疾患詳細

疾患詳細



Fujimoto A et al. Congenital ichthyosis preceding neurologic symptoms in two sibs with type 2 Gaucher disease. Am J Med Genet 59 (3): 356-8, 1995

#230900
Gaucher disease, type II (GD2)
(GD II)
(Gaucher disease, acute neuropathic type)

Gaucher 病 II 型 (GD II)
(Gaucher 病, 急性神経症型)
指定難病19 ライソゾーム病
小児慢性特定疾病 代90 ゴーシェ(Gaucher)病

責任遺伝子:606463 Glucosidase, beta, acid (GBA) <1q22>
遺伝形式:常染色体劣性

(症状)
(GARD)
 <80%-99%>
 Abnormal pattern of respiration (呼吸パターン異常) [HP:0002793] [016]
 Dysphagia (嚥下障害) [HP:0002015] [01820]
 Dystonia (ジストニア) [HP:0001332] [0240]
 Encephalopathy (脳症) [HP:0001298] [0201]
 Hepatomegaly (肝腫) [HP:0002240] [01813]
 Ophthalmoplegia (眼球運動麻痺) [HP:0000602] [0698]
 Spasticity (痙縮) [HP:0001257] [0241]
 Splenomegaly (脾腫) [HP:0001744] [01817]
 Strabismus (斜視) [HP:0000486] [06610]
 
 <30%-79%>
 Cough (咳嗽) [HP:0012735] [016021]
 Flexion contracture (屈曲拘縮) [HP:0001371] [15100]
 Generalized myoclonic seizures (全身性ミオクロニー発作) [HP:0002123] [01405]
 Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] [014230]
 Respiratory distress (呼吸窮迫) [HP:0002098] [01606]
 
 <5%-29%>
 Cardiac arrest (心停止) [HP:0001695] [0171]
 
 
 Anemia (貧血 ) [HP:0001903] [2201]
 Apnea (無呼吸) [HP:0002104] [01600]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Bulbar signs (球症状) [HP:0002483] [02620]
 Cerebral atrophy (大脳萎縮) [HP:0002059] [160121]
 Esotropia (内斜視) [HP:0000565] [06610]
 Failure to thrive (成長障害) [HP:0001508] [01411]
 Feeding difficulties (食餌摂取障害) [HP:0011968] [01411]
 Global developmental delay (全般的発達遅滞) [HP:0001263] [0120]
 Hyperreflexia (反射亢進) [HP:0001347] [0241]
 Oculomotor apraxia (眼球運動失行) [HP:0000657] [0698]
 Progressive neurologic deterioration (進行性神経学的悪化) [HP:0002344]
 Protuberant abdomen (腹部膨満) [HP:0001538] [01801]
 Psychomotor retardation (精神運動発達遅滞) [HP:0025356] [0120]
 Recurrent aspiration pneumonia (反復性誤嚥性肺炎) [HP:0002100] [014230]
 Rigidity (固縮) [HP:0002063] [0240]
 Seizures (けいれん) [HP:0001250] [01405]
 Thrombocytopenia (血小板減少) [HP:0001873] [2218]
 Trismus (牙関緊急) [hp:0000211] [08001]

(UR-DBMS)
【一般】体重増加不良, 成長障害, 哺乳障害
 無呼吸
 反復性嚥下性肺炎
 腹部膨満
 Coombs-陰性胎児水腫
 肝腫
 脾腫
 嚥下困難
 窒息発作
 精神運動発達遅滞, 重度の
 嚥下協調運動不全
 けいれん
【神経】進行性神経症状悪化
 *後弓反張様姿勢 (頭部の背屈)
 痙性
 反射亢進
 強直
 球症状
 後頭スパスム
【眼】輻輳性斜視
 斜視
 眼球不全麻痺
 眼球運動失行
【口】開口障害
【頸部】頭部の背屈
【X線】骨病変
 大脳萎縮
 急速進行性脳幹変性
【皮膚】道化師皮膚
 魚鱗癬
 ぴんと張った皮膚
 過角化症
【血液】脾機能亢進
 血小板減少
 貧血
【検査】 Decreased glucocerebrosidase activity
Acid beta-glucosidase deficiency
【その他】3-6か月で発症
 2歳までに死亡
 perinatal lethal variant (608013), より重症
 Gaucher disease type III (231000), より軽症

