疾患詳細

疾患詳細



両側性股関節炎. 前弯と内臓肥大による腹部膨満. 臍レベルまでの肝腫. 異常な長い下肢を伴うジストロフィー性低身長; 思春期遅発; 骨年齢遅延. 跛行: 左大腿骨頭壊死と頸部破壊を伴う股関節脱臼; 小転子以下の右大腿骨の蓄積巣.

#230800
Gaucher disease, type I (GD I)
(Gaucher disease, noncerebral, juvenile)
(Glucocerebrosidase deficiency)
(Acid beta-glucosidase deficiency)
(GBA deficiency)

Gaucher 病 I 型 (GD I)
(Gaucher 病, 非脳型, 若年性)
(グルコセレブロシダーゼ欠損症)
(酸性β-グルコシダーゼ 欠損症; GBA 欠損症)
(グルコシダーゼ, β, 酸性; GBA)
(グルコセレブロシダーゼ偽遺伝子; GBAP)
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%>
 Anorexia (食思不振) [HP:0002039] [01401]
 Avascular necrosis (無血管性壊死) [HP:0010885] [160018]
 Bone pain (骨痛) [HP:0002653] [01420]
 Cerebral palsy (脳性麻痺) [HP:0100021] [02601]
 Constipation (便秘) [HP:0002019] [01803]
 Cranial nerve paralysis (脳神経麻痺) [HP:0006824] [02603]
 Delayed puberty (思春期遅発) [HP:0000823] [2152]
 Delayed skeletal maturation (骨成熟遅滞) [HP:0002750] [160001]
 Diaphragmatic paralysis (横隔麻痺) [HP:0006597] [1202]
 Hepatomegaly (肝腫) [HP:0002240] [01813]
 Hypersplenism (脾臓機能亢進) [HP:0001971] [1213]
 Increased bone mineral density (骨濃度増加) [HP:0011001] [160016]
 Mydriasis (散瞳)  [HP:0011499] [0617]
 Osteolysis (骨融解) [HP:0002797] [1600036]
 Osteopenia (骨減少) [HP:0000938] [160015]
 Splenomegaly (脾腫) [HP:0001744] [01817]
 Thrombocytopenia (血小板減少) [HP:0001873] [2218]
 
 <30%-79%>
 Abdominal pain (腹痛) [HP:0002027] [01420]
 Anemia (貧血 ) [HP:0001903] [2201]
 Bruising susceptibility (易出血性) [HP:0000978] [2207]
 Diplopia (複視) [HP:0000651] [06004]
 Dysphagia (嚥下障害) [HP:0002015] [01820]
 Dyspnea (呼吸困難) [HP:0002094] [01606]
 Gingival bleeding (歯肉出血) [HP:0000225] [2207]
 Kyphosis (後弯) [HP:0002808] [161500]
 Pancytopenia (汎血球減少) [HP:0001876] [2214]
 Ptosis (眼瞼下垂) [HP:0000508] [06807]
 Respiratory insufficiency due to muscle weakness (筋力低下による呼吸不全) [HP:0002747] [01606]
 
 <5%-29%>
 Abnormal myocardium morphology (心筋形態異常) [HP:0001637]
 Ascites (腹水) [HP:0001541] [01802]
 Biliary tract obstruction (胆道閉塞) [HP:0005230] [12111]
 Cirrhosis (肝硬変) [HP:0001394] [01805]
 Hematuria (血尿)  [HP:0000790] [0193]
 Increased antibody level in blood (血中抗体増加) [HP:0010702] [22091]
 Interstitial pulmonary abnormality (肺間質異常) [HP:0006530] [1111]
 Leukopenia (白血球減少) [HP:0001882] [2210]
 Osteoarthritis (骨関節炎) [HP:0002758] [15115]
 Pathologic fracture (病的骨折) [HP:0002756] [160017]
 Pedal edema (足浮腫) [HP:0010741] [01408]
 Pericardial effusion (心外膜滲出液) [HP:0001698] [1122]
 Proteinuria (蛋白尿) [HP:0000093] [0197]
 Pulmonary arterial hypertension (肺高血圧) [HP:0002092] [01609]
 Pulmonary infiltrates (肺浸潤) [HP:0002113] [2350]
 Vertebral compression fractures (脊椎圧迫骨折) [HP:0002953] [161512]
 
