疾患詳細

疾患詳細





#254130
Miyoshi muscular dystrophy 1 (MMD1)
(Miyoshi myopathy)
(Muscular dystrophy, distal, late-onset, autosomal recessive)
指定難病30 遠位型ミオパチー

三好筋ジストロフィー 1
(三好ミオパチー)
(筋ジストロフィー, 遠位, 遅発性, 常染色体劣性)

責任遺伝子:603009 Dysferlin (DYSF) <2p13.2>
遺伝形式:常染色体優性

(症状)
(GARD)
 <30%-79%>
 Adult onset (成人発症) [HP:0003581]
 Difficulty standing (立位困難) [HP:0003698] [028]
 Difficulty walking (歩行困難) [HP:0002355] [028]
 Distal upper limb amyotrophy (遠位上肢筋萎縮) [HP:0007149] [0270]
 Exercise-induced myalgia (運動誘発性筋痛) [HP:0003738] [01420]
 Pelvic girdle muscle weakness (骨盤肢帯筋筋力低下) [HP:0003749] [0270]
 Proximal amyotrophy (近位筋萎縮) [HP:0007126] [0270]
 Quadriceps muscle weakness (四頭筋筋力低下) [HP:0003731] [0270]
 Shoulder girdle muscle weakness (肩帯筋筋力低下) [HP:0003547] [0270]
 Tibialis atrophy (脛骨筋萎縮) [HP:0011399] [0270]
 Tibialis muscle weakness (脛骨筋筋力低下) [HP:0008963] [0270]
 
 <5%-29%>
 Calf muscle hypertrophy (腓腹筋肥大) [HP:0008981] [0276]
 Decreased/absent ankle reflexes (足関節反射減少/欠損) [HP:0200101] [0242]
 Deposits immunoreactive to beta-amyloid protein (βアミロイドタンパクに免疫反応する沈着物) [HP:0003791] [2010]
 Foot dorsiflexor weakness  (足背筋力低下) [HP:0009027] [156070]
 Loss of ability to walk (歩行能喪失) [HP:0006957] [0125]
 Toe walking (つま先歩行) [HP:0040083] [028]
 Triceps weakness (三頭筋筋力低下) [HP:0031108] [0270]
 
 
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Decreased Achilles reflex (アキレス腱反射低下) [HP:0009072] [0242]
 Difficulty climbing stairs (昇段困難) [HP:0003551] [028]
 Difficulty running (走行困難) [HP:0009046] [028]
 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]
 Lower limb muscle weakness (下肢筋力低下) [HP:0007340] [0270]
 Muscle fibrillation (筋細動) [HP:0010546] [02604]
 Muscular dystrophy (筋ジストロフィー) [HP:0003560] [0275]
 Quadriceps muscle atrophy (四頭筋萎縮) [HP:0009050] [0270]
 Variable expressivity (多様な表現度) [HP:0003828]

(UR-DBMS)
【神経】つま先歩行困難
 踵立ちは保存
 階段のぼり困難
 スクワットから立てない
 下肢の筋力低下
 下肢の筋消耗
 腓腹筋とヒラメ筋が最も侵される
 ハムストリングと四頭筋は軽度侵される
 前脛骨筋は正常
 アキレス腱反射低下または欠損
 前腕筋の軽度の筋力低下
 前腕筋の軽度の筋萎縮
 握力低下
 小手および指筋はのぞく
 MRI は患部筋のシグナル強度の増加 (脂肪浸潤に一致)
 筋生検はジストロフィー変化を示す
 筋生検は炎症性変化を示すかもしれない
 筋生検は dysferlin 染色の減少または欠損を示す
 患部筋の線維性攣縮
 まれに筋線維へのアミロイド沈着が生じる【検査】軽度のCK 高値
【検査】軽度のCK 高値
 ミオパチー性筋電図
 'rimmed' 空胞は acid phosphatase-陽性の自己貪食像があり, 多数のいろんな形の中心層性小体を含む
【その他】15-25歳発症
 2B 型肢帯筋ジストロフィー (LGMD2B, 253601) とアレリック

