疾患詳細

疾患詳細





%147421
Inclusion body myositis (IBM)

封入体筋炎
指定難病15 封入体筋炎

遺伝子座:不明
遺伝形式:常染色体優性

(症状)
(GARD)
<80%-99%>
 Autoimmunity (自己免疫) [HP:0002960] [2203]
 Elevated serum creatine kinase (血清クレアチニンキナーゼ上昇) [HP:0003236] [2045]
 EMG abnormality (筋電図異常) [HP:0003457]
 Inflammatory myopathy (炎症性ミオパチー) [HP:0009071] [0277]
 Quadriceps muscle weakness (四頭筋筋力低下) [HP:0003731] [0270]
 Ragged-red muscle fibers (赤色ぼろ線維) [HP:0003200]
 Rimmed vacuoles (縁取り空胞) [HP:0003805]
 Skeletal muscle atrophy (骨格筋萎縮) [HP:0003202] [0270]
 
 <30%-79%>
 Feeding difficulties in infancy (哺乳障害, 乳児期) [HP:0008872] [01411]
 Reduced tendon reflexes (腱反射低下) [HP:0001315] [0242]
 
 <5%-29%>
 Myalgia (筋痛) [HP:0003326] [01420]
 
 
 Autosomal dominant inheritance (常染色体優性遺伝) [HP:0000006]
 Distal muscle weakness (遠位筋力低下) [HP:0002460] [0270]
 Dysphagia (嚥下障害) [HP:0002015] [01820]
 Hyporeflexia (低反射) [HP:0001265] [0242]
 Proximal muscle weakness (近位筋筋力低下) [HP:0003701] [0270]
 Slow progression (緩徐進行性) [HP:0003677]
 Sporadic (散発性) [HP:0003745]

(UR-DBMS)
【一般】嚥下障害
【神経】筋力低下, 近位
 筋萎縮, 特に四頭筋と前腕筋
 筋力低下, 遠位
 筋生検は T細胞を伴う炎症を示す
 縁のある空胞
 コンゴ好性封入体
 筋生検はβアミロイドとリン酸化された tau 沈着を伴う筋変性変化を示す
【検査】血清CK高値
【その他】老人で最も多い筋疾患
 多様な表現型
 緩徐進行性

<指定難病15 封入体筋炎>
1.概要
 臨床的には中高年以降に緩徐進行性の経過で四肢, 特に大腿部や手指・手首屈筋を侵し, 副腎皮質ステロイドによる効果はないか, あっても一時的である。筋への炎症性細胞浸潤, 特に非壊死線維への浸潤が特徴とされる。筋線維の縁取り空胞と併せて筋病理学的に診断される。

2.原因
 封入体筋炎という病名が初めて使われたのは1971年である。その後, 筋線維内にアミロイドが存在すること, 封入体にはアミロイド前駆蛋白やリン酸化タウが証明できることなど, アルツハイマー病との相同性が指摘されるようになっている。蛋白分解経路の異常の病態への関与が示唆される。

3.症状
 初発症状は, 下肢とくに立ち上がり動作や階段昇降困難, 上肢とくに手指・手首屈筋の筋力低下, 嚥下困難である。左右差が目立つ症例も多い。下肢は大腿屈筋群の障害に比して大腿四頭筋の障害が目立つ。四肢の筋力低下や嚥下障害は進行性である。

4.治療法
 現時点で有効な治療法は確立されていない。本症では, 副腎皮質ステロイドによる効果はないかあっても一時的で, 副作用による悪化を認める場合があるため, 大量の副腎皮質ステロイドを長期に渡って使用することを避けるべきである。免疫グロブリン大量療法の報告があるが, 有効性は限られる。
 
5.予後
 他の免疫疾患合併の報告はあるが, 悪性腫瘍の合併については皮膚筋炎や多発性筋炎のような関連はないと考えられている。多くの症例では, 四肢・体幹筋の筋力低下や嚥下障害の進行により, 寝たきりとなり, 最終的には肺炎などにより死亡する。

<指定難病診断基準>
Definite、Probableを対象とする。
●診断に有用な特徴
A.臨床的特徴
 a.他の部位に比して大腿四頭筋又は手指屈筋(特に深指屈筋)が侵される進行性の筋力低下及び筋萎縮
 b.筋力低下は数か月以上の経過で緩徐に進行する。
  *多くは発症後5年前後で日常生活に支障を来す。数週間で歩行不能などの急性の経過はとらない。
 c.発症年齢は40歳以上
 d.安静時の血清CK値は2,000 IU/Lを越えない。

(以下は参考所見)
 ・嚥下障害が見られる。
 ・針筋電図では随意収縮時の早期動員(急速動員)、線維自発電位/陽性鋭波/(複合反復放電)の存在などの筋原性変化 
 (注:高振幅長持続時間多相性の神経原性を思わせる運動単位電位が高頻度に見られることに注意)

