疾患詳細

疾患詳細





#600072
Familial fatal insomnia (FFI)
(Insomnia, fetal familial)

家族性致死性不眠 (FFI)
(不眠, 家族性, 致死性)
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)
 
 Abnormal autonomic nervous system physiology (自律神経生理学的異常) [HP:0012332] [0200]
 Adult onset (成人発症) [HP:0003581]
 Apnea (無呼吸) [HP:0002104] [01600]
 Ataxia (運動失調) [HP:0001251] [028]
 Autosomal dominant inheritance (常染色体優性遺伝) [HP:0000006]
 Childhood onset (小児期発症) [HP:0011463]
 Constipation (便秘) [HP:0002019] [01803]
 Dementia (認知症) [HP:0000726] [0123]
 Diplopia (複視) [HP:0000651] [06004]
 Dysarthria (構音障害) [HP:0001260] [0230]
 Dysphagia (嚥下障害) [HP:0002015] [01820]
 Fever (発熱) [HP:0001945] [01413]
 Hyperhidrosis (多汗) [HP:0000975] [18016]
 Insomnia (不眠) [HP:0100785] [0152]
 Myoclonus (ミオクローヌス) [HP:0001336] [02612]
 Neuronal loss in central nervous system (中枢神経系ニューロン喪失) [HP:0002529]
 Urinary retention (尿閉) [HP:0000016] [0190]
 Weight loss (体重喪失) [HP:0001824] [01411]

(UR-DBMS)
【一般】体重減少
 無呼吸エピソード
 嚥下障害
 便秘
 残尿
 発熱
【神経】進行性不眠
 自律神経失調 (発熱, 発汗, 縮瞳, 括約筋障害)
 夢状態
 構音障害
 振戦
 ミオクローヌス
 昏睡
 死亡
 運動失調
 夢を演じる
 寝言
 認知症
 視床のニューロン喪失 (特に内背側核で)
 脳幹はニューロン喪失を示すかも
【眼】複視, 間歇性
【X線】ニューロン変性
 前および後中視床核に限定した反応性の astrocytosis
 海綿症または血管性または炎症性変化なし
【皮膚】発汗 (diaphoresis)
【その他】成人発症
 急速な経過
 12か月以内に死亡

(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, 硬直, 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, 致死性家族性不眠症 (FFI) は prion タンパク遺伝子 (PRNP; 176640) の変異と連関するため

● 致死性家族性不眠症が, 常染色体優性遺伝を示す prion 疾患である
 →運動および認知悪化に先行する, 不眠症+/-日中の夢見心地状態, 幻覚, せん妄, および自律神経失調が臨床的特徴である
 FFI は, PRNP 遺伝子の129位のアミノ酸がメチオニンの時 (M129V; 176640.0005), asp178-to-asn 変異と特異的に連関する (D178N; 176640.0010)
 D178N 変異と val129 アレルは Creutzfeldt-Jacob 病 (CJD; 123400)になる (→ 176640.0007) (Goldfarb et al., 1992)
 CJD は, 典型的には, 認知症, 運動失調, ミオクローヌスおよび他の異常運動とともに存在する
 しかし, FFI と CJD には臨床的および病理学的オーバーラップがあり, D178N と met129 をもつ数例は CJD を示唆する表現型とともに存在するかもしれない
 したがって, FFI と CJD は表現型スペクトラムの極端とみなされるかもしれない (Zarranz et al., 2005)

Clinical Features
Lugaresi et al. (1986) reported a 53-year-old man who presented with progressive insomnia and signs of dysautonomia, including pyrexia, diaphoresis, myosis, and sphincter disturbances. Dreamlike status, dysarthria, tremor, and myoclonus subsequently developed and led to coma and death after 9 months. Two sisters of the patient and many relatives over 3 generations had died of a similar disease. Pathologic studies of the brains of the patient and 1 of his sisters showed severe neuronal degeneration, with reactive astrocytosis limited to the anterior and dorsomedial thalamic nuclei and without spongiosis or vascular or inflammatory changes. Although diffuse degenerative processes of the nervous system often affect the thalamus, this disorder appeared to be a genetically determined degenerative disease limited to selected thalamic nuclei.

