疾患詳細

疾患詳細





#232300
Glycogen storage disease II (GSD2)
(GSD II)
(Acid alpha-glucosidase deficiency)
(GAA deficiency)
(Pompe disease)
(Glycogenosis, generalized, cardiac form)
(Cardiomegalia glycogenica diffusa)
(Acid maltase deficiency; AMD)
(Alpha-1, 4-glucosidase deficiency)

グリコーゲン蓄積病 II
(Glucosidase, acid, alpha 欠損症)
(GAA 欠損症)
(Pompe 病)
(全身性糖原病の心型)
(びまん性グリコーゲン性心拡大)
(Acid maltase 欠損症; AMD)
(Alpha-1, 4- glucosidase 欠損症)
(Glucosidase, acid, alpha; GAA)
指定難病19 ライソゾーム病
小児慢性特定疾病 代97 ポンペ(Pompe)病

責任遺伝子:606800 Glucosidase, alpha, acid (GAA) <17q25.3>
遺伝形式:常染色体劣性

(症状)
(GARD)
<80%-99%>
 Abdominal wall muscle weakness (腹壁筋力異常) [HP:0009023] [1200]
 Cardiomegaly (心拡大) [HP:0001640] [1121]
 Cognitive impairment (認知障害) [HP:0100543] [0123]
 Dysphagia (嚥下障害) [HP:0002015] [01820]
 Dysphasia (不全失語症) [HP:0002357] [0231]
 EEG abnormality (脳波異常) [HP:0002353] [01405]
 Elevated serum creatine kinase (血清クレアチニンキナーゼ上昇) [HP:0003236] [2045]
 EMG abnormality (筋電図異常) [HP:0003457]
 Emphysema (肺気腫) [HP:0002097] [01605]
 Gait disturbance (歩行障害) [HP:0001288] [028]
 Generalized muscle weakness (全身性筋力低下) [HP:0003324] [0270]
 Hypertrophic cardiomyopathy (肥大型心筋症) [HP:0001639] [0273]
 Seizures (けいれん) [HP:0001250] [01405]
 Type II diabetes mellitus (II 型糖尿病) [HP:0005978] [2013]
<30%-79%>
 Arrhythmia (不整脈) [HP:0011675] [01700]
 Atrioventricular block (房室ブロック) [HP:0001678] [01700]
 Dyspnea (呼吸困難) [HP:0002094] [01606]
 Muscular hypotonia (筋緊張低下) [HP:0001252] [0242]
 Respiratory insufficiency due to muscle weakness (筋力低下による呼吸不全) [HP:0002747] [01606]
<5%-29%>
 Hepatomegaly (肝腫) [HP:0002240] [01813]
 Macroglossia (巨舌) [HP:0000158] [08109]
 Myopathy (ミオパチー) [HP:0003198] [0277]
 Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] [014230]

 Abnormal CNS myelination (中枢神経髄鞘化異常) [HP:0011400] [160127]
 Areflexia (無反射) [HP:0001284] [0242]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Diaphragmatic paralysis (横隔麻痺) [HP:0006597] [1202]
 Dilatation of the cerebral artery (大脳動脈拡張) [HP:0004944] [1120]
 Fever (発熱) [HP:0001945] [01413]
 Firm muscles (硬い筋) [HP:0003725] [0240]
 Generalized hypotonia (全身性筋緊張低下) [HP:0001290] [0242]
 Hearing impairment (難聴) [HP:0000365] [091]
 Proximal muscle weakness (近位筋筋力低下) [HP:0003701] [0270]
 Respiratory insufficiency (呼吸不全) [HP:0002093] [01606]
 Shortened PR interval (PR間隔短縮) [HP:0005165] [01700]
 Splenomegaly (脾腫) [HP:0001744] [01817]
 Wolff-Parkinson-White syndrome (Wolff-Parkinson-White 症候群) [HP:0001716] [01700]

(UR-DBMS)
【一般】不整脈 (巨大な QRS 複合, 短い PR 間隔, Wolf-Parkinson-White 症候群)
 呼吸不全
 呼吸困難
 呼吸器感染症
 肝腫
 誤嚥
 心不全
 易疲労性
 脾腫
 中枢性発熱
【神経】*進行性筋力低下 (生後1-2か月後)
 近位筋力低下
 筋電図でミオパチーパターン
 固い筋
 筋緊張低下
 *深部腱反射欠損
 ミオトニア
【口】巨舌
【耳】難聴
【消化器】横隔膜麻痺
【心】*進行性心拡大
 心筋症
 大脳動脈瘤
【検査】血清 CK 高値
 AST と LDH 上昇, 特に乳児期発症で
 筋生検で空胞の存在
 alpha-1,4-glucosidase (acid maltase) 欠損 (腎以外の全組織)
【その他】2つの提示がある
 乳児期の急速致死性疾患と小児期の緩徐進行性筋疾患
 遅発患者はよりよい予後をもつ
 全世界での頻度 1/40,000