 
 Abnormality of the eye (眼異常) [HP:0000478] [06]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Epistaxis (鼻出血) [HP:0000421] [2207]
 Erlenmeyer flask deformity of the femurs (Erlenmeyer flask変形(大腿骨)) [HP:0004975] [16067]
 Hyperpigmentation of the skin (皮膚高色素) [HP:0000953] [18017]
 Hypertension (高血圧) [HP:0000822] [01415]
 Macular atrophy (黄斑萎縮) [HP:0007401] [06523]
 Multiple myeloma (多発性骨髄腫) [HP:0006775] [2232]

(UR-DBMS)
【一般】*肝腫 ( 1歳から)
 *脾腫
 肺高血圧
 骨痛
【眼】角膜胸膜脚に Gaucher 細胞の褐色沈着
 白色沈着 (角膜上皮, 前房隅角, 毛様体, 瞳孔縁)
 灰白色の黄斑周囲
 黄斑萎縮
 網膜血管透過性増加
【鼻】鼻出血
【肺】びまん性肺浸潤 (患者の5%以下)
 間質性肺疾患
 拘束性肺疾患
 呼吸困難
【X線】骨融解性病変
 骨粗鬆症
 病的骨折
 骨発症
 脊椎圧迫
 無菌性壊死 (大腿骨頭)
 Erlenmeyer フラスコ変形 (大腿骨)
【皮膚】皮膚色素異常 (顔, 首, 手, 脛)
【血液学】*Gaucher 細胞 (骨髄)
 脾臓機能亢進
 血小板減少
 貧血
 汎血球減少
【検査】Acid beta-glucosidase 欠損 (組織, 白血球)
 モノクローナル免疫グロブリン異常
【その他】小児期発症が多い (10歳未満)
 発症と診断はその後にもありうる (20歳以後)
 非常に多様な表現型, ある成人は無症状かも
 Ashkenazi ユダヤ人に多い (保因者頻度= 1/14)

【一般】*腹部膨満
 浮腫
 腹痛
 肺炎
【神経】脳障害
 ミオクローヌス反射
【眼】強膜の黄色斑 ("pingueculae") (25%)
 単独眼球運動異常
【骨盤】股関節異形成
【四肢】関節痛
【X線】幅広い骨幹端
 骨嚢胞
 管形成不全
 骨皮質肥厚
 骨膜下新骨形成
【皮膚】魚鱗癬
【血液学】出血
【検査】glucocerebrosides 増加 (組織, 血漿)

(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。

(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 I is caused by homozygous or compound heterozygous mutation in the gene encoding acid beta-glucosidase (GBA; 606463) on chromosome 1q22.

Gaucher disease is an autosomal recessive lysosomal storage disorder due to deficient activity of beta-glucocerebrosidase. As a result of this deficiency, there is intracellular accumulation of glucosylceramide (GlcCer, glucosylcerebroside) primarily within cells of mononuclear phagocyte origin, which are the characteristic 'Gaucher cells' identified in most tissues (Jmoudiak and Futerman, 2005).

Gaucher disease is classically categorized phenotypically into 3 main subtypes: nonneuronopathic type I, acute neuronopathic type II (230900), and subacute neuronopathic type III (231000). Type I is the most common form of Gaucher disease and lacks primary central nervous system involvement. Types II and III have central nervous system involvement and neurologic manifestations (Knudson and Kaplan, 1962; Jmoudiak and Futerman, 2005).

All 3 forms of Gaucher disease are caused by mutation in the GBA gene. There are 2 additional phenotypes which may be distinguished: perinatal lethal Gaucher disease (608013), which is a severe form of type II, and Gaucher disease type IIIC (231005), which also has cardiovascular calcifications.

See also 610539 for a form of atypical Gaucher disease caused by mutation in the gene encoding saposin C (PSAP;176801), which is an activator of beta-glucosidase.

Clinical Features
Type I Gaucher disease usually presents in childhood with hepatosplenomegaly, pancytopenia, and manifestations of bone marrow infiltration by characteristic 'Gaucher cells.' Other features include ocular pingueculae, or nodules, and dermal hyperpigmentation. There is a wide spectrum of clinical severity, ranging from affected infants to asymptomatic adults. There is no neurologic involvement in type I Gaucher disease (Goldblatt, 1988).

Choy (1988) reported a French Canadian family in which 5 sibs had type I Gaucher disease. Glucocerebrosidase activity in patients' fibroblasts was 7.5 to 15.5% of normal controls; obligate carriers had approximately 50% normal activity. The 5 affected sibs showed considerable phenotypic heterogeneity: age at diagnosis ranged from 16 to 41 years. The most severely affected patient was very anemic and thrombocytopenic, and had severe orthopedic complications, including vertebral compression, avascular necrosis of the femoral head, and pathologic fractures of long bones. The least affected male had no orthopedic complications at age 49 years and his hematologic complications had been reversed by splenectomy at age 25. There was no clear correlation between residual GBA enzyme activity in cultured fibroblasts and clinical severity.

