疾患詳細

疾患詳細





#105210
Amyloidosis, hereditary, transthyretin-related
(Hereditary amyloidosis, transthyretin-related)
(Transthyretin amyloidosis)
(Amyloidosis, polyneuropathy, familial; FAP)
(Amyloidosis, leptomeningeal, transthyretin-related, included)
(Amyloid cardiomyopathy, transthyretin-related, included)

アミロイドーシス, 遺伝性, transthyretin 関連
(遺伝性アミロイドーシス, transthyretin 関連)
(Transthyretin アミロイドーシス)
(アミロイドポリニューロパチー性, 家族性)
指定難病28 全身性アミロイドーシス

責任遺伝子:176300 Transthyretin (TTR) <18q12.1>
遺伝形式:常染色体優性

(症状)
(GARD)

 Adult onset (成人発症) [HP:0003581]
 Amyloid deposition in the vitreous humor (硝子体液へのアミロイド沈着) [HP:0007841] [064]
 Amyloidosis (アミロイドーシス) [HP:0011034]
 Ataxia (運動失調) [HP:0001251] [028]
 Autosomal dominant inheritance (常染色体優性遺伝) [HP:0000006]
 Cardiomegaly (心拡大) [HP:0001640] [1121]
 Cardiomyopathy (心筋症) [HP:0001638] [0273]
 Constipation (便秘) [HP:0002019] [01803]
 Constrictive median neuropathy (拘束性正中神経症) [HP:0012185] [0204]
 Dementia (認知症) [HP:0000726] [0123]
 Diarrhea (下痢) [HP:0002014] [01806]
 Dysarthria (構音障害) [HP:0001260] [0230]
 Headache (頭痛) [HP:0002315] [01414]
 Hearing impairment (難聴) [HP:0000365] [091]
 Hemiparesis (片不全麻痺) [HP:0001269] [026131]
 Hyporeflexia (低反射) [HP:0001265] [0242]
 Impotence (インポテンツ) [HP:0000802] [1408]
 Increased CSF protein (髄液中蛋白増加) [HP:0002922]
 Muscle weakness (筋力低下) [HP:0001324] [0270]
 Nystagmus (眼振) [HP:0000639] [06609]
 Orthostatic hypotension due to autonomic dysfunction (自律神経機能障害による起立性低血圧) [HP:0004926] [01416]
 Paraplegia (対麻痺) [HP:0010550] [02613]
 Peripheral axonal neuropathy (末梢性軸索ニューロパチー) [HP:0003477] [0204]
 Polyneuropathy (ポリニューロパチー) [HP:0001271] [0204]
 Progressive (進行性) [HP:0003676]
 Seizures (けいれん) [HP:0001250] [01405]
 Spasticity (痙縮) [HP:0001257] [0241]
 Stroke-like episode (卒中様エピソード) [HP:0002401] [1126]
 Tremor (振戦) [HP:0001337] [02604]
 Urinary incontinence (遺尿) [HP:0000020] [0192]
 Visual impairment (視力障害) [HP:0000505] [06011]

(UR-DBMS)
【一般】けいれん
 卒中様エピソード
 頭痛
 認知症
 昏睡
 片麻痺性偏頭痛
 寝たきり
 車椅子生活
【神経】一過性片不全麻痺
 一過性軽減
 運動失調
 痙縮
 精神症状
 ミエロパチー
 軽度の末梢神経障害が生じうる
 片側性感覚過敏
 振戦
 構音障害
【頭】間歇性水頭症
【眼】硝子体易にアミロイド沈着 (差異のある発現)
 視力低下
 *眼機能障害
【耳】難聴 (2)
【皮膚】弛緩性皮膚
【検査】アミロイド沈着 (軟膜血管, 脳幹, 脊髄)
 全身性軟膜下神経膠症およびニューロン喪失
 上衣のアミロイド沈着
 髄液蛋白増加
 MRI はびまん性軟膜強調を示す
【その他】成人発症
 眼症状には差異あり
 軽度の全身性アミロイド沈着が生じうる

(要約) 家族性 Transthyretin アミロイドーシス
(家族性 TTR アミロイドーシス: 家族性アミロイド心筋症, 家族性アミロイドポリニューロパチー I 型 (ポルトガル人-スウェーデン人-日本人型), 家族性アミロイドポリニューロパチー II 型 (インディアナ/スイス人またはメリーランド/ドイツ人型), 軟髄膜アミロイドーシス, 家族性眼軟髄膜アミロイドーシス (FOLMA))
●家族性transthyretin (TTR) アミロイドーシスは, 緩徐進行性末梢感覚運動ニューロパチーと自律神経ニューロパチー, 心筋症, 腎症, 硝子体混濁および中枢神経アミロイドーシスの非ニューロパチー変化が特徴である
 疾患は通常ポルトガルおよび日本の風土病地域の人で20~40歳代で始まる
 発症は他の地域の人ではより遅い
 典型的には, 感覚ニューロパチーは下肢で足の感覚異常と感覚減退で始まり, 2-3年内に運動ニューロパチーが続く
 一部の患者では, 特に早期発症では, 自律神経ニューロパチーが最初の症状である
 →起立性低血圧, 下痢と交互の便秘, 悪心嘔吐発作, 胃内容排出遅延, インポテンツ, 無汗および尿閉と遺尿
・心アミロイドーシスは主に進行性心筋症が特徴である
・軟髄膜アミロイドーシスの患者は中枢神経所見をもつ
 →認知症, 精神病, 視力障害, 頭痛, けいれん, 運動不全麻痺, 脊髄症, 水頭症または頭蓋内出血
●診断:臨床症状, 生検でのアミロイド沈着の証明 (コンゴレッド染色, 抗TTR抗体による免疫組織学的検査), TTR病的変異の証明が必要
 mass spectrometry は, 野生型と TTR タンパクバリアントの血清での違いを証明できあるが, 部位とアミノ酸置換の種類を特定できないので, 遺伝子検査が通常必要となる
●治療:同所性肝移植 (OTLX) →末梢+/-自律神経ニューロパチーの進行を止める
 OTLXの適応:60歳未満で, 疾患期間が5年未満, 下肢に限定されるポリニューロパチーまたは自律神経ニューロパチーのみ, 有意な心または腎機能障害なし
 手根管症候群や硝子体混濁→手術
 sick sinus 症候群または2-3°AVブロック→ペースメーカー
●監視
 連続的神経伝導速度→ポリニューロパチーのモニタリング
 連続的心電図, 心エコー, 血清B-type natriuretic peptide (BNP)→心筋症のモニタリング
 修正BMI→栄養状態のモニタリング
●禁止:湯たんぽ (低温やけど)
●遺伝:常染色体優性
●臨床診断→以下で疑う
・緩徐進行性感覚運動+/-自律神経ニューロパチー
 心伝導ブロック, 心筋症, 腎症+/-硝子体混濁
・常染色体優性遺伝に一致する家族歴
●組織生検:生検組織でのアミロイド沈着の証明が必須である→ Congo red 染色で
 アミロイド沈着は走査電顕鏡で特徴的な黄緑色の複屈折を示す
 適切な組織:腹壁の皮下脂肪組織, 皮膚, 胃または直腸粘膜, 腓腹神経, 手根管手術での腱周囲脂肪
 内視鏡胃腸粘膜の感受性85%
 腓腹神経生検は沈着が斑状なので感受性は落ちる
 アミロイド沈着は抗TTR 抗体で免疫ラベルすることが望ましい
●血清バリアントTTRタンパク
 TTRタンパクは正常ではテトラマー構造をもつ (正常では20-40 mg/dL (0.20-0.40 mg/mL))
 病的変異はテトラマー構造の安定性を破壊し, 容易に pro-amyloidogenic monomersとなる
 少量の TTR モノマー (0.28-0.56 µg/mL)が, 家族性TTRアミロイドーシスと正常対照の血漿に検出できる
 TTRバリアントは抗TTR抗体との免疫沈降により mass spectrometry で検出できる→約90%のTTRバリアントはこの方法で証明された (mass シフトで)
●遺伝子:TTR c.148G>A (Val30Met) 
 4つのエクソンをもち変異はこれまでエクソン2〜4にみられている
●アレリック疾患
・家族性正甲状腺機能正高サイロキシン血漿→正常アレリックバリアントによる (Gly6Ser, Ala109Thr, Ala109Val, Thr119Met)
 TTRタンパクは血清サイロキシンの約15%と結合している
 正常アレリックバリアントはサイロキシンへの親和性増加により血清サイロキシンを増加させるが, free サイロキシンは増加しないため臨床症状は生じない
・老人性全身性アミロイドーシス (SSA)→野生型TTRの病的蓄積による
●家族性TTRアミロイドーシスの臨床型
1) 家族性アミロイドポリニューロパチー I 型 (ポルトガル人-スウェーデン人-日本人型)→代表 Val30Met
 早期:緩徐進行性感覚運動ポリニューロパチー (下肢から始まる→2-3年で運動ニューロパチーへ (グラブ/ストッキング分布の筋萎縮, 四肢筋力低下, 垂足, 垂手, 手/指運動障害); 下肢の錯感覚[焼ける, 撃たれたような痛み]と感覚過敏; 温覚と痛覚が振動覚や位置覚より早く障害される), 自律神経機能障害 (起立性低血圧, 便秘/下痢, 悪心嘔吐, 無汗, 遺尿/排尿困難), 手根管症候群, インポテンツ, 下肢潰瘍
 後半:心筋症, 硝子体混濁, 腎症
 熊本と長野ではVal30Metでの平均発症年齢 40.1±12.8歳 (22-74歳)→それ以外の日本人ではもっと遅い
 ポルトガルのVal30Metは平均 33.5 ±9.4 歳 (17-78 歳)
 スウェーデン, フランス, 英国ではより遅い
2) 家族性アミロイドポリニューロパチー II 型 (インディアナ/スイス人またはメリーランド/ドイツ人型)→代表 Ile84Ser
 早期:手根管症候群
 後半:四肢の感覚運動ポリニューロパチー, 自律神経機能障害, 便秘/下痢, インポテンツ, 心筋症, 硝子体混濁, 腎症
3) 家族性アミロイド心筋症→代表 Val122Ile
 心拡大, 伝導ブロック, 不整脈, アンギーナ, うっ血性心不全, 突然死
4) 軟髄膜アミロイドーシス→代表 Asp18Gly
 下痢, 運動失調, 形成, 出血, 水頭症
5) 家族性眼軟髄膜アミロイドーシス (FOLMA)
●浸透度:100%ではない
 ポルトガル Val30Met は50歳までに80%, 70歳までに91%が発症する
 フランスでは50歳までに14%, 70歳までに50%が発症する
 スウェーデンでは30歳までに1.7%, 40歳までに5%, 50歳までに11%, 60歳までに22%, 70歳までに36%, 80歳までに52%, 90歳までに69%が発症する
 一部のVal30Metホモ接合の人は無症状を維持する
●表現促進
 地方病で TTR アミロイドポリニューロパチーがみられる家系で表現促進が観察される
 Val30Met変異をもつ日本人家系では, 特に子供が男児の場合, 母から伝達されると父からよりも重度である
 男性が TTR アミロイドーシスのリスク因子であることが知られている
●頻度:
 Val30Met が最もよく調べられている→ポルトガル, スウェーデン, 日本に多い
  北部ポルトガル→1/538
  米国の北欧人→1/100,000
  北部スウェーデン→ヘテロ接合の頻度は1.5%
・Val122Ile:アフリカ系米国人 3.0%-3.9%
●バリアント TTR はほとんどが肝で産生される
 →肝移植しなければ致死的である
●ポルトガルの Caxinas 地方の風土病である
 →約500家系1,000例あり, 人口の70%が発症する
 中世にスカンジナビアのバイキングにより持ち込まれた
 →スウェーデンのPiteå, Skellefteå and Umeå では, 集団の1.5%が変異遺伝子をもつ
 全世界に患者あり (日本へはイエズス会経由)