(要約) Dysferlin 異常症
●Dysferlin 異常症は, 2つの主要な表現型が特徴の筋疾患スペクトラムを含む
 →主に遠位筋力低下を伴う三好ミオパチーと主に近位筋力低下を伴う支帯型筋ジストロフィー2B型 (LGMD2B)
・三好ミオパチー (平均発症年齢19歳) は, 筋力低下と筋萎縮が特徴で, 下肢の遠位に最も目立つ (特に腓腹筋とヒラメ筋)
 時間とともに, 筋力低下と萎縮は上腿や殿筋に拡大する
 前腕は握力低下を伴い軽度萎縮がみられるかもしれない
 手の小筋は除かれる
・LGMD2B は, 思春期または若年成人で骨盤および肩支帯筋の早期筋力低下と萎縮が特徴で, 緩徐進行性である
・その他の表現型には, 肩甲腓骨症候群, 前脛骨発症を伴う遠位ミオパチー, 血清CK高値のみ, および先天性筋ジストロフィーがある
●診断:筋生検と分子遺伝学的検査による
 ウェスタン免疫ブロットは常に原発性Dysferlin 異常症を示す
 DYSF の病的バリアントの証明→95%
●遺伝:常染色体劣性
●三好ミオパチー
 小児期中期~後期, または早期成人発症 (平均発症年齢19歳)
 早期は主に腓腹筋を障害する
 緩徐進行性である
 血清 CK 値:正常の10~100倍 (平均 CK: 8,940 IU/L)
 筋電図:筋原性パターン
●LGMD2B
 主に骨盤筋や肩帯筋の筋力低下と萎縮
 10歳代後半またはそれ以後の近位下肢で発症
 血清 CK の大きな上昇
 緩徐進行性
 遠位筋のサブクリニカルな障害→筋CTなどで (一部の患者で)
●検査
 筋生検:縁取り空胞のない慢性活動性ミオパチー; 線維サイズの多様性, 1型線維優位, 炎症の証拠があることが多い
 免疫染色:dysferlin は筋膜にある→欠損または斑状に染色
 免疫ブロット:dysferlin 異常, できれば免疫染色と両方行う
 Dysferlin 発現:モノクローナルdysferlin抗体で末梢血単球でみる
●鑑別診断:
1) その他の常染色体劣性LGMD
 免疫染色→ LGMDのサブタイプの診断 (sarcoglycanopathy , calpainopathy, dysferlinopathy)
2) caveolinopathies (caveolin3の異常)→常染色体優性
 Limb-girdle muscular dystrophy 1C (LGMD1C), 単独高CK血症, Rippling muscle disease (RMD), 遠位ミオパチー, 肥大型心筋症のみ

(解説)
●遠位型ミオパチー
 手足の先の方から筋肉が萎縮していく疾患
 筋ジストロフィーとミオパチーの臨床上の違いは, 前者は筋肉の壊死と再生を激しく繰り返しており, 血中のCK値が跳ね上がっている(正常値の数十倍以上)のに対し, 後者では激しい壊死は見られず血中CK値は比較的安定(正常値の数倍程度)している点である。
●遠位型ミオパチー
(1) 縁取り空胞を伴う遠位型ミオパチー(DMRV, hIBM, IBM2, Nonaka myopathy)
 20〜30歳頃に発病し前頸骨筋が最も侵されやすい
 つま先が上がりにくくつまずきやすい, スリッパが脱げやすい等の症状が出る
 つま先が上がりにくいため, 必然的に鶏歩(垂足)となる
 筋肉の萎縮は10歳前後から確実に始まっているものと考えられるが, 本人にはなかなか自覚することができない
 →ハムストリング, 胸鎖乳突筋等の萎縮が進行し, 発症後10年程度で歩行が不可能となる
 大腿四頭筋は侵されにくい
 手の筋力も遠位から低下し, やがて近位にも及んでくる
 最終的には寝たきりとなるとなる可能性が高い
 筋生検で筋繊維中に縁取り空胞(rimmed vacuoles)が観察される (縁取り空胞が見られる筋疾患は他にも存在する)
 原因遺伝子はGNEであり常染色体劣性遺伝する
 →患者の筋繊維中のある種のタンパク質ではシアリル化(シアル酸の付加の程度)が低下している
  GNEの変異によりシアル酸が過剰に生成されるシアルリア(Sialuria)も生じる
(2) 三好型遠位型ミオパチー(三好型遠位型ジストロフィー)
 20〜30歳頃に発病し腓腹筋とヒラメ筋が侵される
 →つま先立ちができない, よろめいて転倒しやすい等の症状が出る
 発症後10年程度で歩行が不可能となり, 手の筋力も遠位から低下しやがて近位にも及んでくる
 筋ジストロフィーの一種であり血中のCK値が顕著に上昇する
 原因遺伝子は dysferlin であり, 常染色体劣性遺伝する
 肢帯型筋ジストロフィーの患者においても dysferlinの異常が確認されている
(3) 眼咽頭型遠位型ミオパチー
 40〜50歳以降に発症し, 眼瞼下垂, 嚥下困難等の症状が出る
 同時に手足の遠位からの筋力低下が現れるが, 進行は比較的ゆっくりしている
 原因遺伝子は不明であるが優性遺伝である

