疾患詳細

疾患詳細



急速進行性筋力低下と麻痺. 横隔膜性呼吸, 胸郭変形. 膝および股関節拘縮. 全身性無反射. 無表情. 知能発達正常. 漏斗胸, 後側弯, 関節拘縮;頸定なしl; 著明な攣縮を伴う舌の腫大変形.

#253300
Spinal muscular atrophy, type I (SMA1)
(SMA I)
(SMA, infantile acute form)
(Muscular atrophy, infantile)
(Werdnig-Hoffmann disease)

脊髄性筋萎縮 I
(脊髄性筋萎縮, 乳児急性型)
(筋萎縮, 乳児性)
(Werdnig-Hoffmann 病)
指定難病3 脊髄性筋萎縮症
小児慢性特定疾病 神30 脊髄性筋萎縮症

責任遺伝子:600354 Survival of motor neuron 1, telomeric (SMN1) <5q13.2>
遺伝形式:常染色体劣性

(症状)
(GARD)
 
 Areflexia (無反射) [HP:0001284] [0242]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Decreased fetal movement (胎動減弱) [HP:0001558] [01004]
 EMG: neuropathic changes (筋電図: ニューロパチー変化) [HP:0003445]
 Proximal amyotrophy (近位筋萎縮) [HP:0007126] [0270]
 Proximal muscle weakness in lower limbs (下肢の近位筋筋力低下) [HP:0008994] [0270]
 Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] [014230]
 Respiratory failure (呼吸不全) [HP:0002878] [01606]
 Respiratory insufficiency (呼吸不全) [HP:0002093] [01606]
 Spinal muscular atrophy (脊髄性筋萎縮) [HP:0007269] [0270]
 Tongue fasciculations (舌線維束性攣縮) [HP:0001308] [02604]
 Ventricular septal defect (心室中隔欠損) [HP:0001629] [1120]

(UR-DBMS)
A. 臨床所見
(1)脊髄前角細胞の喪失と変性による下位運動ニューロン症候を認める。
 筋力低下(対称性, 近位筋>遠位筋, 下肢>上肢, 躯幹および四肢)
 筋萎縮
 舌, 手指の筋線維束性収縮
 腱反射減弱から消失
(2)上位運動ニューロン症候は認めない。(上位運動ニューロンの障害があると, 錐体路徴候と呼ばれる症状, すなわち痙縮, 筋力低下, 深部腱反射の亢進, バビンスキー反射が現れる。)
(3)経過は進行性である。
B. 臨床検査所見
 血清 creatine kinase (CK) 値が正常上限の 10 倍以下である
 筋電図で高振幅電位や多相性電位などの神経原性所見を認める
 運動神経伝導速度が正常下限の 70%以上である

【一般】呼吸不全
【心】先天性心奇形が数例でみられる
 VSD, ASD
【神経】運動ニューロパチーによる筋力低下, 対称性, 近位 (下肢が上肢より重度)
 筋萎縮
 顔面筋は除く
 舌の筋線維束攣縮/線維性攣縮
 正常な運動神経伝達速度 (最初は)
 筋電図は神経原性異常
 無反射
 脊髄前角と下部脳幹の lower alpha-motor neurons の喪失
【一般】胎動減少
【その他】2歳以前に呼吸器感染症または呼吸器不全で死亡
 出生時ないし6か月令発症
 頻度は 1/6,000 〜 1/8,000 生産児
 約45%の SMA1 患者もneuronal apoptosis inhibitory protein (NAIP, 600355)の両方の遺伝子を欠損する
 重症度を修飾する役割をもつのかも
 SMN1 のエキソン7はSMN1 患者の95.6%で欠損している

(要約) 脊髄性筋萎縮症 (Spinal Muscular Atrophy) (2019.11.14)
(Spinal muscular atrophy 0; Spinal muscular atrophy I; Spinal muscular atrophy II; Spinal muscular atrophy III; Spinal muscular atrophy IV)
●脊髄性筋萎縮症 (SMA) は, 脊髄前角細胞 (下位運動ニューロン)と脳幹核の進行性変性と喪失による筋力低下と筋萎縮が特徴
 筋力低下の発症は, 出生前から思春期または若年成人の範囲がある
 筋力低下は対称性で, 近位>遠位で, 進行性である
 遺伝的基盤が判明する以前は獲得した最大運動機能に基づく臨床的サブタイプに分類されていたが, SMN1-関連SMAは明らかなサブタイプにわけられない症状の連続であることが明らかである
 成長障害, 拘束性肺疾患, 側弯, 関節拘縮, 睡眠障害が多い合併症である
 →新しい標的治療が自然歴を変えている
 代謝性アシドーシスを生じやすい
●診断:運動障害または退行の既往歴, 近位筋筋力低下, 深部腱反射低下/欠損, 運動単位病の証拠+/-SMN1の2アレル変異の証明による
 SMN2コピー数の増加が表現型を修飾することが多い
●治療:
 疾患メカニズムを標的とする治療: nusinersen (Spinraza®; an antisense oligonucleotide) (全タイプに対して)
 onasemnogene abeparvovec-xioi (Zolgensma®; 遺伝子置換療法) → SMA I 型に
 標的療法はいくつかの症状の発生を防止または遅らせるかもしれない
 治療効果は症状発症前の使用で改善する→長期効果はまだ不明
 支持療法の率先が症状改善に必須である
 栄養/嚥下障害→胃瘻を早めに
 胃食道逆流, 慢性便秘→標準的治療
 肺機能の頻回の経過観察→悪化の場合は気管切開, 非信州的呼吸支持
 側弯 (約50%)→外科的修復
 股関節脱臼→疼痛がある場合は外科手術
※長期の飢餓を避ける
●遺伝:常染色体劣性
 (注意) 約2%の患者は1アレルが新生 SMN1 バリアントをもつ→この場合は片親のみが保因者であるり再発危険率はない
(示唆する所見)
●新生児スクリーニング(real-time PCR)異常
 common SMN1 欠失を検出, SMN2 コピー数を検出するかも
 →遺伝子検査へ
●遅発型 SMAまたは乳児期発症 SMAの場合
 運動障害の既往歴 (特に機能喪失)
 近位筋>遠位筋筋力低下
 筋緊張低下
 無反射/反射低下
 舌線維束性攣縮
 手振戦
 生後2-3か月での反復性下気道感染または重症気管支炎
 EMGでの運動単位病の証拠
●診断の確定(遺伝子診断)
○新生児スクリーニング異常の場合
 SMN1 exon 7 の量決定をまず行う→存在すれば配列解析を行う
 SMN1 exon 7 が両コピーで見られる→別の診断を考慮する
○SMN1 配列解析は不活性化したバリアントが SMN1 か SMN2 かを決定できない
 →バリアントが以前に報告されている, または, long-range PCR 産物またはSMN1のサブクローンをシークェンスする
○SMN1の2アレル病的バリアントの証明
 SMN1 ~100%で →配列異常 2%-5% (病的バリアントとSMN1欠失の複合ヘテロ接合) 欠失 95%-98%
 集団の5-8%は1染色体にSMN1を2コピーもっている ( [2+0] configuration) (サブサハラアフリカ人に多い)→偽陰性となる
 予後について→SMN2のコピー数検査 (0-5個もっている) [Quantitative PCR と MLPAで検査]
・SMN2 コピー数の増加が表現型を修飾することが多い
 2つの遺伝子は互いに隣接する
 SMN1 と SMN2 遺伝子は5bpのみ異なる(アミノ酸は違わない)
 大多数の人は各々の染色体に SMN1 の1コピーをもつ
● SMN1 遺伝子検査
 最初にエクソン7の欠失/重複解析を行い遺伝子量を決定する (95~98%はエクソン7欠失のホモ接合)
 →SMN1 の1コピーの欠失がある場合は, 配列解析を行う (2~5%)
  SMN1 の2コピーがある場合は他の鑑別診断を考慮する
 SMN1配列解析は暫定的不活性化バリアントが SMN1 か SMN2 かを決定できない
 →SMN1バリアントの決定には, 過去に報告されているバリアントか, または long-range PCR 産物をシークェンスする必要がある
●SMA 表現型スペクトラム
1) SMA 0 出生前発症 寿命<6 か月 運動は獲得しない 重度の新生児筋緊張低下/重度の筋力低下/無反射/出生時呼吸不全/両顔面麻痺/胎動減弱/ASD/関節拘縮 (遺伝子治療の報告なし)
2) SMA I (Werdnig-Hoffmann) <6 か月発症 寿命;大多数は8-10か月 介助でのみ坐可能 軽度の関節拘縮/正常または最小の顔面筋力低下/多様な吸啜嚥下障害/舌攣縮
3) SMA II (Dubowitz) 6-18 か月発症 70% は25歳時生存 坐位保持可能/発達遅滞, 運動能喪失/深部腱反射低下または欠損/近位筋筋力低下, 指の姿勢性振戦
4) SMA III (Kugelberg-Welander) >18 か月発症 寿命正常 独歩可能/近位筋筋力低下 (昇段走行困難)/運動能喪失/易疲労性/指の姿勢性振戦
5) SMA IV 成人発症 寿命正常 運動正常 易疲労性/近位筋筋力低下
●代謝性アシドーシス→原因不明の潜在的合併症
 dicarboxylic aciduria と血清 carnitine 低値を伴う→遷延性飢餓を避ける
●遺伝子型-表現型相関
1) SMN1 →相関なし
 exon 7 のホモ接合欠失は全ての表現型で同頻度でみられる
2) SMN2
●SMN2 遺伝子について
 SMN2 により産生される完全長転写産物の少量 (1/4まで)は機能的タンパクを産生し, 軽症 SMA II または SMA III 表現型となる
 SMN2コピー数:cis で0~5個 tandem に配列している
 2コピーは88%でSMA I 表現型となる
 3個以上が軽症表現型 (SMA III/IV))と相関する
 4個のSMN2コピーをもつ患児は III 型SMAをもつリスクを88%もつ
 SMN1 欠失がホモ接合+ SMN2 5コピー→ SMN1発現欠損を代償する
○SMN2 コピー数 SMA I SMAII SMAIII/IV
 1       96%  4%   0%)
 2       79%  16%  5%
 3       15%  54%  31%
 4以上     1%   11%  88%
● その他のSMA 表現型の暫定的修飾因子
 SMN2 のエクソン7の c.859G>C (p.Gly287Arg)→軽症となる疾患修飾因子である
 →新しい exon splicing enhancer (ESE) elementをつくる
 PLS3→軸索発生に重要な遺伝子で, SMN1のホモ接合欠失に対して保護的修飾因子として作用する
●命名
SMA I →以前の Werdnig-Hoffmann 病または急性 SMA
SMA II →慢性 SMA または Dubowitz 病
SMA III → Kugelberg-Welander 病, 若年性 SMA
SMA IV →思春期または成人発症 SMA
●頻度: 保因者頻度 推定頻度
 アラブ:1:50
 アジア人:1:48 1:8009
 黒人(サブサハラ) 1:100 1:18,808
 白人 1:45 1:7829
 ヒスパニック 1:77 1:20,134
 ユダヤ人 1:56 1:10,000
●鑑別診断
発症年齢 疾患 遺伝子 遺伝形式 SMAとのオーバーラップ症状 SMAとの違い
1) 先天性〜<6か月発症
 X-linked infantile spinal muscular atrophy UBA1 XL 筋緊張低下, 筋力低下, 無反射 多発性先天性関節拘縮, 骨折
 Spinal muscular atrophy and respiratory distress 1 (SMARD1) (OMIM 604320) IGHMBP2 AR 筋力低下, 呼吸不全, 低/無反射 遠位が有意な筋力低下, 横隔膜麻痺
 Prader-Willi syndrome 15q11.2-q13  筋緊張低下 呼吸不全はまれ
 Myotonic dystrophy type 1 DMPK AD 筋緊張低下 舌攣縮なし
 Congenital muscular dystrophy 多くの遺伝子 AR, AD 筋緊張低下, 筋力低下 中枢神経病変, 眼病変
 Zellweger spectrum disorder PEX 遺伝子群 AR 筋緊張低下 運動喪失, 肝脾腫
 Congenital myasthenic syndromes 多くの遺伝子 AR 筋緊張低下 眼筋麻痺, 眼瞼下垂, 観血的呼吸不全
 Pompe 病 GAA AR 筋緊張低下 心拡大
2) >6 か月発症
 ボツリヌス中毒 - - 近位筋力低下 目立つ脳神経麻痺, 急性発症
3) 後期小児期
 Guillain-Barré 症候群 不明 筋力低下, 亜急性発症, 感覚異常
 Duchenne 筋ジストロフィー DMD XL 筋緊張低下 血清CK 10-20倍以上
 Hexosaminidase A 欠乏症 HEXA AR 下部運動ニューロン秒 緩徐進行, 進行性ジストニア, 脊髄小脳変性
 Fazio-Londe 症候群 SLC52A2/SLC52A3 AR 筋力低下 下部脳神経限定, 1-5年で死亡へ進行
 Monomelic amyotrophy (Hirayama 病) (OMIM 602440) 不明 筋力低下 主に頸部, 舌(まれ), 他の脳神経はのぞく
4) 成人発症
 Spinal and bulbar muscular atrophy AR/XL 近位筋力低下, 筋萎縮, 攣縮 次第に進行, 女性型乳房, 精巣萎縮, 妊孕性減少
 Amyotrophic lateral sclerosis 多くの遺伝子 AD/AR/X 純粋下部運動ニューロンサインで発症するかも 進行性神経変性, 上部および下部運動ニューロンを含む
●標的治療
 2または3コピーのSMN2をもつ患者で推奨される (症状の有無に関係なく)
 SMN2を 1コピーをもつ患者は重症度を考慮して決定する
 SMN2を4期ピー以上もつ患者では症状発症するまで延期する
(治療レジメ)
SMAの全サブタイプ→Nusinersen (Spinraza®) (アンチセンスオリゴヌクレオチド) 髄腔内 12 mg (4-5 mL 年齢による)/14日/全部で3回→第3回30日後に4回目投与→4か月ごとに維持量
I 型 SMA→Onasemnogene abeparvovec-xioi (Zolgensma®; 以前の AVXS-101) (遺伝子置換療法 [SMN1のウイルス配達]) 1回静注