In a retrospective study of 20 untreated Dutch patients with type I Gaucher disease, Maaswinkel-Mooij et al. (2000)found that the clinical manifestations were progressive in most patients, children as well as adults. This appeared to be in contrast with studies among Jewish patients. The results emphasized the need for regular follow-up to enable timely initiation of enzyme therapy.

Park et al. (2001) reported the clinical features and genotypes of 7 African American patients with type I Gaucher disease. Common features included hepatosplenomegaly, epistaxis, bone pain, anemia, and thrombocytopenia. All patients had moderate to severe manifestations, 4 presented before age 3 years, and all developed symptoms by adolescence. No probands shared the same genotype. The authors concluded that significant genotypic heterogeneity exists among African American patients with type I Gaucher disease, and that recombinations in the GBA gene may be common in this patient group.

Biochemical Features
Brady et al. (1965) demonstrated deficiency of the glucocerebrosidase enzyme in the spleen of patients with Gaucher disease. Wiedemann et al. (1965) found typical Gaucher cells in the bone marrow of unaffected obligate heterozygotes from 2 families with Gaucher disease. Danes and Bearn (1968) found giant fibroblasts containing metachromatic material in both affected persons and heterozygotes for the chronic noncerebral form of Gaucher disease. Beutler et al. (1971) demonstrated decreased beta-glucosidase activity in fibroblasts from homozygotes with the adult form of Gaucher disease. Heterozygotes showed intermediate levels of enzyme activity. Chiao et al. (1979)found deficiency of beta-xylosidase (see 278900) in different forms of Gaucher disease and suggested that clinical features such as severity may be related to this epiphenomenon.

Pentchev et al. (1983) found the same glucocerebrosidase crossreacting material in the spleen in all 3 types of Gaucher disease. However, enzyme activity was about 15% of normal in the adult nonneurologic form (type I) and about 2.3% in the neurologic forms (types II and III). The authors concluded that all 3 forms of Gaucher disease result from a structurally mutated enzyme with altered catalytic efficiency. Gravel and Leung (1983) found no complementation from fusion of cultured fibroblasts from the infantile and adult forms of Gaucher disease, suggesting that the 2 forms are allelic.

Using various inhibitors, Grabowski et al. (1985) found 3 distinct groups of residual enzyme activity in patients with Gaucher disease. The groups were designated A, B, and C, but did not correspond to the phenotypic groups I, II, and III. The authors concluded that Gaucher disease type I is biochemically heterogeneous; that the nonneuronopathic and neuronopathic subtypes cannot be distinguished by such inhibitor studies; and that the Ashkenazi Jewish form of Gaucher disease type I results from a unique mutation in a specific active site domain of acid beta-glucosidase that leads to a defective enzyme. With monoclonal antibodies as well as polyclonal sera,Beutler et al. (1985) could demonstrate no differences of glucocerebrosidase in types I, II, and III Gaucher disease.

Based on enzymatic and phenotypic examination of 25 families with type I Gaucher disease, Zlotogora et al. (1986)concluded that the clinical variability results from different mutations at the same locus. The authors noted thatKlibansky et al. (1973) had observed differences in heat activation profiles of glucocerebrosidase in type I patients with varying phenotypic severity.

Graves et al. (1986) found normal amounts of GBA mRNA in fibroblast extracts from patients with several types of Gaucher disease, suggesting single-base gene alterations leading to the synthesis of defective enzyme. Using immunoblotting techniques, Fabbro et al. (1987) found extensive heterogeneity in the nature of the biochemical defects in the various forms of Gaucher disease.

Bergmann and Grabowski (1989) found abnormalities in the posttranslational processing of GBA in patients with Gaucher disease, but the abnormalities could not be correlated firmly with phenotype.

Because glycosphingolipids may be involved in the induction of insulin resistance, and the primary genetic defect in Gaucher disease leads to increased levels of these molecules, Gaucher patients constitute a human model to study the relationship between glucose metabolism and glycosphingolipids. In a study of 6 patients with Gaucher disease and 6 controls, Langeveld et al. (2008) found that noninsulin-mediated glucose uptake during both euglycemia nad hyperglycemia did not differ between patients and controls, but insulin-mediated glucose uptake was lower in Gaucher patients. Suppression of lipolysis by insulin tended to be less effective in Gaucher disease patients. Langeveld et al. (2008) concluded that Gaucher disease is associated with peripheral insulin resistance, possibly through the influence of glycosphingolipids on insulin receptor functioning.