<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

(1) 三好型ミオパチー(MIM# 254130, Miyoshi myopathy, Distal dysferlinopathy)診断基準
●診断に有用な特徴
 A. 臨床的特徴(a-c は必須)
  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:下肢後面特に腓腹筋が侵される
  c. 歩行可能な時期に血清 CK 値が異常高値 (1,000IU/L 以上)を示す 
 (以下は参考所見)
  ・発症年齢は 30 歳までに多い
  ・進行すれば近位筋の筋力低下が出現する
  ・針筋電図で筋原性変化
 B. dysferlin の評価(a または b が必須)
  a. dysferlin 欠損(骨格筋免疫染色またはウェスタンブロット解析)
  b. DYSF (dysferlin)遺伝子のホモ接合型または複合ヘテロ接合型変異
 (以下は参考所見)
  ・CD14 陽性リンパ球のウェスタンブロット解析で dysferlin 欠損

●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
・他の筋ジストロフィー
・多発性筋炎

●診断のカテゴリー
Definite:A+Bを満たす例 
Probable:Aを満たすが, Bが実施されていない例

(責任遺伝子) *603009 Dysferlin (DYSF) <2p13.2>
(1) Miyoshi muscular dystrophy 1 (254130)
.0001 Miyoshi muscular dystrophy 1 [DYSF, GLN605TER] (rs121908953) (RCV000007047...) (Liu et al. 1998)
.0003 Miyoshi muscular dystrophy 1 (253601 Muscular dystrophy, limb-girdle, autosomal recessive 2, included) [DYSF, ILE1298VAL] (rs121908954) (gnomAD:rs121908954) (RCV000007049...) (Liu et al. 1998)
.0004 Miyoshi muscular dystrophy 1 (Muscular dystrophy, limb-girdle, autosomal recessive 2, included) [DYSF, ARG2042CYS] (rs121908955) (gnomAD:rs121908955) (RCV000815134...) (Liu et al. 1998)
.0010 Miyoshi muscular dystrophy 1 [DYSF, TRP999CYS] (rs28937581) (gnomAD:rs28937581) (RCV000007059...) (Takahashi et al. 2003)
.0011 Miyoshi muscular dystrophy 1 [DYSF, ARG1046HIS] (rs121908958) (gnomAD:rs121908958) (RCV000007060...) (Aoki et al. 2001)
.0012 Miyoshi muscular dystrophy 1 (Myopathy, distal, with anterior tibial onset, included) (Muscular dystrophy, limb-girdle, autosomal recessive 2, included) [DYSF, ARG1905TER] (rs121908959) (gnomAD:rs121908959) (RCV000007061...) (Vilchez et al. 2005)
.0015 Miyoshi muscular dystrophy 1 [DYSF, GLY519ARG] (rs121908962) (RCV000007066...) (Illa et al. 2007)
.0018 Miyoshi muscular dystrophy 1 [DYSF, GLY299TRP] (rs121908963) (gnomAD:rs121908963) (RCV000594920...) (Spuler et al. 2008)
(2) Myopathy, distal, with anterior tibial onset (606768)
.0002 Myopathy, distal, with anterior tibial onset [DYSF, 1-BP DEL, 5966G] (rs786205081) (RCV000007048...) (Liu et al. 1998)
(3) Muscular dystrophy, limb-girdle, autosomal recessive 2 (253601)
.0005 Muscular dystrophy, limb-girdle, autosomal recessive 2 [DYSF, 5-BP DEL/4-BP INS, NT4872] (rs786200896) (gnomAD:rs786200896) (RCV000338549...) (Bashir et al. 1998; Sinnreich et al. 2006)
.0006 Muscular dystrophy, limb-girdle, autosomal recessive 2 [DYSF, 23-BP INS] (rs786205082) (RCV000007054) (Bashir et al. 1998)
.0007 Muscular dystrophy, limb-girdle, autosomal recessive 2 (Miyoshi muscular dystrophy 1, included) [DYSF, PRO791ARG] (rs121908956) (gnomAD:rs121908956) (RCV000807968...) (Weiler et al. 1999)