Parchi et al. (1995) found protease-resistant prion protein in gray matter but not white matter of peripheral organs from 9 autopsied subjects with fatal familial insomnia. In general, the degree of histopathologic change correlated with the amount of the abnormal protein. However, the mediodorsal thalamic nucleus showed severe neuronal loss and astrogliosis in association with relatively modest amounts of abnormal prion protein, suggesting to the authors a higher vulnerability of this region.

Medori (1990) reported that despite a thorough search for similar cases in the literature and through neurologists and neuropathologists, the only additional cases they found were members of the same kindred: 4 in a branch of the family that emigrated from Italy to Belgium and France and 1 from the Italian branch of the family.

Harder et al. (1999) presented a large German kindred with fatal familial insomnia. Molecular genetic analysis of the PRNP gene confirmed that the D178N mutation segregated with methionine at the polymorphic codon 129 in all 7 affected patients examined. The authors noted a wide spectrum of clinical presentations and emphasized the difficulty in establishing the diagnosis of fatal familial insomnia on clinical and pathologic grounds alone. They were unable to confirm the previously reported relationship between the status of the M/V polymorphism at codon 129 and age at onset of this disease.

Spacey et al. (2004) described a family of Chinese descent in which at least 6 members spanning 4 generations were affected with autosomal dominant fatal familial insomnia. At age 36 years, the proband presented with myoclonus and refractory insomnia with somniloquism and dream enactment. He later developed intermittent diplopia, dysphagia, dysarthria, ataxia, dementia, and dysautonomia, and died 12 months after onset. Neuropathologic examination showed severe neuronal loss and gliosis in the thalamus, primarily in the ventral anterior, medial dorsal, lateral dorsal, and pulvinar nuclei. PrP(Sc) was widely distributed throughout the brain. Molecular analysis of the PRNP gene identified the D178N mutation and homozygosity for met129.

Dauvilliers et al. (2004) reported a French man with genetically confirmed FFI and heterozygosity for the met/val129 polymorphism (176640.0005) who reported pseudohypersomnia behavior instead of insomnia. He presented at age 41 years with progressive fatigue, severe depression, and episodes of vertical diplopia. Eighteen months later, he developed severe gait ataxia and dysautonomia, including hyperthermia, hyperhidrosis, dysuria, and sexual impotence without changes in blood pressure. He reported hypersomnia with frequent night hallucinations and agitation. Sleep and actigraphy studies performed 2.5 years after disease onset showed total disruption of physiologic sleep structure with dramatic reduction of total sleep, NREM sleep, and REM sleep, and normal rest activity. Neuroendocrine studies showed disruption of the circadian rhythms of plasma melatonin, growth hormone, and cortisol. CSF hypocretin-1 (HCRT; 602358) levels were normal. However, the patient's 24-hour temperature oscillation, sleep-wake cycle, and rest activity conserved a circadian distribution, suggesting normal functioning of the biologic clock, the suprachiasmatic nuclei. Dauvilliers et al. (2004) suggested a central lesion that functionally disrupted the neuroendrocrine rhythms with respect to the suprachiasmatic nuclei.

Dimitri et al. (2006) reported an 18-year-old man with FFI who presented with psychotic mood disturbances with catatonic features. He developed total insomnia, showed rapid progressive neurologic deterioration, and died 7 months after onset of insomnia. The authors emphasized the unusual and early presentation, and they noted that psychiatric treatments, including medications and electroconvulsive therapy (ECT), worsened the disease course in this patient.

Iriarte et al. (2007) reported the polysomnographic findings of a 49-year-old man with FFI. His sleep structure was severely altered, with loss of spindles and REM without atonia. During sleep, the patient was moving, talking, had periodic limb movements, and produced noises such as stridor, nocturnal groaning, and snoring. The results were consistent with the term 'agrypnia excitata,' meaning a peculiar type of lack of sleep associated with generalized overactivity and sympathetic activation.

Krasnianski et al. (2008) evaluated 41 German patients with FFI. The median age at onset was 56 years, and the median disease duration was 11 months. There were some phenotypic differences as determined by M129V genotype. Hallucinations and myoclonus were more common in patients with the MM genotype, whereas vegetative disturbances, bulbar signs, nystagmus, and ataxia were more common with the MV genotype. Those with the homozygous MM genotype had significantly shorter disease duration. Polysomnographic studies in 5 patients showed decreased rapid eye movement, reduction in deep sleep and efficiency, periodic limb movements, and central apnea.