<指定難病3 脊髄性筋萎縮症>
(沖縄型神経原性筋萎縮症)はここ
1.概要
 脊髄性筋萎縮症(spinal muscular atrophy:SMA)は, 脊髄の前角細胞の変性による筋萎縮と進行性筋力低下を特徴とする下位運動ニューロン病である。上位運動ニューロン徴候は伴わない。体幹, 四肢の近位部優位の筋力低下, 筋萎縮を示す。発症年齢, 臨床経過に基づき, I型, II型, III型, IV型に分類される。I型, II型の95%にSMN1遺伝子欠失が認められ, III型の約半数, IV型の1~2割においてSMN1遺伝子変異を認める。SMN1遺伝子に変異がなく早期に呼吸障害を来すI型において, IGHMBP2の遺伝子変異を認めることがある。
●遺伝子
 SMN1 → SMA を生じる
 SMN2 コピー数→表現型を修飾する (0コピーから5コピーまでみられる) 2つの遺伝子は互いに隣接する
 SMN1 と SMN2 遺伝子は5bpのみ異なる(アミノ酸は違わない)
●大多数の人は各々の染色体に SMN1 の1コピーをもつ
 集団の約5-8%は染色体に2コピーの SMN1 をもつ→保因者決定で偽陰性となるので注意
●SMN1 (survival motor neuron 1) が主の SMA-関連遺伝子である
 患者の 95%-98% は, SMN1 の欠失か遺伝子変換のホモ接合である (典型的には両コピーでのエクソン7の欠損) →少なくともエクソン7については欠失のホモ接合である
 患者の 2%-5% は, 少なくとも SMN1 エクソン7の欠失と遺伝子内不活性化変異の複合ヘテロ接合である
●SMN2→3以上のコピー数の存在は軽症表現型と相関する
2.原因
 原因遺伝子は, 1995年, SMN1遺伝子として同定された。I型, II型のSMAにおいては, SMN1遺伝子の欠失の割合は9割を超えることが明らかになっており, 遺伝子診断も可能である。また, SMN1遺伝子の近傍には, NAIP遺伝子, SERF1遺伝子などが存在し, それらはSMAの臨床症状を修飾するといわれている。早期に重症な呼吸障害を示すI型の一部において, IGHMBP2の遺伝子変異を示す例がある。III型, IV型においては, SMN1遺伝子変異が同定されない例も多く, 他の原因も考えられている。
3. 症状
Ⅰ 型:重症型, 急性乳児型, ウェルドニッヒ・ホフマン (Werdnig-Hoffmann)病
 発症は出生直後から生後6ヶ月まで。フロッピーインファントの状態を呈する。肋間筋に対して横隔膜の筋力が維持されているため吸気時に腹部が膨らみ胸部が陥凹する奇異呼吸を示す。定頸の獲得がなく, 支えなしに座ることができず, 哺乳困難, 嚥下困難, 誤嚥, 呼吸不全を伴う。舌の線維束性収縮がみられる。深部腱反射は消失, 上肢の末梢神経の障害によって, 手の尺側偏位と手首が柔らかく屈曲する形の wrist drop が認められる。人工呼吸管理を行わない場合, 死亡年齢は平均6~9カ月である。
Ⅱ 型:中間型, 慢性乳児型, デュボビッツ(Dubowitz)病
 発症は1歳6ヶ月まで。支えなしの起立, 歩行ができず, 座位保持が可能である。舌の線維束性収縮, 手指の振戦がみられる。腱反射の減弱または消失。次第に側彎が著明になる。
 Ⅱ型のうち, より重症な症例は呼吸器感染に伴って, 呼吸不全を示すことがある。
Ⅲ 型:軽症型, 慢性型, クーゲルベルグ.ウェランダー(Kugelberg-Welander)病
 発症は1歳6ヶ月以降。自立歩行を獲得するが, 次第に転びやすい, 歩けない, 立てないという症状がでてくる。
 後に, 上肢の挙上も困難になる。歩行不可能になった時期が思春期前の場合には, II 型と同様に 側弯などの脊柱変形が顕著となりやすい。
Ⅳ 型:成人期以降の発症の SMA を IV 型とする。
 小児期発症の Ⅰ, Ⅱ, Ⅲ 型と同様の SMN 遺伝子変異による SMA もある。
 一方, 孤発性で成人から老年にかけて発症し, 緩徐進行性で, 上肢遠位に始まる筋萎縮, 筋力低下, 筋線維束性収縮, 腱反射低下を示す場合もある。これらの症状は徐々に全身に拡がり, 運動機能が低下する。また, 四肢の近位筋, 特 に肩甲帯の筋萎縮で初発する場合もある。
※SMA においては, それぞれの型の中でも臨床的重症度は多様である。
4.治療法
 根治治療はいまだ確立していない。I型, II型では, 授乳や嚥下が困難なため, 経管栄養が必要な場合がある。また, 呼吸器感染, 無気肺を繰り返す場合は, これが予後を大きく左右する。I型のほぼ全例で, 救命のためには気管内挿管, 後に気管切開と人工呼吸管理が必要となる。I型, II型において, 非侵襲的陽圧換気療法(=鼻マスク陽圧換気療法:NIPPV)は有効と考えられるが, 小児への使用には多くの困難を伴う。また, 全ての型において, 筋力に合わせた運動訓練, 理学療法を行う。III型, IV型では歩行可能な状態の長期の維持や関節拘縮の予防のために, 理学療法や装具の使用などの検討が必要である。小児においても上肢の筋力が弱いため, 手動より電動車椅子の使用によって活動の幅が広くなる。I型やII型では胃食道逆流の治療が必要な場合もある。脊柱変形に対しては脊柱固定術が行われる場合もある。
5.予後
I型は1歳までに呼吸筋の筋力低下による呼吸不全の症状を来す。人工呼吸器の管理を行わない状態では, ほとんどの場合2歳までに死亡する。II型は呼吸器感染, 無気肺を繰り返す例もあり, その際の呼吸不全が予後を左右する。III型, IV型は生命的な予後は良好である。
(指定難病診断基準)
A. 臨床所見
(1)脊髄前角細胞の喪失と変性による下位運動ニューロン症候を認める。
 筋力低下(対称性, 近位筋>遠位筋, 下肢>上肢, 躯幹および四肢)
 筋萎縮
 舌, 手指の筋線維束性収縮
 腱反射減弱から消失
(2)上位運動ニューロン症候は認めない。(上位運動ニューロンの障害があると, 錐体路徴候と呼ばれる症状, すなわち痙縮, 筋力低下, 深部腱反射の亢進, バビンスキー反射が現れる。)
(3)経過は進行性である。
B. 臨床検査所見
 血清 creatine kinase (CK) 値が正常上限の 10 倍以下である
 筋電図で高振幅電位や多相性電位などの神経原性所見を認める
 運動神経伝導速度が正常下限の 70%以上である
C. 以下を含み, 鑑別診断が出来ている
(1)筋萎縮性側索硬化症
(2)球脊髄性筋萎縮症
(3)脳腫瘍・脊髄疾患
(4)頸椎症, 椎間板ヘルニア, 脳および脊髄腫瘍, 脊髄空洞症など
(5)末梢神経疾患
(6)多発性神経炎(遺伝性, 非遺伝性), 多巣性運動ニューロパチーなど
(7)筋疾患: 筋ジストロフィー, 多発筋炎など
(8)感染症に関連した下位運動ニューロン障害 : ポリオ後症候群など
(9)傍腫瘍症候群
(10)先天性多発性関節拘縮症
(11)神経筋接合部疾患
D.遺伝学的検査
 以下の遺伝子変異が認められる。
 (1)SMN1遺伝子欠失
 (2)SMN1遺伝子の点変異または微小変異
 (3)IGHMBP2の変異
 (4)その他の遺伝子変異
<診断のカテゴリー>
Definite:(1)下位運動ニューロン症候を認め, (2)上位運動ニューロン症候は認めず, (3)経過は進行性で, かつBの(1)~(3)を満たし, Cの鑑別すべき疾患を全て除外したもの
Definite:(1)下位運動ニューロン症候を認め, (2)上位運動ニューロン症候は認めず, (3)経過は進行性で, かつDを満たし, Cの鑑別すべき疾患を全て除外したもの
<重症度分類>
生活における重症度分類で2以上
または、modified Rankin Scale (mRS)、食事・栄養、呼吸のそれぞれの評価スケールを用いて、いずれかが3以上を対象とする。