.0008 Muscular dystrophy, limb-girdle, autosomal recessive 2 [DYSF, NT5711, G-A, +5] (rs745891180) (gnomAD:rs745891180) (RCV000007057) (McNally et al. 2000)
.0009 Muscular dystrophy, limb-girdle, autosomal recessive 2 [DYSF, VAL67ASP] (rs121908957) (RCV000007058...) (Illarioshkin et al. 2000)
.0013 Muscular dystrophy, limb-girdle, autosomal recessive 2 [DYSF, ASP625TYR] (rs121908960) (gnomAD:rs121908960) (RCV000007064) (Illa et al. 2007)
.0014 Muscular dystrophy, limb-girdle, autosomal recessive 2 [DYSF, GLU1734GLY] (rs121908961) (RCV000007065) (Illa et al. 2007)
.0016 Muscular dystrophy, limb-girdle, autosomal recessive 2 [DYSF, IVS31DS, A-G, -33] (rs786205083) (RCV000007067) (Sinnreich et al. 2006)
.0017 Muscular dystrophy, limb-girdle, autosomal recessive 2 [DYSF, GLY299ARG] (rs121908963) (gnomAD:rs121908963) (RCV000726614...) (Spuler et al. 2008)
.0019 Muscular dystrophy, limb-girdle, autosomal recessive 2 [DYSF, IVS14AS, A-G, -2] (rs786200897) (RCV000007070) (Spuler et al. 2008)
.0020 Muscular dystrophy, limb-girdle, autosomal recessive 2 [DYSF, 1-BP DEL, 855+1G] (rs786200898) (RCV000007071) (Spuler et al. 2008)
.0021 Muscular dystrophy, limb-girdle, autosomal recessive 2 [DYSF, 1-BP DEL, 2776G] (rs727503909) (RCV000546602...) (Paradas et al. 2009)
.0022 Muscular dystrophy, limb-girdle, autosomal recessive 2 [DYSF, 5492G-A] (rs786205084) (RCV000723469...) (Santos et al. 2010)

*DYSF: Dysferlin (2080 amino acids)
・ferlin ファミリーに属し, 筋鞘に関連する骨格筋タンパクである
・筋収縮に関与し, カルシウム仲介性膜融合で役割をもつ
 →膜再生と修復に関与することを示唆する
・小窩形成に重要な骨格筋膜タンパクである caveolin-3 と結合する
・変異は, 常染色体劣性支帯型筋ジストロフィー2B型と Miyoshi ミオパチーを生じる
・多くの転写バリアントがある
・鍵となるカルシウムイオンセンサーで Ca(2+)-triggered synaptic vesicle-plasma membrane fusionで役割をもつ
・骨格筋と心筋細胞の筋鞘修復メカニズムで役割をもつ
 →機械的ストレスで破綻された膜の急速な再封鎖を許す

(ノート)
●(#) は,三好筋ジストロフィー1 (MMD1) は 2p13 の dysferlin (DYSF; 603009) をコードする遺伝子のホモ接合体変異が原因であるため

●肢帯型筋ジストロフィーの1つの型 (LGMD2B; 253601) も dysferlin 遺伝子変異が原因である

Miyoshi muscular dystrophy is an autosomal recessive skeletal muscle disorder characterized by onset in young adulthood of distal muscle weakness affecting the upper and lower limbs but sparing the intrinsic hand muscles. Muscle weakness and atrophy particularly affects the gastrocnemius and soleus muscles, and can later spread to involve the thigh and gluteal muscles. Patients showed impaired tip-toe standing, difficulty in climbing stairs, and difficulty walking, but usually remain ambulatory. Serum creatine kinase is increased and muscle biopsies show myopathic and dystrophic changes with necrosis (summary by Miyoshi et al., 1986).

