理学的には縁取り空胞を認める。
4. 治療法
 転倒による外傷(歩行障害のため)「眼咽頭遠位型ミオパチー」では, 嚥下障害による誤嚥性肺炎などに 対しては対症療法を行う。
5. 予後
 歩行障害, 嚥下障害, 嚥下性肺炎などが生じる。

<診断基準>
「遠位型ミオパチー」診断基準
Definite, Probableを対象とする。
遠位型ミオパチーとして下記の各疾患群を含める。
(1)三好型ミオパチー
(2)縁取り空胞を伴う遠位型ミオパチー(DMRV/GNE myopathy)
(3)眼咽頭遠位型ミオパチー
(4)その他の遠位型ミオパチー

(2) 縁取り空胞を伴う遠位型ミオパチー(MIM# 605820, Distal myopathy with rimmed vacuoles: DMRV, GNE myopathy*)診断基準
●診断に有用な特徴
 A. 臨床的特徴
  a. 常染色体劣性遺伝または孤発性
  b. 進行性の筋力低下および筋萎縮:前脛骨筋や大腿屈筋群, 大内転筋が侵されるが大腿四頭筋は多くは保たれる
 (以下は参考所見)
 ・発症年齢は 15 歳から 40 歳までが多い
 ・5~20 年の経過で歩行不能となることが多い
 ・血清 CK 値は正常から軽度高値(1,500IU/L 以下)
 ・針筋電図で筋原性変化(fibrillation potential や高振幅 MUP が認められることがある)
 B. 筋生検所見(a は必須)
  a. 縁取り空胞を伴う筋線維

(以下は参考所見)
 ・通常強い炎症反応を伴わない
 ・筋線維内の -アミロイド沈着
 ・筋線維内のユビキチン陽性封入体:
 ・筋線維内の p62 陽性凝集体
 ・筋線維内のリン酸化タウ
 ・(電子顕微鏡にて) 核または細胞質内の 15-20 nm のフィラメント状封入体(tubulofilamentous inclusions)の 存在
 C. 遺伝学的検査
  a. GNE 遺伝子のホモ接合型または複合へテロ接合型変異
●除外すべき疾患
臨床的鑑別
・遠位筋を侵し得る他の筋疾患(他の遠位型ミオパチーを含む。)
・神経原性疾患
病理学的鑑別
・縁取り空胞を来す他のミオパチー

●診断のカテゴリー
Definite:A又はBの少なくとも一方を満たし, かつCを満たすもの。 
Probable:A+Bを満たすもの。
* DMRV又はNonaka Myopathyは国際的にGNE myopathyと統一呼称する動きがある(Huizing et al. Neuromuscul Disord 2014)が, 本診断基準中には現在通用されている呼称と併記した。

(Responsible gene) *603824 UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) <9p13.3>
(1) Sialuria (269921)
.0001 Sialuria [GNE, ARG266TRP] (dbSNP:rs121908621) (Seppala et al. 1999)
.0002 Sialuria [GNE, ARG266GLN] (dbSNP:rs121908622) (Seppala et al. 1999; Leroy et al. 2001)
.0003 Sialuria [GNE, ARG263LEU] (dbSNP:rs121908623) (Seppala et al. 1999)
.0004 MOVED TO 603824.0002
(2) Nonaka myopathy (605820)
.0005 Nonaka myopathy [GNE, MET712THR] (dbSNP:rs28937594) (Eisenberg et al. 2001; Broccolini et al. 2002; Argov et al. 2003; Tomimitsu et al. 2004)
.0006 Nonaka myopathy [GNE, GLY576GLU] (dbSNP:rs121908625) (Eisenberg et al. 2001)
.0007 Nonaka myopathy [GNE, ALA631THR [dbSNP:rs121908626] (Eisenberg et al. 2001)
.0008 Nonaka myopathy [GNE, VAL696MET [dbSNP:rs121908627] (Eisenberg et al. 2001)
.0009 Nonaka myopathy [GNE, CYS303TER [dbSNP:rs121908628] (Eisenberg et al. 2001)
.0010 Nonaka myopathy [GNE, ARG246GLN [dbSNP:rs121908629] (Eisenberg et al. 2001)
.0011 Nonaka myopathy [GNE, ASP225ASN [dbSNP:rs121908630] (Eisenberg et al. 2001)
.0012 Nonaka myopathy [GNE, ALA460VAL [dbSNP:rs121908631] (Kayashima et al. 2002)
.0013 Nonaka myopathy [GNE, VAL572LEU [dbSNP:rs121908632] (Kayashima et al. 2002; Tomimitsu et al. 2002; Arai et al. 2002; Tomimitsu et al. 2004; Kim et al. 2006)
.0014 Nonaka myopathy [GNE, CYS303VAL [dbSNP:rs121908633] (Tomimitsu et al. 2002)
.0015 Nonaka myopathy [GNE, ALA631VAL] (dbSNP:rs62541771) (Tomimitsu et al. 2002; Vasconcelos et al. 2002)
.0016 Nonaka myopathy [GNE, MET171VAL [dbSNP:rs121908634] (Broccolini et al. 2002)
.0017 Nonaka myopathy [GNE, VAL216ALA [dbSNP:rs779694939] (Vasconcelos et al. 2002)

*GNE: UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (722 amino acids)
・二頭酵素で, シアル酸の前駆体であるN-acetylneuraminic acid (NeuAc)合成を開始および調節する
・シアル酸生合成径路での律速酵素である
・細胞表面分子のシアル酸修飾は多くの生物学的プロセスでの機能に責任がある (細胞接着やシグナル伝達, 発癌, 転移)
・早期発生に必須である
・造血細胞での正常なシアル酸付加に必要である

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 vacule 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 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 heterozygotes 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.

(文献)
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2009/08/11
2011/07/04
2013/03/23
2014/01/03 SNP
2015/12/11 600737 Inclusion body myopathy 2, autosomal recessive (IBM2) 統合 ノート/文献追加
2015/12/31 症状追加
2016/10/06 ノート改訂
2016/12/02 SNP