<小児慢性特定疾病 神30 脊髄性筋萎縮症>
診断方法
Ⅰ.主要臨床症状
 1. 運動発達遅滞 (I型,II型)
 2. 筋緊張低下
 3. 筋力低下(必須)進行性
 4. 手指や舌の線維束性収縮 (fasciculation)
 5. 深部腱反射が減弱から消失
Ⅱ.本症では認めない臨床症状
 1. 痙縮
 2. 深部腱反射亢進
 3. 病的反射陽性
Ⅲ.重要な検査所見
 1. 筋電図にて高振幅電位や多相性電位など神経原性所見を認める。
 2. survival motor neuron (SMN)遺伝子に変異を認める。(レポート添付)(必須)
Ⅳ. その他の参考所見
 1. 関節拘縮・側弯
 2. 摂食・嚥下障害
 3. 呼吸障害
IV. 診断基準
必須項目Ⅱを認めず,Ⅰ,Ⅲ-2を満たす場合本症と診断する。
当該事業における対象基準
神経B
運動障害が続く場合又は治療として強心薬, 利尿薬, 抗不整脈薬, 末梢血管拡張薬, β遮断薬, 肺血管拡張薬, 呼吸管理(人工呼吸器, 気管切開術後, 経鼻エアウェイ等の処置を必要とするものをいう。), 酸素療法, 中心静脈栄養若しくは経管栄養のうち一つ以上を継続的に行っている場合
概念・定義
 脊髄性筋萎縮症(spinal muscular arophy; SMA)は, 脊髄の前角細胞の変性による筋萎縮と進行性筋力低下を特徴とする下位運動ニューロン病である。上位運動ニューロン徴候は伴わない。体幹, 四肢の近位部優位の筋力低下, 筋萎縮を示す。発症年齢, 臨床経過に基づき, I型(OMIM#253300), II型(OMIM#253550), III型(OMIM#253400), IV型(OMIM#27115)に分類される。I, II型の95%にSMN遺伝子欠失が認められ, III型の約半数, IV型の1-2割においてSMN(survival motor neuron)遺伝子変異を認める。
疫学
 諸外国の調査では, 発症は出生10,000につき1人, 保因者頻度は50~90人に1人とされている。我が国では, 乳児期~小児期に発症するSMAは10万人あたり1~2人と考えられ, 推定患者数は約1,000人前後との結果が得られている
病因
 原因遺伝子は, 1995年, 第5染色体長腕5q13.2に存在するSMN(survival motor neuron)遺伝子として同定された。I, II型のSMAにおいては, SMN遺伝子の欠失の割合は9割を超えることが明らかになっており, 遺伝子診断も可能である。また,SMN遺伝子の近傍には, NAIP(neuronal apoptosis inhibitory protein)遺伝子, SERF1(small EDRK-rich factor 1)遺伝子などが存在し, それらはSMAの臨床症状を修飾するといわれている。III, IV型においては, SMN遺伝子変異が同定されない例も多く, 他の原因も考えられている
症状
I型:重症型, 急性乳児型, ウェルドニッヒ・ホフマン(Werdnig-Hoffmann)病 
発症は出生直後から生後6ヶ月まで。フロッピーインファントの状態を呈する。肋間筋に対して横隔膜の筋力が維持されているため吸気時に腹部が膨らみ胸部が陥凹する奇異呼吸を示す。定頸の獲得がなく, 支えなしに座ることができず, 哺乳困難, 嚥下困難, 誤嚥, 呼吸不全を伴う。舌の線維束性収縮がみられる。深部腱反射は消失, 上肢の末梢神経の障害によって, 手の尺側偏位と手首が柔らかく屈曲する形のwrist dropが認められる。人工呼吸管理を行わない場合, 死亡年齢は平均6~9カ月である。
II型:中間型, 慢性乳児型, デュボビッツ(Dubowitz)病 
発症は1歳6ヶ月まで。支えなしの起立, 歩行ができず, 座位保持が可能である。舌の線維束性収縮, 手指の振戦がみられる。腱反射の減弱または消失。次第に側彎が著明になる。II型のうち, より重症な症例は呼吸器感染に伴って, 呼吸不全を示すことがある。
III型:軽症型, 慢性型, クーゲルベルグ・ウェランダー(Kugelberg-Welander)病 
発症は1歳6ヶ月以降。自立歩行を獲得するが, 次第に転びやすい, 歩けない, 立てないという症状がでてくる。後に, 上肢の挙上も困難になる。
Ⅳ型:成人期以降の発症のSMAをIV型とする。小児期発症のI, II, III型と同様のSMN遺伝子変異によるSMAもある。一方, 孤発性で成人から老年にかけて発症し, 緩徐進行性で, 上肢遠位に始まる筋萎縮, 筋力低下, 筋線維束性収縮, 腱反射低下を示す場合もある。これらの症状は徐々に全身に拡がり, 運動機能が低下する。また, 四肢の近位筋, 特に肩甲帯の筋萎縮で初発する場合もある。
SMAにおいては, それぞれの型の中でも臨床的重症度は多様である
治療
根本治療はいまだ確立していない。I型, II型では, 授乳や嚥下が困難なため経管栄養が必要な場合がある。また, 呼吸器感染, 無気肺を繰り返す場合は, これが予後を大きく左右する。I型のほぼ全例で, 救命のためには気管内挿管, 後に気管切開と人工呼吸管理が必要となる。II型においては非侵襲的陽圧換気療法(=鼻マスク陽圧換気療法:NIPPV)は有効と考えられるが, 小児への使用には多くの困難を伴う。また, 全ての型において, 筋力にあわせた運動訓練, 理学療法を行う。III型, Ⅳ型では歩行可能な状態の長期の維持や関節拘縮の予防のために, 理学療法や装具の使用などの検討が必要である。小児においても上肢の筋力が弱いため, 手動より電動車椅子の使用によって活動の幅が広くなる。I型やII型では胃食道逆流の治療が必要な場合もある。II型の脊柱変形に対しては脊柱固定術が行われる
予後
I型は1歳までに呼吸筋の筋力低下による呼吸不全の症状をきたす。人工呼吸器の管理を行わない状態では, ほとんどの場合2歳までに死亡する。II型は呼吸器感染, 無気肺を繰り返す例もあり, その際の呼吸不全が予後を左右する。III型, Ⅳ型は生命的な予後は良好である
成人期以降の注意点
 呼吸障害,嚥下障害の進行が予後を左右する.側弯の合併も高頻度であり,重度な例では手術を考慮する.心筋症の合併はない.近年,在宅人工呼吸療法,胃瘻などの適切な介入により,生命予後が改善している

(解説) 脊髄性筋萎縮症(SMA:Spinal Muscular Atrophy)
●脊髄性筋萎縮症(spinal muscular atrophy:SMA)は, 脊髄の前角細胞の変性による筋萎縮と進行性筋力低下を特徴とする下位運動ニューロン病である。上位運動ニューロン徴候は伴わない。体幹, 四肢の近位部優位の筋力低下, 筋萎縮を示す。発症年齢, 臨床経過に基づき, I型, II型, III型, IV型に分類される。I型, II型の95%にSMN1遺伝子欠失が認められ, III型の約半数, IV型の1~2割においてSMN1遺伝子変異を認める。SMN1遺伝子に変異がなく早期に呼吸障害を来すI型において, IGHMBP2の遺伝子変異を認めることがある。
●原因遺伝子は, 1995年, SMN1遺伝子として同定された。I型, II型のSMAにおいては, SMN1遺伝子の欠失の割合は9割を超えることが明らかになっており, 遺伝子診断も可能である。また, SMN1遺伝子の近傍には, NAIP遺伝子, SERF1遺伝子などが存在し, それらはSMAの臨床症状を修飾するといわれている。早期に重症な呼吸障害を示すI型の一部において, IGHMBP2の遺伝子変異を示す例がある。III型, IV型においては, SMN1遺伝子変異が同定されない例も多く, 他の原因も考えられている。
●症状
1) Ⅰ 型:重症型, 急性乳児型, ウェルドニッヒ・ホフマン (Werdnig-Hoffmann)病
 発症は出生直後から生後6ヶ月まで。フロッピーインファントの状態を呈する。肋間筋に対して横隔膜の筋力が維持されているため吸気時に腹部が膨らみ胸部が陥凹する奇異呼吸を示す。定頸の獲得がなく, 支えなしに座ることができず, 哺乳困難, 嚥下困難, 誤嚥, 呼吸不全を伴う。舌の線維束性収縮がみられる。深部腱反射は消失, 上肢の末梢神経の障害によって, 手の尺側偏位と手首が柔らかく屈曲する形の wrist drop が認められる。人工呼吸管理を行わない場合, 死亡年齢は平均6~9カ月である。
2) Ⅱ 型:中間型, 慢性乳児型, デュボビッツ(Dubowitz)病
 発症は1歳6ヶ月まで。支えなしの起立, 歩行ができず, 座位保持が可能である。舌の線維束性収縮, 手指の振戦がみられる。腱反射の減弱または消失。次第に側彎が著明になる。
 Ⅱ型のうち, より重症な症例は呼吸器感染に伴って, 呼吸不全を示すことがある。
3) Ⅲ 型:軽症型, 慢性型, クーゲルベルグ.ウェランダー(Kugelberg-Welander)病
 発症は1歳6ヶ月以降。自立歩行を獲得するが, 次第に転びやすい, 歩けない, 立てないという症状がでてくる。
 後に, 上肢の挙上も困難になる。歩行不可能になった時期が思春期前の場合には, II 型と同様に 側弯などの脊柱変形が顕著となりやすい。
4) Ⅳ 型:成人期以降の発症の SMA を IV 型とする。
 小児期発症の Ⅰ, Ⅱ, Ⅲ 型と同様の SMN 遺伝子変異による SMA もある。
 一方, 孤発性で成人から老年にかけて発症し, 緩徐進行性で, 上肢遠位に始まる筋萎縮, 筋力低下, 筋線維束性収縮, 腱反射低下を示す場合もある。これらの症状は徐々に全身に拡がり, 運動機能が低下する。また, 四肢の近位筋, 特 に肩甲帯の筋萎縮で初発する場合もある。

