疾患詳細

疾患詳細





#164500
Spinocerebellar ataxia 7 (SCA7)
(Olivopontocerebellar atrophy III; OPCA3)
(OPCA III)
(OPCA with retinal degeneration)
(OPCA with macular degeneration and external ophthalmoplegia)
(Autosomal dominant cerebellar ataxia, type II)
(ADCA, type II)

脊髄小脳性運動失調 7
(オリーブ核橋小脳萎縮症 III)
(オリーブ核橋小脳萎縮症-網膜変性)
(オリーブ核橋小脳萎縮症-黄斑変性-外眼筋麻痺)
(常染色体優性小脳性運動失調 II 型)
指定難病17 多系統萎縮症

責任遺伝子:607640 Ataxin 7 (ATXN7) <3p14.1>
遺伝形式:常染色体優性

(症状)
(GARD)
 <100%>
 Dysarthria (構音障害) [HP:0001260] [0230]
 Dysmetria (ジスメトリア) [HP:0001310] [02605]
 Hyperreflexia (反射亢進) [HP:0001347] [0241]
 
 <80%-99%>
 Cone/cone-rod dystrophy (錐体/錐体-杆体ジストロフィー) [HP:0000548] [06524]
 Dysphagia (嚥下障害) [HP:0002015] [01820]
 
 <30%-79%>
 Babinski sign (バビンスキー徴候) [HP:0003487] [0213]
 Cerebellar atrophy (小脳萎縮) [HP:0001272] [16013]
 Cerebral atrophy (大脳萎縮) [HP:0002059] [160121]
 Congestive heart failure (うっ血性心不全) [HP:0001635] [0171]
 Dysdiadochokinesis (ジスジアドコキネーゼ) [HP:0002075] [02605]
 Failure to thrive (成長障害) [HP:0001508] [01411]
 Feeding difficulties (食餌摂取障害) [HP:0011968] [01411]
 Global developmental delay (全般的発達遅滞) [HP:0001263] [0120]
 Mental deterioration (知的悪化) [HP:0001268] [0125]
 Motor delay (運動遅滞) [HP:0001270] [0120]
 Muscle weakness (筋力低下) [HP:0001324] [0270]
 Neonatal hypotonia (新生児筋緊張低下) [HP:0001319] [0242]
 Nystagmus (眼振) [HP:0000639] [06609]
 Ophthalmoplegia (眼球運動麻痺) [HP:0000602] [0698]
 Orofacial dyskinesia (口腔顔面ジスキネジア) [HP:0002310] [02605]
 Restless legs (下肢静止不能) [HP:0012452] [02204]
 Sensory impairment (感覚障害) [HP:0003474] [025]
 Visual loss (視力喪失) [HP:0000572] [06011]
 
 <5%-29%>
 Blindness (盲) [HP:0000618] [06011]
 Hemeralopia (昼盲) [HP:0012047] [06011]
 Macular degeneration (黄斑変性) [HP:0000608] [06523]
 Photophobia (羞明) [HP:0000613] [06008]
 Psychosis (精神病) [HP:0000709] [0206]
 
 <1%-4%>
 Optic atrophy (視神経萎縮) [HP:0000648] [06522]
 Progressive cerebellar ataxia (進行性小脳失調) [HP:0002073] [028]
 Tremor (振戦) [HP:0001337] [02604]
 
 
 Abnormality of extrapyramidal motor function (錐体外路運動機能異常) [HP:0002071] [02141]
 Autosomal dominant inheritance (常染色体優性遺伝) [HP:0000006]
 Chorea (舞踏病) [HP:0002072] [02600]
 Genetic anticipation with paternal anticipation bias (父方促進を伴う遺伝的促進) [HP:0003744]
 Olivopontocerebellar atrophy (オリーブ核橋小脳萎縮) [HP:0002542] [16013] [160133] [160134]
 Pigmentary retinopathy (網膜色素変性症) [HP:0000580] [06524]
 Progressive visual loss (進行性視力喪失) [HP:0000529] [06011]
 Slow saccadic eye movements (遅い衝動性眼球運動) [HP:0000514] [0695]
 Spasticity (痙縮) [HP:0001257] [0241]
 Supranuclear ophthalmoplegia (核上性眼球運動麻痺) [HP:0000623] [0698]

(UR-DBMS)
【一般】嚥下障害
 感染による早期死亡
【神経】*進行性小脳性失調歩行
 構音障害
 錐体路症状
 錐体外路症状
 舞踏病
 反射亢進
 開扇反射
 形成
 口腔顔ジスキネジア
 認知障害 (まれ)
 ジスメトリア
 振戦
 寝たきり状態
【眼】黄斑変性
 色素性網膜変性 (乳児; びまん性の繊細な色素変化, 成人; 牛眼病変)
 *進行性視力喪失
 ハイポメトリックサッケード
 視神経萎縮
 核上性眼筋麻痺
 眼振
【X線】*オリーブ核橋小脳萎縮 (OPCA)
【その他 】平均発症年齢32歳
 遺伝的表現促進
 父方表現促進バイアス