(要約)
●Gaucher 病は, 脂質が細胞や期間に蓄積する遺伝性疾患である
 Gaucher 病は最も多いリソソーム蓄積病である
 glucocerebrosidase (acid β-glucosidase) の遺伝性欠乏が原因である
 → glucocerebroside (glucosylceramide)に作用する
 酵素が障害されると, glucocerebroside が特に白血球(単核球)に蓄積する
 glucocerebrosideは, 脾, 肝, 腎, 肺, 脳および骨髄に蓄積する
 肝脾腫, 肝機能障害, 有痛性骨格疾患および骨病変, 重度の神経症状, リンパ節 (まれに近接関節)腫大, 腹部膨満, 褐色の皮膚色, 貧血, 血小板減少, 強膜の黄色脂肪沈着がある
 重症患者では易感染性あり
 いくつかの型は酵素置換療法で治療可能かも
●Glucosidase, acid beta (GBA) <1q21>変異が原因である
 性差なし
 米国人の1/100は I 型の保因者
 Ashkenazi ユダヤ人では 8.9%, 出生時頻度は 1/450
●3つの型がある
(1) I 型 (非神経病型)
 最も多い型で, 約1/50,000出生, Ashkenazi ユダヤ人で最も多い
 早期または成人で生じ, 肝腫, 非常に大きい脾腫がある
 →脾腫は破裂しうる
 骨格衰弱と骨疾患は高度かもしれない
 脾腫と骨髄置換は, 貧血, 血小板減少および白血球減少を生じる
 脳は病理学的には侵されないが, 肺まれに腎病変を伴う
 この群の患者は易出血性があり, 疲労しやすい
 発症時期と重症度により, 1型患者は成人期へ生存するかもしれない
 多くの患者が軽症型または症状をもたないかもしれない
(2) II 型 (急性乳児期神経病性 Gaucher 病)
 生後6か月内に始まり, 1/100,000出生
 肝脾腫, 高度で進行性の脳障害, 眼球運動障害, 痙性, けいれん, 四肢強直, 吸啜および嚥下障害あり
 通常は2歳までに死亡する
(3) III 型 (慢性神経病型)
 小児期のいつでも, または成人でも生じる
 1/100,000 出生
 緩徐進行性であるが, 2型より神経症状が軽い
 脾腫+/-肝腫, けいれん, 協調運動障害, 骨格不規則性, 眼球運動異常, 貧血を含む血液疾患, 呼吸障害あり
 患者は早期10歳代〜成人となる
●症状
(1) 無痛性肝腫と脾腫
 脾臓サイズは 1500-3000 ml (正常は50-200 ml)
(2) 脾機能亢進
 急速で早期の血球破壊→貧血, 好中球減少, 血小板減少
(3) 肝硬変;まれ
(4) 神経症状
 II 型:重篤なけいれん, 筋緊張亢進, 精神遅滞, 無呼吸
 III 型:ミオクローヌス, けいれん, 認知症, 眼筋失行
(5) 骨粗鬆症
 75%がglucosylceramide蓄積により目に見える骨異常を生じる
 大腿骨遠位の Erlenmeyer flask がよく記載されている
(6) 黄褐色の皮膚色素
●機序 (Acid beta-glucosidase)
 本疾患はハウスキーピング遺伝子であるリソソーム gluco-cerebrosidase (beta-glucosidase) の障害が原因である
 55.6 KD, 497 アミノ酸タンパクで, 赤血球と白血球の膜成分である glucocerebroside の分解を触媒する
 これらの細胞を除去するマクロファージは, 廃産物を削除できず, 線維に蓄積し, Gaucher 細胞となる
 脳では (II 型と III 型), glucocerebroside は脳発生と髄鞘形成中に複雑な脂質回転により蓄積する
 beta-glucosidase の異なる変異が, 酵素の残存活性を決定し, 表現型を決定する
 特定の変異のヘテロ接合体は, 5倍のParkinson 病発生リスクをもち, Parkinson 病で知られている最も多いリスク因子である
 米国の調査では, 癌のリスクは上昇しないが, 特定の悪性疾患 (non-Hodgkin リンパ腫, メラノーマ, 膵癌)のリスクは2-3倍である
●変異との関係
 約80の変異が知られており, 3つの主要なタイプに分けられる
(1) Type I (N370S ホモ接合体), 最も多く "non-neuropathic" type として主に Ashkenazi ユダヤ人にみられる (100倍)
 診断中央年齢は28歳で, 寿命は軽度減少する
 神経症状なし
 48-55世代以前に生じた (中世早期)
(2) Type II (L444Pアレルが1つまたは2つ)
 小児での神経症状が特徴
 酵素はリソソームのほとんど遊離されない
 予後不良で, 大多数は3歳以前に死亡
(3) Type III (L444Pの1-2コピー, 保護的多型により遅れる可能性あり)
 Norrbotten 地方のスウェーデン人に生じる
 いくらか遅発性であるが, 大多数は20歳代で死亡する
●診断
 確定診断は遺伝子診断で
 →多くの変異があるので, シークェンシングが必要である
 出生前診断は遺伝的リスク因子がある場合に有用である
 AlP 高値, ACE高値, 免疫グロブリン高値, "crinkled paper" 細胞質および糖脂質をもつマクロファージがみられる場合に診断が疑われる
 いくつかのリソソーム酵素上昇がみられる
 →tartrate-resistant acid phosphatase, hexosaminidase, chitinase, chitotriosidase
●治療
 1型と大多数の3型は酵素置換 (組換glucocerebrosidase (imiglucerase) 静注)が劇的に効果がある
 →年間 $200,000/個人
 Velaglucerase alfa が FDAにより2010年2月に承認された
 骨髄移植
 摘脾術
 輸血
 関節置換術
●疫学
 The National Gaucher Foundation (USA):1型 は1/100人が保因者, 有病率1/40,000
 Ashkenazi Jews:1/15が保因者
 Type 2 に特定の人種なし
 Type 3 は北部スウェーデンに多い 頻度1/50,000