(要約) グリコーゲン蓄積症 II 型 (Pompe 病)
(Acid Alpha-Glucosidase 欠乏症, Acid Maltase 欠乏症, GAA 欠乏症, 糖原病 II 型; GSD II)
●グリコーゲン蓄積症 II 型 (GSD II)または Pompe 病は, 発症年齢, 内臓病変, 重症度および進行性による分類される
○古典的乳児期発症 Pompe 病は, 子宮内で明らかになるかもしれないが, 生後2か月で, 筋緊張低下, 全身筋力低下, 心拡大と肥大型心筋症, 食餌摂取障害, 発育障害, 呼吸窮迫, および難聴で受診することがより多い
 酵素置換療法 (ERT) しないと古典的乳児期発症 Pompe 病は, 生後1年内に進行性左室流出路閉塞で死亡することが多い
 乳児期発症 Pompe 病の非古典的バリアントは, 通常, 生後1年内に, 運動遅滞+/-緩徐進行性筋力低下がみられ, 典型的には早期小児期に換気不全で死亡する
 心拡大がみられうるが, 心疾患は死亡の主因ではない
○遅発型 (小児期, 若年, 成人発症)の Pompe 病は, 近位筋筋力低下と呼吸不全が特徴である
 臨床的に有意な新病変は遅発型では多くはない
●診断:acid alpha-glucosidase (GAA) 酵素活性の測定が診断的
 GAA が唯一の遺伝子である
●治療
 心筋症:標準薬は頻不整脈および突然死率が高いので禁忌かも
○酵素置換療法:診断確定後すぐMyozyme® または Lumizyme® (alglucosidase alfa) を開始する
 →抗体の発生に対して immunomodulatory protocol を早期に始める
 6か月以前および補助呼吸開始以前に使用した大多数は ERTにより, 生存, 呼吸器なしでの生存, 運動機能改善, 心拡大の改善がみられる
 遅発型では, ERT は換気能と運動能を安定化させるかも
 副反応やアナフィラキシスを生じうる
 slow 静注 20-40 mg/kg/dose/2週ごと
●予防:感染対策, 予防接種 (インフルエンザ, RSウイルスなど)
●遺伝:常染色体劣性
●臨床診断
○乳児期発症型→以下で疑う
 食餌摂取障害/発育障害 (44%-97%)
 運動遅滞/筋力低下 (20%-63%)
 呼吸問題 (感染症/困難) (27%-78%)
 心問題 (PR 間隔短縮と幅広いQRS群, 心拡大, 左室流出路閉塞, 心筋症) (50%-92%)
○遅発型
 近位筋筋力低下と臨床的に明らかな心病変なしでの呼吸不全で疑う
●非特異的検査
 血清 CK: 一定して上昇 (2000 IU/Lまで; normal: 60-305 IU/L) するが成人型では正常かもしれない
 尿中オリゴ糖:特異的尿中 glucose tetrasaccharide 上昇→他のGSDでもみられる
●確定診断用検査
○Acid alpha-glucosidase (GAA) 酵素活性:乾燥血液濾紙で可能→(培養皮膚線維芽細胞または)遺伝子解析で確認することが望ましい
  培養線維芽細胞での測定は時間がかかりすぎる→ERT開始の遅れとなる
 完全欠損(正常の <1%) →古典的乳児期発症型
 部分的欠損 (正常の 2%-40%) →非古典的乳児期発症型や遅発型で
○Acid alpha-glucosidase タンパク定量→培養線維芽細胞で (抗体による方法)
 患者が cross-reactive immunologic material (CRIM)を産生するかどうかを決定するのに重要な検査
 CRIM 産生なしであれば, ERTは使えない
○筋生検:GSD II は他の GSDと異なりリソソーム蓄積症であるので, グリコーゲンの蓄積が筋細胞のリソソームに空胞としてみられる
 → periodic acid-Schiff で染色される
 遅発型の20%-30% にはみられない
○新生児スクリーニング→台湾で研究中
(注意) 偽欠乏アレル c.1726 G>A (p.Gly576Ser)→アジア人に多い
●GAA 遺伝子解析
 p.Arg854Ter:~50%-60% (アフリカ系米国人)
 p.Asp645Glu:~40%-80% (中国人)
 c.336-13T>G ~50%-85% (遅発型成人)
●遺伝子型-表現型相関
○酵素活性欠損となる2つの変異アレルの組み合わせ→乳児期発症型
○ CRIM 陰性の乳児期発症型→2つのヌルバリアントをもつ可能性が高い
○残存酵素活性を生じるアレルの組み合わせ→残存酵素活性に比例した発症年齢と進行度
○ナンセンス変異のようにmRNA 不安定性となる病的バリアントは乳児期発症型でよくみられ酵素活性ほぼ欠損である
○ミスセンスまたはスプライス部位変異は完全か部分欠損となりうる→乳児期発症型と遅発型の両方でみられる
 p.Glu176ArgfsTer45 (c.525delT) →オランダ人(34%), 米国 )8%), 重症表現型となる (ホモまたは複合ヘテロ)
 エクソン18欠失 (p.Gly828_Asn882del; c.2482_2646del) →オランダ人/カナダ人 (25%), 重症表現型
 c.336-13T>G →遅発型の 36% 〜 90% でみられる
 p.Asp645Glu→台湾と中国の乳児型で (創始者効果を示唆)
 p.Arg854Ter →乳児期発症型, アフリカ系の60%にみられる
●頻度:アフリカ系米国人 1:14,000〜欧州人 1:100,000

<指定難病> 筋型糖原病
1.概要
 糖原病は, 先天的なグリコーゲンの代謝異常症で, 大きく肝型, 筋型の病型に大別できる。しかし酵素発現の臓器特異性から, 肝臓, 筋肉以外の他臓器の障害が臨床症状として並存していることもある。
 肝型では低血糖, 肝機能障害, 成人期に肝硬変, 肝腫瘍を呈するものもある。筋型では急性症状として横紋筋融解症, ミオグロビン尿症などを来し, 腎不全に陥る症例もある。また老年期では筋力低下(進行性)を示すものもある。
筋型糖原病の好発病型はII, III, V, VII型で, 全体の90%を占めている。その他の希な筋型病型として0型, IV型, IX型, ホスホグリセリン酸キナーゼ(PGK)欠損症, X型, XI型, XII型, XIII型, XIV型, XV型がある(筋型糖原病対応表参照)。
 
2.原因
 先天性のグリコーゲン代謝に関わる酵素異常症で, それぞれの酵素蛋白をコードする遺伝子異常が同定されている。
 
3.症状
 筋症状:運動時筋痛, 筋硬直, 横紋筋融解症, ミオグロビン尿症, 筋力低下, 筋萎縮, 心筋障害など
 合併症状(一部の病型において):知的障害, てんかん, 小奇形, 黄疸, 肝腫大, 不整脈, 突然死など
 
4.治療法
 現在では根本的な治療法はない。病態に応じた対症療法として, II型(ポンペ(Pompe)病)では酵素補充療法が可能となり, 生命予後が飛躍的に改善した。V型(マッカードル(McArdle)病)でビタミンB6療法が日本人で2例有効な報告がある。その他経験的にアラニン, カルニチン, ATP, ショ糖, コーンスターチなどの投与がされているがエビデンスはない。 
 
5.予後
好発病型: 
 II型(ポンペ(Pompe)病)では生命予後は改善したが, 症例によっては筋力低下が著明で, 呼吸器装着の症例も多い。III型(コーリー(Cori)病)では心筋障害を伴う例では予後が不良で死にいたる。V型は一部進行性の筋力低下, あるいは乳児期に死亡する致死型もある。
稀な病型:
 0型では突然死, IV型では致死型が, PGK欠損症では知的障害, てんかん, 進行性筋力低下, 報告されている。X~XV型は筋症状が主体であり, 比較的予後は良好である。

<診断基準>
Definiteを対象とする。

1.臨床病型(対応表参照)
 ①発作性に筋症状を示す型
 (V型,VII型,IXd型, PGK欠損症, XIV型, XI型)
 ②固定性筋症状を示す型(0型, II型, III型, IV型, XII型)

2.主要症状
 ①発作性に筋症状を示す型では運動不耐, 運動時有痛性筋けいれん, ミオグロビン尿症。強い短時間の等尺性運動で運動不耐, 筋痛, 有痛性筋けいれんが生じる。
 ②固定性筋症状を示す型では持続するあるいは進行する筋力低下を認める。

3.その他の特徴的症状または随伴症状
 ①V型では運動を続けるうちに, 突然筋痛や有痛性筋けいれんが軽快し再び運動の持続が可能となる“セカンドウィンド現象”を高率に認める。
 ②VII型では溶血を認めることがある。
 ③PGK欠損症では溶血を認める。精神遅滞を伴う場合がある。
 ④XII型では溶血, 精神遅滞を伴う場合がある。

