疾患詳細

疾患詳細





#231000
Gaucher disease, type III (GD III)
(Gaucher disease, subacute neuronopathic)
(Gaucher disease, chronic neuropathic type)
(Gaucher disease, juvenile and adult, cerebral)
(Gaucher disease, type IIIA, included)
(Gaucher disease, type IIIB, included)
(Gaucher disease, Norrbottnian type, included)

Gaucher 病 III 型 (GD III)
(Gaucher 病, 若年および成人型, 脳型)
(Gaucher 病, 慢性神経症型)
(Gaucher 病, 亜急性神経症型)
(Norrbottnian Gaucher 病)
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%>
 Avascular necrosis (無血管性壊死) [HP:0010885] [160018]
 Bone pain (骨痛) [HP:0002653] [01420]
 Encephalopathy (脳症) [HP:0001298] [0201]
 Fatigue (疲労) [HP:0012378] [01410]
 Hepatomegaly (肝腫) [HP:0002240] [01813]
 Increased bone mineral density (骨濃度増加) [HP:0011001] [160016]
 Increased susceptibility to fractures (易骨折性) [HP:0002659] [160017]
 Ophthalmoplegia (眼球運動麻痺) [HP:0000602] [0698]
 Osteolysis (骨融解) [HP:0002797] [1600036]
 Splenomegaly (脾腫) [HP:0001744] [01817]
 Strabismus (斜視) [HP:0000486] [06610]
 
 <30%-79%>
 Anemia (貧血 ) [HP:0001903] [2201]
 Ataxia (運動失調) [HP:0001251] [028]
 Delayed puberty (思春期遅発) [HP:0000823] [2152]
 Delayed skeletal maturation (骨成熟遅滞) [HP:0002750] [160001]
 Dementia (認知症) [HP:0000726] [0123]
 Gait disturbance (歩行障害) [HP:0001288] [028]
 Generalized myoclonic seizures (全身性ミオクロニー発作) [HP:0002123] [01405]
 Hydrops fetalis (胎児水腫) [HP:0001789] [01002]
 Increased antibody level in blood (血中抗体増加) [HP:0010702] [22091]
 Pancytopenia (汎血球減少) [HP:0001876] [2214]
 Thrombocytopenia (血小板減少) [HP:0001873] [2218]
 
 <5%-29%>
 Abnormal myocardium morphology (心筋形態異常) [HP:0001637]
 Aortic valve calcification (大動脈弁石灰化) [HP:0004380] [16180]
 Hematuria (血尿)  [HP:0000790] [0193]
 Interstitial pulmonary abnormality (肺間質異常) [HP:0006530] [1111]
 Mitral valve calcification (僧帽弁石灰化) [HP:0004382] [16180]
 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]
 Recurrent respiratory infections (反復性呼吸器感染) [HP:0002205] [014230]
 
 
 Adult onset (成人発症) [HP:0003581]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Decreased beta-glucocerebrosidase activity (beta-glucocerebrosidase 活性減少) [HP:0003656]
 Decreased body weight (体重減少) [HP:0004325] [01411]
 Depressivity (うつ) [HP:0000716] [0206]
 Horizontal supranuclear gaze palsy (水平性核上性注視麻痺) [HP:0007817] [0698]
 Motor delay (運動遅滞) [HP:0001270] [0120]
 Myoclonus (ミオクローヌス) [HP:0001336] [02612]
 Neurological speech impairment (神経学的発語障害) [HP:0002167] [023]
 Progressive neurologic deterioration (進行性神経学的悪化) [HP:0002344]
 Short stature (低身長) [HP:0004322] [0130]
 Spastic paraparesis (痙性対不全麻痺) [HP:0002313] [02613]
 Vascular calcification (血管石灰化) [HP:0004934] [16180]

(UR-DBMS)
【一般】低身長
 体重減少
 肝腫
 脾腫
 けいれん
 運動発達遅滞
 知能退行
 緩徐な痴呆 (中期~後期小児期)
 肺疾患
【神経】亜急性神経学的悪化
 言語異常
 運動失調
 痙性対麻痺
 ミオクローヌス (subtype 3A)
 ミオクローヌスけいれん (subtype 3A)
 痴呆 (subtype 3A)
 うつ
 行動異常
 錐体外路および小脳症状
【眼】眼運動異常
 異常なサッケード (衝動運動)
 核上性注視麻痺, 水平性 (type IIIB)
 垂直眼球運動は通常保持されている
 斜視
【X線】骨病変
【血液】脾臓機能亢進
 Gaucher 細胞 (骨髄)
 汎血球減少
 血小板減少
【検査】beta-glucocerebrosidase タンパクおよび活性低下
【その他】非常に多様な表現型
 発症は通常は小児期 (乳児期~後期小児期)
 成人発症が報告されている
 Subtype 3A: ミオクローヌス+痴呆
 Subtype 3B: 水平性核上性注視麻痺+進行性全身疾患
 Subtype 3C (231005): 心血管石灰化