<小児慢性特定疾病 代90 ゴーシェ(Gaucher)病>
概要・定義
ゴーシェ病は, グルコセレブロシダーゼ(別名β-グルコシダーゼ)の遺伝子変異によりグルコセレブロシダーゼ活性が低下あるいは欠損し, その基質である糖脂質のグルコセレブロシドが組織に蓄積するスフィンゴリピドーシスのひとつで常染色体劣性遺伝形式をとる。グルコセレブロシドは, 体中のマクロファージに蓄積し, 肝脾腫, 骨痛や病的骨折, 中枢神経障害を引き起こす。
疫学
日本におけるゴーシェ病の有病率は33万人に1人とされている。症状と発症時期により, 後述する3つの病型に分類されるが, 日本では欧米に比して, 神経型が多い。
病因
ゴーシェ病は, ライソゾーム酵素の一つであるグルコセレブロシダーゼ(別名:β-グルコシダーゼ)の遺伝子異常に基づく, グルコセレブロシダーゼ活性低下のため, その基質であるグルコセレブロシドがマクロファージに蓄積し, 組織障害を引き起こす。中枢神経系症状は, グルコセレブロシドのリゾ体であるグルコシルスフィンゴシンの脳内蓄積が影響していると考えられている。
症状
グルコセレブロシドが, 肝臓, 脾臓, 骨髄に蓄積するため, 肝脾腫, 骨症状(病的骨折や骨クリーゼ)を認める。脾機能亢進により, 貧血や血小板減少を認める。神経症状の有無と重症度により, I型(非神経型), II型(急性神経型), III型(亜急性神経型)に分類される。II型は乳児期に発症し, 肝脾腫の他, 精神運動発達遅滞, 痙攣, 項部後屈などの神経症状を認め, 急速に進行する。II型のうち最重症型は, 胎児水腫を呈し新生児期に発症する。III型は, 衝動性眼球運動障害, 精神運動発達遅滞・退行, 痙攣, 失調が認められる。本邦では神経型が過半数を占める。
診断
臨床症状, 臨床検査に基づいて行う。
臨床症状
ゴーシェ病には大きく3つの病型に分類される。臨床所見はそれぞれに分けて考える。
1型:おもな症状は, 貧血, 血小板減少, 肝脾腫, 骨症状を認め, 神経症状は伴わない。発症時期は, 幼少期から成人までと幅広い。
2型:肝脾腫, 肺病変の他, けいれん, 後弓反張などの神経症状を伴う。乳児期までに発症し神経症状が急速に進行して, ほとんどの症例が2~3歳までに死に至る。 新生児期に発症する症例では胎児水腫や魚鱗癬を呈する。
3型:神経症状を伴うが2型よりもその程度は軽度で, 進行が緩徐である。 神経症状は異常眼球運動, ミオクローヌス, 小脳失調, けいれんと多様であるが, その重症度や予後, 発症時期により3a, 3b, 3c型の3つの亜型に分類される。 3a型はスウェーデンのNorbotten地方に多い, 古典的な3型の病型を呈する。 3b型はより早期に発症し, 臓器症状が著明であり, 肺高血圧が致死的になることもある。 神経症状は核上性上方注視麻痺のみで1型と誤診される病型である。 3c型では肝脾腫, 骨症状は明らかでなく, 水頭症, 角膜混濁, 心弁膜石灰化が主症状である。
臨床検査
貧血, 血小板減少を認める。
血清酸性ホスファターゼ(ACP)高値,
アンジオテンシン変換酵素(ACE)高値を認める。
骨髄検査でゴーシェ細胞を認める。
培養皮膚線維芽細胞の酸性β-グルコシダーゼ(acid-β-glucosidase)活性低下
遺伝子解析でβ-glucosidase遺伝子に変異を認める。
common mutationが存在し, 病型や重症度の推定がある程度可能。

疑診:上記臨床症状に, a, bかつcを認めれば強く疑う。
確定診断:dあるいはeを認める。

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
酵素補充療法と対症療法がある。対症療法には, 抗痙攣薬, 抗痙縮薬, そして, リハビリ, 気管切開, 経管栄養などがある。酵素補充療法は, 血液脳関門を十分に通過できないため, 中枢神経症状に対する効果は乏しい。そのため, 神経症状に対するシャペロン療法や遺伝子治療などの新規治療法の開発が期待されている。また, グルコセレブロシド類似物質による基質合成阻害剤が開発されており, 経口薬であることが最大の利点で, 効果が期待されている。
予後
I型の予後は, 酵素補充療法により劇的に改善した。しかし, 神経型であるII型の生命予後は不良で, 2歳までに死亡するとされるが, 酵素補充療法によって長期生存例も認められ始めている。III型の中には, 病初期には神経症状を呈さずにI型としてフォローされている場合があり, そのようなIII型は, 始めから神経症状を認める症例に比較して予後は良好であると報告されている。
成人期以降
日本人ゴーシェ病III型患者のうち, 発症時はI型と診断され, のちに神経症状を呈してIII型と診断される移行例は, III型全体の約42.9%であり, I-III型を含めたゴーシェ病患者全体の約12.4%を占めており, ゴーシェ病I型患者でも神経症状に注意しながらフォローすることが大切である1)2)。酵素補充療法は神経型への効果に乏しいため, 予後の改善のためには対症療法も重要である。