(責任遺伝子) *600354 Survival of motor neuron 1, telomeric (SMN1) <5q13.2>
(1) Spinal muscular atrophy, type I (253300)
.0001 Spinal muscular atrophy, type I [SMN1, 11-BP DUP, 801-811] (RCV000009733) (Parsons et al. 1996)
.0004 Spinal muscular atrophy, type I [SMN1, TYR272CYS [dbSNP:rs104893922] (RCV000009737) (Lefebvre et al. 1995)
.0005 Spinal muscular atrophy, type I [SMN1, GLY279VAL] (dbSNP:rs76163360) (RCV000009738) (Talbot et al. 1997)
.0009 Spinal muscular atrophy, type I [SMN1, 5-BP DEL, NT425] (RCV000009744) (Sossi et al. 2001)
.0011 Spinal muscular atrophy, type I (Spinal muscular atrophy, type II, included) (Spinal muscular atrophy, type III, included) (271150 Spinal muscular atrophy, type IV, included) [SMN1, 4-BP DEL, 133AGAG] (RCV000009750...) (Cusco et al. 2003)
.0015 Spinal muscular atrophy, type I (Spinal muscular atrophy, type II, included) [SMN1, ALA111GLY [dbSNP:rs104893935] (RCV000009754...) (Sun et al. 2005)
.0017 Spinal muscular atrophy, type I [SMN1, ILE116PHE [dbSNP:rs104893933] (RCV000009757) (Cusco et al. 2004; Sanchez et al. 2013)
.0018 Spinal muscular atrophy, type I [SMN1, GLN136GLU [dbSNP:rs104893934] (RCV000009758) (Cusco et al. 2004)
(2) Spinal muscular atrophy, type II (253550)
.0002 Spinal muscular atrophy, type II (Spinal muscular atrophy, type III, included) [SMN1, THR274ILE] (dbSNP:rs76871093) (RCV000009734...) (Hahnen et al. 1997)
.0006 Spinal muscular atrophy, type II (Spinal muscular atrophy, type III, included) [SMN1, ALA2GLY] (dbSNP:rs75030631) (RCV000009740...) (Parsons et al. 1998)
.0007 Spinal muscular atrophy, type II (Spinal muscular atrophy, type III, included) [SMN1, EX8DEL] (RCV000009742...) (Gambardella et al. 1998)
.0010 Spinal muscular atrophy, type II (Spinal muscular atrophy, type III, included) [SMN1, TRP102TER] (dbSNP:rs77804083) (RCV000009747...) (Sossi et al. 2001)
.0012 Spinal muscular atrophy, type II [SMN1, ASP30ASN [dbSNP:rs104893930] (RCV000009752) (Sun et al. 2005)
(3) Spinal muscular atrophy, type III (253400)
.0003 Spinal muscular atrophy, type III [SMN1, SER262ILE] (dbSNP:rs75660264) (RCV000009736) (Hahnen et al. 1997)
.0008 Spinal muscular atrophy, type III [SMN1, IVS7DS, T-G, +6] (RCV000009743) (Lorson et al. 1999)
.0013 Spinal muscular atrophy, type III [SMN1, ASP44VAL [dbSNP:rs104893931] (RCV000009745) (Sun et al. 2005)
.0014 Spinal muscular atrophy, type III [SMN1, GLY95ARG [dbSNP:rs104893927] (RCV000009753) (Sun et al. 2005)
.0016 Spinal muscular atrophy, type III [SMN1, SER262GLY [dbSNP:rs104893932] (RCV000009756) (Sun et al. 2005)
.0019 Spinal muscular atrophy, type III [SMN1, TYR130CYS [dbSNP:rs397514517] (RCV000032708) (Fraidakis et al. 2012)
.0020 Spinal muscular atrophy, type III [SMN1, TYR130HIS [dbSNP:rs397514518] (RCV000032709) (Fraidakis et al. 2012)
.0021 Spinal muscular atrophy, type III [SMN1, DEL] (RCV000032710) (Fraidakis et al. 2012)

*SMN1: 29,002 bp, Plus strand; 294 aa, 31849 Da
●本遺伝子は5q13の500 kb逆位重複の一部である
 重複領域には少なくとも4つの遺伝子と反復性配列が含まれ, 再構成と欠失を生じやすくする
 配列の反復性と複雑性は, このゲノム領域の構築決定を困難としている
 この遺伝子のテロメア側および動原体側コピーはほぼ同一で, 同じタンパクをコードする
 しかし, この遺伝子 (テロメア側コピー)の変異は脊髄筋萎縮症と連関している
 動原体側コピーの変異は疾患を生じない
 動原体側コピーはテロメア側コピーの変異が原因で生じる疾患のしmodifierかもしれない
 2つの遺伝子の決定的配列の違いはエクソン7の exon splice enhancer と考えられている1つのヌクレオチドである
 テロメア側および動原体側コピーの両方の9つのエクソンは,歴史的に exon 1, 2a, 2b, および 3-8を命名されている
 遺伝子変換イベントが2つの遺伝子に関与していると考えられる
 →各々の遺伝子のいろんなコピー数を生じる
●コードされるタンパクは細胞質と核の両方に局在する
 核内では, タンパクは germs と呼ばれる核下小体に限局され, 高い濃度のsmall ribonucleoproteins (snRNPs)を含むnear coiled bodies としてみられる
 このタンパクはSIP1 や GEMIN4などのタンパクとヘテロマー複合体をつくり, hnRNP U タンパクや small nucleolar RNA binding proteinなどの snRNPs 合成に関与することが判明しているいくつかのタンパクと相互作用する
 独特の isoforms をコードする多数の転写産物がある
●関係するpathway:遺伝子発現, RNA 輸送
●SMN 複合体は small nuclear ribonucleoproteins (snRNPs)の集合, spliceosome のブロック形成で触媒的役割をもつ
 →すなわち細胞のpre-mRNAsのスプライシングで重要な役割をもつ
 大多数の spliceosomal snRNPs は, Sm タンパクである SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF および SNRPGの共通するセットを含んでいる
 → small nuclear RNAの Sm 部位でheptameric protein ringとして集合し, core snRNPを形成する
 サイトソルでは, Sm タンパクである SNRPD1, SNRPD2, SNRPE, SNRPF および SNRPG はcore snRNP の集合をコントロールするchaperone CLNS1Aにより不活性化 6S pICln-Sm 複合体にトラップされる
 トラップされたSmタンパクからCLNS1AのSMN複合体による解離とそのSMN-Sm complexへの輸送はcore snRNPsの集合と核への輸送の引きがねを引く
 U12 intron-含有遺伝子の正しいスプライシングを保証する
 →正常な運動および感覚ニューロン発生に重要かもしれない
 RNA polymerase II につくられたRNA-DNA hybridsの解体にも必要である
 →適切な転写終止での重要な段階である転写最終領域で R-loopを形成する
 small nucleolar ribonucleoprotein (snoRNPs)の代謝で役割をもつかもしれない

(ノート)
●(#) は, 脊髄性筋萎縮症 I 型 (SMA I)は, SMN1 (600354)として知られる 5q13 のSMN 遺伝子の変異またはテロメア側コピーの欠失が原因であるため

●SMNの動原体側コピー (SMN2 601627) の発現の変化が表現型を修飾することが知られている

● 脊髄性筋萎縮症は, 常染色体劣性神経筋疾患の一群をいう
 →脊髄前角細胞変性が特徴で, 対称性筋力低下と萎縮を生じる (Wirth, 2000)

●発症年齢, 獲得した歳代筋活動性および生存により4つのタイプの SMAが認知されている
 I 型:重症乳児急性 SMA, または Werdnig-Hoffman 病である
 II 型 (253550): 乳児慢性 SMA
 III 型 (253400): 若年性 SMA, または Wohlfart-Kugelberg-Welander 病
 IV 型 (271150), または成人発症 SMA
 全てのタイプが SMN1 遺伝子の劣性変異が原因である

●Lunn and Wang (2008) は, SMA の臨床像, 分子遺伝学的機序, および治療戦略を詳細にレビューした

Clinical Features
Many groups observed the occurrence of different SMA subtypes within the same family, suggesting different manifestations of a single disease entity. Ghetti et al. (1971) reported that in many families 'malignant' Werdnig-Hoffmann disease coexisted with the Werdnig-Hoffmann disease with a prolonged course, the Wohlfart-Kugelberg-Welander disease with infantile onset, and the Wohlfart-Kugelberg-Welander disease with juvenile onset. Pearn et al. (1973) suggested that both the age of onset and the age of death were important in delineating this disorder and that therefore it should be called the infantile acute form of Werdnig and Hoffmann.

Feingold et al. (1977) referred to 'acute' and 'chronic' forms of infantile spinal muscular atrophy.

Zerres and Grimm (1983) presented a pedigree in which 2 males died at the age of 13 and 19 months, respectively, of the Werdnig-Hoffmann type of spinal muscular atrophy; a son and daughter of a great-aunt of theirs died at the age of 6 and 3.4 years, respectively, of Werdnig-Hoffmann disease, and a 59-year-old son of a great-uncle of theirs suffered from SMA of the Kugelberg-Welander type, with onset at age 12 years.

Thomas and Dubowitz (1994) found a correlation between age of onset and age of death in 2 cohorts of patients with spinal muscular atrophy, consisting of 36 and 70 patients, respectively. In one cohort, the shortest survival was 5 hours, and the longest was 19 months. In the other cohort, the mean age of onset was 1.6 months and the mean age of death was 9.6 months. The data further suggested that patients with onset before 2 months of age have a poor prognosis, with earlier death than those with slightly later onset who still fulfill the diagnostic criteria for type I.

Lumaka et al. (2009) reported a boy from central Africa with classic type 1 SMA confirmed by genetic analysis. He presented at birth with axial hypotonia and poor spontaneous movements. By age 5.5 months, he had extreme hypotonia, was unable to hold his head up, and showed psychomotor delay. He had joint laxity, severe proximal muscle weakness, umbilical hernia, atrial septal defect, and recurrent pulmonary infections resulting in death by age 10 months. EMG studies showed evidence for an alpha-motor neuron defect. An older brother who died at 10 months was reportedly similarly affected. Lumaka et al. (2009) noted that this was the first documented report of SMA type 1 in central Africa.