Clinical Variability

Zarranz et al. (2005) reported 13 Spanish families with prion disease. Nine families were of Basque origin, 6 of which were found to be genetically related by haplotype analysis. There were a total of 23 affected individuals. The largest family had 5 affected individuals. The genotype in all was D178N and met129 homozygous, but only 2 presented with FFI. The 3 other family members presented with CJD, 2 with ataxia and 1 with acalculia, aphasia and dementia. In another family with D178N and met129 homozygous, 1 patient had classic FFI presenting with insomnia, 1 had FFI presenting with depression, apathy, and autonomic dysfunction, and 2 other family members presented with CJD. Overall, 7 patients with D178N and homozygous met129 had a clinical and neuropathologic profile compatible with CJD. In addition, 2 patients who were D178N and val/met129 heterozygous had FFI. PrPSc isotype analysis was not informative. Zarranz et al. (2005) concluded that there must be other environmental or genetic factors that influence the phenotypic expression of the D178N mutation, and that FFI and CJD due to this genotype are extremes of a phenotypic spectrum rather than 2 discrete entities.

Saitoh et al. (2010) reported a Japanese mother and son who were D178N and met129 homozygous. He developed a sleep disorder at age 54 years, consistent with FFI, but her phenotype was more consistent with CJD. Both patients had PrPSc type 2. The authors noted the similarities to the report of Zarranz et al. (2005).

Inheritance
Manetto et al. (1992) presented the pedigree as well as the clinical and neuropathologic findings in 5 new cases. Men and women were affected in a pattern consistent with autosomal dominant inheritance. The age at onset varied between 37 and 61 years; the course averaged 13 months, with a range of 7 to 25 months.

Capellari et al. (2008) reported a family in which several members died of FFI associated with the PRNP D178N mutation, but a female family member with the disorder did not carry the D178N mutation and appeared to have sporadic onset of the disorder. Neuropathologic examination of the patient with sporadic disease confirmed the diagnosis, and she was found to be homozygous for the met129 allele.Capellari et al. (2008) commented on the uncertainty that still exists in the etiology of prion diseases.

Pathogenesis
In the study of fatal familial insomnia by Lugaresi et al. (1986), pathologic changes were distinguished from those seen in the thalamic form of Creutzfeldt-Jakob disease, in which there is always cortical spongiosis and the gliosis is not confined to the thalamus. The well-defined location of the pathologic changes in FFI permitted more precise clinicopathologic correlations than had been possible in cases of tumors and vascular lesions. These correlations indicated that the anterior and dorsomedial thalamus has a role in integrating and expressing sleep, autonomic functions, and neuroendocrine circadian rhythm. The authors concluded that the kindred reported by Little et al. (1986) probably had the same disorder because of the identical pattern of inheritance, pathologic changes, and signs and symptoms.

Tateishi et al. (1995) succeeded in transmitting fatal familial insomnia to mice, thus placing FFI within the group of infectious cerebral amyloidoses.

Useful information on the pathogenesis of fatal familial insomnia was provided by the descriptions of sporadic fatal insomnia by Mastrianni et al. (1999) and Parchi et al. (1999), which were reviewed by Gambetti and Parchi (1999). Mastrianni et al. (1999) described a 44-year-old man with insomnia, dysautonomia, and ataxia, followed toward the end of the fatal 16-month course by hallucinations and myoclonus. Histopathologic examination showed lesions that were indistinguishable in type and regional distribution from those of fatal familial insomnia; the amount, distribution, and molecular mass of the pathologic isoform of the prion protein (PrP(Sc)) in the brain were similar to those in fatal familial insomnia. However, a rigorous analysis of the PRNP gene failed to identify the mutation at codon 178 (D178N) that is associated with FFI. Mastrianni et al. (1999) argued that their patient had a sporadic form of fatal insomnia. This conclusion was supported by the description of 5 such patients by Parchi et al. (1999). Mastrianni et al. (1999) also demonstrated experimental transmission of sporadic fatal insomnia to mice. Mice inoculated with brain homogenates from subjects with fatal familial insomnia or sporadic fatal insomnia had lesions of similar types and distributions in their brains. In both familial and sporadic fatal insomnia, the molecular mass of the Prp(Sc) fragment was 19 kD (PrpSc type 2) in these mice. In contrast, these characteristics were different in the mice inoculated with homogenate from patients with typical sporadic or familial Creutzfeldt-Jakob disease, and the molecular mass of their PrP(Sc) was 21 kD (PrpSc type 1). These findings indicated that fatal familial insomnia can be generated in the absence of the D178N mutation. Gambetti and Parchi (1999) suggested that the repertoire of conformational changes of PrP(Sc) may be relatively limited--a factor that may facilitate the discovery of treatments.