4.参考となる検査所見
 血清CK値高値。発作性筋症状出現時には血清CK値は著明に上昇する。ミオグロビン, 血清尿酸, BUN, クレアチニンの上昇。
 溶血所見, 高ビリルビン血症, 網状赤血球の増加(VII型, PGK欠損症, XII型)

5.診断の根拠となる特殊検査
 阻血下前腕運動負荷試験または非阻血下前腕運動負荷試験で, 乳酸・ピルビン酸が上昇しない。(前値の1.5倍未満の乳酸上昇を異常とするが, アンモニアを同時に測定し, アンモニアが上昇しない場合には, 負荷が十分にかかっていないと判断する必要がある。)
 組織化学検査:生検筋組織化学では筋漿膜下にグリコーゲンの蓄積を認める。V型ではホスホリラーゼ染色が陰性である。

参考
 前腕運動負荷試験で, II型とIXd型では乳酸の反応は正常である。XI型ではピルビン酸の著明な上昇に関わらず, 乳酸の上昇がない。

6.Definite(確定診断)のための検査
 ①遺伝子検査:V型の日本人好発変異708/709 del TTC)を同定した場合にはV型と診断する。
 ②酵素活性測定:生検筋の解糖系酵素測定で低下を証明する。PGK欠損症では赤血球でも測定可能である。
 ③日本人好発変異以外の遺伝子検査

7.鑑別診断
 脂肪酸代謝異常症, ミトコンドリア異常症

8.診断のカテゴリー
 Definite:酵素診断又は遺伝子診断をしたものをDefiniteとする。
 Possible:主要症状及び臨床所見の項目のうち, 運動不耐, 運動時有痛性筋痙攣, 筋力低下が存在し, 阻血下(非阻血下)前腕運動負荷試験で乳酸が上昇しない例を筋型糖原病疑診とする。

確定診断
酵素診断または遺伝子診断をしたものを確定診断とする。

(筋型糖原病対応表)
病型  同義語  症状  低下酵素活性  原因遺伝子
0型     運動時失神, 運動不耐   グリコーゲン合成酵素   GYS1
II型   Pompe病   筋力低下, 心筋障害, 肝腫大   酸αグルコシダーゼ   GAA
III型   Cori病   筋力低下, 運動不耐, 肝腫大。低血糖, 心筋障害, 心不全   脱分枝酵素   AGL
IV型   Andersen病   新生児死亡, 呼吸障害, 筋力低下   分枝酵素   GBE1
V型   McArdle病   運動不耐, 筋痛・筋硬直, 横紋筋融解症     筋力低下   筋ホスホリラーゼ   PYGM
VII型   Tarui病   運動不耐, 筋痛・筋硬直, 横紋筋融解症   ホスホフルクトキナーゼ   PFKM
IXd型   運動不耐, 筋痛・筋硬直, 横紋筋融解症   ホスホリラーゼキナーゼ   PHKB  PGK 欠損症     運動不耐, 筋痛・筋硬直, 横紋筋融解症, 知的障害, てんかん, 進行性筋力低下   ホスホグリセリン酸キナーゼ   PGK1
X型     運動不耐, 筋痛・筋硬直, 横紋筋融解症   ホスホグリセリン酸ムターゼ   PGAM2
XI型   Kanno病   運動不耐, 筋痛・筋硬直, 横紋筋融解症   乳酸脱水素酵素   LDHA
XII型     運動不耐, 筋痛・筋硬直, 横紋筋融解症, 黄疸, 発達遅滞   アルドラーゼ   ALDOA
XIII型     運動不耐, 筋痛・筋硬直, 横紋筋融解症   エノラーゼ   ENO3
XIV型     運動不耐, 筋痛・筋硬直, 横紋筋融解症, 糖鎖修飾異常   ホスホグルコムターゼ   PGM1
XV型     筋力低下, 不整脈   グリコゲニン1   GYG1

<小児慢性特定疾病 代97 ポンペ(Pompe)病>
概要・定義
ライソゾームにおける酸性α-グルコシダーゼの活性低下あるいは欠損により, 主に筋細胞のライソゾーム内にグリコーゲンが蓄積して起こる進行性の筋疾患である。
疫学
発生頻度は民族差がある。日本人では約10~20万人に1人と推定される。成人型患者の中に診断されていない症例が多く存在すると推測される。文献的には, 1歳未満の発症は14%で, 1歳以上17歳までの発症は24%, 18歳以上の発症は62%と報告されている。
病因
常染色体性劣性遺伝形式をとる。病初期は, グリコーゲンに満ちた小さなライソゾームが筋細胞質に認められるが, 臨床的には無症状である。次第に, グリコーゲンを蓄積したライソゾームが膨張し, 最終的に細胞質は大きな空胞で占められるようになり, ミトコンドリア等の細胞内小器官も自己貪食され空胞内に取り込まれた状態になる。さらに進むと筋細胞は消失し, 組織は脂肪変性を来す。ライソゾームにグリコーゲンが蓄積することと, ライソゾームの機能障害, 自己貪食の亢進が筋組織を破壊すると考えられている。
症状
1). 乳児型:生後2か月頃哺乳力低下, 筋力低下が出現し, フロッピーインファントとなる。心肥大, 巨舌, 肝腫大を認める。自然歴では, 乳児型は18か月までに全例が死亡する。死因は心機能障害, 呼吸障害である。
2). 遅発型(小児型・成人型):小児型は生後6か月~幼児期に発症。筋力低下が徐々に進行する。2歳以降の発症例では, 心肥大症状は伴わないことが多い。呼吸不全や呼吸器感染症で20~30歳代で死亡する。成人型は10歳以降に発症する。60歳代に気付かれる症例もある。骨格筋の障害が主で, 心筋障害はまれである。
遅発型の重症度には大変幅がある。近位筋優位の筋力低下を来たす。骨格筋の症状として, 運動が下手である, 脊柱側弯症, 腰痛などが認められる。呼吸筋の障害のため, 疲れやすい, 息切れ, 風邪をこじらせやすいなどに気付かれる。また, 夜間睡眠中の低換気のため, 朝起きた時の頭痛や日中の眠気などを訴える。軟口蓋の力が弱く鼻咽腔閉鎖不全となるため, 鼻声になる。脳動脈瘤を起こしやすい
診断
診断方法
(1) 症状・臨床検査
症状:近位筋優位の筋力低下を認める。鼻声や朝の頭痛を認める。乳児型では, 乳児期早期にフロッピーインファントとなり, 心肥大を認める。
臨床検査:血液検査では, CKが上昇する(数百~数千IU/L)。AST, ALT, LDHも上昇する。乳児型では, 心エコーで心筋の肥大を認める。小児型, 成人型では, 呼吸機能検査や睡眠時呼吸検査が有用である。筋生検にて筋組織のライソゾームにグリコーゲンの蓄積を認め, 筋繊維の空胞変性を認める。成人型においては, 時に典型的ではない。生化学的に筋組織中のグリコーゲン含量が増加している。
(2) 確定診断 筋組織あるいは培養皮膚線維芽細胞を用いて酸性α-グルコシダーゼを測定し, 活性欠損を証明することである。血液ろ紙でも測定が可能である。しかし, 末梢血を材料とした場合は, 中性のグルコシダーゼ活性が一緒に測定されてくるので, 阻害剤を用いて測定する必要がある。
乳児型においては, 急速に進行して死に至るため, 早期に診断して治療しなければいけない。このことから, 新生児マススクリーニングの必要性が高まっており, いくつかの研究やパイロットスタディが行われている。
当該事業における対象基準
全A  疾患名に該当する場合
治療
酵素補充療法がある。
予後
乳児型では, 無治療の場合は心不全等で1歳半までに死亡する。遅発型では, 重症度は様々であるが, 呼吸不全や呼吸器感染症で死亡する。酵素補充療法により予後は改善できる。
成人期以降
呼吸器感染症に注意を要する。気胸を発症することもある。