<指定難病診断基準>
指定難病の対象となる病型は,
 免疫グロブリン性アミロイドーシス,
 家族性アミロイドーシス,
 老人性トランスサイレチン型 (TTR)アミロイドーシス
 に限り, 「Definite」例, 「Probable」例を対象とする。
 多発性骨髄腫の診断基準に合致するものは除く。

1 免疫グロブリン性, 反応性 AA 及び老人性 TTR アミロイドーシス
 免疫グロブリン性, 反応性 AA 及び老人性 TTR アミロイドーシスは, 臨床症状の類似点が多く, それのみでは 鑑別することが困難であるので1つの診断基準として作成している。
(1) 概念
 免疫グロブリンに由来する免疫グロブリン性アミロイドーシスは, 旧分類の原発性アミロイドーシスの大部分と骨髄腫に伴うアミロイドーシスが含まれる。
 反応性 AA アミロイドーシスは続発性アミロイドーシスの大部分で, 関節リウマチ, 炎症性腸疾患, 気管支 拡張症, 結核に続発する。
 老人性 TTR アミロイドーシスは, 主として心臓, 手関節を代表とする大関節に沈着し, そのアミロイド蛋白 は野性型トランスサイレチンである。
(2) 主要事項
 まず免疫グロブリン性, 反応性 AA 及び老人性 TTR アミロイドーシスの可能性を思いつくこと, 症状が多彩であるため念頭にないことが多い。生検のみが生前確診の手段であるので, 本症の可能性を考えつつ生検して診断に至るべきである。骨髄腫及び類縁疾患のときはもちろん, 長期にわたる難治性炎症性疾患(特に関節リウマチ)では必ず本疾患の可能性を考えてみることが必要である。
① 主要症状及び所見
 (a) 全身衰弱・体重減少・貧血・浮腫・呼吸困難・胸痛・紫斑
 (b) 心電図における低電位・不整脈・伝導ブロック・QS 型(V1~V3)・低血圧・起立性低血圧・心肥大
 (c) 頑固な便秘・下痢を主徴とする胃腸障害, 吸収不良症候群 (d) 蛋白尿・腎機能障害
 (e) 肝腫大・脾腫・ときにリンパ節腫大
 (f) 巨舌
 (g) shoulder-pad sign, その他関節腫大 (h) 多発性ニューロパチー
 (i) 手根管症候群
 (j) 皮膚の強皮症様肥厚, 結節
 (k) 甲状腺, 唾液腺などの硬性腫大
 (l) 免疫グロブリン異常:血清中に M 蛋白又は尿中にベンス・ジョーンス蛋白をみることがある。
 (m)血中でフリーフライト・チェーンが上昇することがある。
② 参考事項
[皮膚症状からみた全身性アミロイドーシス診断基準]
 全身性アミロイドーシスの中で, 原発性アミロイドーシスと多発性骨髄腫に合併するアミロイドーシ スの半数以上に皮膚症状がみられ, 診断の手がかりになる。アミロイドの沈着しやすい眼瞼, 頸, 頭, 外陰及び肛門周囲に, 沈着量に応じて米粒大位の丘疹から大きな腫瘤まで生じる。硬く, 黄色調を帯び, しばしば紫斑を伴う。強皮症様に硬くなることもある。
(3) 生検
 皮膚・腎などで疑わしい病変があれば生検する。そのような部位がなければ内視鏡下の胃・十二指腸 生検, 直腸生検が望ましい。胃生検は胃前庭部で粘膜筋板以下まで深めにとることが重要であり, 十二 指腸では球部後壁から採取する。また, 従来より行われている直腸生検では浣腸後(通常はグリセリン浣腸液 120ml でよい), 直腸後壁から粘膜下組織を含む小片をとる。また近年, 腹壁の脂肪吸引生検(abdominal fat aspiration biopsy)が広く行われている。臍周囲部の腹壁を局麻後, 18 ゲージの注射針で 脂肪層を強く吸引して脂肪滴を得て, スライドガラス上に脂肪滴を数個載せて 2 枚のスライドガラスで押し つぶすようにして塗抹標本を作製し, 乾燥後に検討を行う。生検組織はヘマトキシリン・エオシン染色の ほかにアルカリコンゴ−赤染色をし, またその標本を偏光顕微鏡下で観察する。偏光観察には簡単に普 通顕微鏡に装着できる偏光板が安価で市販されている。アミロイドは緑色の強く輝く複屈折を呈する。免疫組織化学的染色で AL, AA, トランスサイレチンを証明することができる(もし, 不可能ならば専門家に 連絡することが望ましい)。電子顕微鏡観察も有用であり, それが不可能ならば小片を 2%グルタールアルデヒドで固定し, 4℃に保存して, 専門家に連絡することが望ましい。
(4) 免疫グロブリン性, 反応性 AA 及び老人性 TTR アミロイドーシスの疑いのある患者で避けるべき検査
 ① 肝生検
  出血の危険がある。
 ② 多量のベンス・ジョーンス蛋白尿があるときは IVP(経静脈腎孟撮影)で無尿を誘発する危険があ る。
(5)診断のカテゴリー
 ①Definite
  生検で陽性。
 ②Probable
  主要症状及び所見のうち(a)~(k)の1つ以上を認め, かつ(l)が陽性の場合は免疫グロブリン性(原発性)アミロイドーシスが疑われる。
 ③Possible
  主要症状及び所見のうち(a), (b)の1つ以上が存在する場合は一応免疫グロブリン性, 反応性AAあるいは老人性TTRアミロイドーシスの可能性を考慮してみる。