(要約) 脊髄小脳失調症 7型 (SCA7) (2020.6.23)
●脊髄小脳失調症7型 (SCA7) は, 思春期または成人発症進行性小脳失調症と錐体杆体網膜ジストロフィーから, 乳児または早期小児期発症 (多臓器不全, 急速な経過および早期死亡) までの表現型スペクトラムからなる
 このヌクレオチドリピート疾患の表現促進は非常に劇的で, 家系内で, 乳児期または早期小児期発症が, CAGリピート伸長をもつ両親または祖父母に症状がでるまで, 関連のない神経変性疾患をもつと診断されるかもしれない
 思春期発症 SCA7 では, 最初の症状は, 典型的には視力障害で, 小脳失調が続く
 成人発症では, 進行性小脳失調が通常視力障害発症に先行する
 これら2つの年齢群では進行率に違いがあるが, ほぼ全患者の最終結果は, 視力喪失, 重度の構音障害と嚥下障害, および運動調節喪失をともなう寝たきり状態である
●確定診断:ATXN7の異常なCAGリピート伸長のヘテロ接合
 病的 (浸透度減少): 34-36 CAG repeats→症状発症する場合は後期発症でより軽症
 病的 (完全浸透アレル)  37-460 CAG リピート (以下の患者でも症状ありかも)
 正常 7-27 CAG repeats
 Mutable norma 28-33リピート (異常表現型なし)→次世代で病的範囲に伸長するかも
●遺伝: 常染色体優性
●示唆する所見
(成人発症)
 小脳失調が原因の進行性協調運動障害 (構音障害/嚥下障害, ジスメトリア, ジスアジアドコキネージア)
 錐体-杆体網膜ジストロフィー
  中心視力障害
  色覚検査での tritan-axis (青/黄色) 障害
  黄斑変化 (眼底検査)
  傍中心暗点 (視野検査)
   (ERG) 最初に錐体機能異常→杆体機能異常
(乳児期発症)
 発育障害と運動発達遅滞
 急激な悪化→早期死亡
 運動失調と視力喪失は明らかではない
 家族歴; 常染色体優性
●思春期または成人発症 SCA7の症状頻度 (1000例以上で)
 小脳失調 100% 不安定歩行; 指鼻ジスメトリア
 構音障害 100% 不明瞭発語
 嚥下障害 40%
 眼球運動異常 80% 緩徐なサッカード, 眼球運動麻痺
 運動ニューロン変性 100% 上位運動ニューロン障害 (反射亢進, 痙縮); 遺伝性痙性対麻痺に似るかも
              下位運動ニューロン障害 (線維束性収縮, 筋力低下/筋消耗, 無反射, 遠位感覚喪失)
 感覚喪失 40% 軽い接触, ピン刺し感覚減少+/-関節位置減少
 むずむず脚症候群 35%
 認知低下 20%
 行動異常/精神病 10%
 錐体杆体ジストロフィー 70%
●遺伝子型-表現型相関
 CAG repeat のサイズと重症度に相関あり→長いほど早期発症, より重症, 急速進行
 乳児期発症→ 200 ~ 400
 小児期発症→>100.
 若年発症→ 60-100
●命名 (過去の名称)
 olivopontocerebellar ataxia (OPCA) type III と ADCA type II →SCA7へ
●頻度: < 1:300,000
 すべてのSCAsの2%
 2つの人種に多い→北欧とアフリカ人
 北米,欧州,ユーラシア,オーストラリア,南アフリカ,南米でみられる
 メキシコの Veracruz 州に多い
●鑑別診断
1) CRX Cone-rod dystrophy 2 (OMIM 120970) AD 神経学的症状なし
2) MT-ND1; MT-ND4; MT-ND6  Leber hereditary optic neuropathy 母性遺伝 神経学的症状なし 通常中年で
3) OPA3 Costeff 症候群 (3-methylglutaconic aciduria type 3) AR 両側性視神経萎縮 舞踏病, 痙性対麻痺 軽度の運動失調
 視神経萎縮は小児期 (<10歳), イラクユダヤ人に多い
4) WFS1; CISD2 Wolfram 症候群 両側性視神経萎縮 運動失調, 糖尿病/尿崩症, 難聴
 小児期発症糖尿病と視神経萎縮が特徴
●分子機序
ATXN7: 核と細胞質の間をシャトルする核タンパクであるataxin-7をコードする
 STAGA と呼ばれる転写コアクチベーター複合体の核となる成分である
 微小管の安定で細胞質での役割ももつ
 ヒトの脳と網膜での正常な分布がみられる
○ CAG 伸長による機能獲得が原因である
●CAGリピートの検出について
 正常, 不明, mutable normal, reduced penetrance: <19-36 リピート
 →通常のPCRで検出可能
 病的リピート (完全浸透): 37-~460 リピート
 → ~100 CAG までは通常のPCRで検出可能
  triplet-primed PCR は伸長は検出できるがリピートサイズは決定できない
 サザンブロット解析→おおまかなリピートサイズの決定 (詳細なサイズは診断には不必要)
○ ATXN7 病的バリアントの例 (RS NM_000333.3, NP_000324.1)
 c.89_91AGC[7_27] p.Gln38[7_27] →正常
 c.89_91AGC[28_33] p.Gln38[28_33] →Mutable normal
 c.89_91AGC[34_36] p.Gln38[34_36] →病的 reduced penetrance
 c.89_91AGC[37_~460]  .Gln38[37_~460] →病的 full penetrance

(解説)
●Olivopontocerebellar atrophy (OPCA) は,小脳,橋および下部オリーブ核の神経変性を定義する用語である
 遺伝的基盤がわかるにつれ,用語は相当かわってしまっている
 オリジナルは Joseph Jules Dejerine と André Thomas (1900) である
●現在は,遺伝的基盤が不明の2つの疾患にのみ適応される
OPCA type 2 (258300) Fickler[4]-Winkler 型 OPCA, 常染色体劣性
OPCA type 5 (164700) OPCA と認知症, 錐体外路サイン, 常染色体優性
●廃止
散発例→ 現在は multiple system atrophy に再分類
遺伝性4つ→現在は 脊髄小脳失調症に再分類
 OPCA type 1 ("Menzel type OPCA") → SCA1 (ATXN1変異) 164400
 OPCA type 2, 常染色体優性 ("Holguin type OPCA") →SCA2 (ATXN2) 183090
 OPCA type 3 ("OPCA with retinal degeneration") →SCA7 (ATXN7) 164500
 OPCA type 4 ("Schut-Haymaker type OPCA") →SCA1 (ATXN1) 164400