(責任遺伝子) *606800 Glucosidase, alpha, acid (GAA) <17q25.3>
.0001 Acid alpha-glucosidase allele 2 [GAA, ASP91ASN [dbSNP:rs1800299] (ExAC:rs1800299) (RCV000078177...) (Martiniuk et al. 1990)
.0002 Glycogen storage disease II, infantile form (232300) [GAA, MET318THR] (dbSNP:rs1800299) (ExAC:rs121907936) (RCV000004236) (Zhong et al. 1991)
.0003 Glycogen storage disease II, infantile form [GAA, GLU521LYS [dbSNP:rs121907937] (ExAC:rs121907937) (RCV000169465...) (Hermans et al. 1991)
.0004 Glycogen storage disease II, adult form (232300) [GAA, GLY643ARG] (dbSNP:rs28937909) (ExAC:rs28937909
RCV000004238...) (Hermans et al. 1993)
.0005 Glycogen storage disease II, adult form [GAA, ARG725TRP] (dbSNP:rs28939100) (ExAC:rs121907938) (RCV000004239...) (Hermans et al 1993)
.0006 Glycogen storage disease II, adult form [GAA, IVS1AS, T-G, -13 [dbSNP:rs386834236] (RCV000210721...) (Huie et al. 1994; Boerkoel et al. 1995; Kroos et al. 1995)
.0007 Glycogen storage disease II, infantile form [GAA, LYS903DEL [dbSNP:rs121907939] (RCV000004243) (Boerkoel et al. 1995)
.0008 Glycogen storage disease II, infantile form [GAA, LEU299ARG [dbSNP:rs121907940] (RCV000004240) (Boerkoel et al. 1995)
.0009 Glycogen storage disease II, adult form [GAA, SER529VAL [dbSNP:rs121907941] (RCV000004241) (Tsunoda et al. 1996)
.0010 Glycogen storage disease II, infantile form [GAA, ASP645GLU] (dbSNP:rs28940868) (ExAC:rs28940868) (RCV000004244...) (Lin and Shieh 1996, Shieh and Lin 1998)
.0011 Alpha-glucosidase allele 4 [GAA, GLU689LYS] (dbSNP:rs1800309) (ExAC:rs1800309) (RCV000004245...) (Huie et al. 1996)
.0012 Glycogen storage disease II [GAA, EX18DEL] (RCV000004246) (Van der Kraan et al. 1994; Huie et al. 1994; Boerkoel et al. 1995; Kroos et al. 1995; Vorgerd et al. 1998)
.0013 Glycogen storage disease II, adult form [GAA, PRO545LEU] (dbSNP:rs121907942) (ExAC:rs121907942) (RCV000004247) (Hermans et al. 1994)
.0014 Glycogen storage disease II [GAA, 1-BP DEL, 525T [dbSNP:rs386834235 ] (RCV000078181...) (Hermans et al. 1994; Kroos et al. 1995)
.0015 Glycogen storage disease II [GAA, ARG854TER] (dbSNP:rs121907943) (ExAC:rs121907943) (RCV000004249...) (Becker et al. 1998)
.0016 Glycogen storage disease II, adult form [GAA, ALA237VAL] (dbSNP:rs121907944) (ExAC:rs121907944) (RCV000004250) (Anneser et al. 2005)
.0017 Glycogen storage disease II, adult form [GAA, GLY293ARG] (dbSNP:rs121907945) (ExAC:rs121907945) (RCV000004251) (Anneser et al. 2005)
.0018 Glycogen storage disease II [GAA, IVS1AS, G-C, -1] (RCV000004252) (Gort et al. 2007)

(ノート)
A number sign (#) is used with this entry because glycogen storage disease II (GSD2) is caused by homozygous or compound heterozygous mutation in the GAA gene (606800), which encodes acid alpha-1,4-glucosidase, also known as acid maltase, on chromosome 17q25.

● グリコーゲン蓄積症 II は常染色体劣性疾患で, リソソーム蓄積症のプロトタイプである
 古典的乳児型 (Pompe 病) では, 心筋症や筋緊張低下が主要な特徴である
 若年型や成人型では, 骨格筋病変が臨床像として優位である (Matsuishi et al. 1984)

臨床症状
乳児期発症 (Pompe 病)
● Pompe 病の古典的症例では, 患児は衰弱し大きな心臓を伴って著明に筋緊張低下である
 舌が大きいかもしれない
 酵素は全組織で欠乏しているが, 筋力低下と心病変が最も多い特徴である
 肝はほとんど肥大せず (心不全の場合を除く), 糖原病 I 型 (232200)でみられる低血糖やアシドーシスは生じない
 古典型で心病変が顕著な場合は, 通常生後1年の間に死亡する
 事実, Pompe (1932)は, この疾患を 'idiopathic hypertrophy of the heart' と記載した
 → 'cardiomegalia glycogenica' は同義語である

●Slonim et al. (2000) は, 2番目の乳児型の軽症サブタイプを提唱した
 彼らは, より軽症の心筋症, 左室拍出路閉塞なし, 痕跡的残存 acid maltase 活性 (< 5%) を示した乳児12例を報告した
 12例中9例は補助換気は挿管でより長く生存した

●Smith et al. (1967) は, 本疾患のミオトニア型でほぼ11歳まで生存した男児1例を報告した
 心は有意に侵されていなかった
 Alpha-1,4-glucosidase は, 肝と筋で欠損していた
 重度のグリコーゲン沈着があり, 短い外側鎖をもつ異常な多糖類が証明された
 Smith et al. (1966) は, 4.5歳まで生存した男児の類似例を報告した
●Zellweger et al. (1965) は, 骨格筋に限定した最小の症状をもつ15歳と4.5歳の兄弟を記載した
 筋のalpha-1,4-glucosidase欠乏が証明された
 筋はグリコーゲンの異常な蓄積を示した
 母方おじも患者かもしれない

● Hagemans et al. (2005) は, Pompe 病をもつ小児と成人255例の質問状解析で, 車椅子生活や呼吸補助の使用を含む疾患重症度が疾患の期間とともに増加するが, 患者の年齢と無関係であることを発見した
 しかし, より重症で, 換気補助, 車椅子支援, 栄養支援の利用が増加する15歳以下の患者のサブセットがあった
 この患者サブグループの全例が生後2年以内の症状発症をもっていた