2  家族性アミロイドニューロパチー
(1) 概念
 初期には末梢神経と自律神経に高度のアミロイド沈着が起こり, 進行期には, 心臓, 消化管, 腎臓も障 害される。主要病像は多発性ニューロパチーと自律神経機能不全である。
 沈着するアミロイド蛋白質は ⅠとⅡ型では変異トランスサイレチン, Ⅲ型は変異アポリポ蛋白 AⅠ, Ⅳ型では変異ゲルソリンである。 また新たに変異型β2ミクログロブリンもアミロイド原蛋白質として報告されている。
(2) 主要事項
① 主要症状
 (a) 感覚障害
  左右対称性に, 下肢又は上肢末端から始まる。温度覚, 痛覚が早く, かつ強く侵され(解離性感覚障害), 振動覚, 位置覚は進行期に侵される。手根管症候群で発症する場合もある。
 (b) 運動障害 感覚障害より数年遅れて出現し, 筋萎縮, 筋力低下が下肢又は上肢末端から始まる。
 (c) 自律神経系の障害
  1 陰萎(男性)
  2 胃腸症状(激しい嘔気・嘔吐発作, ひどい便秘と下痢の交代, 不定な腹痛, 腹部重圧感)
  3 起立性低血圧(立ちくらみ, 失神)
  4 膀胱障害(排尿障害, 尿失禁など)
  5 皮膚症状(皮膚栄養障害, 発汗異常, 難治性潰瘍) 
  6 心障害(心伝導障害による不整脈, 心不全)
② 発病は緩徐で, 経過は漸次進行性である。
③ 遺伝様式 常染色体優性(問診のみでは遺伝歴が不明なことがある)
④ 組織所見 末梢神経, 胃・直腸, 皮膚, 腹壁脂肪の吸引生検でアミロイド沈着を認める。
(3) 参考事項
① 発病年齢は通常 20~40 歳代であるが, 集積地以外の家系は 50 歳以後の高齢発症である。
② 初発症状は四肢末端のしびれと自律神経障害
③ 感覚障害が体幹に及ぶと, 胸腹部に島状の感覚低下領域を認める。
④ 心障害, 腎障害は遅れて出現し, 次第に心不全, 尿路感染症, 尿毒症を合併し, 悪液質となる。
⑤ 瞳孔の不整, 対光反射の消失を認めることがある。
⑥ 硝子体混濁を初発症状とすることがある。
⑦ 末梢神経, 皮膚, 胃・直腸などの臓器生検でアミロイド沈着を認める。
⑧ 検査所見
 (a) 心電図:伝導障害と心筋障害
 (b) 心エコー:心筋の肥厚とエコー輝度の増強
 (c) Technetium-99m-Pyrophosphate(Tc-99m-PYP)心筋シンチグラフィー:陽性画像 (d) 末梢神経伝導速度の低下
⑨ Mass spectrometory やラジオイムノアッセイ法による血清中の変異トランスサイレチンの検出
⑩ トランスサイレチン, ゲルソリン等の遺伝子診断
(4)臨床診断のカテゴリー
 ①Definite
  主要事項①の中の(a)~(c)の2つ以上とアミロイド前駆蛋白の遺伝子異常を認める場合
 ②Probable
  家系内に確実(Definite)者があり, 主要事項①の中の(a)~(c)の1つ以上を認める場合