Other Features
Garfinkel et al. (1982) observed an association between Gaucher disease and monoclonal gammopathy or multiple myeloma and suggested that chronic glucocerebroside accumulation may provide a stimulus to the immune system. A possible experimental counterpart is myeloma in Balb/C mice, which develops several months after the intraperitoneal injection of mineral oil.

Calcific constrictive pericarditis was described by several authors in patients with type I Gaucher disease (Harvey et al., 1969; Tamari et al., 1983). The pericardial involvement in these cases was likely related to unrecognized hemorrhagic pericarditis (Chabas et al., 1995).

Choy (1985) found increased bone serum acid phosphatase only in patients with Gaucher disease who had bone involvement. Acid phosphatase was normal in lymphocytes and cultured fibroblasts from these patients, suggesting that it was a secondary feature of the disease in which there is bone involvement and is unreliable for diagnosis.

Ross et al. (1997) noted that aggregations of Gaucher cells within pulmonary alveolar spaces and interstitium in association with bilateral diffuse pulmonary reticulonodular infiltrates had been described in patients with type I Gaucher disease. In addition, there have been rare instances of Gaucher cells occluding pulmonary capillaries, with resulting pulmonary hypertension. The hepatopulmonary syndrome, as manifested by intrapulmonary shunting and hypoxemia, may also complicate type I Gaucher disease. Ross et al. (1997) described a patient with type I Gaucher disease and pulmonary hypertension in whom they identified Gaucher cells in pulmonary capillary blood drawn from a catheter in the wedged position.

Miller et al. (2003) evaluated pulmonary involvement in 150 consecutive patients with type I Gaucher disease. Clinical evidence of pulmonary involvement was noted in 5 patients, each of whom had dyspnea, diffuse infiltrates, restrictive impairment and low single breath carbon monoxide diffusing capacity. Two of these patients underwent exercise testing and showed abnormalities consistent with lung disease. In 13 patients randomly selected from the remaining 145, physical examination, chest radiographs, and pulmonary function were normal. However, responses on exercise testing in 6 patients were consistent with a circulatory impairment. Thus, the study found that less than 5% of patients with type I Gaucher disease have clinical interstitial lung disease. In addition,Miller et al. (2003) found that some patients, without evident lung involvement, experienced limitations in physical exertion and were easily fatigued; this was attributable to impaired pulmonary circulation.

Ocular manifestations in type I Gaucher disease include white deposits in the corneal epithelium, anterior chamber angle, ciliary body, and pupil margin (Petrohelos et al., 1975; Wang et al., 2005). Fundus abnormalities include perimacular grayness and scattered white spots (Cogan et al., 1980). In a 12-year follow-up of a patient with type I GD, Wang et al. (2005) demonstrated the presence of macular atrophy and increased retinal vascular permeability.

▼ Pathogenesis
Pandey et al. (2017) showed that activation of complement C5a (120900) and C5a receptor-1 (C5AR1; 113995) controls glucosylceramide (GC) accumulation and the inflammatory response in experimental and clinical Gaucher disease. Marked local and systemic complement activation occurred in glucocerebrosidase (GCase)-deficient mice or after pharmacologic inhibition of GCase and was associated with GC storage, tissue inflammation, and proinflammatory cytokine production. Whereas all GCase-inhibited mice died within 4 to 5 weeks, mice deficient in both GCase and C5aR1, and wildtype mice in which GCase and C5aR were pharmacologically inhibited, were protected from these adverse effects and consequently survived. In mice and humans, GCase deficiency was associated with strong formation of complement-activating GC-specific IgG autoantibodies, leading to complement activation and C5a generation. Subsequent C5aR1 activation controlled UDP-glucose ceramide glucosyltransferase production, thereby tipping the balance between GC formation and degradation. Thus, extensive GC storage induces complement-activating IgG autoantibodies that drive a pathway of C5a generation and C5aR1 activation that fuels a cycle of cellular GC accumulation and innate and adaptive immune cell recruitment and activation in Gaucher disease. Pandey et al. (2017) suggested that targeting C5AR1 may serve as a treatment option for patients with Gaucher disease and possibly other lysosomal storage diseases.

Inheritance
Based on population studies among Ashkenazi Jewish populations in Israel, Fried (1973) concluded that Gaucher disease is an autosomal recessive disorder. Homozygotes were affected with the disease.