(Comment) mutation in the same gene in type I Gaucher disease (GBA; 230800))
(Responsible gene) *606463 Glucosidase, acid beta (GBA) <1q22>
(1) Gaucher disease, type II (230900)
.0001 Gaucher disease, neuronopathic (Gaucher disease, type III, included; Gaucher disease, type II, included; Parkinson disease, late-onset, susceptibility to, included; Dementia, Lewy body, susceptibility to, included) [GBA, LEU444PRO] (rs421016) (gnomAD:rs421016) (RCV000004510..)
(Zimran et al., 1989; Latham et al., 1990; Saranjam et al., 2013; Reczek et al. 2007)
Gaucher Disease: Tsuji et al. 1987; Wigderson et al. 1989; Dahl et al. 1990; Hong et al. 1990; Koprivica et al. 2000; Saranjam et al. 2013)
Parkinson Disease: (Tan et al. 2007; Gutti et al. 2008; Neumann et al. 2009; Gonzalez-del Rincon et al. 2013)
Lewy Body Dementia: (Mata et al. 2008)
.0002 Gaucher disease, neuronopathic [GBA, PRO415ARG, 5976C-G] (rs121908295) (RCV000004514) (Wigderson et al. 1989)
.0030 Gaucher disease, type II [GBA, GLY325ARG] (rs121908305) (gnomAD:rs121908305) (RCV000004562...) (Eyal et al. 1990)
.0031 Gaucher disease, type II [GBA, CYS342GLY] (rs121908306) (RCV000004563) (Eyal et al. 1990)
.0047 Gaucher disease, type II (Gaucher disease, type III, included) [GBA, HIS255GLN AND ASP409HIS] (rs367968666) (rs1064651) (gnomAD:rs367968666) (gnomAD:rs1064651) (RCV000079338...) (Filocamo et al. 2005)
(2) Gaucher disease, type I (230800)
.0003 Gaucher disease, type I (Parkinson disease, late-onset, susceptibility to, included; Dementia, Lewy body, susceptibility to, included) [GBA, ASN370SER, 1226A-G] (rs76763715) (gnomAD:rs76763715) (RCV000396221...) (Tsuji et al.1988; Kolodny et al. 1989, 1990; Firon et al.1990; Zimran et al. 1991; Sidransky et al.1992; Mistry et al. 1992; Van Weely et al.1993; Walley et al. 1993; Ida et al. 1995; Cormand et al. 1998; Koprivica et al. 2000; Mata et al. 2008; Neumann et al. 2009)
.0004 Gaucher disease, type I (Gaucher disease, perinatal lethal, included) [GBA, ARG119GLN, 3060G-A] (rs79653797) (gnomAD:rs79653797) (RCV000004518...) (Graves et al. 1988)
.0006 Gaucher disease IIIC (231005) (Gaucher disease, type I, included; Gaucher disease, type II, included; Gaucher disease, type III, included; Gaucher disease, prenatal lethal, included) [GBA, ASP409HIS,5957G-C] (rs77369218) (rs1064651) (gnomAD:rs1064651) (RCV000079338...) (Theophilus et al. 1989; Chabas et al. 1995; Cormand et al. 1995; Uyama et al. 1997; Uyama et al. 1992; Inui et al. 2001; Mignot et al. 2003; Emre et al. 2008)
.0008 Gaucher disease, type I (Gaucher disease, type II, included; Gaucher disease, type III, included; Parkinson disease, late-onset, susceptibility to, included) [GBA, ARG463CYS] (rs80356771) (gnomAD:rs80356771) (RCV000004531...) (Hong et al. 1990; Mistry et al. 1992; Park et al. 2003; Neumann et al. 2009)
.0009 Gaucher disease, type I (Gaucher disease, type I, included; Gaucher disease, type II, included; Gaucher disease, type III, included; Gaucher disease, prenatal lethal, included) [GBA,LEU444PRO; ALA456PRO; VAL460VAL] (rs421016) (rs1135675) (rs368060) (gnomAD:rs421016) (gnomAD:rs1135675) (gnomAD:rs368060) (RCV000004510...) (Hong et al. 1990; Latham et al. 1990; Sidransky et al. 1996; Stone et al. 2000)
.0010 Gaucher disease, type I [GBA, PHE255TYR] (rs74500255) (gnomAD:rs74500255) (RCV000498055...) (Beutler and Gelbart 1990)
.0011 Gaucher disease, type I [GBA, ASP140HIS AND GLU326LYS] (rs2230288) (rs147138516) (gnomAD:rs2230288) (gnomAD:rs147138516) (RCV000487503...) (Eyal et al. 1991)
.0012 Gaucher disease, type I [GBA, LYS157GLN] (rs121908297) (RCV000004539) (Eyal et al. 1991)
.0014 Gaucher disease, type I [GBA, 1-BP INS, 84G] (rs387906315) (gnomAD:rs387906315) (RCV000004543...) (Beutler et al. 1991; Rockah et al. 1998; Ida et al. 1995)
.0015 Gaucher disease, type I (Gaucher disease, type II, included) [GBA, IVS2DS, G-A, +1] (rs104886460) (gnomAD:rs104886460) (RCV000762856...) (Beutler et al. 1992; He and Grabowski 1992; Stone et al. 2000)
.0016 Gaucher disease, type I [GBA, PRO289LEU] (rs121908298) (RCV000004547) (He et al. 1992)
.0017 Gaucher disease, type I [GBA, TYR323ILE] (rs76539814) (gnomAD:rs76539814) (RCV000041967...) (He et al. 1992; Saranjam et al. 2013)
.0018 Gaucher disease, type I [GBA, 1-BP DEL, 72C] (rs397518433) (RCV000004549) (Beutler et al. 1993)
.0019 Gaucher disease, type I [GBA, PRO122SER] (rs121908299) (RCV000004550) (Beutler et al. 1993)
.0020 Gaucher disease, type I [GBA, TYR212HIS] (rs121908300) (gnomAD:rs121908300) (RCV000004551) (Beutler et al.1993)
.0021 Gaucher disease, type I [GBA, GLY478SER] (rs121908301) (RCV000004552) (Beutler et al. 1993)
.0022 Gaucher disease, type I [GBA, ARG496HIS] (rs75822236) (gnomAD:rs75822236) (RCV001004108...) (Beutler et al. 1993)
.0023 Gaucher disease, type I (Gaucher disease, prenatal lethal, included) [GBA, 55-BP DEL] (rs80356768) (RCV000020147...) (Beutler et al. 1993; Stone et al. 2000)
.0024 Gaucher disease, type I [GBA, VAL15LEU] (rs121908302) (RCV000004556) (Kim et al. 1996)
.0025 Gaucher disease, type I [GBA, GLY46GLU ] (rs77829017) (gnomAD:rs77829017) (RCV000004532...) (Kim et al. 1996)
.0026 Gaucher disease, type I (Gaucher disease, type III, included) [GBA, ASN188SER] (rs364897) (gnomAD:rs364897) (RCV000723402...) (Kim et al. 1996; Park et al. 2003; Montfort et al. 2004)
.0027 Gaucher disease, type I [GBA, PHE216VAL] (rs121908303) (RCV000004559) (Horowitz and Zimran 1994)
.0028 Gaucher disease, type I [GBA, ALA309VAL] (rs78396650) (gnomAD:rs78396650) (RCV000004560) (Latham et al. 1991)
.0029 Gaucher disease, type I [GBA, TRP312CYS] (rs121908304) (RCV000004561) (Latham et al. 1991)
.0032 Gaucher disease, type I [GBA, SER364THR] (rs121908307) (gnomAD:rs121908307) (RCV000004564) (Latham et al. 1991)
.0033 Gaucher disease, type I [GBA, 259C-T] (rs1141814) (gnomAD:rs1141814) (RCV000004565...) (Rockah et al. 1997)
.0036 Gaucher disease, type I [GBA, PRO401LEU] (rs74598136) (RCV000004568) (Wasserstein et al. 1999)
.0040 Gaucher disease, type I [GBA, GLY377SER] (rs121908311) (gnomAD:rs121908311) (RCV000723428...) (Gaucher disease, type III, included) (Amaral et al. 1999)
.0043 Gaucher disease, type I (Gaucher disease, type III, included) [GBA, LYS79ASN] (rs121908312) (RCV000004576...) (Zhao et al. 2003)
.0045 Gaucher disease, type I [GBA, LEU371VAL] (rs121908314) (RCV000004578) (Shamseddine et al. 2004)
(3) Gaucher disease, type III (231000)
.0005 Gaucher disease, type III (Gaucher disease type I, included) [GBA, VAL394LEU, 5912T] (rs80356769) (gnomAD:rs80356769) (RCV000004521...) (Latham et al. 1990)
.0007 Gaucher disease, type III [GBA, ASP409VAL, 5958A-T] (rs77369218) (RCV000020149...) (Latham et al. 1990)
.0013 Gaucher disease, type III (Gaucher disease type II, included; Gaucher disease type I, included) [GBA, PHE213ILE] (rs381737) (gnomAD:rs381737) (RCV000004542...) (Kawame and Eto 1991)
.0035 Gaucher disease, type III [GBA, ARG353GLY] (rs121908308) (gnomAD:rs121908308) (RCV000004567) (Parenti et al. 1998)
(4) Gaucher disease, prenatal lethal (608013)
.0034 Gaucher disease, prenatal lethal [GBA, 1-BP DEL, CODON 139C] (rs397518434) (RCV000004566) (Tayebi et al. 1997)
.0037 Gaucher disease, prenatal lethal [GBA, HIS311ARG] (rs78198234) (gnomAD:rs78198234) (RCV000004569) (Stone et al. 1999)
.0038 Gaucher disease, prenatal lethal [GBA, ARG359TER] (rs121908309) (gnomAD:rs121908309) (RCV000585360...) (Stone et al. 1999)
.0039 Gaucher disease, prenatal lethal [GBA, VAL398PHE] (rs121908310) (gnomAD:rs121908310) (RCV000004544) (Stone et al. 1999)
.0041 Gaucher disease, prenatal lethal [GBA, ARG257GLU] (rs78973108) (gnomAD:rs78973108) (RCV000762855...) (Stone et al. 2000)
.0042 Gaucher disease, prenatal lethal [GBA, ARG131LEU] (rs80356763) (gnomAD:rs80356763) (RCV000004574...) (Stone et al. 2000)
.0044 Gaucher disease, prenatal lethal [GBA, PHE251LEU] (rs121908313) (RCV000004577) (Zhao et al. 2003)
.0046 Gaucher disease, prenatal lethaI [GBA, IVS10DS, G-A, -1] (RCV000004579) (Felderhoff-Mueser et al. 2004)
(5) Parkinson disease, late-onset, susceptibility to (168600)
.0048 Parkinson disease, susceptibility to [GBA, ASP443ASN] (rs75671029) (gnomAD:rs75671029) (RCV000004582) (Neumann et al. 2009)