(責任遺伝子) *176300 Transthyretin (TTR) <18q12.1>
(1) Amyloid, hereditary, transthyretin-related
.0001 Amyloid, hereditary, transthyretin-related [TTR, VAL30MET] (rs28933979) (RCV000014359...)
Portuguese patients (Andrade 195; Saraiva et al. 1984; Saraiva(2001; Lourenco, 1980; Saraiva et al. 1983; Saraiva et al. 1986)
Swedish patiens (Benson 1980; Dwulet and Benson 1984; Holmgren et al. 1988; Drugge et al. 1993; Holmgren et al. 1994)
Japanese patients (Araki et al. 1968; Kito et al. 1973; Kito et al. 1980; Yoshioka et al. 1986; Ochiai et al. 1986; Furuya et al. 1987; Ikeda et al. 1996; Oide et al. 2004; Imaizumi 1989); Yoshioka et al. 1989; Misu et al. 1999; Yoshioka et al. 2001; Koike et al. 2002)
Other groups (Saraiva et al. 1986; Saraiva et al. 1988; Holt et al. 1989)
Diagnosis
Diagnosis (Sasaki et al. 1984; Nakazato et al. 1984; Benson and Dwulet 1985; Whitehead et al. 1984; Koeppen et al. 1985; Maeda et al. 1986; Almeida et al. 1990)
Homozygosity (Holmgren et al. 1988; Holmgren et al. 2005)
Origin of mutation (Zaros et al. 2008)
Clinical manifestations (Ducla-Soares et al. 1994; Herrick et al. 1996; Ando et al. 1997; Lachmann et al. 2002; Kimura et al. 2003; Koga et al. 2003)
Modification of defect (Soares et al., 1999); Drugge et al., 1993; Tashima et al., 1995; Yamamoto et al. 1998; Munar-Ques et al. 1999; Soares et al. 2004)
.0002 Amyloid, hereditary, transthyretin-related [TTR, PHE33ILE] (rs121918068) (RCV000014360) (Nakazato et al. 1984; Benson 2001)
.0003 Amyloid, hereditary, transthyretin-related [TTR, LEU58HIS] (rs121918069) (RCV000159437...) (Nichols et al. 1989; Mendell et al.1990; Hund et al. 2001l; Jacobson et al. 1992)
.0004 Amyloid, hereditary, transthyretin-related [TTR, THR60ALA] (rs121918070) (RCV000014363...) (Wallace et al. 1986; Koeppen et al. 1990; Staunton et al. 1987; Lachmann et al. 2002)
.0005 Amyloid, hereditary, transthyretin-related [TTR, SER77TYR] (rs121918071) (RCV000014364...) (Wallace et al. 1986; Wallace et al. 1988; Satier et al. 1990; Blanco-Jerez et al. 1998)
.0006 Amyloid, hereditary, transthyretin-related [TTR, ILE84SER] (rs121918072) (RCV000014365) (Benson and Dwulet 1985; Dwulet and Benson 1986; Nichols et al. 1989; Zolyomi et al. 1998)
.0007 Amyloid, hereditary, transthyretin-related [TTR, LEU111MET] (rs121918073) (RCV000014366) (Husby et al. 1986; Nordvag et al.1992; Ranlov et al. 1992; Nordvag et al. 1993; Benson 2001)
.0009 Amyloid, hereditary, transthyretin-related [TTR, VAL122ILE] (rs76992529) (RCV000211747...) (Benson (2001; Jiang et al. 2001; Jacobson et al. 1988, 1990; Gorevic et al. 1989); Snyder et al. 1989; Westermark et al. 1990; Jacobson 1992; Jacobson et al. 1997; Benson 1997; Askanas et al. 2003; Jiang et al. 2001; Lachmann et al. 2002)
.0010 Amyloid, hereditary, transthyretin-related [TTR, HIS90ASN] (rs121918074) (RCV000014369...) (Skare et al. 1989; Skare et al. 1991; Saraiva et al. 1991)
.0011 Amyloid, hereditary, transthyretin-related [TTR, TYR114CYS] (rs121918075) (RCV000014361) (Ueno et al. 1990; Ueno et al. 1992)
.0012 Amyloid, hereditary, transthyretin-related [TTR, GLU42GLY] (rs11541796) (RCV000014370) (Ueno et al. 1990; Uemichi et al.1992)
.0013 Amyloid, hereditary, transthyretin-related [TTR, SER50ARG] (rs121918076) (RCV000014371) (Ueno et al. 1990; Takahashi et al. 1992)
.0014 Amyloid, hereditary, transthyretin-related [TTR, VAL30ALA] (rs79977247) (RCV000014372) (Jones et al. 1990, 1992)
.0016 Amyloid, hereditary, transthyretin-related [TTR, ALA36PRO] (rs121918077) (RCV000014374) (Jones et al. 1991; Jacobson et al. 1992)
.0018 Amyloid, hereditary, transthyretin-related, modifier of [TTR, THR119MET] (rs28933981) (ExAC:rs28933981) (RCV000475117...) (Harrison et al. 1991; Ii et al. 1992; Scrimshaw et al. 1992; Alves et al. 1993)
.0019 Amyloid, hereditary, transthyretin-related [TTR, LEU58ARG] (rs121918069) (RCV000014377) (Saeki et al. 1991)
.0020 Amyloid, hereditary, transthyretin-related [TTR, GLY47ARG] (rs387906523) (RCV000014378) (Murakami et al. 1992; Ferlini et al. 2000)
.0021 Amyloid, hereditary, transthyretin-related [TTR, ALA45THR] (rs104894664) (rs121918078) (RCV000014379) (Saraiva et al. 1992)
.0022 Amyloid, hereditary, transthyretin-related [TTR, LEU55PRO] (rs121918079) (RCV000014380) (Jacobson et al. 1992; Yamamoto et al. 1994; McCutchen et al. 1993)
.0023 Amyloid, hereditary, transthyretin-related [TTR, SER50ILE] (rs121918080) (gnomAD:rs121918080) (RCV000014381) (Nishi et al. 1992; Saeki et al. 1992)
.0024 Amyloid, hereditary, transthyretin-related [TTR, VAL30LEU] (rs28933979) (RCV000014382) (Murakami et al. 1992; Utsugisawa et al. 1998)
.0025 Amyloid, hereditary, transthyretin-related [TTR, THR49ALA] (rs121918081) (RCV000014383) (Almeida et al. 1992; Benson et al. 1993)
.0026 Amyloid, hereditary, transthyretin-related [TTR, GLU89GLN] (rs121918082) (RCV000236028...) (Almeida et al. 1992)
.0027 Amyloid, hereditary, transthyretin-related [TTR, LYS70ASN] (rs267607160) (RCV000014385) (Izumoto et al. 1992)
.0028 Amyloid, hereditary, transthyretin-related [TTR, CYS10ARG] (rs121918083) (RCV000014386) (Uemichi et al. 1992)
.0029 Amyloid, hereditary, transthyretin-related [TTR, VAL71ALA] (rs121918084) (RCV000014387) (Benson et al. 1993; Almeida et al. 1993)
.0030 Amyloid, hereditary, transthyretin-related [TTR, ILE68LEU] (rs121918085) (RCV000014388) (Hesse et al. 1993)
.0031 Amyloid, hereditary, transthyretin-related [TTR, GLU61LYS] (rs121918086) (RCV000014389) (Shiomi et al. 1993)
.0032 Amyloid, hereditary, transthyretin-related [TTR, ALA97GLY] (rs121918087) (RCV000014390) (Yasuda et al. 1994)
.0034 Amyloid, hereditary, transthyretin-related [TTR, ILE107VAL] (rs121918089) (RCV000506089...) (Uemichi et al. 1994)
.0035 Amyloid, hereditary, transthyretin-related [TTR, GLY47ALA] (rs121918090) (RCV000516227...) (Ferlini et al. 1994; Ferlini et al. 2000)
.0037 Amyloid, hereditary, transthyretin-related [TTR, PHE64LEU] (rs121918091) (RCV000236623...) (Ii et al. 1991; Ferlini et al.1996)
.0039 Amyloid, hereditary, transthyretin-related [TTR, VAL20ILE ] (rs121918093) (RCV000014397...) (Jenne et al. 1996; Jacobson et al. 1997)
.0040 Amyloid, hereditary, transthyretin-related [TTR, PHE33LEU] (rs121918068) (RCV000014398) (Ii et al. 1991, Harding et al. 1991, Myers et al. 1998)
.0041 Amyloid, hereditary, transthyretin-related [TTR, LEU12PRO] (rs121918094) (RCV000014399) (Brett et al. 1999)
.0042 Amyloid, hereditary, transthyretin-related [TTR, ARG104HIS] (rs121918095) (RCV000621591...) (Terazaki et al. 1999)
.0043 Amyloid, hereditary, transthyretin-related [TTR, GLY47ARG, G-A] (rs387906523) (RCV000014401) (Ferlini et al. 2000)
.0044 Amyloid, hereditary, transthyretin-related [TTR, VAL122DEL] (rs121918096) (RCV000014402) (Uemichi et al. 1997; Munar-Ques et al. 2000)
.0045 Amyloid, hereditary, transthyretin-related [TTR, PHE44SER] (rs104894665) (RCV000014403...) (Klein et al. 1998; Murakami et al. 2002)
.0046 Amyloid, hereditary, transthyretin-related [TTR, GLY53GLU] (rs121918097) (RCV000014404) (Ellie et al. 2001)
.0047 Amyloid, hereditary, transthyretin-related [TTR, ASP18GLY] (rs121918098) (RCV000036373...) (Garzuly et al. 1996; Vidal et al. 1996)
.0048 Amyloid, hereditary, transthyretin-related [TTR, PHE64SER] (rs104894665) (rs121918099) (RCV000014403...) (Uemichi et al. 1999)
.0049 Amyloid, hereditary, transthyretin-related [TTR, VAL30GLY] (rs79977247) (RCV000014407) Petersen et al. 1995)
.0050 Amyloid, hereditary, transthyretin-related [TTR, TYR69HIS] (rs121918100) (RCV000756861...) (Blevins et al. 2003)
.0051 Amyloid, hereditary, leptomeningeal, transthyretin-related [TTR, ALA25THR] (RCV000014409) (Hagiwara et al. 2009)
.0052 Amyloid, hereditary, transthyretin-related [TTR, ALA97SER [rs267607161] (RCV000014410...) (Liu et al. 2008; Yang et al. 2010)
(2) Dysprealbuminemic hyperthyroxinemia (145680)
.0015 Dysprealbuminemic hyperthyroxinemia [TTR, ALA109THR] (RCV000014373) (Moses et al. 1990; Refetoff et al. 1996)
.0038 Dysprealbuminemic hyperthyroxinemia [TTR, ALA109VAL [rs121918092] (rs121918092) (RCV000014396...) (Refetoff et al. 1996)
(3) Transthyretin polymorphism
.0008 Transthyretin polymorphism [TTR, TYR116VAL] (rs121918092) (RCV000014367) (Strahler et al. 1987)
.0017 MOVED TO 176300.0010
.0036 Transthyretin SER-6 polymorphism [TTR, GLY6SER] (rs1800458) (gnomAD:rs1800458) (RCV000036379...) (Jacobson et al. 1995)
(4) Carpal tunnel syndrome, familial (115430)
.0033 Carpal tunnel syndrome, familial [TTR, TYR114HIS] (rs121918088) (RCV000014391) (Murakami et al. 1994)