●Forsha et al. (2011) は, 遅発性 Pompe 病の患者で, 心血管異常の頻度と酵素置換両方の有効性と安全性を調べた
 90例が酵素置換療法とプラセボに二重盲検法で2:1にランダマイズされた
 ECGs と心エコーは, 最初と78週の間隔で行われた
 87例が含まれた
 中央年齢は44歳で半数は男性であった
 最初では, PR間隔短縮が10%にみられ, 7%は左室収縮機能の低下が, 5%は心エコーで左室容量の増加があった (全てが軽度)
 酵素置換療法での心血管状況に変化はなかった
 有意な安全性での問題はなかった
 遅発性 Pompe 病の一部の患者は EEGや心エコーに異常をもっていたが, 乳児性 Pompe 病でみられる優位な心室肥大などの古典的所見はなかった

●Banugaria et al. (2011)は, Pompe 病の乳児34例を後方視的に解析した
 11例は交叉反応性免疫物質 (CRIM) 陰性の患者で, 9例はCRIMが高値の陽性患者, 14例はCRIM低値の陽性患者であった
 臨床的転帰には, 生存, 呼吸器 free 生存, 左室容量インデックス, Alberta Infant Motor Scale スコア, および尿中 Glc4 値が調べられた
 CRIM 高値群での臨床的転帰は, 低値群より全ての面で不良であった
 CRIM陰性群と高値群では, いろんな転帰因子で統計学的有意差はみられず, 両群とも不良であった
 Banugaria et al. (2011) は, CRIM 物質状態に関係なく, 乳児 Pompe 病と高い抗体値が持続する患者は, 酵素置換療法への反応が悪いと結論した
 Banugaria et al. (2011)は, 免疫調節療法と持続する高抗体価のリスクをもつ患者の証明の試みが決定的であると結論した

●Prater et al. (2012) は, 乳児 Pompe 病の長期生存例の表現型を記載した
 含まれる基準には, 呼吸器 free の状態と治療開始年齢6か月未満, 5歳以上の生存が含まれた
 17例中11例がこの研究基準に合致した
 全例が CRIM 陽性で, 生存し, 直近での呼吸器管理なしであり, 中央年齢は8.0歳であった (5.4-12.0 歳)
 全例が, 心パラメーターの著明な改善をもっていた
 多くみられたものは, 粗大運動筋力低下, 運動性発語欠乏, 観音+/-伝音難聴, 骨減少, 胃食道逆流, 誤嚥のリスクを伴う嚥下障害であった
 11例中7例は独歩でき, 4例は補助装具を必要とした
 全ての長期生存例は, anti-alglucosidase alfa antibody 抗体の低値または検出不能をもっていた
 Prater et al. (2012) は, 長期生存例は心パラメーターと粗大運動機能の持続的開扇を示すと結論した
 残存する筋力低下, 難聴, 不整脈のリスク, 鼻声, 誤嚥のリスクのある嚥下障害, 骨減少がよくみられる所見であった

Korlimarla et al. (2020) examined CNS involvement in 12 children with infantile-onset Pompe disease (IPD) and 2 children with late-onset Pompe disease (LOPD) who were receiving enzyme replacement therapy. They quantified brain white matter hyperintense foci by using the Fazekas scale (FS) grading system to score MRI findings in 10 brain areas. The FS scores were then compared to measurements of cognition and language. In 10 of the 12 children with IPD, with a median age of 10.6 years, mild to severe white matter hyperintense foci were seen. The lesions were seen throughout the corticospinal tracts of the brain. Two children with IPD had no white matter hyperintense foci. There were no significant relationships between total FS scores and age of the patient, anatomic areas of the brain, duration of treatment, duration of disease, or the patients' GAA mutations. No white matter hyperintense foci were seen in the 2 children with LOPD. Ten children with IPD and 2 children with LOPD completed cognitive assessments. Full-scale Wechsler IQ scores in patients with IPD ranged from significantly below average in 3 children to significantly above average in 1 child. These scores were average or above average in the 2 patients with LOPD. CELF-5 scores in patients with IPD on core language, language index, and expressive language index ranged from below average to above average. All language scores were above average in 1 LOPD patient and average and below average in the other LOPD patient. There were no significant relationships between FS scores and standard scores on each cognitive or language domain. Korlimarla et al. (2020) concluded that characterizing baseline and serial white matter hyperintense lesions in patients with Pompe disease is important for the longitudinal follow-up of disease.

成人発症
●Hudgson et al. (1968) は, ポルトガル人の19歳で死亡した女性と生存している44歳の主婦を報告した
●糖原症 II 型に1つ以上のタイプが存在することを示唆するその他の経験が Swaiman et al. (1968)により報告された

●成人発症 acid maltase 欠乏症は, 肢帯型筋ジストロフィーに類似し, 唯一の臨床的な手がかりは横隔膜の早期の病変かもしれない (Engel, 1970; Newsom-Davis et al., 1976; Sivak et al., 1981)
●Trend et al. (1985) は, 急性呼吸不全または慢性夜間換気不全をもつ患者5例中4例を報告した
 彼らは, 揺動ベッドまたは気管切開での間歇的陽圧呼吸を使っての長期の在宅換気補助が, 職場復帰を可能とすると報告した
●Molho et al. (1987)は, 50歳時に両側性横隔膜麻痺を生じた一卵性双生児兄弟例を報告した
 仰臥位での重度の呼吸困難が夜間に pneumobelts による機械的換気を必要とした
 成人 acid maltase 欠乏症の可能性がこれらの症例では考慮すべきである

●Francesconi and Auff (1982) は, Wolff-Parkinson-White 症候群 (194200) と2°房室ブロックを成人型糖原症 II の患者1例で記載した
●Byrne et al. (1986) は, '心病変は非乳児性 acid maltase 欠乏症の1例でのみ報告されている'と述べた

●Makos et al. (1987) は, alpha-glucosidase 欠乏症の兄弟3例を記載した
 各々が, 若年成人で紡錘型基底動脈瘤を生じ, 2例で致死的破裂を, 3例目で小脳梗塞を合併した
 剖検は, 骨格筋, 肝および血管平滑筋の重度の空胞化とグリコーゲンの蓄積を証明した
 生存している兄弟1例では, 類似のグリコーゲン蓄積が浅側頭動脈の平滑筋で証明された
 血管平滑筋のグリコーゲン蓄積は, 以前に本疾患で証明されていたが, 臨床的意義があるとは考えられていなかった
 兄弟の1例は, 9歳児筋力低下の発症, 大脳アンギオにより27歳時に基底動脈瘤の証明 (拍動, 後頭部痛, 32歳時の小脳梗塞のため行われた)をもった
 彼は正常な2人の息子をもった
 この家系の患者たちは, 白血球では正常なalpha-glucosidase活性をもっていたが, 筋ホモジネートでは酸性 pHでalpha-glucosidaseをほぼ検出できなかった
 Kretzschmar et al. (1990) は, 成人 acid maltase 欠乏症をもつ40歳男性を記載した
 肝と骨格筋の病変に加え, 動脈瘤形成を伴う大および小大脳動脈の高度の病変をもっていた