Diagnosis
Desnick et al. (1971) demonstrated that both homozygotes and heterozygotes for Gaucher disease could be identified by chemical analysis of the sediment from a 24-hour urine collection. Individual neutral glycosphingolipids were separated by thin-layer chromatography and quantitatively estimated by gas-liquid chromatography.

By an assay of leukocyte beta-glucosidase, Raghavan et al. (1980) devised a method for identifying both heterozygotes and homozygotes.

Magnetic resonance imaging is a sensitive method for detecting bone involvement in Gaucher disease, evaluating complications such as osteonecrosis (Lanir et al., 1986).

Zuckerman et al. (2007) reviewed the outcome of screening for Gaucher disease among Ashkenazi Jewish individuals in Israel between 1995 and 2003. The carrier frequency was 5.7% in testing for 4 or 6 main GBA mutations. N370S (606463.0003) was by far the most common variant identified. Importantly, most individuals homozygous for the mild N370S mutation are mildly symptomatic or even asymptomatic (Beutler et al., 1993). Of 82 couples at risk for offspring with type 1 GD, 70 (85%) were at risk for asymptomatic or mildly affected offspring, and 12 (15%) were at risk for moderately affected offspring. Prenatal diagnosis performed in 68 pregnancies detected 16 fetuses with GD. Pregnancies were terminated in 2 (15%) of 13 fetuses predicted to be asymptomatic or mildly affected and in 2 (67%) of 3 fetuses with predicted moderate disease. There were significantly fewer pregnancy terminations (1 of 13) in couples who consulted with a GD expert in addition to genetic counseling compared to those who had not consulted with a GD expert (3 of 3). Two of the 3 terminations performed in the group without medical consult were homozygous for N370S. In an accompanying editorial, Beutler (2007)commented that carrier screening for Gaucher disease may do more harm than good given the extreme phenotypic variability and the inability to predict disease severity, especially in those with the common N370S mutation who may remain asymptomatic. Beutler (2007) recalled a 72-year-old patient with Gaucher disease who had low levels of enzyme activity but remained asymptomatic (Beutler, 1977).

In a review of the molecular genetics of Gaucher disease, Hruska et al. (2008) noted that most GBA mutations can be found in patients with various forms of the disorder. The phenotype is mainly determined by the combination of mutations on both alleles; thus the prediction of phenotype from genotypic data has limited utility. In addition, it has become increasingly difficult to categorize patients into 1 of the 3 classic types of Gaucher disease, indicating that the phenotypes fall into a continuum, with the major distinction being the presence and degree of neurologic function.

Clinical Management
Most patients with type I Gaucher disease require splenectomy for management of thrombocytopenia and anemia; however, splenectomy is often followed by an increase in bone involvement, with osteolytic lesions within a few months of surgery (Ashkenazi et al., 1986). Partial splenectomy has been advocated with the dual goals of minimizing the deleterious effect on bone and avoiding postsplenectomy sepsis (Rubin et al., 1986).

Goldblatt et al. (1988) reported that of 8 patients with Gaucher disease treated with 15 total hip arthroplasties, 11 (73%) remained fully mobile and asymptomatic with a follow-up time of up to 14 years after surgery.

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

Charrow et al. (2018) reported results from a phase 3, randomized, double-blind trial comparing the effectiveness of a once-daily versus the approved twice-daily regimen of eliglustat at the same total daily dose in 121 adult patients with type I Gaucher Disease. After 1 year, 80.4% of patients receiving once-daily dosing and 83.1% of patients receiving twice-daily dosing remained stable. Mean values for hematologic and visceral measures were within therapeutic goal thresholds in both groups. Because patients with twice-daily dosing also showed greater tolerance for the drug, the study confirmed the twice-daily dosing recommendation on the drug label.

Gene Therapy
In vitro, Sorge et al. (1987) reported complete correction of the enzyme defect in fibroblasts from patients with type I Gaucher disease after retroviral-mediated GBA gene transfer. Fink et al. (1990) demonstrated that retroviral gene transfer could be used to correct the GBA deficiency in primary hematopoietic cells from patients with Gaucher disease. Correction was achieved in the progeny of transduced hematopoietic progenitor cells. Nolta et al. (1992)demonstrated that retroviral vectors can efficiently transfer the GBA gene into long-lived hematopoietic progenitor cells from the bone marrow of patients with Gaucher disease and express physiologically relevant levels of enzyme activity.

Starzl et al. (1993) reported that liver transplantation in a patient with type I Gaucher disease resulted in dramatic reduction in the lymph node deposits of glucocerebroside. They concluded that microchimerism corrected the metabolic abnormality.