B.筋生検所見
 筋内鞘への単核球浸潤を伴っており、かつ以下の所見を認める。
 a.縁取り空胞を伴う筋線維
 b.非壊死線維への単核球の侵入や単核球による包囲
 (以下は参考所見)
 ・筋線維の壊死・再生
 ・免疫染色が可能なら非壊死線維への単核細胞浸潤は主にCD8陽性T細胞
 ・形態学的に正常な筋線維におけるMHC class I発現
 ・筋線維内のユビキチン陽性封入体とアミロイド沈着
 ・COX染色陰性の筋線維:年齢に比して高頻度
 ・(電子顕微鏡にて)核や細胞質における16~20nmのフィラメント状封入体の存在

●合併しうる病態
HIV、HTLV-I、C型肝炎ウイルス感染症

●除外すべき疾患
・縁取り空胞を伴う筋疾患*(眼咽頭型筋ジストロフィー・縁取り空胞を伴う遠位型ミオパチー・多発性筋炎を含む。)
・他の炎症性筋疾患(多発性筋炎・皮膚筋炎)
・筋萎縮性側索硬化症などの運動ニューロン病
* 筋原線維性ミオパチー(FHL1、Desmin、Filamin-C、Myotilin、BAG3、ZASP、Plectin変異例)やベッカー型筋ジストロフィーも縁取り空胞が出現しうるので、鑑別として念頭に入れる。特に、家族性の場合は検討を要する。

●診断カテゴリー:診断には筋生検の施行が必須である。
Definite:Aのa~dおよびBのa、bの全てを満たすもの
Probable:Aのa~dおよびBのa、bのうち、いずれか5項目を満たすもの
Possible:Aのa~dのみ満たすもの(筋生検でBのa、bのいずれも見られないもの)

(Note)
Sporadic inclusion body myositis (IBM) is the most common age-related muscle disease in the elderly that results in severe disability. Although traditionally considered an inflammatory myopathy, it is now considered to be more consistent with a myodegenerative disease (Sugarman et al., 2002; Askanas and Engel, 2006).

Clinical Features
The vast majority of IBM occurs sporadically; however, rare familial occurrence has been reported. Inclusion body myositis is a slowly progressive inflammatory myopathy characterized clinically by weakness of the proximal parts of the limbs, diminished deep tendon reflexes, dysphagia, and mixed myopathic and neurogenic changes on electromyography. Baumbach et al. (1990) reported the first familial cases. Six persons in 2 generations were affected in an autosomal dominant pattern of inheritance. All 5 affected males had significant clinical findings with age of onset at 20 to 30 years. The only affected female was clinically asymptomatic but on muscle biopsy showed mild changes consistent with IBM. Garlepp et al. (1995) found particularly severe involvement of the quadriceps femoris muscles in the lower extremity and of the forearm flexor muscles in the upper limbs.

Pathologic Findings

Garlepp et al. (1995) defined IBM histologically by the presence of characteristic rimmed vacuoles with immunohistochemical evidence of the beta-amyloid fragment of the beta-amyloid precursor protein (beta-APP; 104760) and ubiquitin (see UBB; 191339).

Askanas et al. (2003) reported a 70-year-old African American man with sporadic IBM and cardiac amyloidosis associated with a mutation in the transthyretin gene (TTR; 176300.0009). Cultured skeletal muscle fibers from the patient showed vacuolar degeneration, congophilic inclusions, and clusters of colocalizing beta-amyloid and TTR immunoreactivities, none of which were found in normal cultured muscle fibers. Overexpression of the APP gene resulted in accelerated fiber degeneration, greater congophilic inclusions, and accumulation of heavy beta-amyloid oligomers. Askanas et al. (2003) suggested that the TTR mutation may have predisposed the patient to IBM by increasing beta-amyloid deposition in skeletal muscle.

Fratta et al. (2004) found that 70 to 80% of the vacuolated muscle fibers in samples from 10 patients with sporadic inclusion body myositis contained strong immunoreactivity to mutant ubiquitin (UBB+1) in the form of numerous well-defined plaque-like, dotted, or elongated aggregates. Similar aggregates were identified in 10 to 15% of the nonvacuolated normal-appearing fibers. In the abnormal fibers, these aggregates were concurrently immunoreactive for wildtype UBB and either beta-amyloid or phosphorylated tau (MAPT; 157140). None of the control biopsies were immunoreactive to UBB+1. Fratta et al. (2004) suggested that the UBB+1-inhibited proteasome cannot properly degrade toxic proteins, resulting in their accumulation and aggregation.

Pathogenesis
In a review of the pathogenesis of sporadic IBM, Askanas and Engel (2006) noted the striking similarities to Alzheimer disease (AD; 104300). Muscle fibers and brain tissue from the 2 disorders, respectively, share abnormal protein accumulation, including beta-amyloid, phosphorylated tau, ubiquitin, ApoE (107741), and presenilin-1 (PSEN1; 104311). The authors discussed the abnormalities of APP processing, the role of abnormal intracellular protein folding, oxidative stress, and the potential role of cholesterol in the pathogenic cascade of IBM.