<指定難病17 多系統萎縮症>
概要
 多系統萎縮症 (multiple system atrophy: MSA) は, 成年期 (30 歳以降, 多くは 40 歳以降)に発症し, 組織学的には神経細胞とオリゴデンドログリアに不溶化したαシヌクレインが蓄積し, 進行性の細胞変性脱落をきたす疾患である。
 初発から病初期の症候が
 ●小脳性運動失調であるものはオリーブ橋小脳萎縮症 (olivopontocerebellar atrophy: OPCA),
 OPCA1/ OPCA4 Spinocerebellar ataxia 1 (SCA1)  Ataxin 1 (ATXN1) <6p22.3>
 OPCA2 Spinocerebellar ataxia 2 (SCA2) Ataxin-2 (ATXN2) <12q24.12>
 OPCA3  Spinocerebellar ataxia 7 (SCA7)  Spinocerebellar ataxia 7 (SCA7)
 OPCA5 ?
 OPCA, X-linked  Spinocerebellar ataxia, X-linked 1 (SCAX1)  ATPase, Ca(2+)-transporting, plasma membrane, 3 (ATP2B3)
 ●パーキンソニズムであるものは線条体黒質変性症,  (Nucleoporin, 62-kD (NUP62))
 ●そして特に起立性低血圧など自律神経障害の顕著であるものは各々の原著に従いシャイ・ドレーカー症候群 (現在は破棄) と称されてきた。
 いずれも進行するとこれら三大症候は重複してくること, 画像診断でも脳幹と小脳の萎縮や線条体の異 常等の所見が認められ, かつ組織病理も共通していることから多系統萎縮症と総称されるようになった。

※α-シヌクレイン はSNCA (Synuclein, alpha) 遺伝子によってエンコードされるアミノ酸140残基からなるタンパク質.
このタンパクの断片が, アルツハイマー病に蓄積するアミロイド中の (主な構成成分であるアミロイドベータとは別の) 成分として発見され, もとのタンパク質がNACP (Non-Abeta component precursor 非アミロイド成分の前駆体) と命名された。後にこれがシビレエイ属のシヌクレインタンパクと相同であることがわかり, ヒトα-シヌクレインと呼ばれるようになった。
α-シヌクレインの蓄積は, パーキンソン病をはじめとする神経変性疾患 (いわゆるシヌクレイノパチー) の原因とされている

原因
 MSA は小脳皮質, 橋核, オリーブ核, 線条体, 黒質, 脳幹や脊髄の自律神経核に加えて大脳皮質運動野などの神経細胞の変性, オリゴデンドログリア細胞質内の不溶化したαシヌクレインからなる封入体 (グリア 細胞質内封入体: GCI)を特徴とするが, 神経細胞質内やグリア・神経細胞核内にも封入体が見られる。殆どは孤発例であるが, ごく希に家族内発症がみられ, その一部では遺伝子変異が同定されている。現在, 発症機序について封入体や遺伝要因を手がかりに研究が進められているが, まだ十分には解明されていない。

症状
 わが国で最も頻度の高い病型は OPCA である。OPCA は中年以降に起立歩行時のふらつきなどの小脳性運動失調で初発し主要症候となる。初期には皮質性小脳萎縮症との区別が付きにくく二次性小脳失調症との鑑別が重要である。
 線条体黒質変性症は,筋固縮, 無動, 姿勢反射障害などの症候が初発時よりみられるのでパーキンソン病との鑑別を要する。パーキンソン病と比べて, 安静時振戦が少なく, 進行は早く, 抗パーキンソン病薬の反応に乏しい。
 起立性低血圧や排尿障害など自律神経症候で初発するものは, シャイ・ドレーガー (Shy-Drager)症候群とよばれる。その他, 頻度の高い自律神経症候としては, 勃起障害(男性), 呼吸障害, 発汗障害などがある。注意すべきは睡眠時の喘鳴や無呼吸などの呼吸障害であり, 早期から単独で 認められることがある。呼吸障害の原因として声帯外転障害が知られているが, 呼吸中枢の障害によるも のもあるので気管切開しても突然死があり得ることに注意して説明が必要である。
 何れの病型においても, 経過と共に小脳症候, パーキンソニズム, 自律神経障害は重複し, さらに錐体路徴候を伴うことが多い。自律神経障害で発症して数年を経過しても, 小脳症候やパーキンソニズムなど他の系統障害の症候を欠く場合は, 他の疾患との鑑別を要する。
 多系統萎縮症は頭部の X 線 CT や MRI で, 小脳, 橋(特に底部)の萎縮を比較的早期から認める。この変化をとらえるには T1 強調画像矢状断が有用である。また, T2 強調画像水平断にて,比較的早期から橋中部に十字状の高信号(十字サイン), 中小脳脚の高信号化が認められる。これらの所見は診断的価値が高い。
 被殻の萎縮や鉄沈着による被殻外側部の直線状の T2 高信号, 被殻後部の低信号化などもよく認められる。