Genetic Heterogeneity of Miyoshi Muscular Dystrophy

●三好筋ジストロフィーは遺伝的異質性のある疾患である
 MMD2 (613318) → 10p
 MMD3 (613319) → 11p14 の ANO5 遺伝子 (608662) 変異が原因

●Welander ミオパチー (604454)も参照
 →常染色体優性型の遅発型遠位ミオパチー

臨床症状
Miyoshi et al. (1967) reported 4 patients from 2 Japanese families with distal myopathy inherited in an autosomal recessive pattern. Sasaki et al. (1969) and Ideta et al. (1973) each reported 4 affected patients. Kuhn and Schroder (1981) reported 2 affected Caucasian brothers born of consanguineous parents. They had early-adult onset in the distal leg muscles and elevated creatine kinase.

Miyoshi et al. (1986) described in detail 17 cases from 8 families including an autopsy case. Consanguinity was found in 7 of the 8 families and in 2 families there was pseudodominance, i.e., affected father and children. Eighty percent of the cases had onset between 16 and 20 years with long survival. Serum CK activity was markedly elevated in all except 1 patient, aged 56 years; CK was mildly elevated in preclinical stages. The pattern of muscle involvement was distinctive; the muscles of the lower legs and forearms were involved, whereas the small muscles of the feet and hands were relatively spared. Skilled movements of the fingers were not disturbed, but grip strength was decreased early in the disease. No lesions were detected in the brain, spinal cord, or peripheral nerves. Miyoshi et al. (1986) noted that the disorder could be distinguished from Welander myopathy, which shows atrophy of small muscles of the hands and extensor muscles of the legs with inability to stand on the heels but ability to stand on tip-toes, whereas in Miyoshi myopathy, impaired toe-standing was an early symptom and heel-standing was normal.

Isaacs et al. (1988) described 5 patients with autosomal recessive distal myopathy of late onset; 3 of the patients belonged to a single sibship. One of the cases resembled the Nonaka form (605820). The authors concluded that autosomal recessive distal myopathy can occur in different ethnic groups.

Yamanouchi et al. (1994) examined 19 muscle biopsies from 14 patients with autosomal recessive distal muscular dystrophy. The histologic features were similar to those of Duchenne muscular dystrophy (DMD; 310200) with active muscle fiber necrosis and regeneration, as well as disorganization of the intermyofibrillar network. In half of the patients, small angular fibers and scattered rimmed vacuoles were found. However, dystrophin (300377) and utrophin (128240) were expressed normally, even in severely affected gastrocnemius muscles.

In a large, inbred, aboriginal Canadian kindred with 9 muscular dystrophy patients, Weiler et al. (1996) found that the ancestry of all but 2 of the carrier parents could be traced to a founder couple 7 generations earlier. Seven patients presented with proximal myopathy consistent with limb-girdle muscular dystrophy, whereas 2 patients manifested predominantly distal wasting and weakness consistent with Miyoshi myopathy. Age at onset of symptoms, degree of creatine kinase elevation, and muscle histology were similar in both phenotypes. Segregation of LGMD/MD was consistent with autosomal recessive inheritance.

Rowin et al. (1999) described 2 patients with a clinical diagnosis of Miyoshi myopathy who demonstrated marked inflammatory changes on muscle biopsy of clinically less affected muscles. The findings illustrated the importance of recognizing the marked variability in histopathology of Miyoshi myopathy, which may include an inflammatory infiltrate on muscle biopsy, mimicking the histopathologic picture of an inflammatory myopathy. One patient was a 25-year-old Pakistani man, born of consanguineous parents, with a 1.5-year history of progressive atrophy of both calves associated with 'limping.' He denied involvement of the upper extremities. The second patient was a 29-year-old woman who had had progressive difficulty in walking, particularly in high-heeled shoes, beginning at the age of 18 and progressing to include difficulty walking up stairs and stumbling over her feet.

