疾患詳細

疾患詳細





#137440
Gerstmann-Straussler disease (GSD)
(Encephalopathy, subacute spongiform, Gerstmann-Straussler type)
(Gerstmann-Straussler-Scheiker disease; GSSD)
(Cerebellar ataxia, progressive dementia, and amyloid deposits in CNS)
(Amyloidosis, cerebral, with spongiform encephalopathy)
(Prion dementia)

Gerstmann-Straussler 病 (GSD)
(脳症, 亜急性海綿状, Gerstmann-Straussler 型)
(Gerstmann- Straussler- Scheiker 病; GSSD)
(小脳性運動失調-進行性認知症-中枢神経へのアミロイド沈着
(アミロイドーシス, 大脳-海綿状脳症)
(プリオン認知症)
指定難病23 プリオン病

責任遺伝子:176640 Prion- related protein (PRNP) <20p13>
遺伝形式:常染色体優性

(症状)
(GARD)
 
 Adult onset (成人発症) [HP:0003581]
 Aggressive behavior (攻撃的行動) [HP:0000718] [02200]
 Apraxia (失行症) [HP:0002186] [028]
 Areflexia (無反射) [HP:0001284] [0242]
 Autosomal dominant inheritance (常染色体優性遺伝) [HP:0000006]
 Bradykinesia (寡動) [HP:0002067] [02608]
 Cerebellar atrophy (小脳萎縮) [HP:0001272] [16013]
 Dementia (認知症) [HP:0000726] [0123]
 Depressivity (うつ) [HP:0000716] [0206]
 Dysarthria (構音障害) [HP:0001260] [0230]
 Emotional lability (情緒不安定) [HP:0000712 ) [02205]
 Gait ataxia (歩行失調) [HP:0002066] [028]
 Hyperreflexia (反射亢進) [HP:0001347] [0241]
 Impaired smooth pursuit (円滑な追視障害) [HP:0007772] [0695]
 Limb ataxia (四肢運動失調) [HP:0002070] [028]
 Lower limb muscle weakness (下肢筋力低下) [HP:0007340] [0270]
 Memory impairment (記憶障害) [HP:0002354] [0123]
 Myoclonus (ミオクローヌス) [HP:0001336] [02612]
 Neurofibrillary tangles (神経線維のもつれ) [HP:0002185]
 Parkinsonism (パーキンソニズム) [HP:0001300] [028]
 Perseveration (固執) [HP:0030223] [02202]
 Personality changes (性格変化) [HP:0000751] [02217]
 Psychosis (精神病) [HP:0000709] [0206]
 Rapidly progressive (急速進行性) [HP:0003678]
 Rigidity (固縮) [HP:0002063] [0240]
 Spasticity (痙縮) [HP:0001257] [0241]
 Tremor (振戦) [HP:0001337] [02604]
 Truncal ataxia (体幹失調) [HP:0002078] [028]
 Weight loss (体重喪失) [HP:0001824] [01411]

(UR-DBMS)
【一般】*進行性痴呆
 ある患者は脳波で periodic wave complexes をもつ
 けいれん
 下腿痛
 嚥下困難
 後半に急速な体重減少
【神経】小脳失調
 失調歩行 (40歳代で発症)
 体幹失調
 四肢失調
 構音障害
 パーキンソン症状
 固縮
 動作緩慢
 振戦
 失行
 痙性
 反射亢進
 ミオクローヌス
 保続症
 性格変化
 攻撃行動
 情緒不安定
 うつ
 精神病
 *下肢反射欠損
 下肢虚弱
 車椅子生活
 断節言語
 共同運動失調
 開扇反射
 アミロイド様局面, びまん性, PrP へ免疫反応性
 アミロイド様局面は APP (104760) へは免疫反応なし
 Neurofibrillary tangles があるかも
 海綿様変化は軽度またはなし
【眼】眼振
 スムースな追跡眼球運動の障害
【骨盤】(先天性股関節異形成)
【X線】小脳萎縮
 軽度のびまん性脳萎縮
【検査】中枢神経系全体のアミロイド局面
 皮質脊髄変性
 海綿状変性
 星状細胞グリオーシス
【その他】成人発症, 通常歳代〜30歳代だが50歳代までみられる
 急速に進行性だが, Creutzfeldt-Jakob 病 (123400) より緩徐である
 平均有病期間は7年
 Creutzfeldt-Jakob 病より有病期間は長い