See also ANIMAL MODEL section below.

Enzyme Replacement Therapy
Barton et al. (1990) found that weekly intravenous infusions of macrophage-targeted human placental glucocerebrosidase resulted in clinical improvement in a patient with type I Gaucher disease. Sequential deglycosylation of the oligosaccharide chains of the native enzyme were used to yield a mannose-terminated preparation that is specifically bound by lectin on the membrane of macrophages. Twenty-week treatment resulted in increased hemoglobin, increased platelet count, and radiographic evidence of skeletal improvement. Barton et al. (1991) reported clinical improvement with intravenous infusion of macrophage-targeted enzyme therapy in 12 patients with type I disease. Serum hemoglobin concentration increased in all 12 patients, platelet count increased in 7, serum acid phosphatase decreased in 10, and plasma glucocerebroside level decreased in 9. After 6 months of treatment, splenic volume decreased in all patients, and hepatic volume in 5. Early signs of skeletal improvement were seen in 3 patients. The enzyme infusions were well tolerated, and no antibody to the exogenous enzyme developed.

Economic and other societal aspects of the use of modified glucocerebrosidase, alglucerase ('Ceredase'), in the treatment of Gaucher disease were discussed by Beutler et al. (1991) and Zimran et al. (1991). Theoretical considerations suggested to Figueroa et al. (1992) that more frequent administration might be more efficient. A series of 7 letters beginning with one by Moscicki and Taunton-Rigby (1993) discussed the economics and related aspects of alglucerase therapy. Ceredase, derived from human placental tissues and produced by Genzyme Corporation of Cambridge, Massachusetts, was approved by the Food and Drug Administration in 1991. In mid-1994, the FDA approved a recombinant alternative to Ceredase, Cerezyme, which is also produced by Genzyme (Fox, 1995). From a retrospective analysis, Kaplan et al. (1996) noted that in most children with type I Gaucher disease with subnormal growth velocity, adequate alglucerase (Ceredase) treatment resulted in growth velocity improvement.

In a review of 1,028 Gaucher patients treated with macrophage-targeted enzyme replacement therapy for 2 to 5 years, Weinreb et al. (2002) found improvement in anemia, thrombocytopenia, organomegaly, bone pain, and bone crises.

Hollak et al. (1994) observed a very marked increase (more than 600-fold) of chitotriosidase (CHIT1; 600031) activity in the plasma of 30 of 32 symptomatic patients with type I Gaucher disease. Chitotriosidase activity declined dramatically during enzyme supplementation therapy, suggesting that it could be used as a biomarker of therapeutic efficacy. In contrast, 3 GBA-deficient individuals without clinical symptoms had only slight increases in chitotriosidase. The authors considered it unlikely that chitotriosidase itself contributes to the clinical presentation of Gaucher disease. Hollak et al. (1994) suggested that the macrophages loaded with glucosylceramide in Gaucher disease are the main source of the plasma CHIT1 enzyme activity.

Approximately 6% of Caucasians have chitotriosidase deficiency (614122) without clinical symptoms. Grace et al. (2007) noted that the identification of CHIT1 gene mutations that alter plasma chitotriosidase activity is important for the use of this biomarker to monitor disease activity and therapeutic response in Gaucher disease. The authors thus genotyped the CHIT1 gene in 320 unrelated patients with Gaucher disease, including 272 of Ashkenazi Jewish descent. Among all patients, 4% and 37.2% were homozygous and heterozygous, respectively, for a common 24-bp duplication in the CHIT1 gene (600031.0001) that results in decreased enzyme activity. In addition, Grace et al. (2007) identified 3 novel mutations in the CHIT1 gene (600031.0002-600031.0005) in individuals with Gaucher disease and chitotriosidase deficiency. The findings were important for use and interpretation of plasma chitotriosidase activity in patients with Gaucher disease.