(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。

(責任遺伝子) *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

(ノート)
●(#) は, ゴーシェ病 III 型が, 1q22の acid beta-glucosidase (GBA; 606463) をコードする遺伝子のホモ接合または複合ヘテロ接合変異が原因であるため

●同じ遺伝子の変異は, ゴーシェ病 I 型 (230800) と II 型 (230900)を生じる

●ゴーシェ病 III 型は, 神経病性ゴーシェ病の亜急性型である
 神経病性ゴーシェ病 II 型である急性型に比べると, 遅発性で, 緩徐進行性をもつ

●Patterson et al. (1993) は, ゴーシェ病 III 型には2つの表現型サブグループがあると示唆した
 IIIA 型→ミオクローヌスと認知症が特徴
 IIIB 型→単独水平性核上性注視魔歯と侵襲性全身疾患の早期発症
 が特徴である
 ゴーシェ病 IIIC 型 (231005)は, 心血管石灰化を伴う

Clinical Features
Herrlin and Hillborg (1962) reported a pedigree with juvenile Gaucher disease and neurologic signs.

Miller et al. (1973) described Gaucher disease with neurologic manifestations in 3 adult sibs. Features included seizures and decreased beta-glucocerebrosidase activity.

Dreborg et al. (1980) reported clinical studies of a large number of patients with a distinctive type of Gaucher disease that they termed the 'Norrbottnian type' because of its origin from the province of Norrbotten, the northern-most county in Sweden. Median age at onset was 2.5 years (range 8 months to 14.5 years). Initially, affected patients had normal intelligence and short stature with splenomegaly. Patients later developed abnormal eye movements and some developed seizures. The severity of the clinical symptoms and signs and course of the disease differed markedly not only between families but also between sibs. Splenectomy accelerated deterioration, especially with regard to skeletal and central nervous system manifestations. Biochemical studies were performed by Hakansson (1979).

Tibblin et al. (1982) reported anemia, leukopenia, and thrombocytopenia in patients with the Norrbottnian type of Gaucher disease. Splenectomy resulted in improvement of these hematologic parameters.

Erikson and Wahlberg (1985) found that patients with the Norrbottnian type of Gaucher disease showed horizontal gaze abnormalities during the first 10 years of life, similar to congenital oculomotor apraxia. Other ocular features included squint, white retinal infiltrations, and myopia.

Gross-Tsur et al. (1989) reported 2 sisters, aged 6.5 and 5.5 years, respectively, in whom the presenting sign of Gaucher disease was oculomotor apraxia. The authors noted that the oculomotor deficit in Gaucher disease is usually characterized by failure of volitional horizontal gaze with preservation of vertical ocular movements.

Raja et al. (2007) reported 2 brothers with Gaucher disease diagnosed as adults who both developed severe parkinsonism, cognitive impairment, and mood disorders. They were of southern Italian descent, and consanguinity was suspected. One brother presented with symptoms of bipolar disorder at age 49 and developed parkinsonism a few months later. Further studies showed brain hyperintensities on MRI and EEG abnormalities. The second brother presented with depressive symptoms at age 49 that worsened over the following years. He then developed parkinsonism with dystonic features. Both patients also had biliary lithiasis. The first brother had a history of meningitis, and at least 2 presumably unaffected family members had depression. Genetic analysis identified a homozygous mutation (606463.0001) in the GBA gene in both brothers. Raja et al. (2007) suggested that some Gaucher patients may develop motor or cognitive neurologic symptoms later in life.

Benko et al. (2008) reported an unusual case in which a 3-year-old boy had both Gaucher disease type III, resulting from a homozygous mutation in the GBA gene (L444P; 606463.0001) on chromosome 1q22, and Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), resulting from a homozygous mutation in the MPZ gene (159440) on chromosome 1q23.3. Further analysis showed that the father also carried the MPZ mutation and had CMT1B, and that the boy had complete paternal isodisomy of chromosome 1 with no evidence of the maternal chromosome 1. Benko et al. (2008) noted the atypical form of inheritance as well as the unique molecular mechanism of 2 concurrent mendelian disorders in this patient.

Clinical Variability
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 and 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. Neurologic features included spasticity with persistent retroflexion of the neck, convergent strabismus, oculomotor apraxia, and abnormal MRI changes. Genetic analysis identified homozygosity for a complex allele containing 2 GBA mutations in cis (H255Q and D409H; see 606463.0047).

Mapping
In 10 Swedish families with the Norrbottnian form of Gaucher disease, Dahl et al. (1988) found linkage to an MspI polymorphism in the GBA gene. The results suggested that the mutation occurred only once in the Swedish population.