*TTR: transthyretin; (147 aa)
・甲状腺ホルモン結合タンパクで, おそらくサイロキシンを血流から脳へ輸送する
・alpha-1-antitrypsin, transthyretin および orosomucoidを含む3つのプレアルブミンの1つである transthyretin をコードする
・transthyretin はキャリアタンパクである
 →血漿および髄液で甲状腺ホルモンを輸送し, 血漿の retinol (vitamin A) も輸送する
・このタンパクは同じサブユニットのテトラマーからなる
・40以上の異なる変異が報告されている
 大多数の変異はアミロイド沈着に関係する
 →主に末梢神経+/-心を傷害し, 少数は非アミロイド源性である
・変異はアミロイド・ポリニューロパチー, 甲状腺機能正常性高サイロキシン血症, アミロイド性硝子体混濁, 心筋症, 眼軟髄膜アミロイド症, 髄膜大脳血管性アミロイド症, 手根管症候群などを生じる

(ノート)
A number sign (#) is used with this entry because this form of hereditary amyloidosis is caused by heterozygous mutation in the TTR gene (176300) on chromosome 18q12.

●遺伝性アミロイドーシスは,常染色体優性の臨床的および遺伝的に異質性のあるグループである
 →細胞外基質に不溶性タンパク原線維の沈着が特徴である (summary by Hund et al., 2001)
 transthyretin アミロイドーシスの患者は,典型的には,ポリニューロパチー,手根管症候群,自律神経不全,心筋症および胃腸管症状が特徴で,まれに硝子体混濁や腎不全を伴う
 後期には,吸収不全を伴う重症下痢,悪液質,身体障害となるニューロパチー,重度の心障害および著明な起立性低血圧が臨床像として優位となる
 死亡は通常症状発症後5〜15年で生じる

●分子遺伝学の参入以前は,遺伝的アミロイドーシスは症状と人種により4つのサブタイプに分類された (Hund et al., 2001)
○家族性アミロイドポリニューロパチー (FAP I) は,早期成人で下肢に対称性に始まる知覚運動ポリニューロパチーで,2〜3年内に急速に身体の自由を奪う
 →ポルトガル型,ポルトガル-スウェーデン-日本型,または Andrade 型としても知られる
  遺伝性 TTR アミロイドーシス症状のプロトタイプと考えることができる
  ほぼ全症例が val30-to-met (V30M; 176300.0001) 置換による
○FAP II →手に始まるニューロパチーと頻回の手根管手術を受ける
 インディアナ/スイス型 (176300.0006) またはメリーランド/ドイツ型 (176300.0003) としても知られる
 硝子体混濁が早期に生じるが,インポテンツや腎不全はまれである
○ FAP III またはアイオワ型→ APOA1 遺伝子 (107650) 変異によるアミロイドーシス (105200 および 107680.0010)
○FAP IV; フィンランド型アミロイドーシス (105120) → gelsolin (137350)遺伝子変異による

●臨床表現型に基づくシステムがアミロイドーシス分類に歴史的に用いられたが,アミロイド原線維タンパク性状による分類がより有用であることが強調されている (Saraiva, 2002)
 遺伝性アミロイドーシスに加え,全身性アミロイドーシスの他の2つの主要な型が存在する
○免疫グロブリンアミロイドーシス (AL)や以前に原発性アミロイドーシスとして知られる
 →アミロイド原線維としてモノクローナル免疫グロブリン軽鎖の蓄積が原因である
○二次性アミロイドーシスとして知られる反応性アミロイドーシス (AA)
 →慢性炎症性疾患に伴う (例, 関節リウマチ, 180300; 家族性地中海熱, 249100)
  原線維は循環性急性期反応物質である血清 amyloid A protein (104750) 由来である

●Ando et al. (2005) は,transthyretin 関連家族性アミロイドポリニューロパチーをレビューした
 表現型は,ニューロパチー型,眼軟膜型および心型に分類できると述べた

臨床症状
家族性アミロイドポリニューロパチー
●家族性アミロイドポリニューロパチー (FAP) は,ポルトガル北部で Andrade (1952)により最初に記載された (Saraiva, 2001).
 家系は臨床症状発症年齢が20-30歳代であった
 足の温覚と痛覚の早期障害と不全麻痺,吸収障害,括約筋機能障害,心電図異常,るいそう,死亡に至る自律神経障害が典型的臨床像であった

●発症年齢には大きな多様性があった
 人種的および遺伝的に均質なポルトガル人集団では,発症年齢は1995年までに調べた1,233例では17〜78歳であった (Hund et al., 2001)
 大多数の患者は,20〜30歳代で受診したが,症状の発症はより後年まで遅れた (Benson, 2001)
 臨床像は通常5-15年かけて進行し,心不全,腎不全または栄養障害で死亡した
 しかし,遅発性の一部のヘテロ接合体患者は90歳以上生存した

●De Navasquez and Treble (1938) は,FAP I 型の可能性の症例を報告した
 → De Bruyn and Stern (1929) により Dejerine-Sottas 進行性肥大性ポリニューロパチー (145900) として報告された患者が,実際はアミロイドポリニューロパチーであった
  Since the disorder began with 'pains in the arms, which worried him particularly at night whilst in bed,' he may have suffered from the Indiana variety (176300.0006). Onset was in the 40s. Two brothers and a sister had died of an identical condition 3 years after onset of symptoms. 'The father died of tubercle, the mother of old age.' The disease is milder in females. Vitreous opacities are frequent (Kaufman and Thomas, 1959). In both FAP I and FAP II (see 176300.0006), the amyloid is pericollagenous. In familial Mediterranean fever, it is perireticular.

Costa et al. (1978) concluded that the amyloid of familial amyloid polyneuropathy is distinct from the amyloid of acquired 'primary' and 'secondary' amyloidosis and of familial Mediterranean fever. They also concluded that it is closely related to prealbumin, or transthyretin. Interestingly, 'senile' cardiac amyloid (see later) is also derived from prealbumin and is indistinguishable from the amyloid of the hereditary amyloid neuropathies (Gorevic et al., 1982). (Immunoglobulin light chains are the origin of primary amyloid and AA protein is the origin of secondary amyloid.) Costa et al. (1978) were studying cases of the Andrade type of familial amyloidosis; Benson (1980, 1981) was presumably studying cases of the Indiana or Rukavina type (176300.0006).

In a Swedish kindred reported by Benson and Cohen (1977), affected persons presented with peripheral neuropathy in the fourth and fifth decades. A progressive sensory and motor loss started in the legs. Subsequently, renal, cardiac, gastrointestinal, ocular, and cutaneous involvement occurred. Histologically, amyloid deposition was mainly in connective tissue, including the unusual sites of the meninges and central nervous system. No abnormality of immunoglobulin or elevation of protein SAA (the serum precursor of secondary amyloid; 104750) was found. Some of the patients had been misdiagnosed as having syringomyelia. Benson (1981) showed partial amino acid sequence homology between human plasma prealbumin and the amyloid deposited in a member of this kindred. Libbey et al. (1984) reported a Texas kindred of German-English ancestry with familial amyloid polyneuropathy showing onset in the seventh decade. By an immunoperoxidase technique, prealbumin was demonstrated in the amyloid deposits. Munsat and Poussaint (1962) described the case of a patient also born in Texas with onset of type I FAP at age 59 years. Sequeiros (1984) suggested that this variation may be due to genetic heterogeneity and that these may be allelic disorders. By amino acid sequencing of abnormal transthyretin in these cases, it is now possible to confirm or reject this hypothesis.