Chemical Chaperone Therapy
Some lysosomal storage diseases appear to be caused by lysosomal enzyme variants that retain catalytic activity but are predisposed to misfolding or mistrafficking in the cell (Berg-Fussman et al., 1993). The use of chemical chaperones to template proper folding within the secretory pathway, prevent postsecretory misfolding, or stabilize proteins with a predilection to misfold is well documented (Morello et al., 2000). Pursuant to experience in Fabry disease (301500), Sawkar et al. (2002) found that addition of subinhibitory concentrations of the GBA inhibitor deoxynojirimycin (NN-DNJ) to fibroblasts in vitro resulted in a 2-fold increase in the activity of the N370S mutant (606463.0003) GBA enzyme. The increased activity persisted for at least 6 days after withdrawal of the putative chaperone. The same chaperone increased wildtype beta-glucosidase activity, but not that of the L444P mutation (606463.0001). Beta-glucosidase was stabilized against heat denaturation in a dose-dependent fashion. Sawkar et al. (2002) proposed that NN-DNJ chaperones beta-glucosidase folding at neutral pH, thus allowing the stabilized enzyme to transit from the endoplasmic reticulum to the Golgi, enabling proper trafficking to the lysosome. Importantly, a modest increase in beta-glucosidase activity seemed to be sufficient to achieve a therapeutic effect.

Steet et al. (2006) found that the iminosugar isofagomine (IFG), an active-site inhibitor of beta-glucosidase, facilitated the folding and transport of newly synthesized mutant N370S GBA from the endoplasmic reticulum to lysosomes. IFG increased beta-glucosidase activity approximately 3-fold in N370S fibroblasts and the enzyme showed some altered kinetic properties. Although IFG inhibited the enzyme in situ, washout of the drug resulted in full recovery of enzyme activity by 24 hours.

Substrate Reduction Therapy
Pastores et al. (2005) reported results from treatment with N-butyldeoxynojirimycin (NB-DNJ; Miglustat), an inhibitor of glucosylceramide synthase (UGCG; 602874), in 10 adult patients with type I Gaucher disease. Treatment over 24 months resulted in decreased liver and spleen volumes and clinical improvement. Bone involvement and platelet and hemoglobin levels remained stable and the treatment was well tolerated.

Bone Marrow Transplantation
Ringden et al. (1995) reported experience with allogenic bone marrow transplantation (BMT) in 6 patients, ranging from 2 to 9 years, with severe Gaucher disease in Sweden. The donors were HLA-identical sibs in 4 cases, the father with 1 incompatible HLA antigen in one case, and an HLA-A, -B, and -DR-identical unrelated donor in the sixth case. Among the donors, 3 were heterozygous for glucocerebrosidase and 3 were healthy homozygotes. Before transplantation, 4 patients underwent total splenectomy and 2 had partial splenectomy. In the former, 1 of the 4 patients developed pneumococcal meningitis. In the group with partial splenectomy, transfusion requirements were increased. The parental graft was rejected, but 4 of 5 other patients had donor enzyme levels from 2 to 11 years after BMT. Two patients became mixed chimeras with approximately 40% of donor erythrocyte markers for 1 and 80% for the other. One of these had low enzyme activity in his lymphocytes, but the clinical outcome was excellent. Gaucher cells disappeared from the bone marrow and liver size normalized or decreased within 2 to 3 years after BMT. All patients with engraftment had a growth spurt. Ringden et al. (1995) suggested that if an HLA-compatible donor is available, BMT is the treatment of choice in advanced Gaucher disease.

Molecular Genetics
Tsuji et al. (1987) identified an L444P substitution in the GBA gene (606463.0001) in patients with Gaucher disease types I, II, and III. All 4 patients with type I disease had the mutation as a single allele and were presumably compound heterozygous with another unidentified pathogenic GBA mutation.

In 3 unrelated Ashkenazi Jewish patients with type I Gaucher disease, Tsuji et al. (1988) identified a homozygous mutation in the GBA gene (N370S; 606463.0003). Further studies showed that 15 of 21 additional type I patients had 1 allele with this mutation. The N370S mutation was not identified in patients with the type II or type III phenotype. One patient with type I disease was compound heterozygous for N370S and L444P.

Among 62 Ashkenazi Jewish patients with Gaucher disease, Zimran et al. (1991) found that N370S represented 73% of the 124 mutant alleles, making N370S the most common mutant GBA allele among Ashkenazi Jewish patients with type I disease.

Population Genetics
Choy et al. (1987) described a method for identification of the carrier state in French Canadians.

In 1982, approximately 20,000 cases of Gaucher disease were reported in the United States. Over two-thirds of these persons were of Ashkenazi extraction (Brady, 1982).

By examination of glucocerebrosidase activity in leukocytes of a series of blood donors, Matoth et al. (1987)estimated the frequency of carriers among Ashkenazi Jews in Israel as 4.6%. This figure was in close agreement with the carrier rate of 4% estimated from the number of known cases of Gaucher disease in Israel.

Zimran et al. (1991) estimated the total gene frequency for Gaucher disease among Ashkenazi Jews to be 0.047, which is equivalent to a carrier frequency of 8.9% and a birth incidence of 1 in 450.