Ro et al. (2004) reported 4 Chinese patients from 2 unrelated families living in Taiwan with MM confirmed by molecular identification of mutations in the dysferlin gene. Three sibs in 1 family experienced difficulty in toe walking beginning at ages 17 to 18 years. In the following 2 to 5 years, all had difficulty in climbing stairs and rising from a squatting position accompanied by moderate to severe weakness in the gastrocnemius and soleus muscles and mild weakness in the hamstring and quadriceps muscles. The tibialis anterior muscle was relatively spared. Two patients had muscle wasting and weakness in the lower legs. Reflexes were decreased or absent in the ankles. CK was elevated and muscle biopsies showed dystrophic patterns with decreased or absent dysferlin staining. MRI showed a mild to moderate increase of signal intensity in the affected muscles of the lower legs, reflecting fatty infiltration. The 1 patient from the other family had a similar clinical course and MRI findings.

Illa et al. (2007) reported 2 sibs with Miyoshi myopathy due to a homozygous mutation in the DYSF gene (G519R; 603009.0015). Age at onset was 18 and 15 years, respectively, of distal weakness of the lower limbs with progression to proximal muscle involvement and later upper limb involvement. Both were wheelchair-bound in their thirties. The patients' father, who was heterozygous for the G519R mutation, developed calf myalgias and mild progressive difficulties in walking at age 65 years. He had moderately increased serum creatine kinase and decreased dysferlin immunostaining on muscle biopsy, although DYSF mRNA levels were normal. The findings indicated that heterozygous DYSF mutation carriers may develop late-onset milder manifestations of the disorder.

Spuler et al. (2008) reported 2 sibs with Miyoshi myopathy caused by mutation in the DYSF gene (G299W; 603009.0018). Skeletal muscle biopsy of 1 showed amyloid fibrils on skeletal muscle biopsy. Amyloid was located in the sarcolemma of muscle cells as well as in blood vessel walls and interstitium. Spuler et al. (2008) postulated that the mutation destabilized the protein structure of dysferlin and increased the propensity to form amyloid fibrils.

Diagnosis
Cacciottolo et al. (2011) found that all of 55 patients with an undetermined LGMD clinical phenotype and 10 patients with a Miyoshi myopathy phenotype who had less than 20% dysferlin on skeletal muscle biopsy determined by Western blot analysis had pathogenic mutations in the DYSF gene. Exhaustive mutation analysis was performed, including genomic DNA sequencing, mRNA analysis, array CGH, and PCR. Sixty-five different mutations were identified throughout the gene and there were no mutation hotspots. Cacciottolo et al. (2011) noted the difficulty of sequencing the DYSF gene because of its larger size, and concluded that protein analysis showing a dysferlin reduction to 20% of normal values in skeletal muscle or in peripheral blood monocytes can be used to identify LGMD2B/MMD1 caused by DYSF mutations with 100% accuracy.

Mapping
Bejaoui et al. (1995) identified a putative Miyoshi myopathy disease locus on chromosome 2p14-p12 (lod score of 15.3 at marker D2S291) by a study of 12 families with MM. Five of the families were consanguineous.

Weiler et al. (1996) linked a Canadian family in which some members had features of limb-girdle muscular dystrophy and others had features of distal myopathy to 2p (lod score greater than 3.0). The putative region included the LGMD2B locus on 2p. Analysis of microsatellite markers surrounding the disease locus disputed the original hypothesis that the affected patients would be homozygous by descent. Rather, 2 different core haplotypes, encompassing a 4-cM region spanned by D2S291-D2S145-D2S286, segregated with the disease, indicating 2 mutant alleles of independent origin. There was no association between phenotype and haplotype. Weiler et al. (1996) concluded that LGMD and MM in this population were caused by the same mutation at the LGMD2B locus and that additional factors, both genetic and nongenetic, contributed to the clinical phenotype.

By examining critical recombination events in 2 consanguineous families of Tunisian origin with MM, Bejaoui et al. (1998) refined the MM locus to a 360-kb segment. They mapped the cytoskeletal protein beta-adducin gene (102681) within the MM candidate region, but failed to find a consistent pattern of mutation of this gene in MM patients.

Although Welander distal myopathy also links to 2p13, von Tell et al. (2003) used extended linkage analysis to exclude the dysferlin gene as the cause of that disease.