治療法
 パーキンソン症候があった場合は, 抗パーキンソン病薬は, 初期にはある程度は有効であるので治療を 試みる価値はある。また, 自律神経症状や小脳失調症が加わってきたときには, それぞれの対症療法を行 う。呼吸障害には非侵襲性陽圧換気法などの補助が有用で, 気管切開を必要とする場合が在る。嚥下障害が高度なときは胃瘻が必要となることも多い。リハビリテーションは残っている運動機能の活用, 維持に有効であり積極的に勧め, 日常生活も工夫して寝たきりになることを少しでも遅らせることが大切である。

予後
 多系統萎縮症では線条体が変性するので, パーキンソン病に比べて抗パーキンソン病薬は効きが悪い。 また, 小脳症状や自律神経障害も加わってくるため全体として進行性に増悪することが多い。我が国での 230 人の患者を対象とした研究結果では, それぞれ中央値として発症後平均約 5 年で車椅子使用, 約 8 年 で臥床状態となり, 罹病期間は 9 年程度と報告されている。

<診断基準>
Probable MSA, Definite MSA を対象とする。

1.共通事項
 成年期 (>30 歳)以降)に発症する。主要症候は小脳性運動失調, パーキンソニズム, 自律神経障害である。発病初期から前半期にはいずれかの主要症候が中心となるが, 進行期には重複してくる。殆どは孤発性 であるが, ごく希に家族発症がみられることがある。

2.主要症候
 ①小脳症候:歩行失調(歩行障害)と声帯麻痺, 構音障害, 四肢の運動失調又は小脳性眼球運動障害
 ②パーキンソニズム:筋強剛を伴う動作緩慢, 姿勢反射障害(姿勢保持障害)が主で(安静時)振戦などの不随意運動はまれである。特に, パーキンソニズムは本態性パーキンソン病と比較してレボドパへの反応に乏しく, 進行が早いのが特徴である。例えば, パーキンソニズムで発病して3年以内に姿勢保持障害, 5年以内に嚥下障害をきたす場合はMSAの可能性が高い。
 ③自律神経障害:排尿障害, 頻尿, 尿失禁, 頑固な便秘, 勃起障害(男性の場合), 起立性低血圧, 発汗低下, 睡眠時障害(睡眠時喘鳴, 睡眠時無呼吸, REM睡眠行動異常(RBD))など。
 ④錐体路徴候:腱反射亢進とバビンスキー徴候・チャドック反射陽性, 他人の手徴候/把握反射/反射性ミオクローヌス
 ⑤認知機能・ 精神症状:幻覚(非薬剤性), 失語, 失認, 失行(肢節運動失行以外), 認知症・認知機能低下

3.画像検査所見
 ①MRI/CT:小脳・脳幹・橋の萎縮を認め※, 橋に十字状のT2高信号, 中小脳脚のT2高信号化を認める。被殻の萎縮と外縁の直線状のT2高信号, 鉄沈着による後部の低信号化を認めることがある。(※X線CTで認める小脳と脳幹萎縮も, 同等の診断的意義があるが, 信号変化を見られるMRIが望ましい。)
 ②脳PET/SPECT:小脳・脳幹・基底核の脳血流・糖代謝低下を認める。黒質線条体系シナプス前ドパミン障害の所見を認めることがある。

4.病型分類
 初発症状による分類(MSA の疾患概念が確立する以前の分類)
 オリーブ橋小脳萎縮症: 小脳性運動失調で初発し, 主要症候であるもの。
 線条体黒質変性症:パーキンソニズムで初発し, 主要症候であるもの。
 シャイ・ドレーガー症候群:自律神経障害で初発し, 主要症候であるもの。

 国際的 Consensus criteria による分類
 MSA-C: 診察時に小脳性運動失調が主体であるもの
 MSA-P:診察時にパーキンソニズムが主体であるもの

5.診断のカテゴリー
 ①Possible MSA:パーキンソニズム(筋強剛を伴う運動緩慢, 振戦若しくは姿勢反射障害)又は小脳症候(歩行失調, 小脳性構音障害, 小脳性眼球運動障害, 四肢運動失調)に自律神経症候(②の基準に満たない程度の起立性低血圧や排尿障害, 睡眠時喘鳴, 睡眠時無呼吸若しくは勃起不全)を伴い, かつ錐体路徴候が陽性であるか, 若しくは画像検査所見(MRI若しくはPET・SPECT)で異常を認めるもの。
 ②Probable MSA:レボドパに反応性の乏しいパーキンソニズムもしくは小脳症候のいずれかに明瞭な自律神経障害を呈するもの(抑制困難な尿失禁, 残尿などの排尿力低下, 勃起障害, 起立後3分以内において収縮期血圧が30mmHgもしくは拡張期血圧が15mmHg以上の下降, のうちの1つを認める。)。
 ③Definite MSA:病理学的に確定診断されたもの。

6.鑑別診断
 皮質性小脳萎縮症, 遺伝性脊髄小脳変性症, 二次性小脳失調症, パーキンソン病, 皮質基底核変性症, 進行性核上性麻痺, レビー小体型認知症, 2 次性パーキンソニズム, 純粋自律神経不全症, 自律神経ニュー ロパチーなど。

(Responsible gene) *607640 Ataxin 7 (ATXN7) <3p14.1>
.0001 Spinocerebellar ataxia 7 (164500) [ATXN7, (CAG)n EXPANSION] (rs193922929) (RCV001256206...) (David et al. 1997)

(Note)
A number sign (#) is used with this entry because spinocerebellar ataxia-7 (SCA7) is caused by a heterozygous expanded trinucleotide repeat in the gene encoding ataxin-7 (ATXN7; 607640) on chromosome 3p14.