(要約) 遺伝性プリオン病
(遺伝可能な海綿状脳症)
●遺伝性プリオン病は, 一般的に, 認知障害, 運動失調, およびミオクローヌス (筋群+/-全四肢の急激なけいれん)としてみられる
 これらの特徴や他の神経学的および精神的所見の出現順序+/-優位性は多様である
 家族性 Creutzfeldt-Jakob 病 (fCJD), Gerstmann-Sträussler-Scheinker (GSS) 症候群, および致死性家族性不眠 (FFI) が遺伝性プリオン病の核となる表現型である
 4番目の臨床表現型である Huntington 病様-1 (HDL-1) が提唱されているが, 1報告のみであり, 基盤となる病理所見は GSSに分類されるものである
 これらの4つのサブタイプは, オーバーラップする臨床および病理学的特徴を示すことが明らかであるが, これらの表現型は予測される臨床経過を説明するのに有用である
 発症年齢は, 20歳代〜80歳代の範囲である
 経過は2-3か月から数年 (典型的には5-7年, まれに10年以上) である
●診断:PRNP の病的バリアントが確定に必要
 PRNP 病的変異がないことで診断を除外できない
●治療:けいれん (diphenylhydantoin, carbamazepine): ミオクローヌス (clonazepam); 嚥下障害 (経管栄養)
 手術道具の汚染に注意
●治験薬:quinacrine (CJD, 無効?)
 抗PrP抗体, RNA inhibitorsによる遺伝子沈黙, 抗アミロイド剤:動物実験段階
●遺伝:常染色体優性
●臨床診断
○臨床症状
 認知症, 精神症状, 協調運動障害 (運動失調, 構音障害), ミオクローヌス, 筋力低下+/-痙性, 舞踏病, 卒中様エピソード, けいれん, 自律神経障害
○神経学的所見
 脳の皮質および深部核全体にびまん性に分布する海綿状変性とアストログリア増加 (fCJD)
 抗プリオン蛋白 (PrP) 抗体と結合する多発性アミロイド局面 (GSS)
 比較的海綿状変性がなく, 視床と脳幹下部オリーブ核内のニューロン喪失とグリオーシスの存在 (FFI)
○家族歴:常染色体優性
○PRNP 病的バリアントの存在
●CJDの改訂WHO診断基準→散発性CJD用である
●家族性 Creutzfeldt-Jakob 病
 進行性錯乱と記憶障害が最初に生じ, 運動失調とミオクローヌスが続く
 典型的には30-50歳代で生じるが, 少数は30歳未満や80歳代で発症する
 発症から死亡までの経過は2-3か月〜5年である
 末期には, 患者は寝たきり, 唖およびミオクローヌス以外は無動となる
 認知障害は最初は軽度の錯乱か, 特定の皮質機能 (言語や建設能など) に特異的であるが, 結果として全般的認知症となる
 進行するにつれ, 神経行動症状は非常に多様となる
 妄想や幻覚などの精神症状も生じうる
 運動失調は, 体幹性または四肢性で, 不安定歩行, 不器用, または進行性構音障害としてみられる
 運動失調が進行するにつれ, 繰り返し転倒し, 車椅子が必要となる
 ミオクローヌスは一般的に認知障害が明らかとなった後に生じる
 →1四肢に巣状に生じるが, 後に全身性となる
 "驚愕ミオクローヌス"が手をたたくまたは室内灯をつけるなどの単純な行動や騒音により誘発されるかもしれない
 巣状または全身性筋力低下, 固縮, 寡動, 振戦, 舞踏病, 他人の手症候群, 卒中様症状, 視力障害, けいれんなどが報告されている
●Gerstmann-Sträussler-Scheinker 症候群 (GSS)
 典型的には30-50歳代で小脳機能障害 (不安定歩行や軽度の構音障害) が潜行性に発症する
 認知障害は早期には明らかではないが, 進行につて, 精神緩慢が明らかとなる
 錐体路 (痙性)+/-錐体外路症状 (寡動, 筋緊張亢進+/-歯車様運動)と仮面様顔貌も多く見られる
 精神または行動異常は非典型的である
 疾患は比較的緩徐に進行するが, 2-3年〜7年または以上の経過で進行する
 小脳機能障害は, 重度の構音障害, 歩行および四肢失調, 眼球ジスメトリア, 嚥下協調運動喪失となる
 認知低下 (特に集中) が末期で進行するにつれ明らかとなる
 末期では, 患者は運動失調のため寝たきりとなり, 嚥下障害のため摂食できず, 最重度構音障害のため会話できないが, 自分こ状態はわかっている
  小脳→脳幹→大脳の順の進行による
●致死性家族性不眠 (FFI)
 典型的には中年 (40-50歳代) に不眠が潜行性または亜急性発症する
 最初は, 軽度の次により重度の全睡眠時間の減少としてみられる
 睡眠した時は, 明瞭な夢をみることが多い
 次に自律神経障害が生じる→血圧上昇, エピソード性過換気, 過剰な発見, 泌尿生殖器機能障害, +/-基礎体温の変化
 脳幹病変のサイン (上方視能減少, 二重視, けいれん性追跡眼球運動, 構音障害)もみられる
 次に, 患者は体幹+/-四肢運動失調を生じる
 思考過程の速度も減少する
 記憶障害は多様である
 進行するにつれ, 睡眠時間はより減少し, 運動失調は悪化し, 最重度の錯乱が生じ, 愚鈍の状態のまま覚醒した状態となり死亡する
 典型的疾患期間は12-16か月である
●頻度:遺伝的および非遺伝的プリオン病 1-5/100万人 (遺伝型はその約10%)
 最も多い疾患関連PRNPバリアント= p.Glu200Lys →中東 (リビアのユダヤ人), スロバキア
 p.Asp178Asn→全世界で
 イタリア人では18%が p.Val210Ile, p.Glu200Lys

<指定難病23 プリオン病>
1.概要
 プリオン病は, 正常プリオン蛋白が何らかの理由で伝播性を有する異常プリオン蛋白に変化し, 主に中枢神経内に蓄積することにより急速に神経細胞変性を起こすまれな致死性疾患である。プリオン病の代表的なタイプである孤発性クロイツフェルト・ヤコブ病(Creutzfeldt-Jakob disease:CJD)は, 1年間に100万人に1人程度の割合で発症することが知られている。ヒトのプリオン病は病因により, 原因不明の特発性(孤発性CJD(sporadic CJD:sCJD)), プリオン蛋白遺伝子変異による遺伝性(家族性CJD, ゲルストマン・ストロイスラー・シャインカー病(Gerstman-Sträussler-Scheinker:GSS), 致死性家族性不眠症(fatal familial insomnia:FFI)), 他からのプリオン感染による獲得性(environmentally acquired)(クールー, 医原性, 変異型(variant Creutzfeldt-Jakob disease:vCJD))の3種類に分類される。プリオン病は, 人獣共通感染症であり, ヒト以外では, 牛の牛海綿状脳症(BSE)などが知られている。
2.原因
 プリオン蛋白(PrP)は正常の人でも脳に発現しているが, その機能に関しては諸説があり, まだ分かっていない。正常PrPはPrPCと称されており蛋白分解酵素で消化される。一方, プリオン病の脳内に見られる異常なPrPはPrPScと呼ばれ, 蛋白分解酵素で消化されにくい。PrPScは, PrPCに比べアミノ酸配列は同一であるが立体構造が異なっており, βシート構造がより豊富なため不溶性となり, 凝集しやすいというアミロイドの性質を有している。
 獲得性プリオン病ではPrPCに外来のPrPScが接触してPrPCがPrPScに変換する連鎖反応を介して, 脳内に蓄積して発病すると考えられているが, 変換の機序に関しては複数の説があり, 機序の解明と感染性の不活化のための様々な研究が行われている。
 遺伝性CJDでは, PrP遺伝子の変異がアミノ酸配列に変異を起こし, PrPの高次構造が変化しやすいため, PrPScが産生されやすいと考えられている。
3.症状
 CJDの臨床病期は一般に3期に分けられる。
(1) 第1期:倦怠感, ふらつき, めまい, 日常生活の活動性の低下, 視覚異常, 抑鬱傾向, もの忘れ, 失調症状等の非特異的症状。
(2) 第2期:認知症が急速に顕著となり, 言葉が出にくくなり, 意思の疎通ができなくなって, ミオクローヌスが出現する。歩行は徐々に困難となり, やがて寝たきりとなる。神経学的所見では腱反射の亢進, 病的反射の出現, 小脳失調, ふらつき歩行, 筋固縮, ジストニア, 抵抗症(gegenhalten), 驚愕反応(startle response)等が認められる。
(3) 第3期:無動無言状態から更に除皮質硬直や屈曲拘縮に進展する。ミオクローヌスは消失。感染症で1~2年程度で死亡する。
4.治療法
 治療法は未確立である。
5.予後
孤発性症例では進行が速く1~2年で死亡する。遺伝性CJDや一部の孤発性CJDは進行が遅く数年に及ぶものもある。