●Chancellor et al. (1991) は, 65歳時に最初の歩行障害を生じ, 数ヶ月間運動での遺尿をもった68歳の男性を記載した
 Chancellor et al. (1991) は, 排尿筋不安定性をもつ多くの患者は無症状であり, おそらく括約筋の横紋筋活性の増加により尿道閉鎖圧を増すためだと指摘した
 彼らは, 運動による横紋筋骨盤底筋の疲労がある時のみ排尿筋圧増加への抵抗ができないためだと主張した
 二社選択的には, 脊髄運動ニューロンの病変のため神経原性筋力低下があるのかもしれない

●Laforet et al. (2000) は, 若年性または成人発症性GAA欠乏症をもつ関連のない21例での臨床的特徴を報告した
 明らかな筋主訴の平均発症年齢は36歳であったが, 大多数の患者 (16/21) は小児期から軽度の筋症状が報告されていた
 →翼状肩甲骨, 側弯および走行困難
 大多数の患者は, 有意な遠位四肢病変なしに骨盤支持筋の優位な病変をもっていた
 8例(40%) は, 四肢筋筋力低下の重症度と相関しない重度の呼吸筋病変をもっていた
 生化学的検査は, 白血球で残存 GAA 活性を示した (正常の 0-17%)
 白血球 GAA 活性と臨床重症度とは相関はなかった
 遺伝子解析は, 17例で GAA 遺伝子の多い -13T-G transversion を証明した (606800.0006) (16 は複合ヘテロ接合, 1つはホモ接合)
 遺伝子型/表現型相関はなかった

●Anneser et al. (2005) は, GAA 遺伝子変異により確認された alpha-glucosidase 欠乏症の30歳女性を報告した (606800.0016;606800.0017)
 彼女は, 進行性近位筋筋力低下の4年の既往歴をもち, 診察は著明な空胞化ミオパチー, 著明な GAA 酵素活性減少, 血清CK増加, transaminase 増加を示した
 診断後, 彼女は3か月以内に3回の卒中様エピソードを経験した
 脳 CT は, 特に基底動脈瘤の大脳内血管の拡張性血管症と頸動脈および中大脳動脈の石灰化を示した
 MRI は, いくつかの白質病変を示した
 彼女は, 他の動脈硬化のリスク因子をもっていなかった
 Anneser et al. (2005) は, 類似の筋肉外血管変化は緩徐進行性 Pompe 病を伴う成人患者のもっと多い予後因子かもしれないと示唆した

●Groen et al. (2006) は, 成人発症 GSD II 12例中4例(33%)が眼瞼下垂をもつことを発見した
 →3例で主な特徴であった
 12例中6例 (50%) は, 眼瞼挙上筋機能の減少の証拠をもっていた
 眼瞼下垂の有病率は一般集団より有意に高く, 成人発症 GSD II の臨床的特徴と考えられることを示唆した

遺伝子型/表現型相関
●Koster et al. (1978) と Loonen et al. (1981) は, 52歳以後階段の昇段困難となった acid maltase 欠乏症をもつ祖父と, 16週で死亡した典型的 Pompe 病をもつ孫娘1例を記載した
 両者の筋は, 残存活性を示した
 祖父は遺伝的複合体である可能性が考えられた
● Hoefsloot et al. (1990) は, 同じ家系で, 同胞3例が acid alpha-glucosidase の完全欠損を生じるアレルホモ接合であることを示した
 これらの患者は重度の乳児型をもっていた
 非常に軽い臨床症状をもつこの家系の最年長患者は, このアレルと部分的酵素欠乏となる触媒活性のあるacid alpha-glucosidaseの正味産生の減少が特徴の2番目のアレルとの複合ヘテロ接合であることが示された
 変異アレルはその個々の機能を調べるためヒト-マウス体細胞融合で分離された

●Danon et al. (1986) も, おそらく遺伝的複合例を報告した
●Nishimoto et al. (1988) は, 15歳の発端者が糖原病 II 型の若年性筋ジストロフィー型をもつが, 両親と姉妹2例がacid alpha-glucosidaseの偽欠乏症をもつ1家系を記載した
 リンパ球アッセーのみではホモ接合からヘテロ接合患者を区別するのはほぼ不可能であった
 両親は偽欠乏アレルと若年型アレルの複合ヘテロ接合なのかもしれない

●アレル異質性はSuzuki et al. (1988)により報告された患者でさらに証明された
 男性1例が12歳時に心筋症を生じ, 臨床的にも組織学的にも骨格筋病変のサインなしに15歳で心不全で死亡した
 acid alpha-glucosidase の Km 変異体が証明された
●Iancu et al. (1988) は, 局所的仮性肥大のようにみえる右腰部腫瘤をもつ12歳男児を記載した

機序
●II 型糖原病での欠損は, リソソーム酵素であるacid alpha-1,4-glucosidase (acid maltase)を含む
 グリコーゲンは他の糖原病では細胞質に一様に分布するが, この型ではリソソーム膜に封入されている

● Beratis et al. (1978)は, 乳児 acid alpha-glucosidase 欠乏症の1例で, 障害は触媒的に不活性な交叉反応物質 (CRM)が陽性の酵素タンパクの合成を生じる構造的変異であると結論した
 一方, 成人型の変異は, 酵素タンパク量の減少を生じる
● Beratis et al. (1983) は, 乳児型 acid alpha-glucosidase 欠乏症の患者の9つの線維芽細胞株で, 8つが CRM 陰性で, 1つが CRM 陽性であることを発見した
 明らかな酵素活性の違いは, 2つの型には検出されなかった
 2つの成人型線維芽細胞株では, rocket immunoelectrophoresisは, 酵素活性と直接的に比例する酵素タンパク量の減少を示した
 もう一つの成人型線維芽細胞株では, 酵素活性は乳児型と同じ範囲であり, CRM は証明されなかった
 正常バリアントと考えられた acid alpha-glucosidaseの表現型2をもつ線維芽細胞は, 酵素タンパク量とグリコーゲン分割能の両方の減少を示したが, マルトースへの触媒活性は正常であった

Reuser et al. (1978) studied fibroblasts from the infantile, juvenile, and adult forms of acid alpha-glucosidase deficiency. An inverse correlation was found between the severity of clinical manifestations and the level of residual enzyme activity in fibroblasts. The kinetic and electrophoretic properties of residual enzyme in fibroblasts from adult patients were identical to those from controls. The mutation may, therefore, affect the production or degradation of enzyme rather than its catalytic function. Complementation studies by fusion of fibroblasts from different types yielded no sign of nonallelism of the several forms.