Spinocerebellar ataxia-7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive cerebellar ataxia associated with pigmental macular dystrophy. In her classification of ataxia, Harding (1982) referred to progressive cerebellar ataxia with pigmentary macular degeneration as type II ADCA (autosomal dominant cerebellar ataxia). The age at onset, degree of severity, and rate of progression vary among and within families. Associated neurologic signs, such as ophthalmoplegia, pyramidal or extrapyramidal signs, deep sensory loss, or dementia, are also variable. Genetic anticipation is observed and is greater in paternal than in maternal transmissions (Benomar et al., 1994; summary by David et al., 1996).

For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Clinical Features
Froment et al. (1937) described a neurologic lesion, which they referred to as spinocerebellar degeneration, in association with retinal degeneration, in 4 affected persons in 3 successive generations. The character of the retinopathy was variable, being peripheral in the first generation, macular in the second, and macular and circumpapillary in the third. Retinal degeneration with cerebellar ataxia in a dominant pedigree pattern was also reported by Bjork et al. (1956). Havener (1951) described macular degeneration with cerebellar ataxia in a 28-year-old black. Cerebellar involvement was much less severe than in a daughter who died at 3 years of age with profound involvement. Jampel et al. (1961) reported spinocerebellar ataxia with external ophthalmoplegia and retinal degeneration in 8 members of a black family (in 4 sibships of 3 generations). Ophthalmoplegia was progressive and appeared to have a supranuclear basis. Ptosis never occurred. Retinal degeneration began in the macular area and progressed to the periphery. Reports of the same syndrome were found in the literature, e.g., Alfano and Berger (1957). In other reports only external ophthalmoplegia or only retinal degeneration was associated with ataxia.

Foster and Ingram (1962) described a family with at least 7 affected members of 3 generations. Severity varied widely with infant death in at least 1 case and survival to middle age in other affected persons. Weiner et al. (1967) found 27 affected persons in 5 generations of a black family. The proband had a 'peculiar glistening pale area sprinkled with fine pigment granules in the macular region' of each eye. Blurred vision and a periodic slight head tremor were first noted at age 22. Weiner et al. (1967) suggested that the families of Woodworth et al. (1959) and of Carpenter and Schumacher (1966) may have suffered from the same entity. Halsey et al. (1967) found degenerative changes in the retina and cerebellum of 11 persons in 3 generations of a North Carolina black family. Blindness and ataxia were the clinical features. Fundus changes were mainly macular. Onset was usually in middle age although 3 had onset in adolescence. Consanguinity and skipped generations suggest recessive inheritance. However, a high illegitimacy rate in this population could explain the pedigree pattern by accounting for apparently 'skipped' generations with a dominant trait.

In Finland, Anttinen et al. (1986) observed a family with 9 affected persons. The first symptom was insidious, progressive visual loss caused by macular degeneration. Another early sign was slow saccades (Wadia and Swami, 1971). Gradually progressing cerebellar dysfunction and pyramidal signs developed some years after the visual symptoms. Cerebellar and pontine atrophy was demonstrated by computerized tomography (CT scan). Anttinen et al. (1986) found reports of 20 similar families with 120 affected persons, including families reported by Duinkerke-Eerola et al. (1980) and by Harding (1982). Anttinen et al. (1986) stated a preference for 'macular degeneration' rather than 'retinal degeneration.' (One of the patients described by Duinkerke-Eerola et al. (1980) was restudied by Cruysberg et al. (2002), who concluded that he had a separate neurodegenerative entity characterized by autosomal recessive cerebellar ataxia and progressive macular dystrophy with a bull's eye pattern. The patient did not show CAG trinucleotide repeat expansion in various SCA genes, including ATXN7.)

Cooles et al. (1988) described a black Dominican family in which a large number of individuals in at least 5 generations had cerebellar and retinal degeneration with morphologically abnormal mitochondria. Cooles et al. (1988) suggested that the clinical picture most closely resembled that of the black families reported by Jampel et al. (1961) and Weiner et al. (1967). Abnormally large mitochondria with irregular cristae were found in muscle biopsy specimens. None of the affected males in this family had offspring.

Enevoldson et al. (1994) described 8 families segregating autosomal dominant cerebellar ataxia associated with pigmentary macular degeneration. Two-thirds of the 14 patients presented with ataxia, and the other third with visual failure with or without ataxia. Pedigree analysis demonstrated nonmanifesting obligate carriers and anticipation in the offspring of affected fathers. Dysarthria was invariably present early in the disease. Deep tendon reflexes were usually brisk, but extrapyramidal features were rare and were limited to small choreic movements in the distal limbs. Only 1 patient had orofacial dyskinesias. Sphincter control was normal until terminal disease. Saccadic slowing occurred early in the disease and developed into almost complete external ophthalmoparesis. Progressive visual loss occurred in all patients, although in 1 patient it followed the onset of ataxia by 22 years. All 3 children who developed symptoms before the age of 14 months were dead by 22 months. Unlike the adult-onset cases, early-onset cases presented with depressed or absent deep tendon reflexes. Although linkage analysis was not performed on these patients, the authors argued that the macular degeneration and the presence of early onset of fulminant disease after transmission from fathers are distinctive features of this disorder, clearly distinguishing it from spinocerebellar atrophy types I and II.

Gouw et al. (1995) reported 4 families with SCA and associated retinal degeneration. Two of the kindreds were Caucasian and 2 were African American. The disorder was manifested by early loss of color discrimination in the tritan axis (blue-yellow) followed by loss of vision and progressive ataxia. Index cases presented initially with visual problems and subsequent episodes of instability and incoordination that worsened inexorably. Dysmetria and dysarthria were present on examination, although no extrapyramidal signs or dementia were seen. Tritan colorblindness (190900) is an exceedingly rare dichromatic deficiency; thus it is a highly sensitive and specific symptom seen before the other manifestations in this disease.