Sequeiros and Saraiva (1987) reported a Portuguese-American family originating from Madeira in which amyloid neuropathy due to the usual met30 mutation had its onset in the seventh decade in all affected members of the family. Three asymptomatic relatives (aged 90, 73, and 48) were shown to carry the mutation. Possible mechanisms for the lack of penetrance and the variation in severity were discussed. Ikeda et al. (1987)reported clinicopathologic studies of patients with amyloid polyneuropathy in Japan. One group of patients was from Arao City in the southern island of Kiushu; a second group was from Ogawa village in Nagano Prefecture, located in a mountain valley in the central highlands of Japan. Considerable variability of the clinical picture was noted in the second group.

Yamada et al. (1987) described 2 Japanese nonfamilial cases of prealbumin-related amyloid polyneuropathy and referred to other published cases. These may represent new mutations. The molecular nature of the mutations was not determined. The findings of Tanaka et al. (1988) are pertinent. They described a 47-year-old Japanese woman with FAP without apparent familial occurrence of the disorder; however, her 81-year-old mother and 53-year-old sister were found to be asymptomatic carriers of the variant transthyretin as determined by radioimmunoassay. Biopsy of abdominal adipose tissue in the elderly mother showed amyloid deposits.

It seems well established that the clinical picture differs in persons from different genetic backgrounds. For example, the methionine-30 mutation in a U.S. family of English descent invariably produces cardiomyopathy, whereas among the Swedes the same mutation is rarely accompanied by cardiomyopathy and instead shows the kidneys as the main target, with patients dying of renal failure (Holmgren et al., 1988).

An autosomal dominant form of familial amyloid polyneuropathy in a Japanese kindred originating in the Nagasaki region was described byUeno et al. (1988). The clinical phenotype most closely resembled that of type I FAP. Clinical manifestations began in the third decade. Affected individuals developed a polyneuropathy of the lower limbs and autonomic dysfunction. Vitreous opacities were seen in 6 of the 9 patients. Typically, death occurred 6 to 15 years after the onset of symptoms. Biopsy specimens from stomach, rectum, and sural nerve stained positive with Congo red. By electron microscopic analysis, amyloid was identified. Immunohistochemical staining with antisera to immunoglobulin light chain, A protein, and prealbumin was negative. Extracted amyloid fibrils did not react with anti-prealbumin serum. Biochemical analysis of the extracted protein showed no resemblance to prealbumin. Southern blot analysis failed to demonstrate any of the restriction fragment sites generated by known prealbumin variants in familial amyloid polyneuropathy. The authors concluded that this is an autosomal dominant variety of amyloidosis, which is not associated with the deposition of a prealbumin-related protein.

Coutinho and Sequeiros (1989) described a Portuguese family in which the Andrade type of familial amyloidopathy coexisted with Machado-Joseph disease (109150). Although no individual with both diseases was observed, they considered it not unexpected that they might occur together because of the relatively high frequency of both conditions in one area of Portugal.

Sandgren et al. (1991) published skeleton pedigrees showing the common ancestry in the 17th century of seemingly unrelated individuals alive currently. Patients who had vitreous opacities as a first symptom seemed to form a separate group with a later average age of onset. Sandgren et al. (1991) speculated that additional familial factors may modify the expression of the FAP gene, resulting in vitreous opacities. The mean age of onset for vitreous opacities was lower for homozygous than for heterozygous patients. Six homozygotes were shown in their pedigree charts.

Although the clinical manifestations and natural history vary, most forms of amyloidosis have polyneuropathy as the predominant feature. The amyloid polyneuropathy tends to involve small unmyelinated fibers, disproportionately affecting the autonomic nervous system in sensations of pain and temperature. Ando et al. (1994) demonstrated that blood flow was decreased in the peripheral tissues of amyloidosis patients and suggested that this effect could be mediated in part by a decreased production of nitric oxide, also known as endothelial-derived relaxing factor.

A substitution of methionine for valine at position 30 (GTG-to-ATG) results in the classic Swedish-Portuguese-Japanese amyloid polyneuropathy first delineated by Andrade of Porto, Portugal. The clinical phenotype is a progressive small fiber neuropathy leading predominantly to sensory and autonomic dysfunction. Ducla-Soares et al. (1994) studied 47 individuals with this disorder and found that autonomic dysfunction is the first manifestation in a significant proportion of patients, frequently preceding standard clinical neurologic or electroneurodiagnostic abnormalities.

Ando et al. (1995) found that in a patient with type I familial amyloidotic polyneuropathy who underwent liver transplantation without blood transfusion during the operation, variant TTR levels decreased in a time-dependent manner. Plasma half-life of variant TTR was calculated to be 2.1 days. Total protein, normal, and variant TTR levels in cerebrospinal fluid remained unchanged after liver transplantation, however. The authors speculated that, since autonomic dysfunction and sensorineuropathy significantly improve after liver transplantation (see later), the variant TTR produced by the choroid plexus may play only a small role in amyloid deposition in tissues.

Kyle (2001) provided a historical review of the development of knowledge concerning amyloidosis, including familial forms. He cited the family reported by De Bruyn and Stern (1929) as one of the earliest. The proband was a 52-year-old man who had had pain and numbness in his limbs for 3 years. He had a loss of energy and appetite and then developed severe diarrhea. Two brothers and a sister had died of a similar illness.

Ikeda et al. (2002) reviewed clinical findings and other aspects of familial amyloid polyneuropathy in Japan. They concluded that there is wide variability in phenotype, even among those with the same genotype.

Koike et al. (2004) compared the pathologic findings of 11 Japanese patients with onset of FAP before age 50 years who were from the 2 FAP-endemic regions in Japan to that of 11 Japanese patients with later-onset who were not from the 2 endemic regions. All patients carried the common V30M mutation in the TTR gene (176300.0001). Sural nerve biopsies in the early-onset cases showed predominant loss of small myelinated fibers. Sural nerve biopsies of late-onset cases showed variable fiber size distribution, axonal sprouting, more total loss of myelinated fibers, and relatively preserved unmyelinated fibers. Postmortem studies in both groups showed amyloid deposition throughout the length of nerves and in sympathetic and sensory ganglia, but deposition was greater in the early-onset cases. Early-onset cases also showed greater neuronal cell loss in sympathetic ganglia compared to dorsal root ganglia; the opposite was true in late-onset cases. TTR-positive, Congo red-negative amorphous material was more conspicuous in nerves from late- than early-onset cases. In extraneural sites, amyloid was more conspicuous in thyroid and kidney from early-onset cases, and in heart and hypophysis from late-onset cases. In early-onset cases, cardiac amyloid deposition was prominent in the atrium and subendocardium, but was conspicuous throughout the myocardium in late-onset cases.Koike et al. (2004) concluded that the pathology of early- and late-onset FAP TTR V30M mutation carriers correlated well with differences in clinical findings.

Liu et al. (2008) reported 5 unrelated Chinese Taiwanese patients with adult-onset rapidly progressive TTR-related amyloidosis. The average age at onset was 51 years. Four presented with paresthesia of the limbs and 1 with diarrhea. Clinical features related to the polyneuropathy included areflexia, impaired sensation, muscle weakness, and carpal tunnel syndrome. Sural nerve biopsy showed axonal degeneration and amyloid deposits. Autonomic dysfunction manifested as orthostatic hypotension, gastrointestinal dysautonomia, erectile dysfunction, and urinary retention. Two patients, and the affected mother of 1 of the patients, had cardiac dysfunction, including arrhythmia, cardiac hypertrophy, and heart failure. One patient had chronic renal dysfunction. All carried the same heterozygous mutation in the TTR gene (A97S; 176300.0052). Yang et al. (2010) reported 19 unrelated Taiwanese patients with FAP and the A97S mutation. Symptom onset ranged from 48 to 68 years, and severe disease progression occurred within 5 years. All had motor, sensory, and autonomic symptoms with loss of sensation to thermal stimuli and loss of proprioception. Seven patients showed additional rapid declines in neurologic function associated with elevation of protein content in the CSF. Sural nerve biopsies showed an eosinophilic deposition of TTR-positive amyloid and a pattern of axonal degeneration with loss of large and small myelinated fibers. Skin biopsies of all patients showed a severe loss of intraepidermal nerve fiber density and sparse degenerated fragmented dermal nerve fibers compared to controls; degree of loss of these fibers correlated with clinical severity.