Pathologic Findings

Muscle biopsies of infantile spinal muscular atrophy demonstrate large numbers of round atrophic fibers and clumps of hypertrophic fibers that are type 1 by the ATPase reaction. Soubrouillard et al. (1995) performed immunohistochemical analyses of biopsied skeletal muscle from 23 cases of infantile SMA to determine the expression of developmentally regulated cytoskeletal components, including desmin (125660), NCAM (116930), vimentin (193060), and embryonic and fetal forms of the myosin heavy chain. Strong NCAM and developmental myosin heavy chain expression was present in atrophic fibers.

Other Features
By analysis of a questionnaire-based retrospective study of 65 patients with SMA type 1, Rudnik-Schoneborn et al. (2008) concluded that congenital heart defects may result from severe SMN deficiency. Among these patients, 4 (6%) had 1 copy of SMN2, 56 (86%) had 2 copies, and 5 (8%) had 3 copies. Three (75%) of the 4 patients with a single SMN2 copy had congenital SMA with atrial or ventricular septal defects. Six of the 56 patients with 2 copies of SMN2 showed minor cardiac anomalies that resolved spontaneously, including a patent foramen ovale (PFO) in 4 infants, associated with a hypertrophic septum in 1, a patent ductus arteriosus (PDA) in 1 patient, and a PDA combined with a PFO in another patient. A small apical ventricular septal defect along with PDA was seen in 1 patient with classic SMA I who died at 11 months. She was the child of consanguineous parents who had lost 4 other children due to alleged sudden infant death syndrome. No cardiac malformation was documented in the 5 patients with 3 SMN2 copies. In a literature review, Rudnik-Schoneborn et al. (2008) noted that most reported SMA patients with heart defects had a severe disease course, prenatal or congenital onset, congenital contractures, respiratory distress from birth, and a very short life span, most likely associated with only 1 SMN2 copy.

Ebert et al. (2009) reported the generation of induced pluripotent stem cells from skin fibroblast samples taken from a child with spinal muscular atrophy type 1. These cells expanded robustly in culture, maintained the disease genotype, and generated motor neurons that showed selective deficits compared to those derived from the child's unaffected mother. Ebert et al. (2009) stated that this was the first study to show that human induced pluripotent stem cells can be used to model the specific pathology seen in a genetically inherited disease. Ebert et al. (2009) suggested that since animal models for SMA1 are nonviable, the generation of these pluripotent stem cells would allow more detailed studies of the pathophysiology of SMA1 in the motor neuron.

Inheritance
Brandt (1949) reported a large study of familial infantile progressive muscular atrophy involving 112 cases in 70 families. Segregation analysis yielded results consistent with autosomal recessive inheritance. Almost 6% of the parents were consanguineous, a value 8 times that in controls.

Marquardt et al. (1962), among others, described the disorder in twins. Hogenhuis et al. (1967) reported studies of a Chinese family in which 4 of 8 sibs succumbed to Werdnig-Hoffmann disease.

Diagnosis
See 600354 for details on the molecular diagnosis of SMA.

Prenatal Diagnosis
Daniels et al. (1992) and Melki et al. (1992) demonstrated the feasibility of prenatal diagnosis of SMA by the linkage principle.

Wirth et al. (1995) presented their experience with 109 prenatal diagnoses performed in 91 families at risk of SMA by use of polymorphic microsatellites in the region 5q11.2-q13.3. Of the 109 prenatal diagnoses performed, 29 fetuses were diagnosed to be at more than 99% risk of developing the disease, while in 7 additional pregnancies no exact prediction could be made due to a recombination event in 1 parental haplotype.

Pathogenesis
Oprea et al. (2008) discovered that unaffected SMN1-deleted females exhibit significantly higher expression of plastin-3 (PLS3; 300131) than their SMA-affected counterparts. The authors demonstrated that PLS3 is important for axonogenesis through increasing the F-actin level. Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN downregulation in motor neurons of SMA mouse embryos and in zebrafish. Oprea et al. (2008) concluded that defects in axonogenesis are the major cause of SMA, thereby opening new therapeutic options for SMA and similar neuromuscular diseases.

Wen et al. (2010) described a potential link between stathmin (STMN1; 151442) and microtubule defects in SMA. Stathmin was identified by screening Smn-knockdown NSC34 cells through proteomics analysis. Stathmin was aberrantly upregulated in vitro and in vivo, leading to a decreased level of polymerized tubulin, which was correlated with disease severity. Reduced microtubule densities and beta-3-tubulin (TUBB3;602661) levels in distal axons of affected SMA-like mice and an impaired microtubule network in Smn-deficient cells were observed, suggesting an involvement of stathmin in those microtubule defects. Furthermore, knockdown of stathmin restored the microtubule network defects of Smn-deficient cells, promoted axon outgrowth, and reduced the defect in mitochondria transport in SMA-like motor neurons. The authors concluded that aberrant stathmin levels may play a detrimental role in SMA.

Kye et al. (2014) found that expression of microRNA-183 (MIR183; 611608), but not its primary transcript, was increased in Smn-knockdown rat primary neurons, concomitant with impaired axonal growth, impaired local translation of Mtor (601231) in neurites, and reduced Mtor pathway-dependent neurite protein synthesis. Mir183 was also elevated in SMA model mice and in SMA patient-derived fibroblasts. Codepletion of Mir183 and Smn in rat neurons rescued the axonal phenotype and increased Mtor expression in neurites. Kye et al. (2014) identified an Mir183-binding site in the 3-prime UTR of the Mtor transcript, and Mir183 bound directly to this site and inhibited Mtor translation. Inhibition of Mir183 in vivo partly alleviated the disease phenotype in SMA model mice. Kye et al. (2014) concluded that axonal MIR183 and the MTOR pathway contribute to SMA pathology.

Clinical Management
Chang et al. (2001) reported results suggesting that sodium butyrate may be helpful in the treatment of SMA. They found that this agent increased the amount of exon 7-containing SMN protein in lymphoid cell lines from SMA patients by changing the alternative splicing pattern of exon 7 in the SMN2 gene. Oral administration of sodium butyrate to intercrosses of heterozygous pregnant knockout-transgenic SMA-like mice decreased the birth rate of severe types of SMA-like mice, and SMA symptoms were ameliorated for all 3 types of SMA-like mice.

Brichta et al. (2003) showed that in fibroblast cultures derived from SMA patients treated with therapeutic doses of valproic acid (VPA), the level of full-length SMN2 mRNA/protein increased 2- to 4-fold. This upregulation of SMN was most likely attributable to increased levels of HTRA2-beta-1 (see 606441) as well as to SMN gene transcription activation. VPA was also able to increase SMN protein levels through transcription activation in organotypic hippocampal rat brain slices. Additionally, valproic acid increased the expression of other serine-arginine (SR) family proteins, which may have important implications for other disorders affected by alternative splicing.

In a study of valproic acid (VPA) treatment in 10 SMA carriers and 20 patients with SMA1, SMA2, or SMA3, Brichta et al. (2006) found that VPA increased peripheral blood full-length SMN mRNA and protein levels in 7 carriers, increased full-length SMN2 mRNA in 7 patients, and left full-length SMN2 mRNA levels unchanged or decreased in 13 patients. The effect on protein levels in carriers was more pronounced than on mRNA levels, and the variability in augmentation among carriers and patients suggested to the authors that valproic acid interferes with transcription of genes encoding translation factors or regulates translation or SMN protein stability.

In fibroblast cultures from patients with SMA I, SMA II, or SMA III, Andreassi et al. (2004) found a significant increase in SMN2 gene expression (increase in SMN2 transcripts of 50 to 160% in SMA1, and of 80 to 400% in SMA2 and SMA3) and a more moderate increase in SMN protein expression in response to treatment with 4-phenylbutyrate (PBA). PBA treatment also resulted in an increase in the number of SMN-containing nuclear structures (GEMS). The authors suggested a potential use for PBA in treatment of various types of SMA.

Grzeschik et al. (2005) reported that cultured lymphocytes from patients with SMA showed increased production of the full-length SMN mRNA and protein in response to treatment with hydroxyurea. The findings suggested that hydroxyurea promoted inclusion of exon 7 during SMN2 transcription.

In a review of questionnaire-based data on 143 SMA patients, Oskoui et al. (2007) found that patients born from 1995 to 2006 had a 70% reduction in the risk of death compared to patients born from 1980 to 1994. However, when controlling for demographic and clinical care variables, the association was no longer significant. Treatment with ventilation for more than 16 hours per day, use of a mechanical insufflation-exsufflation device, and gastrostomy tube feedings showed a significant effect in reducing the risk of death. An amino acid diet had no significant effect on survival. Oskoui et al. (2007) concluded that the increased use of specific proactive management tools has been successful in enhancing survival of patients with SMA.

Angelozzi et al. (2008) found that salbutamol increased full-length SMN2 mRNA transcript levels in fibroblasts derived from patients with SMA I, II, and III. The maximum increase (over 200%) was observed after 30 to 60 minutes. This rapid rise correlated with decreased levels of SMN2 with deletion of exon 7. Salbutamol treatment also resulted in increased SMN protein levels and nuclear gems.

Yuo et al. (2008) found that treatment of SMA lymphoid cell lines with an Na+/H+ exchange inhibitor resulted in increased expression of SMN2 mRNA with exon 7 and increased SMN protein production in SMA cells. The underlying mechanism appeared to be upregulation of the splicing factor SRp20 (603364) in the nucleus. The findings were consistent with an effect of cellular pH on SMN splicing.

Ebert et al. (2009) reported the generation of induced pluripotent stem cells from skin fibroblast samples taken from a child with spinal muscular atrophy type 1. These cells expanded robustly in culture, maintained the disease genotype, and generated motor neurons that showed selective deficits compared to those derived from the child's unaffected mother. Ebert et al. (2009) stated that this was the first study to show that human induced pluripotent stem cells can be used to model the specific pathology seen in a genetically inherited disease. Ebert et al. (2009) suggested that since animal models for SMA1 are nonviable, the generation of these pluripotent stem cells would allow more detailed studies of the pathophysiology of SMA1 in the motor neuron.

Through chemical screening and optimization, Naryshkin et al. (2014) identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 mRNA with high selectivity. Administration of these compounds to delta-7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice.

Mapping
By homozygosity testing of 4 consanguineous families with SMA type I, Gilliam et al. (1990) linked the disorder to chromosome 5q11.2-q13.3, the same region to which the more chronic forms SMA II and SMA III had been mapped.

Melki et al. (1990) independently demonstrated that SMA type I, like types II and III, was linked to markers at chromosome 5q12-q14. By in situ hybridization of 2 markers closely flanking the SMA I gene, Mattei et al. (1991) refined the assignment to 5q12-q13.3.