Reuser et al. (1987) investigated the nature of the acid alpha-glucosidase deficiency in cultured fibroblasts from 30 patients. Deficiency of catalytically active mature enzyme in lysosomes was common to all clinical phenotypes but, in most cases, was more profound in early-onset than in late-onset forms of the disease. The role of secondary factors cannot be excluded, however, because 3 adult patients were found with very low activity and little enzyme in the lysosomes.

Diagnosis
Angelini et al. (1972) showed that the adult form of the disease can be diagnosed in cultured skin fibroblasts. Askanas et al. (1976)established muscle tissue cultures from a 34-year-old patient with the adult-onset myopathy. Morphologically and biochemically, the newly grown fibers of cultured muscle showed the same changes as did biopsied muscle.

Ausems et al. (1999) found that creatine kinase (CK) elevation is a sensitive marker of GSD II. CK levels were elevated in all 18 patients in their cohort and in 94.3% of GSD II patients reported in the literature. They proposed a diagnostic protocol for adult-onset GSD II. In patients presenting with a slowly progressive proximal muscle weakness or with respiratory insufficiency, they recommended measurement of serum levels of CK, followed by measurement of acid alpha-glucosidase activity in leukocytes, using glycogen as a substrate. To rule out the pseudodeficiency state seen in carriers of the GAA2 allele, they recommended that patients with depressed leukocyte activity have a repeat assay in cultured fibroblasts using artificial substrate.

Kallwass et al. (2007) reported a simple and reliable method to measure alpha-glucosidase activity in dried blood spots using Acarbose, a highly selective alpha-glucosidase inhibitor, to eliminate isoenzyme interference. The authors demonstrated that this method efficiently detected late-onset Pompe patients who were frequently misdiagnosed by conventional methods due to residual GAA activity in other tissue types.

Bembi et al. (2008) provided a detailed guide to the diagnosis of GSD II, with emphasis on the importance of early recognition of clinical manifestations. Diagnosis is confirmed by biochemical assays showing absent or decreased GAA enzyme and enzyme activity in peripheral blood cells, skin fibroblasts, or muscle biopsy. Affected adults usually present with skeletal muscle weakness and cramps and may often have respiratory failure. Progression is usually slow. Muscle imaging may be useful to assess the extent of involvement in older patients. Affected infants can present with hypertrophic cardiomyopathy in the first months of life and show rapid progression, often leading to death within the first 2 years. Patients with juvenile onset have a more attenuated course compared to infantile onset, and do not have cardiomyopathy. Other features include generalized hypotonia and hepatomegaly.

Clinical Management
Slonim et al. (1983) and Margolis and Hill (1986) concluded that a high-protein diet is effective therapy in adults with acid maltase deficiency. Striking improvement in respiratory function was observed. The effect was serendipitously discovered when a high-protein diet for weight reduction was given. Correction of obesity was not thought to be the exclusive or even the major mechanism of the respiratory improvement. Isaacs et al. (1986) observed benefit from a high-protein, low-carbohydrate diet in a patient with adult acid maltase deficiency.

Amalfitano et al. (2001) reported the results of a phase I/II open-label single-dose study of recombinant human alpha-glucosidase infused intravenously twice weekly in 3 infants with infantile GSD II. The results of more than 250 infusions showed that recombinant human GAA was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all 3 infants. These infants lived well past the critical age of 1 year (16, 18, and 22 months old at the time of this study) and continued to have normal cardiac function. Improvements of skeletal muscle functions were also noted; 1 patient showed marked improvement and had normal muscle tone and strength as well as normal neurologic and developmental evaluations.

Van den Hout et al. (2003) studied the natural course of infantile Pompe disease in 20 Dutch patients and reviewed the findings in 133 published cases. They concluded that survival, decrease of the diastolic thickness of the left ventricular posterior wall, and achievement of major motor milestones are valid endpoints for therapeutic studies.

Bembi et al. (2008) provided a detailed review of the clinical management of GSD II and emphasized a multidisciplinary approach. Enzyme replacement therapy with alglucosidase-alpha has been shown to be effective, particularly in infants.

Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases.

Inheritance
Glycogen storage disease type II is inherited as an autosomal recessive trait.

Smith et al. (2007) studied sib phenotype discordance in classic infantile Pompe disease by reviewing the medical literature for affected sibships in which at least 1 sib had clinical or biochemical findings consistent with infantile Pompe disease, including symptoms beginning in infancy, early hypotonia, cardiomegaly by 6 months of age, and early death. Since 1931, the literature has documented 13 families with 31 affected infants (11 probands; 20 affected sibs). The median age at symptom onset for all affected infants was 3 months (range, 0 to 6 months) with a significant correlation between probands and affected sibs (R = 0.60, p = 0.04). The median age at death for all affected infants was 6 months (range, 1.5 to 13 months); probands were slightly older at death than their sibs. The median length of disease course for all affected infants was 3 months (range, 0 to 10 months) and was slightly longer for probands. There was phenotypic concordance, particularly with respect to cardiomyopathy. Smith et al. (2007) concluded that there is minimal phenotypic and life span variation among sibs with infantile Pompe disease, which is important for genetic counseling.

Molecular Genetics
Multiple mutations in the acid maltase gene have been shown to cause glycogen storage disease II. Martiniuk et al. (1990) demonstrated a single basepair substitution of G to A at position 271 (606800.0001). Wokke et al. (1995) found a single mutation in intron 1 of the acid maltase (606800.0006) in 16 patients with adult-onset acid maltase deficiency.

Lam et al. (2003) reported compound heterozygosity for mutations in the GAA gene in a 16-year-old Chinese boy with juvenile-onset GSD II. The patient had mild symptoms in early childhood, but his condition worsened at age 12 years, with severe weakness, sleep-disordered breathing, and respiratory difficulties. His asymptomatic 13-year-old brother, who had the same mutations, had only biochemical abnormalities suggestive of disease (elevated CK, lack of GAA activity in leukocytes). The authors commented on the intrafamilial variability.

Amartino et al. (2006) reported severe infantile and asymptomatic adult forms of GSD II in 2 generations of the same family. The proband was a 2-month-old male infant of nonconsanguineous Argentinian parents who was admitted to the hospital at 5 days with cyanosis and found to have cardiomegaly, an elevated CK level, high-voltage QRS complexes on ECG, and a thick interventricular septum and hypertrophic ventricular walls on echocardiogram. Pompe disease was suspected and confirmed by measuring GAA activity in leukocytes, and Amartino et al. (2006) identified homozygosity for mutations in the GAA gene, inherited from the parents, respectively. The asymptomatic father was found to have a second mutation on his other allele, the common adult-onset IVS1 splice site mutation (606800.0006). Subsequent evaluation revealed a normal physical examination with no neuromuscular complaints and normal ECG and echocardiogram, but he had elevated CK, short duration potentials on electromyography, and reductions in maximal expiratory and inspiratory pressures on spirometry.

Among 40 Italian patients with late-onset GSD II, Montalvo et al. (2006) identified 26 different mutations, including 12 novel mutations, in the GAA gene. The most common mutation was a splice site mutation in intron 1 (606800.0006), present in heterozygosity in 34 (85%) of 40 patients (allele frequency 42.3%).