Cardiac Amyloidosis

Three mutations in TTR are notable for their association with amyloidosis presenting as cardiomyopathy without a significant degree of peripheral neuropathy (Benson, 1991). A thr60-to-ala substitution (T60A; 176300.0004) resulted in amyloidosis formerly termed 'Appalachian type' that was characterized by restrictive cardiomyopathy and autonomic dysfunction. A leu111-to-met mutation (L111M; 176300.0007) was identified in a single Danish family with cardiac amyloidosis and no evidence of peripheral neuropathy. A val122-to-ile substitution (V122I;176300.0009) is associated with late-onset restrictive cardiomyopathy without significant peripheral neuropathy. This mutation is particularly frequent in African Americans, with an estimated allele frequency of 3.9%; after the age of 60, isolated cardiac amyloidosis is 4 times more common among blacks than whites in the United States (Jacobson et al., 1997).

Leptomeningeal Amyloidosis

Leptomeningeal amyloidosis is distinct from other forms of transthyretin amyloidosis in that it exhibits primary involvement of the central nervous system. Neuropathologic examination shows amyloid in the walls of leptomeningeal vessels, in pia arachnoid, and subpial deposits. Some patients also develop vitreous amyloid deposition that leads to visual impairment ('oculoleptomeningeal amyloidosis') (Vidal et al., 1996).

In a Hessian (German) kindred living in Ohio, Goren et al. (1980) described a form of autosomal dominant amyloidosis with manifestations limited to central nervous and ocular dysfunction: dementia, seizures, strokes, coma, and visual deterioration. The cerebrospinal fluid was xanthochromic with lymphocytic pleocytosis and elevated protein. Neurologic dysfunction was episodic, suggesting transient cortical ischemia. The seizures were attributed to small, superficial cortical infarcts resulting from occluded subarachnoid vessels. Obtundation and headache were attributed to intermittent hydrocephalus. Pathologic examinations showed severe, diffuse amyloidosis of the leptomeninges and subarachnoid vessels associated with patchy fibrosis and obliteration of the subarachnoid space. Amyloid deposits were prominent on the ependymal surfaces. Severe and diffuse neuronal loss and generalized subpial gliosis were found in the cerebrum and cerebellum, as well as occasional superficial brain infarcts. Amyloid was also found in the vitreous, the retinal internal limiting membrane, and the retinal vessels, particularly those in the nerve fiber layer. Only minimal amyloid deposition was found elsewhere. At least 5 instances of male-to-male transmission were observed.

Dowell et al. (2007) reported another affected member of the family reported by Goren et al. (1980). She was a 45-year-old woman who presented with progressive central nervous system (CNS) dysfunction over 4 months. Initial symptoms included headache, emesis, aphasia, facial weakness, and lower extremity paresthesias and weakness which progressed to paraplegia, incontinence, visual impairment, and deafness. She had hydrocephalus and died 3 months later. Postmortem examination showed extensive granulomatous vasculitis and inflammation of the leptomeninges consistent with primary angiitis of the CNS. Cerebral blood vessels showed congophilic red staining, and there was infarction and degeneration at all levels of the spinal cord. Dowell et al. (2007) suggested that amyloid deposition may have induced an inflammatory reaction resulting in vasculitis in this patient.

Uitti et al. (1988) described a Canadian family of Italian origin in which 3 members had oculoleptomeningeal amyloidosis. The 3 affected members of the family were twin brothers and the son of 1 of them. The clinical features were hemiplegic migraine, periodic obtundation, psychiatric symptoms, seizures, intracerebral hemorrhage, visual impairment, deafness, dysarthria, myelopathy, spasticity, and polyneuropathy. Onset was in the teens or twenties, with death ranging from age 29 to 62. Histopathologic findings were mainly amyloid deposition in the leptomeningeal and retinal vessels, in the vitreous humor, and in perivascular tissue throughout the body. Evaluation of the amyloid showed it to be derived from transthyretin. Uitti et al. (1988) pointed to cases reported by Hamburg (1971) and by Okayama et al. (1978) as representing probable cases of oculoleptomeningeal amyloidosis.

Garzuly et al. (1996) described a Hungarian family with autosomal dominant meningocerebrovascular amyloidosis. There were 4 definitely and 3 probably affected members over 4 generations. Clinical features included adult onset, memory disturbances, psychomotor deterioration, ataxia, and hearing loss. Other variable features included migraine-like headaches with vomiting, tremor, spastic paraparesis, nystagmus, hallucinations, and urinary retention. Progressive visual disturbance was absent. CSF protein was markedly elevated in all patients. Postmortem examination of 2 patients showed amyloid deposition in the leptomeninges, brainstem, and spinal cord. There was some systemic amyloid deposition in the heart, kidney, and skin.

Hagiwara et al. (2009) reported a 53-year-old Japanese man with leptomeningeal amyloidosis. The patient presented at age 48 years with chronic progressive polyradiculoneuropathy, severe sensory ataxia, bilateral sensorineural hearing loss, and cerebellar ataxia. There was no visceral organ involvement. He died at age 52 of multiple intracranial hemorrhages. Postmortem examination showed dense hyaline material in the piaarachnoid and leptomeningeal vessels of the brain that were positive for anti-TTR antibodies. Amyloid deposits involved the adventitia, media, and external elastic lamina of the vessels, and no amyloid deposits were identified within the spinal cord, nerve roots, dorsal root ganglia, and peripheral nerves. The spinal cord was compressed by thickened leptomeninges, in which massive amyloid deposits and reactive connective tissue formation was observed. The acoustic nerves and spinal nerve roots were entrapped by thickened leptomeninges. There were varying degrees of demyelination and axonal degeneration depending on the nerve fasicles. There was no visceral organ involvement.

Senile Systemic Amyloidosis

Wildtype TTR is mildly amyloidogenic and is deposited as amyloid primarily in the heart of up to 25% of elderly persons, a condition termed senile systemic amyloidosis (Saraiva, 2002; Westermark et al., 1990).

Senile systemic amyloidosis, also referred to as senile cardiac amyloidosis, involves the lungs, liver, and kidneys as well as the heart. Crossreaction of antiserum to human prealbumin provides a test for distinguishing senile systemic amyloid from other forms of senile amyloid as well as from amyloid associated with multiple myeloma or primary systemic amyloidosis (Cornwell et al., 1981).

Inheritance
In reviewing 1,233 cases of FAP from 489 Portuguese families registered at the Centro de Estudos de Paramiloidose in Porto, Portugal, Coelho et al. (1994) found 159 cases in which neither parent had shown symptoms of this hereditary dominant form of peripheral neuropathy. These cases appeared to form a distinct group with a later age of onset (mean 45.1 years) than the group of patients with 1 affected parent (mean 31.2 years) and a geographic origin somewhat different from the areas where the disease is most prevalent. Although this group was not significantly different from the general group of patients in clinical presentation at onset and severity of the disease, the average interval between onset and diagnosis (mean 4.5 years) reflected the difficulties in diagnosing these patients in the absence of a positive family history. Coelho et al. (1994)suggested that in some families the FAP gene may result in a milder expression or even remain 'silent' for several generations. They pointed out that in Sweden a large proportion of cases are isolated (Drugge et al., 1993) and that in Majorca, 13.6% of patients are said to lack affected antecedents. Coelho et al. (1994) suggested that investigation of the reason for reduced penetrance might lead to elucidation of mechanisms involved in the pathogenetic process.

Clinical Management
Holmgren et al. (1991) found that orthotopic liver transplantation caused prompt replacement of variant transthyretin by the donor wildtype in the plasma of patients with the met30 variant of familial amyloid polyneuropathy. Holmgren et al. (1993) reported clinical outcome 1 to 2 years after transplantation in 4 patients. Three of them showed improved general well being, walking ability, and bowel function, and 1 had regained normal bladder and bowel function. There had been little objective improvement in peripheral neuropathy. Although the fourth patient, who had the most severe neurologic deficits and a complicated postoperative course, had not improved, there had been no further deterioration. Two patients followed serially with quantitative scintigraphy using radiolabeled serum amyloid P component showed regression of visceral deposits after transplantation. Another FAP patient, who was monitored prospectively for 2 years but did not undergo transplantation, showed, as expected, progression of neuropathy and increased visceral amyloid deposition. See 176300.0004 for an example of combined heart and liver transplantation for autosomal dominant familial amyloidosis.thy and increased visceral amyloid deposition.