Daniels et al. (1992) used in situ hybridization to refine the mapping of SMA I to 5q12.2-q13 near marker D5S6. Brzustowicz et al. (1992)identified 2 flanking loci, MAP1B (157129) and D5S6, which are separated by an interval of approximately 2 cM. Wirth et al. (1993) narrowed the assignment to a region of about 4 cM and defined a new proximal genetic border by the locus D5S125. The closest marker on the distal side of SMA was found to be MAP1B, which has its 5-prime end directed toward the centromere.

Lien et al. (1991) used a polyclonal antiserum directed against the C-terminal domain of dystrophin (300377) to isolate a cDNA encoding an antigenically cross-reactive protein. Physical mapping of this gene placed it at 5q13 in close proximity to the SMA locus. A genetic linkage analysis of SMA families using a dinucleotide repeat polymorphism related to the dystrophin-like gene showed tight linkage to SMA mutations. The brain-specific expression of the gene likewise suggested possible association with SMA.

By a combination of genetic and physical mapping, Melki et al. (1994) constructed a yeast artificial chromosome (YAC) contig of the 5q13 region spanning the SMN disease locus and showing the presence of low copy repeats. Analysis of allele segregation at the closest genetic loci in 201 SMA families demonstrated inherited and de novo deletions in 9 unrelated SMA patients. Moreover, deletions were strongly suggested in at least 18% of SMA type I patients by the observation of marked deficiency of heterozygosity for the loci studied. The results indicated that deletion events were statistically associated with the severe form of spinal muscular atrophy.

Thompson et al. (1995) identified several coding sequences unique to the SMA region. A genomic fragment detected by 1 cDNA was homozygously deleted in 17 of 29 (58%) type I SMA patients. Only 2 of 235 unaffected controls showed the deletion, and both were carriers of the disease. These data suggested that deletion of at least part of this novel gene is directly related to the phenotype of SMA.

Molecular Genetics
Biros and Forrest (1999), Wirth (2000), and Ogino and Wilson (2004) provided reviews of the complex molecular basis of SMA. SMN1 and SMN2 lie within the telomeric and centromeric halves, respectively, of a large inverted repeat on chromosome 5q. The coding sequence of SMN2 differs from that of SMN1 by a single nucleotide in exon 7 (840C-T), which results in decreased transcription and deficiency of the normal stable SMN protein. Approximately 94% of individuals with SMA lack both copies of SMN1 exon 7, resulting in substantial loss of the protein. Loss of exon 7 can result from deletion or the 840C-T change, in which SMN1 is essentially converted to SMN2 (gene conversion) (Lorson et al., 1999). Loss of SMN1 can also occur by other mechanisms, such as large deletions or point mutations. Most of the SMN protein is derived from the SMN1 gene; however, the SMN2 gene can contribute a small amount of SMN protein, thus modifying the genotype. For a detailed discussion of the molecular genetics of SMA, see 600354.

Lefebvre et al. (1995) identified the SMN gene, which they termed 'survival motor neuron,' within the SMA candidate region on chromosome 5q13, and demonstrated deletion or disruption of the gene in 226 of 229 patients with SMA.

In a separate publication accompanying that by Lefebvre et al. (1995), Roy et al. (1995) identified a different gene on chromosome 5q13.1, neuronal apoptosis inhibitory protein (NAIP; 600355). They found that the first 2 coding exons of this gene were deleted in approximately 67% of type I SMA chromosomes compared with 2% of non-SMA chromosomes, and reverse transcriptase-PCR analysis revealed internally deleted and mutated forms of the NAIP transcript in type I SMA individuals and not in unaffected individuals. Roy et al. (1995) suggested that mutations in the NAIP locus resulted in a failure of a normally occurring inhibition of motor neuron apoptosis that occurs during development, thus contributing to the SMA phenotype. In a discussion of these seemingly discordant findings, Lewin (1995) suggested that a mutation in either of the 2 genes could result in SMA or that a mutation in both genes was necessary for the disease. Gilliam (1995) discussed the evidence that either the NAIP gene or the SMN gene, or perhaps both, are involved in the causation of SMA.

Matthijs et al. (1996) identified homozygous deletion of exon 7 of the SMN1 gene in 34 of 38 patients with SMA. Of these 34 patients, the deletion was associated with homozygous deletion of exon 8 in 31 patients and with heterozygous deletion of exon 8 in 2 patients; both copies of exon 8 were present in 1 patient. In 1 family, a normal father of the proband had only 1 copy of the SMN gene and lacked both copies of the SMN2 gene, showing that a reduction of the total number of SMN genes to a single SMN copy is compatible with normal life. In another family, a de novo deletion of a paternal SMN2 gene was found in a normal sister of a girl with SMA I. Matthijs et al. (1996) suggested that 'this region of chromosome 5q shows some special characteristics which should lead to caution' in the molecular diagnosis of SMA I. Deletions of the SMN gene were not found in 4 of the patients with SMA I.

Hahnen et al. (1996) reported molecular analysis of 42 SMA patients who carried homozygous deletions of exon 7 but not of exon 8 in the SMN1 gene. Additional homozygous deletions of exon 8 in the SMN2 gene were found in 2 of the patients. By a simple PCR test, Hahnen et al. (1996)demonstrated the existence of hybrid SMN genes (i.e., genes composed of both the centromeric SMN2 and the telomeric SMN1). They reported a high frequency of hybrid SMN genes in SMA patients with Czech or Polish background. Hahnen et al. (1996) identified a single haplotype for half of the hybrid genes analyzed, suggesting that in these cases the SMA chromosomes shared a common origin.

Alias et al. (2009) found homozygous absence of SMN1 exons 7 and 8 in 671 (90%) of 745 Spanish SMA patients. Thirty-seven patients (5%) had homozygous absence of exon 7 but not exon 8, due to the presence of hybrid genes. The majority of the remaining 5% of patients had smaller deletions or point mutations. However, only 1 mutant allele was identified in 7 (0.9%) patients. Data stratification by SMA type showed that females had a significantly higher frequency of type I SMA compared to males.

Modifying Factors
Stratigopoulos et al. (2010) evaluated blood levels of PLS3 (300131) mRNA transcripts in 88 patients with SMA, including 29 males under age 11 years, 12 males over age 11, 29 prepubertal girls, and 18 postpubertal girls in an attempt to examine whether PLS3 was a modifier of the phenotype. PLS3 expression was decreased in the older patients of both sexes. However, expression correlated with phenotype only in postpubertal girls: expression was greatest in those with SMA type III, intermediate in those with SMA type II, and lowest in those with SMA type I, and correlated with residual motor function as well as SMN2 copy number. Stratigopoulos et al. (2010) concluded that the PLS3 gene may be an age- and/or puberty-specific and sex-specific modifier of SMA.

Genotype/Phenotype Correlations
For a detailed discussion of genotype/phenotype correlations in spinal muscular atrophy, see 600354.

Burlet et al. (1996) found large-scale deletions involving both the SMN gene and its upstream (C212-C272) and downstream (NAIP) flanking markers in 43% of 106 unrelated SMA patients. However, they noted that smaller rearrangements can still result in disease, since 27% of patients with severe disease lacked only the SMN gene. They also pointed out that deletion of the SMN gene may produce mild disease and referred to an article by Cobben et al. (l995) in which deletions of the SMN gene were found in unaffected sibs of patients with SMA. Burlet et al. (1996) suggested that other genetic mechanisms might be involved in the variable clinical expression of the disease.

Using pulsed field gel electrophoresis to map deletions in the SMN gene, Campbell et al. (1997) found that mutations in SMA types II and III, previously classed as deletions, were in fact due to gene-conversion events in which the telomeric SMN1 was replaced by its centromeric counterpart, SMN2. This resulted in a greater number of SMN2 copies in type II and type III patients compared with type I patients and enabled a genotype/phenotype correlation to be made. Campbell et al. (1997) also demonstrated individual DNA-content variations of several hundred kilobases, even in a relatively isolated population from Finland. This explained why no consensus map of this region of 5q had been produced. They suggested that this DNA variation may be due to a 'midisatellite' array, which would promote the observed high deletion and gene conversion rate. Burghes (1997) discussed the significance of the findings of Campbell et al. (1997) and presented a model (Figure 3) of alleles present in the normal population and in severe and mild forms of SMA. Campbell et al. (1997), Burghes (1997) raised the question of whether the centromeric SMN2 gene might be activated to compensate for the deficiency of SMN1 as a therapeutic strategy in SMA.

Samilchuk et al. (1996) carried out deletion analysis of the SMN and NAIP genes in 11 cases of type I SMA and 4 cases of type II SMA. The patients were of Kuwaiti origin. They also analyzed samples from 41 healthy relatives of these patients and 44 control individuals of Arabic origin. They found homozygous deletions of exons 7 and 8 of the SMN gene in all SMA patients studied. Exon 5 of the NAIP gene was homozygously absent in all type I SMA patients, but was retained in the type II patients. Among relatives, they identified 1 mother was had homozygous deletion of NAIP. All of the control individuals had normal SMN and NAIP. Samilchuk et al. (1996) concluded that the incidence of NAIP deletion is much higher in the clinically more severe cases (type I SMA) than in the milder forms, and all of the type II SMA patients in their study had at least one copy of the intact NAIP gene.

Somerville et al. (1997) presented a compilation of genotypes for the SMN1 and NAIP genes from their own laboratory and those of others as reported in the literature. Bayesian analyses were used to generate probabilities for SMA when deletions were present or absent in SMN1. They found that when the SMN1 exon 7 was deleted, the probability of SMA could reach greater than 98% in some populations, and when SMN1 was present, the probability of SMA was approximately 17 times less than the prior population risk. Deletion of NAIP exon 5, as well as SMN1 exon 7, was associated with a 5-fold increased risk of type I SMA. Case studies were used to illustrate differing disease risks for pre- and postnatal testing, depending on the presence of information about clinical status or molecular results. These analyses demonstrated that deletion screening of candidate genes can be a powerful tool in the diagnosis of SMA.

Novelli et al. (1997) investigated the effects of gender on the association between NAIP gene deletion and disease severity in SMA. NAIP deletions were screened in 197 SMA patients lacking SMN; the results obtained were correlated with disease severity in male and female samples separately. No significant relationship between deletion size and clinical phenotype was observed among male patients, whereas in females the absence of NAIP was strongly associated with a severe phenotype (p less than 0.0001). SMA I was found in 75.6% of females and only 52.5% of males lacking NAIP. These results provided a possible molecular explanation for the sex-dependent phenotypic variation observed in SMA patients.

Using comparative genomics to screen for modifying factors in SMA among sequences evolutionarily conserved between mouse and human,Scharf et al. (1998) identified a novel transcript, H4F5 (603011), which lay closer to SMN1 than any previously identified gene in the region. They found that a multicopy microsatellite marker that was deleted in more than 90% of type I SMA chromosomes was embedded in an intron of the SMN1 gene, indicating that H4F5 may also be deleted in type I SMA, and thus was a candidate phenotypic modifier for SMA. In comparison with the high rate of H4F5 deletions in type I SMA, Scharf et al. (1998) found that the deletion frequency in type II SMA chromosomes was between that of type I and control chromosomes, whereas the frequency in type III chromosomes was only slightly higher than in controls.