Scaravilli et al. (2000) reported another case of sporadic fatal insomnia, confirmed by polysomnography and neuropathologic findings, in which there was no mutation detected in the prion gene. The patient was homozygous for methionine at codon 129.

Molecular Genetics
Goldfarb et al. (1992) demonstrated that an asp178-to-asn (D178N) substitution in the PRNP gene in conjunction with the met129 polymorphism on the same allele (176640.0010) was responsible for FFI. Creutzfeldt-Jakob disease was associated with val129 in all 15 affected members of 6 kindreds (see 176640.0007), whereas met129 was associated with FFI in all 15 affected members of 5 kindreds.

Medori et al. (1992) identified the D178N mutation in all 4 affected persons and 11 of 29 unaffected persons from a kindred with FFI.

Genotype/Phenotype Correlations
In an analysis of 14 patients with FFI from 5 unrelated families, Montagna et al. (1998) found that patients who were homozygous for the met129 polymorphism had more prominent oneiric episodes, insomnia, and dysautonomia at disease onset, whereas patients heterozygous for met/val129 showed ataxia and dysarthria at disease onset, earlier sphincter loss, and seizures.

Dauvilliers et al. (2004) stated that FFI patients with met129 homozygosity tended to have a clinical course of less than 1 year, severe insomnia, recurrent oneiric episodes, continuous motor overactivity, and severe dysautonomia. In contrast, FFI patients with met/val129 heterozygosity tended to have a clinical course of greater than 2 years, insomnia or pseudohypersomnia, severe ataxia and dysarthria at disease onset, normal rest activity, and mild dysautonomia.

Animal Model
Tobler et al. (1996) reported alterations in circadian rhythm and sleep in PrP null mice. They stressed that the changes in these mice show intriguing similarities with the sleep alterations in FFI.

Jackson et al. (2009) found that mice expressing a mutant murine D177N Prnp protein, which is equivalent to the FFI-associated D178N mutation in humans, developed biochemical, physiologic, behavioral, and neuropathologic abnormalities that were similar to FFI in humans and different from other animal prion diseases. Pathologic brain changes in homozygous mice included atrophy of neural nuclei, enlarged ventricles, vacuolization and reactive gliosis in the deep cerebellar white matter, and neuronal loss and gliosis of the thalamus. There were very low amounts of proteinase K-resistant PrP, as seen in human FFI. Mutant mice showed age-related changes in behavior reflecting sleep interruption. Injection of a brain homogenate from mutant animals into wildtype animals resulted in a similar pathology in serial recipients, indicating that the disorder was transmissible and that a single amino acid change in Prnp is sufficient for the spontaneous generation of prion infectivity. Prnp-null mice who were injected remained normal, indicating that physiologic amounts of Prnp protein are required for disease transmission. The disease induced by the D177N mutant protein was distinct from scrapie, indicating that the FFI-associated mutant represents a unique strain of prion infectivity.

(文献)
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(17) Zarranz, J. J.; Digon, A.; Atares, B.; Rodriguez-Martinez, A. B.; Arce, A.; Carrera, N.; Fernandez-Manchola, I.; Fernandez-Martinez, M.; Fernandez-Maiztegui, C.; Forcadas, I.; Galdos, L.; Gomez-Esteban, J. C.; and 10 others : Phenotypic variability in familial prion diseases due to the D178N mutation. J. Neurol. Neurosurg. Psychiat. 76: 1491-1496, 2005
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