<指定難病診断基準>
1.診断上、脳血管造影などの画像診断は必須であり、少なくとも次の所見がある。
(1)頭蓋内内頸動脈終末部を中心とした領域に狭窄又は閉塞がみられる。
(2)もやもや血管(異常血管網)が動脈相においてみられる。

2.もやもや病(ウィリス動脈輪閉塞症)は原因不明の疾患であり、下記に伴う類似の脳血管病変は除外する。
(1)動脈硬化が原因と考えられる内頸動脈閉塞性病変
(2)自己免疫疾患
(3)髄膜炎
(4)脳腫瘍
(5)ダウン症候群
(6)フォンレックリングハウゼン病
(7)頭部外傷
(8)頭部放射線照射の既往
(9)その他

【画像診断法】
 1.もやもや病(ウィリス動脈輪閉塞症)の確定診断に脳血管造影は必須である。特に、片側性病変や動脈硬化を合併する病変の場合には脳血管造影を行うことが必須である。

 2.ただし、MRIでは1.5テスラ(T)以上((3.0Tでは更に有用))の静磁場強度の機種を用いたTOF(Time of Flight)法により、以下の所見を見た場合には、Definite(確定診断)としてよい。
 (1) MRAで頭蓋内内頸動脈終末部に狭窄又は閉塞がみられる。
 (2) MRAで大脳基底核部に異常血管網がみられる。
 注:MRI上、大脳基底核部に少なくとも一側で2つ以上の明らかなflow voidを認める場合、もやもや血管(異常血管網)と判定してよい。

表:MRI・MRA (magnetic resonance imaging・angiography)による画像診断のための指針
(1)磁気共鳴画像(MRI)と磁気共鳴血管画像(MRA)により、通常の脳血管撮影における診断基準に照らして、下記の全ての項目を満たしうる場合は、通常の脳血管撮影は省いてもよい。
 ①頭蓋内内頸動脈終末部、前及び中大脳動脈近位部に狭窄又は閉塞がみられる。
 ②大脳基底核部に異常血管網がみられる。
 ③ ①と②の所見が両側性にある。
(2)撮像法及び判定
 ①磁場強度は1.0T以上の機種を用いることが望ましい。
 ②MRA撮像法は特に規定しない。
 ③磁場強度・撮像法・造影剤の使用の有無などの情報をもやもや病臨床調査個人票に記入すること。
 ④MRI上、両側大脳基底核部に少なくとも一側で2つ以上の明らかな flow voidを認める場合、異常血管網と判定してよい。
 ⑤撮像条件により病変の過大・過小評価が起こり疑陽性病変が得られる可能性があるので、確診例のみを提出すること。
(3)成人例では他の疾患に伴う血管病変と紛らわしいことが多いので、MRI・MRAのみでの診断は小児例を対象とすることが望ましい。
(4)MRI・MRAのみで診断した場合は、キーフィルムを審査のため提出すること。

注釈
現在、もやもや病の診断は脳血管の形態学的変化に基づいて行われている。片側病変の場合、特に成人例では、動脈硬化性病変等との鑑別を目的に診断基準では脳血管造影を要するとした。一方、もやもや病の家族内発症が多い患者に診断基準に合致しない脳血管変化を有する症例をしばしば経験する。今後、画像、血液検体等からなる各種バイオマーカーにより発症要因に基づいた客観的分類ができる可能性はある。これらの点を考慮し、臨床個人調査票には診断として「1.両側型 2.片側型 3.疑われるが診断基準に該当しない例」の3項目を設けた。

参照
もやもや血管に関して(Fig.1)
脳血管造影検査を行うと、a:脳底部の穿通枝が拡張した血管群から形成されるbasal moyamoya、b:眼動脈から篩骨動脈を経由して前大脳動脈の皮質枝と吻合するethmoidal moyamoya、c:中硬膜動脈から脳表の皮質枝と吻合するvault moyamoyaの所見がもやもや病患者に見られることがある。典型的なもやもや病には、内頸動脈終末部を中心とした閉塞性変化とこれらの特徴的な側副路の発達が観察される。