Amyloidogenic mutations in the TTR gene lead to decreased stability of the protein. Using isoelectric focusing in urea gradients, Altland and Winter (1999) were able to demonstrate a stabilizing effect of sulfite on TTR monomers and tetramers, as well as an increase in the tetramer/monomer ratio. They demonstrated that this ratio, which is decreased in FAP patients, can be increased to beyond normal levels. Altland and Winter (1999) showed that doses of sulfite that are tolerable in vivo produce a significant increase in the tetramer/monomer ratio, and they postulated that sulfite may be a potent drug for delaying the onset and progression of FAP.

Ikeda et al. (2002) noted that although results with liver transplantation had been favorable, the authors noted the need for less invasive and more effective treatments.

Ray and Lansbury (2004) noted that the general strategy of inhibiting potentially pathogenic aggregation by stabilizing native oligomers was proposed and accomplished by Koo et al. (1999), in the context of the aggregation-dependent degenerative disease familial amyloid polyneuropathy. Several approved drugs bind the TTR tetramer in an analogous manner as thyroxine (T4), inhibit TTR dissociation and aggregation, and prevent aggregation-associated toxicity in cell culture (Reixach et al., 2004).

Coelho et al. (2013) reported the results of 2 phase 1 clinical trials of RNAi against transthyretin. Two distinct first- and second-generation formulations were evaluated, the first in 32 patients with transthyretin amyloidosis and the second in 17 healthy volunteers. Rapid dose-dependent durable lowering of transthyretin levels was observed in both trials. Both compounds suppressed the production of both mutant and nonmutant transthyretin, establishing proof of concept for RNAi therapy targeting mRNA transcribed from a disease-causing gene.

Benson et al. (2018) conducted an international randomized double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen, an antisense oligonucleotide inhibitor of the hepatic production of transthyretin, in adults with stage 1 (ambulatory) or stage 2 (ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least 1 dose of a trial regimen, and 139 (81%) completed the intervention period. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire. A decrease in scores indicated improvement. Both primary efficacy assessments favored inotersen. Improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were 5 deaths in the inotersen group (4 consistent with progression or complication of underlying disease and 1 from intracranial hemorrhage associated with thrombocytopenia) and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients (3%)) and thrombocytopenia (in 3 patients (3%)), with 1 death associated with 1 of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring. Benson et al. (2018) concluded that inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring.


Molecular Genetics
The genetic defect in the kindreds from northern Portugal described by Andrade (1952) was heterozygosity for a valine-to-methionine substitution at residue 30 of transthyretin (V30M; 176300.0001) (Saraiva et al., 1984). Saraiva (2001) reported that over 500 kindreds had been identified in Portugal, constituting the largest focus of FAP worldwide. The second largest focus of V30M FAP is northern Sweden, where more than 350 families have been diagnosed (Holmgren et al., 1994). A few cases of homozygosity for the V30M mutation have been reported but do not lead to a more severe form of the disease (Holmgren et al., 1988).

In a Hungarian family with meningocerebrovascular amyloidosis, Garzuly et al. (1996) and Vidal et al. (1996) identified a mutation in the transthyretin gene (D18G; 176300.0047). Herrick et al. (1996) identified a common mutation in the TTR gene (V30M; 176300.0001) in a woman with leptomeningeal amyloidosis.

In a family with oculoleptomeningeal amyloidosis reported by Goren et al. (1980), Petersen et al. (1997) identified a mutation in the TTR gene (176300.0049). In affected members of the family with oculoleptomeningeal amyloidosis reported by Uitti et al. (1988), Uemichi et al. (1999)identified a heterozygous mutation in the transthyretin gene (176300.0048).

In a large Swedish family with autosomal dominant oculoleptomeningeal amyloidosis characterized by seizures, dementia, stroke-like episodes, ataxia, and, in some, vitreous amyloid, Blevins et al. (2003) identified a mutation in the TTR gene (176300.0050).

In 5 American and 1 Brazilian case of hereditary amyloid polyneuropathy, and in 1 Brazilian case that was typical except for the absence of a positive family history, Dalakas and Engel (1981) demonstrated that the amyloid stained with antiprealbumin, as had been shown in the Portuguese type. No staining was demonstrated with antibodies specific for kappa and lambda proteins. The patients studied included 1 from the large kindred reported by Mahloudji et al. (1969); patients who represented an aggressive, early-adult-onset, autosomal dominant type reported byKaufman (1958) and Wong and McFarlin (1967), and shown by Jacobson et al. (1992) to have a leu55-to-pro substitution in the TTR gene (176300.0022); and persons of Portuguese extraction and brothers of Greek extraction with an aggressive, mid-adult-onset, autosomal dominant form. The authors suggested that prealbumin-like protein may be a feature common to the amyloid deposits in many and perhaps all the forms of hereditary amyloid polyneuropathy.

Hagiwara et al. (2009) reported a 53-year-old Japanese man with leptomeningeal amyloidosis in whom they identified a heterozygous mutation in the TTR gene (A25T; {176300.051}). Hagiwara et al. (2009) referred to the studies of Sekijima et al. (2005) who showed that TTR variants of the leptomeningeal type of amyloidosis, such as A25T, have faster homotetrameric dissociation rates compared to other TTR variants. The A25T variant was secreted more efficiently from choroid plexus cells compared to hamster kidney and mouse liver cells, possibly via a T4-chaperoning mechanism. The D18G variant did not form tetramers and was targeted for endoplasmic reticulum (ER)-associated degradation, leading to low secretion levels.

Animal Model
Yi et al. (1991) introduced the human TTR gene carrying the val30-to-met mutation into transgenic mice and demonstrated that amyloid deposition started in the gastrointestinal tract, cardiovascular system, and kidneys 6 months after birth and extended to various other organs and tissues with advancing age. By the age of 24 months, the pattern of amyloid deposition was similar to that observed in human autopsy cases, except for its absence in the choroid plexus and in the peripheral and autonomic nervous systems.

History
Benson (1986) was of the view that the Portuguese disease was imported from Sweden. From Portugal, it appeared to have spread to Japan.

Coimbra and Andrade (1971) reported somewhat unexpected electron microscopic findings demonstrating that the primary change is one of myelin degeneration, followed by axoplasmic degeneration and only subsequently by accumulation of amyloid deposits which do not cause nerve compression. This suggested that the amyloid accumulations are secondary to the peripheral nerve degeneration.

Coutinho and Sequeiros (1989) suggested that the so-called Iiyama type of FAP seen in Japan and characterized by the same met30 mutation of the TTR gene as in the Portuguese cases but associated with cerebellar and pyramidal signs (Furuya et al., 1987) may represent the simultaneous occurrence of FAP type I and Machado-Joseph disease (MJD; 109150), both disorders of relatively high frequency in Portuguese. The MJD mutation was later determined to be in the ataxin-3 gene (ATXN3; 607047) on chromosome 14q24.3-q33. Ikeda et al. (1996) found that the family studied byFuruya et al. (1987) and others carried mutations in both the TTR and ATXN1 (601556) genes and thus represented the coexistence of FAP and spinocerebellar ataxia-1 (164400).

Ironically, George G. Glenner, who made major contributions to the understanding of amyloidosis, succumbed to cardiac amyloidosis of the transthyretin type (Sipe, 1995). Glenner et al. (1971) reported that the fibrils in primary amyloidosis, or amyloidosis associated with multiple myeloma, are composed of the N-terminal variable region of the immunoglobulin light chain. Glenner et al. (1974) defined the beta-pleated sheet structure of the amyloid fibril. Glenner and Wong (1984) defined the A-beta fibril protein associated with Alzheimer disease (104760).

(文献)
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