*GBA (Glucosylceramidase Beta)
 Genome size 10,415 bp, Minus strand; 536 aa, 59716 Da
 Exons: 11, Coding exons: 11, Transcript length: 2,291 bps, Translation length: 536 residues
●糖脂質代謝の中間産物である glycosylceramide のβグルコシド連結を分割するリソソーム膜タンパクをコードする
 glucosylceramide/GlcCer の free ceramide と glucoseへの水解を触媒するリソソーム内の glucosylceramidase である
 →複合脂質の分解と細胞膜のターンオーバーで中心的役割をもつ
 ceramides 産生をとおして,ceramide 形成の PKC-activated salvage pathway に参加する
 コレステロール代謝で役割をもつ
 glucosylceramideからコレステロールへブドウ糖を輸送するtransglucosylation反応をとおしてコレステロールのグルコシル化を触媒するかも
 C8:0-GlcCerを飽和した短鎖とmono-unsaturated C18:0-GlcCerがtransglucosylation反応での最も効率的なブドウ糖ドナーである
 特殊な状況では,逆の反応を触媒するかもしれない
 → cholesteryl-beta-D-glucoside から ceramideへ,ブドウ糖を輸送する
 cholesteryl-beta-D-glucoside を水解し D-glucose とコレステロールを産生する
●関係する pathways: Sphingolipid metabolism; Chaperonin-mediated protein folding