もやもや病閉塞性変化の病期分類に関して(Fig.2)
脳底部主幹動脈の閉塞性変化の程度により病期を区分する代表的なものに鈴木分類が挙げられる。脳循環は側副路により代償されるため、形態学的に進行したものが臨床的に重症とは必ずしも言えない。現在、診断は形態的特徴により行われているため、初期変化の時点で発見されたものに関しては他疾患による動脈閉塞との鑑別が必要となる。
脳血管撮影上の所見を鈴木分類に従って記載すると以下のようになる。
第1期:Carotid fork狭小期。内頸動脈終末部の狭窄
第2期:もやもや初発期。内頸動脈終末部の狭窄にもやもや血管が見られ始め、中大脳動脈の皮質動脈が拡張して見える(aに相当)。
第3期:もやもや増勢期。もやもや血管が増勢し前大脳動脈、中大脳動脈群が脱落し始める(bに相当)。
第4期:もやもや細微期。もやもや血管は退縮し、前大脳動脈、中大脳動脈群がほとんど見えなくなる。後大脳動脈が脱落し始める(cに相当)。
第5期:もやもや縮小期。内頸動脈系主幹動脈がほとんど消失(dに相当)
第6期:もやもや消失期。外頸動脈および椎骨動脈系よりのみ血流保全(dに相当)

(責任遺伝子) *176640 Prion- related protein (PRNP) <20p13>
(1) Creutzfeld-Jacob disease (123400)
.0001 Creutzfeld-Jacob disease (Gerstmann-Straussler disease, included) (Huntington disease-like 1, included) [PRNP, EXTRA OCTAPEPTIDE CODING REPEATS] (rs193922906) (RCV000014326...) (Owen et al. 1989, 1990; Collinge et al. 1989; Poulter et al. 1992; Goldfarb et al. 1991; Krasemann et al. 1995; Campbell et al. 1996; Laplanche et al. 1999; Lewis et al. 2003; Pietrini et al. 2003; Nishida et al. 2004; Chiesa et al. 2000)
.0006 Creutzfeld-Jacob disease (Fatal familial insomnia, included) [PRNP, GLU200LYS] (rs28933385) (gnomAD:rs28933385) (RCV000014335...) (Goldgaber et al. 1989; Goldfarb et al. 1990; Mitrova et al. 1990; Goldfarb et al. 1991; Gajdusek 1991; Goldfarb et al. 1994; Bertoni et al. 1992; Meiner et al. 1997; Lee et al. 1999; Colombo 2000; Simon et al. 2000; Chapman et al. 1996; Taratuto et al. 2002)
.0007 Creutzfeld-Jacob disease (Fatal familial insomnia, included) [PRNP, ASP178ASN AND MET129VAL] (rs1799990) (rs74315403) (gnomAD:rs1799990
RCV000014331...) (Goldfarb et al. 1991; Nieto et al. 1991; Goldfarb et al. 1992; Brown et al. 1992; Laplanche et al. 1992; Riek et al. 1998; Goldfarb et al. 1992; Kretzschmar et al. 1995; Dagvadorj et al. 2002; Zarranz et al. 2005; Dossena et al. 2008)
.0014 Creutzfeld-Jacob disease [PRNP, VAL210ILE] (rs74315407) (gnomAD:rs74315407) (RCV000014342...) (Pocchiari et al. 1993; Mouillet-Richard et al. 1999)
.0016 Creutzfeld-Jacob disease [PRNP, VAL180ILE] (rs74315408) (gnomAD:rs74315408) (RCV000020249...) (Kitamoto et al. 1993; Jin et al. 2004)
.0023 Creutzfeld-Jacob disease [PRNP, ARG208HIS] (rs74315412) (gnomAD:rs74315412) (RCV000014352...) (Mastrianni et al. 1996; Capellari et al. 2005; Basset-Leobon et al. 2006)
.0030 Creutzfeld-Jacob disease [PRNP, GLU211GLN] (rs398122370) (RCV000074468) (Peoc'h et al. 2012)
(2) Gerstmann-Straussler disease (137440)
.0002 Gerstmann-Straussler disease [PRNP, PRO102LEU] (rs74315401) (RCV000014329...) (Hsiao et al. 1989; Goldgaber et al. 1989; Speer et al. 1991; Kretzschmar et al. 1991; Goldfarb et al. 1990; Goldhammer et al. 1993; Doh-ura et al. 1990; Parchi et al. 1998; Mishra et al. 2002)
.0004 Gerstmann-Straussler disease [PRNP, ALA117VAL] (rs74315402) (RCV000014330...) (Doh-ura et al. 1989; Mastrianni et al. 1995; Hegde et al. 1998; Mallucci et al. 1999)
.0011 Gerstmann-Straussler disease [PRNP, PHE198SER] (rs74315405) (RCV000020252...) (Hsiao et al. 1992; Farlow et al. 1989; Vanik and Surewicz 2002)
.0012 Gerstmann-Straussler disease [PRNP, GLN217ARG] (rs74315406) (RCV000014341...) (Hsiao et al. 1992)
.0015 Gerstmann-Straussler disease [PRNP, PRO105LEU] (rs11538758) (RCV000014343...) (Yamada et al. 1993)
.0021 Gerstmann-Straussler disease [PRNP, GLY131VAL] (rs74315410) (gnomAD:rs74315410) (RCV000014351) (Panegyres et al. 2001)
.0024 Gerstmann-Straussler disease (Spongioform encephalopathy with neuropsychiatric features, included) [PRNP, HIS187ARG] (rs74315413) (RCV000014353...) (Cervenakova et al. 1999; Butefisch et al. 2000; Hall et al. 2005)
.0026 Gerstmann-Straussler disease [PRNP, ALA133VAL] (rs74315415) (RCV000014356) (Rowe et al. 2007)
.0027 Gerstmann-Straussler disease [PRNP, PRO105SER] (rs74315414) (gnomAD:rs74315414) (RCV000014357...) (Tunnell et al. 2008)
.0029 Gerstmann-Straussler disease [PRNP, GLU211ASP] (rs398122413) (RCV000074467) (Peoc'h et al. 2012)
.0034 Gerstmann-Straussler disease [PRNP, GLN227TER] (rs17852079) (RCV000074472) (Jansen et al. 2010)
(3) Prion disease, susceptibility to
.0005 Prion disease, susceptibility to (Alzheimer disease, early-onset, susceptibility to, included) (Aphasia, primary progressive, susceptibility to, included) [PRNP, MET129VAL] (rs1799990) (gnomAD:rs1799990) (RCV000014331...) (Doh-ura et al. 1989; Collinge et al. 1991; Palmer et al. 1991; Doh-ura et al. 1991; De Silva et al. 1994; Goldfarb et al. 1992; Monari et al. 1994; Aguzzi 1997; Cervenakova et al. 1998; Deslys et al. 1998; Riek et al. 1998; Head et al. 2001; Plaitakis et al. 2001; Erginel-Unaltuna et al. 2001; Petchanikow et al. 2001; Brandel et al. 2003; Croes et al. 2004; Wadsworth et al. 2004; Jeong et al. 2005; Papassotiropoulos et al. 2005; Zan et al. 2006; Mead et al. 2009)
Alzheimer Disease and Dementia
(Croes et al. 2003; Riemenschneider et al. 2004; Combarros et al. 2000; Casadei et al. 2001; Ohkubo et al. 2003; Li et al. 2005)
(4) Fatal familial insomnia (600072)
.0010 Fatal familial insomnia (Creutzfeld-Jacob disease, included) [PRNP, ASP178ASN AND MET129] (rs74315403) (RCV000014331...) (Goldfarb et al. 1992; Medori et al. 1992; Medori and Tritschler 1993; Tateishi et al. 1995; Spacey et al. 2004; Dauvilliers et al. 2004; Rodriguez-Martinez et al. 2005; Zarranz et al. 2005; Saitoh et al. 2010)
(5) Spongioform encephalopathy with neuropsychiatric features (606688)
.0022 Spongioform encephalopathy with neuropsychiatric features [PRNP, THR183ALA] (rs74315411) (RCV000014347...) (Nitrini et al. 1997)
.0025 Spongioform encephalopathy with neuropsychiatric features [PRNP, PRO105THR] (rs74315414) (gnomAD:rs74315414) (RCV000014355...) (Rogaeva et al. 2006)
(6) Kuru, protection against (245300)
.0028 Kuru, protection against [PRNP, GLY127VAL] (rs267606980) (gnomAD:rs267606980) (RCV000014358) (Mead et al. 2009; Asante et al. 2015)
(7) Cerebral amyloid angiopathy, PRNP-related (137440)
.0031 Cerebral amyloid angiopathy, PRNP-related [PRNP, TYR145TER] (rs80356710) (RCV000020245...) (Ghetti et al. 1996)
.0032 Cerebral amyloid angiopathy, PRNP-related [PRNP, GLN160TER] (rs80356711) (RCV000020246...) (Jayadev et al. 2011)
.0033 Cerebral amyloid angiopathy, PRNP-related [PRNP, TYR226TER] (rs398122414) (RCV000074471) (Jansen et al. 2010)
.0035 Cerebral amyloid angiopathy, PRNP-related [PRNP, TYR163TER) (rs1555782101) (RCV000074473) (Revesz et al. 2009; Mead et al. 2013)