David et al. (1997) noted that SCA7 is the first of the neurodegenerative disorders caused by an expanded trinucleotide repeat in which the degenerative process also affects the retina. In 5 families with 18 affected individuals, the mean age at onset of visual failure was 22 years with a range from 1 to 45 years. Decreased visual acuity occurred in 83%, with blindness in 28%. Optic atrophy was present in 69%; pigmentary retinopathy in 43%; supranuclear ophthalmoplegia in 56%; and viscosity of eye movements in 79%.

In 19 of 27 (70%) patients with confirmed SCA types 1, 2 (183090), 3 (109150), 6 (183086), or 7, van de Warrenburg et al. (2004) found electrophysiologic evidence of peripheral nerve involvement. Eight patients (30%) had findings compatible with a dying-back axonopathy, whereas 11 patients (40%) had findings consistent with a primary neuronopathy involving dorsal root ganglion and/or anterior horn cells; the 2 types were clinically almost indistinguishable. Two of 4 patients with SCA7 had an axonopathy and 2 had a neuronopathy.

Pathologic Findings

Holmberg et al. (1998) performed postmortem brain examination of a 10-year-old boy with genetically confirmed SCA7 (85 CAG repeats). Neuronal intranuclear inclusions, identified by an antibody directed against the expanded polyglutamine domain, were identified in multiple areas of the brain. Inclusions were most frequent in the inferior olivary complex, a site of severe neuronal loss in SCA7, the lateral geniculate body, and the substantia nigra, but were also present in other brain regions, including the cerebral cortex which is not considered to be affected in the disease. Some cytoplasmic staining was also identified. Some inclusions stained positively for ubiquitin, but the degree was highly variable. Holmberg et al. (1998) noted that nuclear inclusions are a common feature of polyglutamine disorders.

Michalik et al. (2004) presented a detailed clinical, pathologic, and molecular review of SCA7.

Ansorge et al. (2004) reported an infant with SCA7 and 180 CAG repeats in the ATXN7 gene. Signs and symptoms appeared at 9 months of age with developmental delay, failure to thrive, and limb tremor. Retinal pigmentary degeneration, nystagmus, hypotonia, and cerebellar ataxia were present by 19 months, and the patient died at 29 months. Postmortem examination showed severe olivopontocerebellar atrophy and thinning of the spinal cord. Ataxin-7 nuclear inclusions were seen throughout the nervous system; however, inclusions were not always associated with neuronal loss, as was particularly evident in the hippocampus. Nuclear inclusions were also present in endothelial cells, cardiac and skeletal muscle, pancreas, and epithelial cells of Brunner glands in the duodenum. In contrast to neuronal inclusions, nonneuronal inclusions did not stain with ubiquitin. Ansorge et al. (2004) discussed differential ubiquitination of aggregates and the effect on cell survival.

Diagnosis
Koob et al. (1998) described a novel procedure for quick isolation of expanded trinucleotide repeats and the corresponding flanking nucleotide sequence directly from small amounts of genomic DNA by a process called Repeat Analysis, Pooled Isolation, and Detection (RAPID cloning) of individual clones containing expanded trinucleotide repeats. They used this technique to clone the pathogenic SCA7 CAG expansion from an archived DNA sample from an individual affected with ataxia and retinal degeneration.

Mapping
Gouw et al. (1994) excluded linkage to SCA1 (164400) and SCA2 (183090) in a 4-generation pedigree segregating retinal degeneration, cerebellar ataxia, slow saccades, ophthalmoparesis, and pyramidal dysfunction. Autopsy of the proband showed degeneration of cerebellum, basis pontis, inferior olive, and retinal ganglion cells. Gouw et al. (1994) concluded that OPCA III is genetically distinct from SCA1 and SCA2.

Benomar et al. (1995) mapped the gene for this disorder to 3p21.1-p12. No genetic heterogeneity was found among the 4 Moroccan, Belgian, and French families studied. Multipoint analysis identified a candidate interval of 8-cM around D3S1285. Gouw et al. (1995) mapped the disorder to 3p21.1-p14 in 4 families. Holmberg et al. (1995) found linkage to microsatellite markers on 3p21.1-p12 in a Swedish family with ataxia, dysarthria, and severely impaired vision in an autosomal dominant pedigree pattern.

David et al. (1996) investigated 2 families with the disorder that they referred to as ADCA type II. Linkage analysis of these families of different geographic origins (one from Brazil and the other from the UK) confirmed the genetic homogeneity of ADCA type II, distinguishing it from ADCA type I. They mapped the gene to a 5-cM region on 3p13-p12. In contrast to the genetic homogeneity, considerable clinical heterogeneity was demonstrated by variability in age at onset, initial symptoms, and associated signs. Krols et al. (1997) refined the assignment of the SCA7 locus on 3p.

Inheritance
SCA7 is an autosomal dominant disorder. Gonadal instability is pronounced and is associated with paternal transmission (David et al., 1997).

Mittal et al. (2005) reported an Indian patient with SCA7 confirmed by genetic analysis. There was no family history of the disorder. Genetic analysis identified a de novo expansion of 59 CAG repeats on the paternal allele of the ATXN7 gene. His unaffected father had an expansion in the intermediate range, with 31 repeats. Analysis of the father's sperm sample did not show gonadal mosaicism, suggesting that the expansion was postzygotic.