(Note)
A number sign (#) is used with this entry because Gaucher disease type II is caused by homozygous or compound heterozygous mutation in the gene encoding acid beta-glucosidase (GBA; 606463) on chromosome 1q22.

Mutation in the same gene causes nonneuronopathic Gaucher disease type I (230800) and subacute neuronopathic type III (231000). See also the perinatal lethal variant (608013), which is often considered to be a severe form of type II.

Type II Gaucher disease is an acute neuronopathic form of the disorder with onset in infancy and death often by 2 years of age. Patients are usually normal at birth, but develop hepatosplenomegaly, developmental regression, and growth arrest within a few months of age. Neurologic deterioration proceeds rapidly, with cranial nerve and extrapyramidal tract involvement (Stone et al., 2000).

Clinical Features
Owada et al. (1977) reported 3 Japanese patients with neuronopathic Gaucher disease. Glucocerebrosidase activity was almost normal in the liver, but markedly reduced in the spleen and fibroblasts.

Saranjam et al. (2013) reported 2 unrelated infants with severe, lethal type II Gaucher disease. The first was a girl of multiple ethnic descent who presented early in life with respiratory difficulties, poor feeding, failure to thrive, ophthalmoplegia, and developmental delay. Laboratory studies showed anemia and thrombocytopenia, and bone marrow biopsy revealed lipid-laden macrophages characteristic of Gaucher disease. A lysosomal enzyme panel showed severely decreased glucocerebrosidase activity. The patient died at 11 months of age. The second infant was a boy, born to an unrelated Ashkenazi Jewish father and a Sephardic Jewish mother. He was diagnosed at the age of 7 months after a bone marrow aspiration revealed Gaucher cells. The diagnosis was confirmed by deficient glucocerebrosidase activity, and he died at 10 months secondary to respiratory failure.

Heterogeneity
Phenotypic Heterogeneity

Although patients with Gaucher disease type II typically have acute neurologic progression and those with type III have slow progression, Goker-Alpan et al. (2003) described 9 children with an intermediate phenotype of delayed age of onset, rapid progression of neurologic disease with refractory seizures, and oculomotor abnormalities. Based on the clinical presentation along with the detected genotypic heterogeneity found by identification of all 18 alleles, Goker-Alpan et al. (2003) concluded that neuronopathic Gaucher disease is more likely to be a continuum of phenotypes from the severe perinatal cases to mild involvement with oculomotor problems.

Filocamo et al. (2005) reported a 25-month-old girl with an atypical form of neuronopathic Gaucher disease between types II and III caused by a homozygous double mutation in the GBA gene (606463.0047). Onset of symptoms occurred at age 5 months with hepatosplenomegaly. A few months later, she developed neurologic features, including spasticity with persistent retroflexion of the neck, convergent strabismus, oculomotor apraxia, and abnormal MRI changes. At age 25 months, she showed slow symptom progression and was able to sit alone, walk with support, and pronounce some words.

Biochemical Features
Svennerholm et al. (1986) found an average residual activity of beta-glucosidase in forebrain tissue from 3 patients with the infantile type of Gaucher disease to be 5%, compared to 12% in 6 patients with Gaucher disease type III.

Beutler and Kuhl (1986) studied processing of glucocerebrosidase in the 3 types of Gaucher disease. Normal cells initially formed a 60-kD polypeptide antigen that was gradually replaced by a broad band of antigen averaging 63 kD, which they thought represented the mature enzyme. While processing in 6 unrelated patients with Gaucher disease type I and in 1 patient with type III was similar to normals, 3 patients with the severe infantile form (type II) showed an unstable enzyme. The 60-kD band appeared only transiently and the mature 63-kD band was never seen. The authors concluded that an unstable precursor characterizes type II Gaucher disease.

Gornati et al. (2002) examined the lipid composition of the liver, spleen, brain, cerebellum, and cerebrospinal fluid of a type II Gaucher patient who died at age 5 months. The glycolipid analysis demonstrated a marked increase of total amounts not only in the peripheral tissues but also in the cerebellum and cerebrospinal fluid, with a prevalence of glucosylceramide. A relative reduction in gangliosides was observed in all analyzed tissue, with a relative increase in ganglioside GD3 in the nervous tissue. The fatty acid composition of glucosylceramide showed a prevalence of stearic acid in the central nervous system, while in the peripheral tissues palmitic acid was prevalent. Gornati et al. (2002) suggested that their results indicated a different origin of the glucosylceramide stored in different tissues.