Jedrzejowska et al. (2008) reported 3 unrelated families with asymptomatic carriers of a biallelic deletion of the SMN1 gene. In the first family, the biallelic deletion was found in 3 sibs: 2 affected brothers with SMA3 and a 25-year-old asymptomatic sister. All of them had 4 copies of the SMN2 gene. In the second family, 4 sibs were affected, 3 with SMA2 and 1 with SMA3, and each had 3 copies of SMN2. The clinically asymptomatic 47-year-old father had the biallelic deletion and 4 copies of SMN2. In the third family, the biallelic SMN1 deletion was found in a girl affected with SMA1 and in her healthy 53-year-old father who had 5 copies of SMN2. The findings again confirmed that an increased number of SMN2 copies in healthy carriers of the biallelic SMN1 deletion is an important SMA phenotype modifier, but also suggested that other factors play a role in disease modification.

Rudnik-Schoneborn et al. (2009) reviewed the clinical features of 66 German patients with SMA type 1 caused by homozygous deletion of the SMN1 gene. Reduced fetal movements were recorded in 33% of pregnancies. Sixteen (24%) patients showed onset of weakness in the first week of life; the overall mean age at death was 9 months. Four (6.1%) patients with 1 SMN2 gene copy had severe SMA type '0' with joint contractures and respiratory distress from birth. All died within a few months of age. Among the 57 (86.3%) patients with 2 SMN2 copies, the mean age at onset was 1.3 months, and the mean age at disease endpoint (death or need for permanent ventilation) was 7.8 months. Among the 5 (7.6%) of patients with 3 SMN2 copies, the mean age at onset was 3.4 months and the mean age at endpoint was 28.9 months (range, 10 to 55 months).Rudnik-Schoneborn et al. (2009) noted that much of the observed clinical variability in SMA type 1 likely depends on the number of SMN2 copies, and suggested that the SMN2 copy number should be considered in clinical trials.

Population Genetics
Czeizel and Hamula (1989) and Czeizel (1991) estimated the prevalence of Werdnig-Hoffmann disease in Hungary to be 1 per 10,000 live births. The occurrence in sibs was 32%, a figure considered consistent with autosomal recessive inheritance complicated by greater ascertainment of families with more than 1 affected child.

From an epidemiologic study of acute and chronic childhood SMA in Poland, Spiegler et al. (1990) cited a frequency of 1.026 cases per 10,000, a gene frequency of 0.01428, and a carrier frequency of 1 in 35. Spiegler et al. (1990) reviewed various other reports on the frequency of SMA. For an 8-year period (1980-1987) in the State of North Dakota, Burd et al. (1991) found an incidence of 1 in 6,720 births (14 in 94,092). In an Italian population, Mostacciuolo et al. (1992) found an overall prevalence at birth for SMA types I, II, and III to be 7.8 in 100,000 live births. Type I alone accounted for 4.1 in 100,000 live births. Assuming that the 3 types are clinical manifestations of allelic mutations, the locus mutation rate would be about 70 x 10(-6) and the frequency of heterozygotes about 1 in 57.

Wilmshurst et al. (2002) performed DNA studies in 30 unrelated and racially diverse patients with SMA residing in the Western Cape of South Africa. Four had SMA type I, 16 had type II, and 10 had type III. All patients were found to be homozygous for the loss of either exon 7 or exons 7 and 8 of the SMN1 gene. Thus, all patients from the Western Cape, which included 12 black South Africans, were no different genetically or phenotypically from the internationally recognized form of typical SMA.

Zaldivar et al. (2005) found that the incidence of SMA type I in Cuba was 3.53 per 100,000 live births. When the population was classified according to self-reported ethnicity, the incidence was 8 per 100,000 for whites, 0.89 per 100,000 for blacks, and 0.96 per 100,000 for those of mixed ethnicity. Zaldivar et al. (2005) concluded that SMA I may occur less frequently in those of African ancestry.

In a detailed review, Lunn and Wang (2008) stated that the incidence of SMA was 1 in 10,000 livebirths and that the carrier frequency was 1 in 50. In a reply, Wilson and Ogino (2008) stated that carrier testing had revealed a carried frequency of 1 in 38, which extrapolates to an incidence of 1 in 6,000 livebirths under Hardy-Weinberg equilibrium. Wilson and Ogino (2008) postulated that the numerical differences could be due to embryonic lethality or clinically atypical SMA.

Hendrickson et al. (2009) genotyped more than 1,000 specimens from various ethnic groups using a quantitative real-time PCR assay specific for the 840C-T change in exon 7, which results in loss of SMN1. The observed 1-copy SMN1 carrier rate was 1 in 37 (2.7%) among Caucasians, 1 in 46 (2.2%) among Ashkenazi Jews, 1 in 56 (1.8%) 56 among Asians, 1 in 91 (1.1%) among African Americans, and 1 in 125 (0.8%) among Hispanics. In all groups except African Americans the 2-copy genotype was the most common. However, African American specimens had an unusually high frequency of alleles with multiple copies of SMN1 (27% compared to 3.3-8.1%). The authors noted that alleles with increased numbers of SMN1 copies increase the relative risk of being a carrier due to the inability of many methods to detect the rare SMN1 genotype consisting of 1 allele with zero copies and the other allele with 2 or more copies.

Using denaturing high-performance liquid chromatography (DHPLC) as a screening tool to determine SMN copy number, Sheng-Yuan et al. (2010) found a heterozygous deletion of SMN1 exon 7 in 41 (2.39%) of 1,712 cord blood samples from Chinese infants, indicating a carrier state. Thirteen different genotypic groups characterized by SMN1:SMN2 copy number ratio were identified overall. Carrier genotypes were similar among 25 core families with the disorder, with the '1+0' SMN1 genotype accounting for 90.9% of carriers, although 2 of 44 parents had the rare '2+0' genotype. Sheng-Yuan et al. (2010) developed an assay based on reverse dot blot for rapid genotyping of exon 7 deletional SMA. Sheng-Yuan et al. (2010) concluded that the carrier rate of SMA in China is 1 in 42 and that approximately 2,306 newborns are affected each year.

Chong et al. (2011) identified a shared haplotype encompassing the SMN1/SMN2 genes in a Hutterite patient from South Dakota and 3 Hutterite patients from Montana. An 8-generation pedigree connected these 4 individuals to their most recent common ancestors, who were a couple born in the 1790s. All 4 patients carried zero copies of SMN1 and 4 copies of SMN2, indicating that the haplotype carrying the deletion of SMN1 also carries 2 copies of SMN2. The carrier frequency for this haplotype was 12.9% in South Dakota Hutterites. The phenotypic expression of this phenotype was relatively mild, and 1 asymptomatic homozygous adult was identified. Chong et al. (2011) identified a 26-SNP haplotype that could be used for screening in this population.

Among 23,127 ethnically diverse individuals screened for SMA1 carrier status, Lazarin et al. (2013) identified 405 carriers (1.8%), for an estimated carrier frequency of approximately 1 in 57. Fifteen 'carrier couples' were identified.

History
Becker (1964) suggested an allelic model for the clinically distinct subtypes of SMA: 3 or more normal alleles (a, a', a'') in addition to the pathologic gene a(+). The genotype a'a(+) was thought to lead to Kugelberg-Welander phenotype and the a''a(+) genotype to the Werdnig-Hoffmann phenotype. Bouwsma and Leschot (1986) extended the allele hypothesis of Becker. They presented clinical and genetic findings in 18 patients from 7 pedigrees showing an unusual genetic pattern not consistent with simple autosomal recessive inheritance. In 6 of the 7 pedigrees, different types of SMA were present. However, Muller et al. (1992) presented evidence rejecting the Becker hypothesis. In a sample of 4 sibships in which both SMA type II and SMA type III occurred, the segregation of linked markers indicated that the same allele was involved. The finding suggested that other factors, genetic or environmental, must determine disease severity in SMA.

Kleyn et al. (1991) excluded both the HEXB locus (606873) and the GM2-activator protein locus (GM2A; 613109), both of which are located on chromosome 5, as the site of the mutation in SMA. Recombination between HEXB and SMA eliminated this enzyme as a candidate site. Furthermore, the gene encoding the activator protein was found to map distal to the SMA I locus (Heng et al., 1993).

Animal Model
Exclusion of the Wobbler Mouse and a Canine Model
Kaupmann et al. (1992) mapped the 'wobbler' locus (wr) (see 614633) to proximal mouse chromosome 11. The wobbler mouse (genotype wr/wr) shows motoneuron disease and gonadal dysfunction. Kaupmann et al. (1992) stated that the wobbler was an unlikely model for human SMA because it shows also a striking spermiogenesis defect which has not been reported for male SMA patients who have reached adolescence.

Des Portes et al. (1994) also mapped the mouse 'wobbler' mutation to mouse chromosome 11, about 1 cM from the glutamine synthetase gene (138290); several crossovers excluded glutamine synthetase from being a candidate gene for the wobbler mutation. The murine equivalent of the human 5q region is mainly situated on chromosomes 13 and 11, and the closest published marker for human spinal muscular atrophy, D5S39, was mapped to mouse chromosome 13. Thus, it seemed unlikely that the wobbler mutation and the common human spinal muscular atrophies were genetically identical, despite their similar phenotype.

Blazej et al. (1998) concluded that autosomal dominant canine spinal muscular atrophy, which has pathologic and clinical features similar to various forms of human motor neuron disease, was molecularly distinct from human spinal muscular atrophy. They studied the canine SMN gene in affected and unaffected dogs and found no germline mutations in the SMN gene in affected dogs. Analysis of a panel of canine/rodent hybrid cell lines revealed that the SMN gene did not map to the same chromosome in the dog as did the canine spinal muscular atrophy.

Other Animal Models
Hsieh-Li et al. (2000) produced mouse lines deficient for mouse Smn and transgenic mouse lines that expressed human SMN2 (601627). Smn -/- mice died during the periimplantation stage. In contrast, transgenic mice harboring SMN2 in the Smn -/- background showed pathologic changes in the spinal cord and skeletal muscles similar to those of SMA patients. The severity of the pathologic changes in these mice correlated with the amount of SMN protein that contained the region encoded by exon 7. The results demonstrated that SMN2 can partially compensate for lack of SMN1. The variable phenotypes of Smn -/- SMN2 mice reflected those seen in SMA patients, thus providing a mouse model for that disease.