Molecular Genetics
Using a monoclonal antibody that recognizes expanded polyglutamine stretches in TATA box-binding protein (600075), expanded huntingtin (613004), expanded ataxin-1 (601556), and 3 expanded proteins from individuals affected with SCA3 (109150), Trottier et al. (1995) demonstrated a 130-kD protein in 2 unrelated patients with SCA7. By analogy with other triplet repeat disorders, the authors suggested that this was the protein encoded by the gene whose mutation causes this disorder.

Using repeat expansion detection (RED), a method in which a thermolabile ligase is used to detect repeat expansions directly from genomic DNA, Lindblad et al. (1996) analyzed 8 SCA7 families for the presence of (CAG)n repeat expansion. RED products of 150 to 240 bp were found in all affected individuals and were found to cosegregate with the disease, suggesting strongly that a (CAG)n expansion is the cause of SCA7. On the basis of a previously established correlation between RED product sizes and actual repeat sizes in Machado-Joseph disease (109150), they were able to estimate the average expansion size in SCA7 to be 64 CAG copies.

In 18 patients from 5 families with SCA7, David et al. (1997) identified expanded CAG repeats in the ATXN7 gene (607640.0001). CAG repeat size was highly variable, ranging from 38 to 130 repeats, whereas on normal alleles it ranged from 7 to 17 repeats. Gonadal instability in SCA7 was greater than that observed in any of the known neurodegenerative disorders caused by translated CAG repeat expansions, and the instability was particularly striking on paternal transmission.

Genetic Anticipation

Gouw et al. (1995) found genetic anticipation in one family with the disorder. Two affected members of generation II first noted mild symptoms at ages 52 and 53; in generation III, onset of symptoms was between ages 31 and 49 with more marked phenotype; in generation IV, 2 members were reported ataxic at birth, both dying within 2 years; other members of generation IV were affected between the ages of 14 and 34 with earlier onset corresponding to more rapid progression to severe disease. Notably, no affected children in any of the 4 kindreds had age of onset later than their parents.

Holmberg et al. (1995) reported a 5-generation Swedish family with the disorder descended from a couple born in the latter part of the 19th century in the Province of Vasterbotten in northern Sweden. DNA was studied from 9 patients in 3 generations alive at the beginning of the study, as well as from 2 deceased patients. The family showed anticipation resulting in infantile onset in the latest generation with severe and rapid course of disease; earlier generations had onset in the fourth or fifth decade with relatively slow progression.

Analysis of 23 affected parent-child pairs by David et al. (1996) demonstrated marked anticipation that was greater in paternal than in maternal transmissions and a more rapid clinical course in successive generations.

Stevanin et al. (1998) stated that normal ATXN7 alleles carry from 4 to 35 CAG repeats, whereas pathologic alleles carry from 37 to approximately 200. Intermediate ATXN7 alleles, with 28 to 35 repeats, are exceedingly rare in the general population and are not associated with the SCA7 phenotype, although they were found among relatives of 4 SCA7 patients. In 2 such families, intermediate alleles bearing 35 and 28 CAG repeats gave rise, during paternal transmission, to ATXN7 expansions of 57 and 47 repeats, respectively, that were confirmed by haplotype reconstructions in one case and by inference in the other. Furthermore, in these and 2 other families in which relatives had intermediate alleles, the 4 haplotypes segregating with the intermediate alleles were identical to the expanded alleles in each family, but differed among the families, indicating multiple origins of the ATXN7 mutation in these families with different geographic origins. The results provided the first evidence of de novo ATXN7 expansions from intermediate alleles that are not associated with the phenotype but can expand to the pathologic range during some paternal transmissions. Intermediate alleles that segregate in unaffected branches of the pedigrees may, therefore, constitute a reservoir for future de novo mutations that occur in a recurrent but random manner. This would explain the persistence of the disorder in spite of the great anticipation (approximately 20 years per generation) characteristic of SCA7. Previously, de novo expansions among the disorders caused by translated CAG repeat expansion (polyglutamine repeat) have been demonstrated only in Huntington disease.

In Spain, the Ataxia Study Group (Pujana et al., 1999) found that it was in a family with SCA7 that the highest CAG repeat variation in meiotic transmission of expanded alleles was detected, this being an expansion of 67 units in 1 paternal transmission, giving rise to a 113 CAG repeat allele in a patient who died at 3 years of age. Analysis of CAG repeat variation in meiosis also showed a tendency to more frequent paternal transmission of expanded alleles in SCA1 (164400) and SCA7.

Giunti et al. (1999) found the SCA7 mutation in 54 patients and 7 at-risk subjects from 17 families who had autosomal dominant cerebellar ataxia with progressive pigmentary maculopathy. Haplotype reconstruction through 3 generations of 1 family confirmed a de novo mutation owing to paternal meiotic instability. Different disease-associated haplotypes segregated among the SCA7-positive kindreds, which indicated a multiple origin of the mutation. One family with a clinical phenotype did not have the CAG expansion, thus indicating locus heterogeneity. Distribution of the repeat size in 944 independent normal chromosomes from controls, unaffected at-risk subjects, and one affected individual fell into 2 ranges; most of the alleles were in the range of 7 to 19 CAG repeats. A second range could be identified with 28 to 35 repeats, and Giunti et al. (1999) provided evidence that these repeats represent intermediate alleles that are prone to further expansion. The repeat size of the pathologic allele, said to be the widest reported for any CAG-repeat disorder, ranged from 37 to approximately 220. The repeat size showed negative correlation with both age at onset and age at death. The most frequently associated features in patients with SCA7 were pigmentary maculopathy, pyramidal tract involvement, and slow saccades. The subjects with repeat numbers less than 49 tended to have a less complicated neurologic phenotype and a longer disease duration, whereas the converse applied to subjects with 49 repeats or more. The degree of instability during meiotic transmission was greater than in all other CAG-repeat disorders and was particularly striking in paternal transmission, in which a median increase in repeat size of 6 and an interquartile range of 12 was observed, versus a median increase of 3 and interquartile range of 3.5 in maternal transmission.