Holleran et al. (2006) reported an infant with type II Gaucher disease in whom ultrastructural abnormalities in the skin were identified prior to development of the more typical neurologic manifestations of the disease. At 5 weeks of age, his neurologic examination and skin appearance were described as normal. A skin biopsy performed at age 9 weeks showed disorganized lamellar membranes within the stratum corneum interspersed with amorphous nonlamellar microclefts presumably resulting from pockets of accumulated hydrophilic glucosylceramide, consistent with an epidermal lipid processing defect. The infant developed more severe neurologic complications by age 6 months.Holleran et al. (2006) noted that these skin abnormalities have been described only in patients with type II Gaucher disease and thus can be used for early discrimination among the several forms of the disorder.

Inheritance
Type II Gaucher disease shows autosomal recessive inheritance. Saranjam et al. (2013) reported 2 unrelated infants with severe, lethal type II Gaucher disease who were compound heterozygous for 2 mutations in the GBA gene, one of which was L444P (606463.0001). While the other mutation was identified in the paternal line of each patient (see, e.g., T323I, 606463.0017), the L444P allele was not detected in DNA samples from either patient's mother, suggesting that it occurred either as a result of germline mosaicism or as a de novo mutation in 1 ovum that took place during cell devision. The findings had implications for genetic counseling, in that even if only 1 parent is found to be a carrier for a recessive disorder, the chance of having an affected child may not be zero. Saranjam et al. (2013) noted that the L444P change occurs at a known mutational hotspot.

Clinical Management
Vellodi et al. (2001) reported a European consensus on the management of Gaucher disease. They recommended enzyme replacement therapy with macrophage-targeted recombinant human glucocerebrosidase and found that it ameliorates systemic involvement in nonneuronopathic as well as neuronopathic Gaucher disease, enhancing the quality of life. There was also evidence that enzyme replacement therapy reversed, stabilized, or slowed the progression of neurologic involvement in some patients. In patients with established acute neuronopathic disease, enzyme replacement therapy had little effect on the progressively downhill course.

Molecular Genetics
Tsuji et al. (1987) identified a homozygous mutation in the GBA gene (L444P; 606463.0001) in patients with Gaucher disease type II.

Wigderson et al. (1989) reported a patient with type II disease who was compound heterozygous for 2 mutations in the GBA gene: L444P and P415R (606463.0002).

Grace et al. (1990) used site-directed mutagenesis and characterization of the expressed mutant beta-glucosidase to understand the molecular basis of the phenotypic variation between type II and type III Gaucher disease. The results suggested that the presence of at least 1 nonfunctional GBA allele in type II patients may provide a molecular basis for the distinct phenotypes between types II and III.

Stone et al. (2000) identified mutations in the GBA gene in 17 unrelated patients with type II Gaucher disease with onset ranging from 3 to 12 months of age.

Pathogenesis
Wei et al. (2008) proposed that activation of the unfolded protein response (UPR) may be a common mediator of apoptosis in neuronopathic lysosomal storage diseases (LSDs), such as Gaucher disease type II. Farfel-Becker et al. (2009) examined whether the UPR is activated in neuronal forms of GD using a selection of neuronal disease models and a combination of Western blotting and semiquantitative and quantitative real-time PCR analysis. There were no changes in either protein or mRNA levels of a number of typical UPR markers including BiP (HSPA5; 138120), CHOP (DDIT3; 126337), XBP1 (194355), HERP (HERPUD1; 608070), and GRP58 (PDIA3; 602046), in either cultured Gaucher neurons or astrocytes, or in brain regions from mouse models, even at late symptomatic stages. Farfel-Becker et al. (2009) concluded that the unfolded protein response is not necessarily a common mediator for apoptosis in all neurodegenerative lysosomal storage diseases.

Animal Model
Enquist et al. (2007) generated transgenic mice with targeted disruption of the Gba gene, but low expression of the gene in skin to prevent early lethality. The mice showed a phenotype similar to the severe neuronopathic form of GD, including rapid motor dysfunction, seizures, and hyperextension of the neck associated with severe neurodegeneration and apoptotic neuronal cell death. Some neurons had large vacuoles indicating neuronal lipid accumulation. A second mouse model with Gba deficiency restricted to neural and glial cell progenitors demonstrated a similar neuropathology as the first mouse model, but with a delayed onset and slower disease progression. These findings indicated that Gba deficiency within microglial cells of hematopoietic origin is not the primary determinant of the CNS pathology, but may influence disease progression. The findings also showed that normal hematopoietic-derived microglial cells could not rescue the neurodegenerative phenotype.

In a mouse model of neuronopathic GD in which glucocerebrosidase deficiency is limited to neural and glial progenitor cells (Enquist et al., 2007), Vitner et al. (2010) showed significant changes in the levels and distribution of cathepsins in brain. Cathepsin mRNA expression, activity, and protein levels were significantly elevated, with the time course of the increase correlating with the progression of disease severity. Significant changes in cathepsin D (CTSD; 116840) distribution in the brain were detected, with cathepsin D elevated in areas where neuronal loss, astrogliosis, and microgliosis were observed. Cathepsin D elevation was greatest in microglia and astrocytes, and also in neurons in a manner consistent with its release from the lysosome to the cytosol. Ibubrofen treatment significantly reduced cathepsin D mRNA levels in the cortex of these mice, and cathepsin levels were also altered in mouse models of other sphingolipidoses. Vitner et al. (2010) suggested the involvement of cathepsins in the neuropathology of neuronal forms of GD and of other lysosomal storage diseases, and hypothesized a crucial role for reactive microglia in neuronal degeneration in these diseases.