Among 593 unrelated normal Ashkenazi Jewish individuals, Zimran et al. (1991) identified 37 heterozygotes and 2 homozygotes for the N370S mutation, yielding an allele frequency of 0.035. Among 1,528 Ashkenazi Jewish individuals, Beutler et al. (1993) identified 87 heterozygotes and 4 homozygotes for N370S, yielding a frequency of 0.0311; pooling with data reported by Zimran et al. (1991) yielded a frequency of 0.032 for the N370S allele. Beutler et al. (1993) found that 10 of 2,305 normal Ashkenazi Jewish individuals were heterozygous for the 84GG insertion mutation (606463.0014), yielding an allele frequency of 0.00217. The authors found that the ratio of N370S to 84GG was higher in the general Jewish population than in the patient population, which was presumably due to the fact that N370S homozygotes may have late-onset disease or no significant clinical manifestations at all. To bring the gene frequency in the patient population into conformity with the gene frequency in the general population, nearly two-thirds of persons with a Gaucher disease genotype would be missing from the patient population, presumably because their clinical manifestations were very mild.

Both Tay-Sachs disease (TSD; 272800) and Gaucher disease have a high frequency in the Ashkenazi Jewish population, reaching a frequency of about 1:29 for TSD carriers and 1:16 for Gaucher disease carriers. By comparing the frequencies of the common GBA N370S mutation among carriers of the common TSD mutation, 1277TATC (606869.0001), and in the general Ashkenazi population, Peleg et al. (1998) determined that carriers of both diseases do not possess additional evolutionary advantage over single mutation carriers. The frequency of GD carriers among 308 TSD heterozygotes was 1:28, which is about half that expected (p = 0.03). The authors concluded that one or both mutations arose relatively recently in different regions of Europe and had not yet reached genetic equilibrium.

Rockah et al. (1998) found linkage disequilibrium between the 2 common Ashkenazi Gaucher disease mutations N370S and 84GG and polymorphic sites in the PKLR gene (609712). One hundred of 104 (96%) alleles carrying N370S also carried the A1 allele of the PKLR gene, which was present in only 6.7% of the control population, yielding a calculated linkage disequilibrium of 0.957. The mutation 84GG was found to be associated uniquely with the PKLR A6 allele, with a linkage disequilibrium of 1.00. These results suggested that the N3670S and 84GG mutations each originated in a single founder in the Ashkenazi Jewish population. Thus, founder effect followed by genetic drift rather than an evolutionary advantage for heterozygotes best explains the high frequency of these mutations in Ashkenazi Jews.

Despite considerable uncertainty about the demographic history of Ashkenazi Jews and their ancestors, Slatkin (2004) considered available genetic data to be consistent with a founder effect resulting from a severe bottleneck in population size between 1100 A.D. and 1400 A.D. and an earlier bottleneck in 75 A.D., at the beginning of the Jewish Diaspora. Slatkin (2004) concluded that a founder effect could account for the relatively high frequency of alleles causing 4 different lysosomal storage disorders, including Tay-Sachs disease and Gaucher disease, if the disease-associated alleles are recessive in their effects on reproductive fitness.

Charrow et al. (2018) stated that GD I is estimated to affect 1 in 40,000 in the general population and 1 in 850 among those of Ashkenazi Jewish ancestry.

History
Type I Gaucher disease was first described in a doctoral thesis by Gaucher (1882) as a nonleukemic splenic epithelioma (Goldblatt, 1988). Brill et al. (1905) first used the eponym 'Gaucher disease.'

Although Gaucher disease is clearly autosomal recessive, a dominant form was suggested by Hsia et al. (1959) on the basis of affected father and son. The father was German-Jewish and the mother Swedish-English. The mother may have been a carrier; this quasi-dominant mechanism is even more likely in reports of presumed dominant inheritance in Jewish groups where the frequency of the Gaucher disease is relatively high.

Animal Model
Enquist et al. (2006) used the Cre/loxP system to conditionally delete exons 9-11 of the Gba gene in mice after birth. The mice were viable, demonstrated deficiency of glucocerebrosidase, and developed splenomegaly and microcytic anemia similar to type I Gaucher disease, including infiltration of Gaucher cells in the bone marrow, spleen, and liver. Both bone marrow transplantation and gene therapy with a retroviral vector prevented the disease and corrected an already established Gaucher phenotype. Both therapies resulted in increased Gba activity and decreased numbers of Gaucher cells 5 to 6 months after treatment.

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