Clinical Management
IBM has traditionally been considered an inflammatory myopathy that has been resistant to treatment, even with immunosuppressive agents. Barohn et al. (2006) reported that 9 IBM patients treated with a TNF-alpha (TNFA; 191160) inhibitor demonstrated a small but significant improvement in handgrip at 12 months. However, other functional measurements did not show improvement.

Molecular Genetics
Garlepp et al. (1995) found the frequency of the apolipoprotein E4 allele to be 0.29 in a group of 14 patients with IBM. This was considerably higher than that found in their control group of other inflammatory diseases (0.15) and the general population (0.13).

Fifteen- to 18-nm tubulofilament inclusions similar to those found in IBM have been observed in some cases of oculopharyngeal dystrophy (164300), which is caused by short expansions of a GCG trinucleotide repeat in the gene encoding poly(A)-binding protein-2 (PABP2; 602279). However, Mezei et al. (1999) did not observe any expansions in PABP2 in 22 sporadic or 3 familial cases of IBM.

Animal Model
Sugarman et al. (2002) noted that affected muscle fibers in IBM are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer disease (104300). Accumulation of the amyloid-beta peptide, which is derived from proteolysis of the larger beta-APP, seems to be an early pathologic event in both Alzheimer disease and IBM; in the latter, it occurs predominantly intracellularly within affected myofibers. To elucidate the possible role of beta-APP mismetabolism in the pathogenesis of IBM, Sugarman et al. (2002) selectively targeted beta-APP overexpression to skeletal muscle in transgenic mice, using the muscle creatine kinase promoter. They reported that older (more than 10 months) transgenic mice exhibited intracellular immunoreactivity to beta-APP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of beta-APP led to the development of a subset of other histopathologic and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results were considered consistent with a pathogenic role for beta-APP mismetabolism in human IBM.

In a transgenic mouse model of IBM with increased expression of beta-amyloid-42 in skeletal muscle, Kitazawa et al. (2008) observed signs of acute and chronic inflammation after administration of lipopolysaccharide (LPS), as well as exacerbation of motor decline compared to untreated mice. LPS activated glycogen synthase kinase 3-beta (GSK3B; 605004) with concomitantly increased levels of phosphorylated tau and beta-amyloid. Treatment with a specific GSK3B inhibitor or lithium reduced muscle phospho-tau levels and partially rescued motor impairment. Samples of human IBM muscle showed colocalization of GSK3B and phospho-tau. Murine C2C12 myoblasts treated with proinflammatory molecules also showed activated GSK3B and increased tau phosphorylation. Kitazawa et al. (2008) suggested a role for inflammation in IBM and identified GSK3B as a key signaling molecule.

(文献)
(1) Baumbach LL et al. Familial inclusion body myositis: evidence for autosomal dominant inheritance. Am J Hum Genet 47 (suppl.) Pa48, 1990
(2) Garlepp MJ et al. Apolipoprotein E epsilon-4 in inclusion body myositis. Ann Neurol 38: 957-959, 1995
(3) Mezei MM et al. Minimal expansion of the GCG repeat in the PABP2 gene does not predispose to sporadic inclusion body myositis. Neurology 52: 669-670, 1999
(4) Sugarman MC et al. Inclusion body myositis-like phenotype induced by transgenic overexpression of beta-APP in skeletal muscle. Proc. Nat. Acad. Sci. 99: 6334-6339, 2002
(5) Askanas, V.; Engel, W. K.; McFerrin, J.; Vattemi, G. : Transthyretin val122ile, accumulated A-beta, and inclusion-body myositis aspects in cultured muscle. Neurology 61: 257-260, 2003
(6) Fratta, P.; Engel, W. K.; Van Leeuwen, F. W.; Hol, E. M.; Vattemi, G.; Askanas, V. : Mutant ubiquitin UBB+1 is accumulated in sporadic inclusion-body myositis muscle fibers. Neurology 63: 1114-1117, 2004
(7) Askanas, V.; Engel, W. K. : Inclusion-body myositis: a myodegenerative conformational disorder associated with A-beta, protein misfolding, and proteasome inhibition. Neurology 66 (Suppl. 1): S39-S48, 2006
(8) Barohn, R. J.; Herbelin, L.; Kissel, J. T.; King, W.; McVey, A. L.; Saperstein, D. S; Mendell, J. R. : Pilot trial of etanercept in the treatment of inclusion-body myositis. Neurology 66 (Suppl. 1): S123-S124, 2006
(9) Kitazawa, M.; Trinh, D. N.; LaFerla, F. M. :
Inflammation induces tau pathology in inclusion body myositis model via glycogen synthase kinase-3-beta. Ann. Neurol. 64: 15-24, 2008

2008/12/09
2015/12/13 ノート改訂