Clinical Management
Svennerholm et al. (1991) described the beneficial effects of bone marrow transplantation in Gaucher disease type III.

Erikson et al. (1995) reported that infusion therapy with a macrophage-targeted glucosylceramidase decreased hepatosplenomegaly, normalized hematologic parameters, and prevented progression of neurologic deterioration in all 8 of their patients treated from 13 to 29 months.

Rice et al. (1996) reported a 5-year-old patient with type III Gaucher disease who was treated with enzyme replacement therapy at a dose of 60 U/kg every 2 weeks since age 2.5 years and showed no progression of neurologic involvement. Two other type III patients who were treated at the same dose beginning at ages 14 years and 41 years, respectively, showed no measurable neurologic change.

Vellodi et al. (2001) reported a European consensus on the management of neuronopathic 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.

Schiffmann et al. (2008) reported the results of a randomized control study of miglustat, a substrate reduction therapy that inhibits glucosylceramide synthase (UGCG; 602874), in 30 adult patients with Gaucher disease type III. Twenty-nine patients received enzyme replacement therapy during the 24-month study period. There were no significant differences in vertical saccadic eye movement velocity or in other neurologic or neuropsychologic evaluations between the patients who received miglustat and those who did not. Organ volumes and hematologic parameters remained stable in both treatment groups. However, patients receiving miglustat showed some improvement in pulmonary function and decrease of chitotriosidase (600031) levels compared to patients receiving enzyme replacement therapy alone. Schiffmann et al. (2008) concluded that this therapy did not appear to have significant benefits on the neurologic manifestations of GD type III, but may have positive effects on systemic disease.

Molecular Genetics
Dahl et al. (1990) showed that the Norrbottnian form of Gaucher disease is caused by homozygosity for the leu444-to-pro (L444P; 606463.0001) mutation in the GBA gene.

Koprivica et al. (2000) found that homozygosity for L444P was associated with type III Gaucher disease.

Park et al. (2003) studied 16 patients with Gaucher disease type III who were part of a rare patient subgroup manifesting progressive myoclonic epilepsy (IIIA). Fourteen different genotypes were found, yet there were several shared alleles, including V394L (606463.0005), G377S (606463.0040), and N188S (606463.0026). The genotypes differed from those found in most patients with type III, and some of the shared alleles in these patients had previously been associated with nonneuronopathic Gaucher disease. Western studies showed that the patients lacked the processed 56-kD enzyme isoform usually indicative of neuronopathic disease. Although the genotype spectrum was distinct from the rest of Gaucher type III disease,Park et al. (2003) concluded that lack of a specific shared genotype and the variability of clinical presentations indicated a contribution by other genetic and environmental modifiers.

Population Genetics
The Swedish families with the Norrbottnian type of Gaucher disease are found in 2 geographically distinct clusters. {6,5:Dahl et al. (1990; 1993}) demonstrated that both clusters are caused by the same GBA mutation (L444P). Mutation analysis was combined with a genealogic reconstruction of 19 contemporary index families. Each cluster was traced back to a single ancestral couple who were not known to be related to each other; however, the molecular studies were considered compatible with a single founder who arrived in northern Sweden in or before the 16th century. There was a single connection between the 2 pedigrees as published: the mother of an affected individual in one cluster came from the other isolate.

Animal Model
Sun et al. (2010) backcrossed saposin C (PSAP; 176801)-deficient mice (C -/-) to point-mutated GCase (V394L/V394L) (606463.0005) mice. The resultant mice (4L;C*) began to exhibit CNS abnormalities at 30 days, and death occurred at 48 days due to neurological deficits. Axonal degeneration was evident in brain stem, spinal cord, and white matter of cerebellum accompanied by increasing infiltration of the brain stem, cortex, and thalamus by microglial cells and activation of astrocytes. Electron microscopy showed inclusion bodies in neuronal processes and degenerating cells. Accumulation of p62 (SQSTM1; 601530) and Lamp2 (309060) were prominent in the brain, suggesting the impairment of autophagosome/lysosome function. This phenotype was different from either V394L/V394L or C -/- alone. Relative to V394L/V394L mice, 4L;C* mice had diminished GCase protein and activity. Marked increases of glucosylsphingosine (GS) and moderate elevation of glucosylceramide (GC) were found in 4L;C* brains. Visceral tissues had increases of GS and GC, but no storage cells were found. Neuronal cells in thick hippocampal slices from 4L;C* mice had significantly attenuated long-term potentiation, presumably resulting from substrate accumulation. The 4L;C* mouse mimicked the CNS phenotype and biochemistry of some type 3 (subacute neuronopathic) variants of Gaucher disease.

(文献)
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