.0003 REMOVED FROM DATABASE
.0008 MOVED TO 176640.0005
.0009 REMOVED FROM DATABASE
.0013 MOVED TO 176640.0006
.0017 Reclassified - variant of unknown significance [PRNP, MET232ARG] (rs74315409) (gnomAD:rs74315409) (RCV000014345...) (Beck et al. 2010; Beck et al. 2012) (formerly titled Creutzfeld-Jacob disease and Dementia, Lewy body, included) (Kitamoto et al. 1993; Koide et al. 2002; Soldevila et al. 2006)
.0018 Reclassified - variant of unknown significance [PRNP, ASN171SER] (rs16990018) (gnomAD:rs16990018) (RCV000014348...) (Beck et al. 2010) (formerly titled Spongioform encephalopathy with neuropsychiatric features and Epilepsy, focal, due to cortical malformation, susceptibility to, included) (Samaia et al. 1997; Walz et al. 2003; Walz et al. 2004)
.0019 Reclassified - variant of unknown significance [PRNP, GLU219LYS] (rs1800014) (gnomAD:rs1800014) (RCV000020257...) (Beck et al. 2010; Lukic et al. 2010) (formerly titled Creutzfeld-Jacob disease, protection against) (Shibuya et al. 1998; Shibuya et al. 1998; Soldevila et al. 2003; Nishida et al. 2004; Nishida et al. 2004; Jeong et al. 2005; Lukic et al. 2010
.0020 MOVED TO 176640.0001

*PRNP: Prion-related protein (253 amino acids)
・PRNPタンパクは, 膜のglycosylphosphatidylinositol固定性糖タンパクで, 杆状体構造に集簇する傾向がある
・PRNPタンパクは, 5つの縦裂5ペプチドリピートの非常に不安定な領域を含む
・PRNP遺伝子は20番染色体のこの遺伝子に生物学的および構造的に類似した遺伝子の約 20 kb 上流に位置する
・リピート領域やその他の部位の変異は Creutzfeldt-Jakob 病, 致死性家族性不眠症, Gerstmann-Straussler 病, Huntington 病様1およびクールーと連関する
・この遺伝子とオーバーラップする ORF が発見されている (より小さな構造的に無関係のタンパク, AltPrp)
・多くの転写バリアントがある
・ニューロン発生とシナプス可塑性で役割をもつ
・ニューロン髄鞘の維持に必要かもしれない
・鉄アップテークと鉄ホメオスターシスで役割をもつかもしれない
・可溶性のオリゴマーは培養神経芽腫細胞に毒性がありアポトーシスを誘導する

(ノート)
●(#) は,Gerstmann-Straussler 病 (GSD) と大脳アミロイド血管症の1つの型は 20p13の prion protein 遺伝子 (PRNP; 176640)のヘテロ接合変異が原因なため