Molecular Genetics
In 9 families with either Miyoshi myopathy or LGMD2B, Liu et al. (1998) identified 9 mutations in the dysferlin gene (see, e.g., 603009.0001), indicating that they are allelic disorders.

Nomenclature
In a review of limb-girdle muscular dystrophies, Bushby (1999) referred to LGMD2B and Miyoshi myopathy as dysferlinopathies.

(文献)
(0) Welander L: Myopathia distalis tarda hereditaria. Acta Med. Scand. 141 (suppl. 265): 1-124, 1951
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(3) Ideta T et al. Distal myopathy--report of 4 cases in two families. Clin Neurol 13: 579-586, 1973
(4) Kuhn E, Schroder JM: A new type of distal myopathy in two brothers. J Neurol 226: 181-185, 1981
(5) Nonaka I et al. Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J Neurol Sci 51: 141-155, 1981
(6) Miyoshi K et al. Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy: seventeen cases in eight families including an autopsied case. Brain 109: 31-54, 1986
(7) Isaac H et al. Autosomal recessive distal myopathy. J Clin Path 41: 188-194, 1988
(8) Yamanouchi Y et al. Autosomal recessive distal muscular dystrophy: normal expression of dystrophin, utrophin and dystrophin-associated proteins in muscle fibers. J Neurol Sci 126: 70-76, 1994
(9) Bejaoui K et al. Linkage of Miyoshi myopathy (distal autosomal recessive muscular dystrophy) locus to chromosome 2p12-14. Neurology 45: 768-772, 1995
(10) Kiyomoto BH et al. Reducing bodies in distal myopathy with rimmed vacuole formation. Acta Neuropath 89: 109-111, 1995
(11) Murakami N et al. Muscle fiber degeneration in distal myopathy with rimmed vacuole formation. Acta Neuropath 89: 29-34, 1995
(12) Weiler T et al. Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype. Am. J. Hum. Genet. 59: 872-878, 1996
(13) Bashir R et al. A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nature Genet. 20: 37-42, 1998
(14) Bejaoui K et al. Genetic fine mapping of the Miyoshi myopathy locus and exclusion of eight candidate genes. Neurogenetics 1: 189-196, 1998
(15) Liu J et al. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nature Genet. 20: 31-36, 1998
(16) Bushby KMD: The limb-girdle muscular dystrophies--multiple genes, multiple mechanisms. Hum. Molec. Genet. 8: 1875-1882, 1999
(17) Rowin J et al. Prominent inflammatory changes on muscle biopsy in patients with Miyoshi myopathy. Neuromusc. Disord. 9: 417-420, 1999
(18) von Tell, D.; Bruder, C. E. G.; Anderson, L. V. B.; Anvret, M.; Ahlberg, G. : Refined mapping of the Welander distal myopathy region on chromosome 2p13 positions the new candidate region telomeric of the DYSF locus. Neurogenetics 4: 173-177, 2003
(19) Ro, L.-S.; Lee-Chen, G.-J.; Lin, T.-C.; Wu, Y.-R.; Chen, C.-M.; Lin, C.-Y.; Chen, S.-T. : Phenotypic features and genetic findings in 2 Chinese families with Miyoshi distal myopathy. Arch. Neurol. 61: 1594-1599, 2004
(20) Illa, I.; De Luna, N.; Dominguez-Perles, R.; Rojas-Garcia, R.; Paradas, C.; Palmer, J.; Marquez, C.; Gallano, P.; Gallardo, E. : Symptomatic dysferlin gene mutation carriers: characterization of two cases. Neurology 68: 1284-1289, 2007
(21) Spuler, S.; Carl, M.; Zabojszcza, J.; Straub, V.; Bushby, K.; Moore, S. A.; Bahring, S.; Wenzel, K.; Vinkemeier, U.; Rocken, C. : Dysferlin-deficient muscular dystrophy features amyloidosis. Ann. Neurol. 63: 323-328, 2008
(22) Cacciottolo, M., Numitone, G., Aurino, S., Caserta, I. R., Fanin, M., Politano, L., Minetti, C., Ricci, E., Piluso, G., Angelini, C., Nigro, V. Muscular dystrophy with marked dysferlin deficiency is consistently caused by primary dysferlin gene mutations. Europ. J. Hum. Genet. 19: 974-980, 2011

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