(文献)
(1) Drukker A et al. The infantile form of Gaucher's disease in an infant of Jewish Sephardic origin. Pediatrics 45: 1017-1023, 1970
(2) Schneider EL et al. Infantile (type II) Gaucher's disease: in utero diagnosis and fetal pathology. J Pediat 81: 1134-1139, 1972
(3) Owada M et al. Neuropathic Gaucher's disease with normal 4-methylumbelliferyl-beta-glucosidase activity in the liver. J Pediat Res 11: 641-646, 1977
(4) Wenger DA et al. Biochemical studies in a patient with subacute storage. Pediat Res 17: 344-348, 1983
(5) Beutler E et al. Glucocerebrosidase processing in normal fibroblasts and in fibroblasts from patients with type I, type II, and type III Gaucher disease. Proc Nat Acad Sci 83: 7472-7474, 1986
(6) Svennerholm L et al. Cerebroside-beta-glucosidase activity in Gaucher brain. Clin Genet 30: 131-135, 1986
(7) Chitayat D et al. Evaluation of serum beta-hexosaminidase and alpha-mannosidase in type 2 Gaucher disease: a clinical and biochemical study. J Inherit Metab Dis 10: 111-114, 1987
(8) Laks Y, Posswell J: The varied clinical and laboratory manifestations of type II Gaucer's disease. Acta Paediatri Scand 76: 378-380, 1987
(9) Sun CC et al. Hydrops fetalis associated with GAucher disease. Pathol Res Pract 179: 101-104, 1987
(10) Grafe M et al. Gaucher's disease: a case with neuronal storage. Ann Neurol 23: 300-303, 1988
(11) Lui K et al. collodion babied with Gaucher's disease. Arch Dis Child 63: 854-856, 1988
(12) Harzer K et al. sphingolipid activator protein deficiency in a 16-week-old atypical Gaucher disease patient and his fetal siblings: biochemical signs of combined sphingolipidoses. Eur J Pediatr 149: 31-39, 1989
(13) Grace ME et al. Gaucher disease: a molecular basis for the type 2 and type 3 phenotypes. Am J Hum Genet 47 (suppl.): A156, 1990
(14) Sidransky E et al. Gaucher disease in the neonate: a distinct Gaucher phenotype is analogous to a mouse model created by targeted disruption of the glucocerebrosidase gene. Pediat Res 32: 494-498, 1992
(15) Fujimoto A et al. Congenital ichthyosis preceding neurologic symptoms in two sibs with type 2 Gaucher disease. Am J Med Genet 59 (3): 356-8, 1995
(16) Finn LS et al. Severe type II Gaucher disease with ichthyosis, arthrogryposis and neuronal apoptosis: molecular and pathological analyses. Am J Med Genet 91: 222-226, 2000
(17) Orvisky E et al. Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation. Pediat. Res. 48: 233-237, 2000
(18) Stone DL et al. Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease. Hum. Mutat. 15: 181-188, 2000
(19) Vellodi A et al. Management of neuronopathic Gaucher disease: a European consensus. J. Inherit. Metab. Dis. 24: 319-327, 2001
(20) Gornati, R.; Berra, B.; Montorfano, G.; Martini, C.; Ciana, G.; Ferrari, P.; Romano, M.; Bembi, B. : Glycolipid analysis of different tissues and cerebrospinal fluid in type II Gaucher disease. J. Inherit. Metab. Dis. 25: 47-55, 2002
(21) Goker-Alpan, O.; Schiffmann, R.; Park, J. K.; Stubblefield, B. K.; Tayebi, N.; Sidransky, E. : Phenotypic continuum in neuronopathic Gaucher disease: an intermediate phenotype between type 2 and type 3. J. Pediat. 143: 273-276, 2003
(22) Holleran, W. M.; Ziegler, S. G.; Goker-Alpan, O.; Eblan, M. J.; Elias, P. M.; Schiffmann, R.; Sidransky, E. : Skin abnormalities as an early predictor of neurologic outcome in Gaucher disease. (Letter) Clin. Genet. 69: 355-357, 2006
(23) Enquist, I. B.; Lo Bianco, C.; Ooka, A.; Nilsson, E.; Mansson, J.-E.; Ehinger, M.; Richter, J.; Brady, R. O.; Kirik, D.; Karlsson, S. : Murine models of acute neuronopathic Gaucher disease. Proc. Nat. Acad. Sci. 104: 17483-17488, 2007
(24) Wei, H.; Kim, S. J.; Zhang, Z.; Tsai, P. C.; Wisniewski, K. E.; Mukherjee, A. B. : ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones. Hum. Molec. Genet. 17: 469-477, 2008
(25) Vitner, E. B., Dekel, H., Zigdon, H., Shachar, T., Farfel-Becker, T., Eilam, R., Karlsson, S., Futerman, A. H. Altered expression and distribution of cathepsins in neuronopathic forms of Gaucher disease and in other sphingolipidoses. Hum. Molec. Genet. 19: 3583-3590, 2010
(26) Saranjam, H., Chopra, S. S., Levy, H., Stubblefield, B. K., Maniwang, E., Cohen, I. J., Baris, H., Sidransky, E., Tayebi, N. A germline or de novo mutation in two families with Gaucher disease: implications for recessive disorders. Europ. J. Hum. Genet. 21: 115-117, 2013

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2013/05/02
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2015/03/20 SNP
2017/06/22 RCV
2017/06/23 ノート/文献追加
2018/12/07 症状改訂