Frugier et al. (2000) used the Cre/loxP recombination system and a neuron-specific promoter to generate transgenic mice with selective expression in neural tissue of an SMN construct missing exon 7. Unlike mice missing SMN exon 7 in all tissues (an embryonic lethal phenotype), those with a neuron-specific defect displayed a severe motor deficit with tremors. The mutated SMN protein lacked the normal C terminus and was dramatically reduced in motor neuron nuclei. Histologic analysis revealed a lack of GEMS (gemini of coiled bodies, which are normal nuclear structures) and the presence of large aggregates of coilin, a coiled body-specific protein (600272). The authors concluded that the lack of nuclear targeting of SMN is the biochemical defect in SMA, which leads to muscle denervation of neurogenic origin.

Studying Brown-Swiss cattle, Medugorac et al. (2003) mapped the bovine spinal muscular atrophy locus to chromosome 24. Before performing a genomewide linkage analysis, they investigated 2 candidate chromosome segments: the proximal part of bovine chromosome 20 and the complete bovine chromosome 29. These regions are orthologous to human chromosome segments responsible for SMA1 and SMA with respiratory distress (SMARD1; 604320), respectively. No abnormalities were found in these regions. The linkage region on chromosome 24 contains the homolog of the BCL2 gene (151430) on human chromosome 18q. Medugorac et al. (2003) suggested that the gene encoding the apoptosis-inhibiting protein BCL2 is a promising candidate for bovine SMA and that the disorder in Brown-Swiss cattle offers an attractive animal model for a better understanding of human SMA and for a probable antiapoptotic synergy of SMN-BCL2 aggregates in mammals.

Chan et al. (2003) isolated a Drosophila smn mutant with point mutations in the smn gene similar to those found in SMA patients. Zygotic smn mutant animals showed abnormal motor behavior; smn gene activity was required in both neurons and muscle to alleviate this phenotype. Excitatory postsynaptic currents were reduced while synaptic motor neuron boutons were disorganized in mutants, indicating defects at the neuromuscular junction. Clustering of a neurotransmitter receptor subunit in the muscle at the neuromuscular junction was also severely reduced.

In a mouse model of SMA, Kariya et al. (2008) demonstrated that the earliest structural defects of the disorder appeared in the distal muscles and involved the neuromuscular synapse even before the appearance of overt symptoms. Insufficient SMN protein arrested the postnatal development of the neuromuscular junction (NMJ), impairing the maturation of postsynaptic acetylcholine receptor (AChR) clusters. Presynaptic defects at the distal ends of alpha-motor neurons included poor terminal arborization, intermediate filament aggregates, and misplaced synaptic vesicles. These defects were reflected in functional deficits at the NMJ characterized by intermittent neurotransmission failures. Kariya et al. (2008) suggested that SMA might best be described as a NMJ synaptopathy.

In severe SMA mice (Smn -/-;SMN2 +/+) Gavrilina et al. (2008) found that transgenic embryonic expression of full-length SMN under the prion (176640) promoter in brain and spinal cord neurons rescued the phenotype. Mice homozygous for the transgene survived for an average of 210 days, compared to 4.6 days in control SMA mice, and lumbar motor neuron root counts in the transgenic mice were normal. High levels of SMN in neurons were observed at embryonic day 15. In contrast, transgenic expression of SMN solely in skeletal muscle using the human skeletal actin promoter resulted in no improvement of the SMA phenotype or extension of survival in SMA mice. However, 1 transgenic strain with high SMN expression in muscle and low SMN expression in brain showed increased survival to 160 days, indicating that even mild neuronal SMN expression can affect the phenotype. Gavrilina et al. (2008) concluded that expression of full-length SMN in neurons can correct the severe SMA phenotype in mice, whereas high SMN levels in mature skeletal muscle alone has no impact.

Murray et al. (2010) investigated the presymptomatic development of neuromuscular connectivity in differentially vulnerable motor neuron populations in Smn -/-;SMN2 +/+ mice. Reduced Smn levels had no detectable effect on morphologic correlates of presymptomatic development in either vulnerable or stable motor units, indicating that abnormal presymptomatic developmental processes were unlikely to be a prerequisite for subsequent pathologic changes to occur in vivo. Microarray analyses of spinal cord from 2 different severe SMA mouse models demonstrated that only minimal changes in gene expression were present in presymptomatic mice. In contrast, microarray analysis of late-symptomatic spinal cord revealed widespread changes in gene expression, implicating extracellular matrix integrity, growth factor signaling, and myelination pathways in SMA pathogenesis. Murray et al. (2010) suggested that reduced Smn levels induce SMA pathology by instigating rapidly progressive neurodegenerative pathways in lower motor neurons around the time of disease onset, rather than by modulating presymptomatic neurodevelopmental pathways.

Wishart et al. (2010) showed that reduced levels of Smn led to impaired perinatal brain development in a mouse model of severe SMA. Regionally selective changes in brain morphology were apparent in areas normally associated with higher Smn levels in the healthy postnatal brain, including the hippocampus, and were associated with decreased cell density, reduced cell proliferation, and impaired hippocampal neurogenesis. A comparative proteomics analysis of the hippocampus from SMA and wildtype littermate mice revealed widespread modifications in expression levels of proteins regulating cellular proliferation, migration, and development when Smn levels were reduced. Wishart et al. (2010) proposed roles for SMN protein in brain development and maintenance.

Therapeutic Strategies
In SMA-like mouse embryonic fibroblasts and human SMN2-transfected motor neuron cells, Ting et al. (2007) found that sodium vanadate, trichostatin A, and aclarubicin effectively enhanced SMN2 expression by inducing Stat5 (601511) activation. This resulted in enhanced SMN2 promoter activity with an increase in both full-length and deletion exon 7 SMN transcripts in human cells with SMN2. Knockdown of Stat5 expression disrupted the effects of sodium vanadate on SMN2 activation, but did not influence SMN2 splicing, suggesting that Stat5 signaling is involved in SMN2 transcriptional regulation. Constitutive expression of the activated Stat5 mutant Stat5A1*6 profoundly increased the number of nuclear gems in SMA patient lymphocytes and reduced SMA-like motor neuron axon outgrowth defects.

Narver et al. (2008) found that in a transgenic mouse model of SMA (Smn +/-, SMN2 +/+, SMN-delta-7) early treatment with the HDAC (601241) inhibitor, trichostatin A (TSA), plus nutritional support extended median survival by 170%. Treated mice continued to gain weight, maintained stable motor function, and retained intact neuromuscular junctions long after TSA was discontinued. In many cases, ultimate decline of mice appeared to result from vascular necrosis, raising the possibility that vascular dysfunction is part of the clinical spectrum of severe SMA. Narver et al. (2008) concluded that early SMA disease detection and treatment initiation combined with aggressive ancillary care may be integral to the optimization of HDAC inhibitor treatment in human patients.

Meyer et al. (2009) created an optimal exon 7 inclusion strategy based on a bifunctional U7 snRNA construct that targets the 3-prime part of exon 7 and carries an ESE sequence that can attract stimulatory splice factors. This construct induced nearly complete exon 7 inclusion of an SMN2-reporter in HeLa cells and of endogenous SMN2 in SMA type I patient fibroblasts. Introduction of the U7-ESE-B construct in a severe mouse model of SMA resulted in a clear suppression of disease-associated symptoms, ranging from normal life span with pronounced SMA symptoms to full weight development, muscular function, and ability of female mice to carry to term and feed a normal-sized litter. Exon 7 inclusion in total spinal RNA increased from 26% to 52%, and SMN protein levels increased, albeit only to levels one-fifth of that seen wildtype mice.

Workman et al. (2009) showed that SMN(A111G), an allele capable of snRNP assembly (A111G; 600354.0015), can rescue mice that lacked Smn and contained either 1 or 2 copies of SMN2 (SMA mice). The correction of SMA in these animals was directly correlated with snRNP assembly activity in spinal cord, as was correction of snRNA levels. These data support snRNP assembly as being the critical function affected in SMA and suggests that the levels of snRNPs are critical to motor neurons. Furthermore, SMN(A111G) could not rescue Smn-null mice without SMN2, suggesting that both SMN(A111G) and SMN from SMN2 may undergo intragenic complementation in vivo to function in heteromeric complexes that have greater function than either allele alone. The oligomer composed of limiting full-length SMN and SMN(A111G) had substantial snRNP assembly activity. The SMN(A2G) (A2G; 600354.0002) and SMN(A111G) alleles in vivo did not complement each other, leading to the possibility that these mutations could affect the same function.

Mattis et al. (2009) examined the potential therapeutic capabilities of a novel aminoglycoside, TC007. In an intermediate SMA mouse model (Smn -/-; SMN2 +/+; SMN-delta-7), when delivered directly to the central nervous system, TC007 induced SMN in both the brain and spinal cord, significantly increased life span (approximately 30%), and increased ventral horn cell number, consistent with its ability to increase SMN levels in induced pluripotent stem cell-derived human SMA motor neuron cultures.

Butchbach et al. (2010) tested a series of C5-quinazoline derivatives for their ability to increase SMN expression in vivo. Oral administration of 3 compounds (D152344, D153249, and D156844) to neonatal SMN-delta-7 mice resulted in a dose-dependent increase in Smn promoter activity in the central nervous system. Oral administration of D156844 significantly increased the mean life span of SMN-delta-7 SMA mice by approximately 20-30% when given prior to motor neuron loss.

Bowerman et al. (2010) showed that Smn depletion led to increased activation of RhoA (165390), a major regulator of actin dynamics, in the spinal cord of an intermediate SMA mouse model. Treating these mice with Y-27632, which inhibits ROCK (601702), a direct downstream effector of RhoA, dramatically improved their survival. This life span rescue was independent of Smn expression and was accompanied by an improvement in the maturation of the neuromuscular junctions and an increase in muscle fiber size in the SMA mice. Bowerman et al. (2010)proposed a role for disruption of actin cytoskeletal dynamics to SMA pathogenesis and suggested that RhoA effectors may be viable targets for therapeutic intervention in the disease.

Ackermann et al. (2013) found that ubiquitous overexpression of human PLS3 (300131) in mice with a mild SMA phenotype improved motor ability and neuromuscular junction function and moderately increased survival compared with control SMA mice. Expression of PLS3 did not improve the morphology of heart, lung, or intestine, and it did not improve motor ability or survival in mice with a severe SMA phenotype. The authors noted that these findings were consistent with observations in humans showing that PLS3 provides full protection against SMA only in SMN1-deleted individuals with 3 to 4 SMN2 copies, but not in those with 2 SMN2 copies. In mildly affected SMA mice, PLS3 delayed axon pruning until postnatal day 8, which counteracted the poor synaptic activity observed in control SMA mice. F-actin content was increased in presynapses, leading to improved neuromuscular connectivity, restored active zone content of synaptic vesicles, improved organization of the ready releasable vesicle pool, increased endplate and muscle fiber size, and improved neurotransmission.

(文献)
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