Modifier Genes
De Filippi et al. (2010) studied 38 patients with late-onset Pompe disease, aged 44.6 +/- 19.8 years, and compared the distribution of angiotensin I-converting enzyme (ACE) polymorphism (106180.0001) according to demographic and disease parameters. The distribution of ACE polymorphism was in line with the general population, with 16% of patients carrying the II genotype, 37% carrying the DD genotype, and the remaining patients with the ID genotype. The 3 groups did not differ in mean age, disease duration, Walton score, and other scores used to measure disease severity. The DD polymorphism was associated with earlier onset of disease (P = 0.041), higher creatine kinase levels at diagnosis (P = 0.024), presence of muscle pain (P = 0.014), and more severe rate of disease progression (P = 0.037, analysis of variance test for interaction).

Population Genetics
In Israel, almost all cases of Pompe disease have occurred in Palestinian Arabs (Bashan et al., 1988).

On the basis of Hardy-Weinberg equilibrium and the fact that 7 mutations they tested represented only 29% of the total, Martiniuk et al. (1998) estimated the actual carrier frequency to be about 1 in 100. Mutant gene frequency, q, was calculated to be 0.005. The expected number of individuals born with GSD II was estimated to be 1 in 40,000 births.

Three mutations in the GAA gene are common in the Dutch patient population: IVS1, T-G,-13 (606800.0006), 525delT (606800.0014), and EX18DEL (606800.0012). Sixty-three percent of Dutch GSD II patients carry 1 or 2 of these mutations, and the genotype-phenotype correlation is known (Kroos et al., 1995). To determine the frequency of GSD II, Ausems et al. (1999) screened an unselected sample of neonates for these 3 mutations. Based on the calculated carrier frequencies so derived, the predicted frequency of the disease was 1 in 40,000, divided into 1 in 138,000 for infantile GSD II and 1 in 57,000 for adult GSD II. This was about 2 to 4 times higher than previously suggested.

Animal Model
Acid maltase-deficient Japanese quails exhibit progressive myopathy and cannot lift their wings, fly, or right themselves from the supine position in the flip test. Kikuchi et al. (1998) injected 6 4-week-old acid maltase-deficient quails, with the clinical symptoms listed, with 14 or 4.2 mg/kg of the precursor form of recombinant human GAA enzyme or buffer alone every 2 to 3 days for 18 days (7 injections). On day 18, both high dose-treated birds (14 mg/kg) scored positive flip tests and flapped their wings, and 1 bird flew up more than 100 cm. GAA activity increased in most of the tissues examined. In heart and liver, glycogen levels dropped to normal and histopathology was normal. In pectoralis muscle, morphology was essentially normal, except for increased glycogen granules. In sharp contrast, sham-treated quail muscle had markedly increased glycogen granules, multivesicular autophagosomes, and inter- and intrafascicular fatty infiltrations. Low dose-treated birds (4.2 mg/kg) improved less biochemically and histopathologically than high dose birds, indicating a dose-dependent response. Additional experiments with intermediate doses and extended treatment halted the progression of the disease. Data were claimed to be the first to show that an exogenous protein can target to muscle and produce muscle improvement. The data also suggested that enzyme replacement with recombinant human GAA is a promising therapy for human Pompe disease.

In mice in whom the Gaa gene was disrupted by gene targeting in embryonic stem cells, Raben et al. (1998) found that homozygosity for the knockout was associated with lack of enzyme activity and accumulation of glycogen in cardiac and skeletal muscle lysosomes by 3 weeks of age, with a progressive increase thereafter. By 3.5 weeks of age, these mice had markedly reduced mobility and strength. They grew normally, however, reached adulthood, remained fertile, and, as in the human adult disease, older mice accumulated glycogen in the diaphragm. By 8 to 9 months of age, the animals developed obvious muscle wasting and a weak, waddling gait. In contrast, in a second model, mutant mice with deletion of exon 6, like the knockout mice with disruption of exon 13 reported by Bijvoet et al., 1998, had unimpaired strength and mobility (up to 6.5 months of age) despite indistinguishable biochemical and pathologic changes.

Bijvoet et al. (1999) produced recombinant human acid alpha-glucosidase on an industrial scale in the milk of transgenic rabbits, and administered the purified enzyme intravenously to knockout mice. Full correction of acid alpha-glucosidase activity was obtained in all tissues except brain after a single dose of 17mg/kg. Weekly enzyme infusions over a period of 6 months resulted in normalization of hepatic glycogen, but only partial degradation of lysosomal glycogen in heart, skeletal and smooth muscle. The tissue morphology improved substantially despite the advanced state of disease at the start of treatment. The authors stated that although neurologic symptoms had not been documented in human GSD II patients, the inability of the enzyme to cross the blood-brain barrier in the mouse model remained a point of concern.

Dennis et al. (2000) identified mutations in the bovine Gaa gene that led to generalized glycogenosis in Brahman and Shorthorn bovine breeds. All 3 mutations resulted in premature termination of translation. The authors also presented evidence for a missense mutation segregating with the Brahman population, which is responsible for a 70 to 80% reduction in alpha-glucosidase activity.

Using Gaa-knockout mice and transgenes containing cDNA for the human enzyme under muscle- or liver-specific promoters controlled by tetracycline, Raben et al. (2001) demonstrated that the liver provided enzyme far more efficiently. The achievement of therapeutic levels with skeletal muscle transduction required the entire muscle mass to produce high levels of enzyme of which little found its way to the plasma, whereas liver, comprising less than 5% of body weight, secreted 100-fold more enzyme, all of which was in the active 110-kD precursor form. Skeletal and cardiac muscle pathology was completely reversible if the treatment was begun early.

DeRuisseau et al. (2009) found that Gaa-null mice had increased glycogen levels in cervical spinal cord motor neurons and larger soma size of phrenic neurons. Gaa-null mice had decreased ventilation during quiet breathing and hypercapnic challenge compared to wildtype mice, indicating respiratory insufficiency. Mice with skeletal muscle-specific Gaa expression (MTP) showed normal diaphragm force generation similar to wildtype mice, but decreased ventilation during quiet breathing, similar to Gaa-null mice. The compromised ventilation observed in both mutant mouse models was associated with decreased phrenic nerve motor output. Spinal cord samples from a patient with Pompe disease showed increased neuronal glycogen. DeRuisseau et al. (2009) suggested that respiratory impairment in individuals with Pompe disease results from a combination of muscular and neural deficits.

Douillard-Guilloux et al. (2010) analyzed the effect of a complete genetic elimination of glycogen synthesis in a murine GSDII model. Gaa/Gys1 (138570) double-knockout mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in Gaa/Gys1 double-knockout mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in Gaa/Gys1 double-knockout mice, resulting in improved exercise capacity. Douillard-Guilloux et al. (2010) concluded that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in the GSDII mouse model and offers a novel perspective for the treatment of Pompe disease.

(文献)
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