●Creutzfeldt-Jakob 病 (CJD; 123400) と家族性致死性不眠症 (FFI; 600072) は PRNP 遺伝子変異が原因の他の2つの遺伝性プリオン病である

●Gerstmann-Straussler 病はまれな遺伝性プリオン病で、記憶喪失、認知症、運動失調および脳でのアミロイド様局面の病的蓄積の成人発症が特徴である (Gerstmann et al., 1936)
 Gerstmann-Straussler 病は、典型的には、20〜30歳代での、進行性四肢および体幹失調、構音障害、および認知低下としてみられる
 平均疾患期間は7年である
 GSS は CJD とは、早期発症年齢、長い疾患期間、および目立つ小脳失調により区別できる (Masters et al., 1981)

● Hsiao et al. (1989) は、臨床および病理学的基準をもとに、Gerstmann-Straussler 症候群は2つの型に分類できると示唆した
 '運動失調'型
 '認知症'型
 神経線維のもつれの病的量を伴う認知症型
 しかし、これらの区別は本疾患の提示と進行の表現型多様性を強調するにすぎないかもしれない (Panegyres et al., 2001).

Clinical Features
Seitelberger (1962) described a kindred with a unique neurologic disorder traced through 5 generations. Plaque-like deposits were found in the cerebral cortex, basal ganglia, and (most extremely) all layers of the cerebellum. Clinically and pathologically the disorder most closely resembled kuru, although the authors noted some differences in the plaque distribution. Kretzschmar et al. (1991) noted that the family reported by Seitelberger (1962) was the same family originally reported by Gerstmann et al. (1936).

Peiffer (1982) described a family of sheepbreeders in which a father and 2 sons had GSD. All 3 also had congenital hip dysplasia, as did at least 3 other members of the kindred, all females. The main clinical features included ataxia, dysarthria, and personality changes. Peiffer (1982) noted that GSD was characterized neuropathologically by large plaques distributed throughout the cerebral cortex, basal ganglia, and white matter.

Hudson et al. (1983) reported a family in which Gerstmann-Straussler disease occurred in 3 members of 2 generations. The clinical picture included visual loss in 1 patient and sensory loss in another patient. Dementia only occurred late in the illness in 2 patients. Neuropathologic examination showed multicentric amyloid plaques in the cerebral and cerebellar cortices, basal ganglia, and white matter, as well as degeneration of the corticospinal tract, spinocerebellar tract, and dorsal columns. Spongiform changes were limited to the superficial cerebral cortex. Vinters et al. (1986) presented the postmortem neuropathologic findings in 1 of the patients reported byHudson et al. (1983). The disorder had lasted 8 years. There were severe spongy changes in the neocortex, extensive and often large amyloid deposits throughout the cerebral hemispheres and cerebellum, and severe astrocytic gliosis throughout all areas of gray and white matter within the brain. The degree of cortical spongy change was much greater than that in relatives who died with a similar clinical history.

Farlow et al. (1989) reported a large kindred from Indiana with Gerstmann-Straussler disease inherited in an autosomal dominant pattern. Sixty-four patients showed progressive ataxia, dementia, and parkinsonism with onset in the late thirties to early sixties. Early features included impaired smooth pursuit eye movements, impaired short-term memory, and clumsiness of the hands. In late stages of the disease, there was dementia, psychosis, and/or severe depression with weight loss. Death occurred 6 months to 2 years after onset. Farlow et al. (1989) noted that the neuropathologic findings in affected members of the Indiana kindred included widespread amyloid plaques in the cerebrum and cerebellum as well as widespread Alzheimer (104300)-like neurofibrillary tangles composed of paired helical filaments in the cerebral cortex and subcortical nuclei. The amyloid core of plaques was immunolabeled with antibodies raised to PrP, but not with antibodies raised to beta-amyloid (APP; 104760). Spongiform changes were mild. The disease in the Indiana kindred was traced to the year 1792 (Farlow et al., 1989;Ghetti et al., 1989). In each of the generations since 1792, affected members had been identified by either history or clinical examination.

Yamada et al. (1999) found intense deposition of prion protein in the posterior horn of the spinal cord but not in the dorsal root ganglia or peripheral nerves in an autopsy of a 38-year-old woman with GSD confirmed by mutation in the PRNP gene (P102L; 176640.0002). The findings seemed to account for the painful dysesthesias and arreflexia seen in this variant of the disorder.

Panegyres et al. (2001) reported a man with GSD confirmed by mutation in the PRNP gene (176640.0021). He had no family history of neurologic disease. At disease onset in his forties, he developed impaired short-term memory function, reduced learning capacity, and personality changes, including emotional immaturity, anxiety, and increasing anger. Neurologic examination showed apraxia, tremor, rigidity, and hyperreflexia, but no ataxia. Eventually he developed ataxia and his dementia progressed. He died at age 51, 9 years after symptom onset. Neuropathologic examination showed mild cerebral and cerebellar atrophy. There were numerous congophilic amyloid plaques throughout the brain that were immunoreactive to PrP. There was no spongiform degeneration; occasional neurofibrillary tangles were seen.

Arata et al. (2006) reported detailed clinical features of 11 individuals from 9 families with GSS, all of whom had the common P102L mutation of the PRNP gene. Age at onset ranged from 38 to 70 years, with an average of 60.2 years. Nine patients presented with gait disturbance, 1 with dysarthria, and 1 with dysesthesia of the lower limbs. Common features of the early stage of disease were unsteady gait, truncal ataxia, painful dysesthesias of the lower limbs, weakness of the proximal lower limbs, loss of deep tendon reflexes, and mild dysarthria. Ten of the 11 patients were initially evaluated by orthopedic surgeons on the suspicion of lumbar spine disease, none of whom diagnosed GSS. Only 1 patient had clear dementia on initial examination. Brain MRIs were normal during the initial stages and no patients had cerebellar changes. However, all patients developed cortical and diffuse brain atrophy with disease progression and onset of dementia. Brain SPECT studies of 5 patients showed hypoperfusion of the occipital lobes and patchy decreased blood flow in the cerebrum, with normal flow in the cerebellum. Arata et al. (2006) concluded that the sites of pathology in this group of patients were in the cerebrum and spinal cord, including the posterior horn and spinocerebellar tracts, instead of the cerebellum proper.

Yamamoto et al. (2007) reported a 72-year-old man with GSS who presented with a 1-year history of progressive limb weakness, aphasia, and apathy. Diffusion-weighted brain MRI at the initial examination showed hyperintense signal changes in the frontal, temporal, occipital, and parietal cortical gyri of both hemispheres, although CT scan showed no abnormalities. His condition deteriorated over the next 8 months, resulting in mutism, akinesia, and spastic tetraplegia. CT scans performed at 2 and 8 months after the initial examination showed remarkable progression of cortical atrophy in the bilateral frontotemporal lobes and hypodense lesions in frontal subcortical areas.

Rowe et al. (2007) reported a 62-year-old woman with a phenotype most consistent with Gerstmann-Straussler disease. The phenotype was somewhat unusual in that she exhibited supranuclear gaze palsy early in the disease course and had absence of myoclonus, lack of 14-3-3 proteins (see 113508) in the CSF, and no significant EEG or MRI findings. The patient later developed more typical features of the disorder with rapid progression to death 4 months after presentation. Postmortem examination showed typical diffuse spongiform encephalopathy with amyloid-like plaques restricted to the cerebellum. Genetic analysis identified a heterozygous mutation in the PRNP gene (176640.0026).

PRNP-Related Amyloid Angiopathy

Ghetti et al. (1996) reported a Japanese woman who developed progressive dementia at age 38 resulting in death at age 59 years and associated with PrP-immunoreactive cerebral amyloid angiopathy. Family history was not contributory. Neuropathologic examination showed severe cortical atrophy with amyloid deposits in the parenchymal and leptomeningeal blood vessels and in the perivascular neuropil, as well as marked tau (MAPT;157140)-immunoreactive neurofibrillary tangles, similar to those observed in Alzheimer disease. Amyloid was also present in the surrounding parenchyma. Amyloid was immunoreactive to PrP, and immunoblot analysis detected mainly a 7.5-kD peptide that was truncated at the N- and C-termini, with immunoreactivity between residues 90 and 147. Amyloid-laden vessels were also labeled by antibodies against the C terminus, suggesting that PrP from the normal allele was also involved in the pathologic process. Genetic analysis revealed a heterozygous truncating mutation in the PRNP gene (Y145X; 176640.0031). Ghetti et al. (1996) noted that abnormal PRNP truncation at a similar site (between residues 144 and 150) occurs in GSS variants in which the amyloid protein has been analyzed, suggesting that this truncated PrP peptide is important for amyloid formation.

Jansen et al. (2010) reported a 57-year-old Dutch woman with PRNP-related cerebral amyloid angiopathy. She presented at age 55 years with a 12-month history of increasing cognitive impairment, forgetfulness, and decreased concentration associated with hallucinations. She also had aphasia, but no extrapyramidal signs, ataxia, or myoclonic jerks. EEG showed generalized slowing with a typical pattern of periodic synchronous wave complexes. The disorder progressed, and she developed parkinsonism as a result of neuroleptic treatment, mutism, akinesia, and myoclonic jerks. She died 27 months after onset. Neuropathologic examination showed severe PRNP-reactive amyloid angiopathy and parenchymal plaques; neurofibrillary tangles were not present, but there were focal tau accumulations. Her mother was diagnosed with probable CJD on the basis of comparable symptoms and signs. Genetic analysis identified a heterozygous truncating mutation in the PRNP gene (Y226X; 176640.0033). The patient was heterozygous for M129V (176640.0005). An unrelated patient had a similar truncating PRNP mutation, Q227X (176640.0034), associated with amyloid plaques and extensive neurofibrillary tangles, but not amyloid angiopathy. Both Y226X and Q227X result in C-terminally truncated proteins lack the GPI anchor and thus cannot localize to the plasma membrane, suggesting that absence of this anchor predisposes to amyloid formation.

Jayadev et al. (2011) reported a woman with onset of progressive memory impairment and depression beginning at age 39 years and resulting in death at age 47. The patient was initially diagnosed with Alzheimer disease. Neuropathologic examination showed frontotemporal atrophy, severe tau-immunoreactive neurofibrillary tangles, and amyloid plaques that were immunoreactive to PRNP. The prion deposits were immunopositive to residues 90-102, but not to 220-231, consistent with C-terminal truncation. Western blot analysis showed a smear of proteinase K-resistant PrP, the most prominent of which was 11 kD. PrP-immunoreactive amyloid angiopathy was observed. There was also immunoreactivity to alpha-synuclein (SNCA; 163890), in the form of Lewy bodies and Lewy neurites. Spongiform changes were not observed. The patient's deceased mother had a history of a similar disorder with later onset and accompanied by severe chronic diarrhea. She was diagnosed with Alzheimer disease, but reexamination of her pathology showed the same abnormalities as observed in her daughter. Genetic analysis identified a heterozygous mutation in the PRNP gene (Q160X; 176640.0032) in the proband and her mother. The proband was heterozygous for M129V, whereas her mother was homozygous for M129. Jayadev et al. (2011) postulated a link between truncating PRNP mutations and the development of a disorder with a relatively prolonged clinical course and features similar to AD.

Pathogenesis
Masters et al. (1981) reported that inoculation of brain tissue from 3 patients with GSD resulted in spongiform encephalopathy in nonhuman primates, supporting a relation to Creutzfeldt-Jakob disease. One of these patients was a member of the family reported by Adam et al. (1982) as an instance of familial cerebral amyloidosis.

Prusiner (1987) reviewed the possible role of prions in GSD as well as in other diseases such as CJD and kuru. Brown et al. (1993) examined the question of whether 'prion dementia' should replace 'spongiform encephalopathy' to accommodate the existence of atypical forms of these 'prion protein' cerebral amyloidoses that may not show spongiform changes in the brain. They tested for the presence of PrP in brain tissue extracts from 46 cases, including 13 familial cases, of nonspongiform dementias with a variety of associated neurologic signs. None of the cases transmitted disease to primates, and none had PrP detectable by Western immunoblots. Brown et al. (1993) concluded that the clinicopathologic limits of prion dementias are, except for a small number of previously reported familial cases, essentially those of spongiform encephalopathy.

Molecular Genetics
In affected members of 2 unrelated families with autosomal dominant inheritance of Gerstmann-Straussler disease, Hsiao et al. (1989) identified a heterozygous mutation in the PRNP gene (P102L; 176640.0002).

In a 36-year-old woman who belonged to the original family reported by Gerstmann et al. (1936) and Seitelberger (1962), Kretzschmar et al. (1991) identified a heterozygous P102L mutation in the PRNP gene.

In affected members of a large Indiana kindred with Gerstmann-Straussler disease reported by Ghetti et al. (1989), Hsiao et al. (1992) identified a mutation in the PRNP gene (176640.0011). Dlouhy et al. (1992) showed absolute linkage of the PRNP mutation to the clinical phenotype in the Indiana kindred. Their studies suggested that patients who were heterozygous for the PRNP met/val129 (176640.0005) polymorphism had a later age of onset of the disease than individuals who were either met129 or val129 homozygotes.

In a patient with GSD, Peoc'h et al. (2012) identified a heterozygous mutation in the PRNP gene (E211D; 176640.0029). The patient was homozygous for val129 (176640.0005). Neuropathologic studies showed typical features of GSS, including multicentric amyloid PrP-immunoreactive plaques, spongiform changes, mild gliosis, and neurofibrillary tangles. Proteinase K-resistant prion protein was found, and immunochemical studies showed accumulation of a C-terminal-truncated PrP fragment (roughly covering residues 80 to 150). Biophysical studies showed that the mutant protein had an increased tendency to aggregate, with a different effect on the PrP structural dynamics compared to the E211Q mutation (176640.0030), which was found in a patient with CJD.

PRNP-Related Amyloid Angiopathy

In a Japanese woman with PrP-immunoreactive cerebral amyloid angiopathy, Ghetti et al. (1996) identified a heterozygous truncating mutation in the PRNP gene (Y145X; 176640.0031). Ghetti et al. (1996) noted that abnormal PRNP truncation at a similar site (between residues 144 and 150) occurs in GSS variants in which the amyloid protein has been analyzed, suggesting that this truncated PrP peptide is important for amyloid formation.

In a patient with PRNP-related cerebral amyloid angiopathy, Revesz et al. (2009) reported a tyr163-to-ter (Y163X) substitution in the PRNP gene. Clinical data was not provided, but neuropathologic studies showed vascular and parenchymal PRNP-immunoreactive amyloid deposition and extensive neurofibrillary tangle pathology.

Jansen et al. (2010) identified a heterozygous truncating mutation in the PRNP gene (Y226X; 176640.0033) in a 57-year-old Dutch woman with PRNP-related cerebral amyloid angiopathy.

Animal Model
Telling et al. (1996) showed that the presence of wildtype PRNP genes, the level of PRNP transgene expression, and the sequence of the transgene can profoundly modify experimental prion disease in a transgenic mouse model with a murine P101L mutation in the Prnp gene, which is homologous to the human P102L mutation. They produced a homozygous animal for the mutant transgene array which caused spontaneous disease in a consistently shorter period of time than in the hemizygous animal. The authors concluded that the murine P101L mutation is required for CNS degeneration, that the clinical and neuropathic phenotypes of transgenic mice can be dramatically altered by ablation of the wildtype Prnp gene, and that this mouse model recapitulated virtually all features of human GSD.

Choi et al. (2010) established a Drosophila model of GSD by expressing mouse prion protein (PrP) with a leucine substitution at residue 101 (MoPrP(P101L)). Flies expressing MoPrP(P101L), but not wildtype MoPrP (MoPrP(3F4)), showed severe defects in climbing ability and early death. Expressed MoPrP(P101L) in Drosophila was differentially glycosylated, localized at the synaptic terminals, and mainly present as deposits in adult brains. Behavioral defects and early death of MoPrP(P101L) flies were not due to caspase-3 (CASP3; 600636)-dependent programmed cell death signaling. In addition, type 1 glutamatergic synaptic boutons in larval neuromuscular junctions of MoPrP(P101L) flies showed significantly increased numbers of satellite synaptic boutons. The amount of bruchpilot and discs large (DLG1; 601014) in MoPrP(P101L) flies was significantly reduced. Brains from scrapie-infected mice showed significantly decreased ELKS (ERC1; 607127), an active zone matrix marker, compared with control mice. The authors proposed that altered active zone structures at the molecular level may be involved in the pathogenesis of GSD in Drosophila and scrapie-infected mice.

(文献)
(1) Gerstmann J, Straussler E, Scheinker I: Ueber eine eigenartige hereditaer-familiaere Erkrankung des Zentralnervensystems. Z. Ges. Neurol Psychiat 154: 736-762, 1936
(2) Seitelberger, F. : Eigenartige familiaer-hereditaere Krankheit des Zentralnervensystems in einer Niederoesterreichischen Sippe (zugleich ein Beitrag zur vergleichenden Neuropathologie des Kuru). Wien. Klin. Wschr. 74: 687-691, 1962
(3) Masters CL et al. Creutzfeldt-Jakob disease virus isolations from the Gerstmann-Straussler syndrome, with an analysis of various forms of amyloid plaque deposition in the virus-induced spongiform encephalopathies. Brain 104: 559-588, 1981
(4) Masters CL et al. The familial occurrence of Creutzfeldt-Jakob disease and Alzheimer's disease. Brain 104: 535-558, 1981
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