Gu et al. (2000) evaluated 4 Chinese kindreds with autosomal dominant cerebellar ataxia and decreased visual acuity for mutations in the ATXN7 gene. A mutation was identified in 2 families which showed great variation in age of onset, initial symptoms, and associated signs. Marked inter- and intrafamilial clinical variability was manifest. Analysis of 11 parent-child couples demonstrated the existence of marked anticipation. The CAG repeats ranged from 44 to 85, with strong negative correlation between repeat size and age of onset. Repeat length of expanded alleles showed somatic mosaicism in leukocyte DNA.

Van de Warrenburg et al. (2005) applied statistical analysis to examine the relationship between age at onset and number of expanded triplet repeats from a Dutch-French cohort of 802 patients with SCA1 (138 patients), SCA2 (166 patients), SCA3 (342 patients), SCA6 (53 patients), and SCA7 (103 patients). The size of the expanded repeat explained 66 to 75% of the variance in age at onset for SCA1, SCA2, and SCA7, but less than 50% for SCA3 and SCA6. The relation between age at onset and CAG repeat was similar for all groups except for SCA2, suggesting that the polyglutamine repeat in the ataxin-2 protein exerts its pathologic effect in a different way. A contribution of the nonexpanded allele to age at onset was observed for only SCA1 and SCA6. Van de Warrenburg et al. (2005) acknowledged that their results were purely mathematical, but suggested that they reflected biologic variations among the diseases.

Population Genetics
Storey et al. (2000) examined the frequency of mutations for SCA types 1, 2, 3, 6, and 7 in southeastern Australia. Of 63 pedigrees or individuals with positive tests, 30% had SCA1, 15% had SCA2, 22% had SCA3, 30% had SCA6, and 3% had SCA7. Ethnic origin was of importance in determining SCA type: 4 of 9 SCA2 index cases were of Italian origin, and 4 of 14 SCA3 index cases were of Chinese origin.

Whereas SCA7 is considered to be one of the most rare forms of genetically verified autosomal dominant cerebellar ataxia, Jonasson et al. (2000) found it to be the most frequent subtype in Sweden and Finland in a survey of hereditary ataxias in Scandinavia. They identified SCA7 in 8 Swedish and 7 Finnish families but found no affected Norwegian or Danish families. All 37 affected patients displayed expanded CAG repeats, and 9 clinically unaffected relatives also showed CAG expansions ranging from 38 to 53 repeats. Two carriers with 39 and 40 CAG repeats were still healthy at ages 68 and 85, respectively, and 1 individual with 39 CAG repeats presented with symptoms as late as age 74. Haplotype analysis using 9 microsatellite markers and 1 intragenic polymorphism covering a 10.2-cM region of chromosome 3p containing the ATXN7 gene showed that all 15 Swedish/Finnish families shared a common haplotype for the intragenic polymorphism and the centromeric markers D3S1287 and D3S1228, covering more than 1.9 cM of the ATXN7 gene region. Larger haplotypes were shared by families within a geographic region than by families from different geographic regions within the 2 countries. Linkage disequilibrium calculations were highly significant for the segregation of 1 haplotype on disease-bearing chromosomes, providing evidence for a strong founder effect for SCA7 in Scandinavia.

In South Africa, spinocerebellar ataxia type 7 occurs exclusively in indigenous Black African patients and seems to have a higher incidence in South Africa compared with the rest of the world (Bryer et al., 2003). Greenberg et al. (2006) performed haplotype studies in 13 SCA7 families from the indigenous Black African population and found a probable SCA7 founder effect. Most of the 13 Black SCA7 families originated in different geographic regions of South Africa. Greenberg et al. (2006) suggested an alternative hypothesis, namely that the area centromeric to the SCA7 mutation harbors a susceptibility factor rendering the SCA7 locus unstable and at risk for repeated expansion to premutation and mutation states.

Magana et al. (2014) used a PCR-based method to screen 10 families with late-onset cerebellar ataxia from the Veracruz state of Mexico for SCA1, SCA2, SCA3, SCA6, and SCA7 mutations. Eight of the 10 families were determined to have SCA7 and 2 had SCA2. The 8 SCA7 families comprised 55 affected individuals, most of whom came from 1 very large 6-generation family. Expanded pathogenic ataxin-7 alleles ranged from 34 to 72 CAG repeats. The patients had typical symptomatology of their respective diseases. The findings indicated a high prevalence of SCA7 (85.94%) among all forms of SCA in this Mexican population, consistent with a founder effect.

Animal Model
By using constructs with tissue-specific promoters, Yvert et al. (2000) generated transgenic mice that expressed mutant human ataxin-7 in either Purkinje cells or retinal rod photoreceptors. Mice overexpressing full-length mutant ataxin-7(Q90) either in Purkinje cells or in rod photoreceptors had deficiencies in motor coordination and vision, respectively. In both models, an N-terminal fragment of mutant ataxin-7 accumulated within ubiquitinated nuclear inclusions that recruited a distinct set of chaperone/proteasome subunits. A severe degeneration was caused by overexpression of ataxin-7(Q90) in rods, whereas a similar overexpression of normal ataxin-7(Q10) had no obvious effect. The degenerative process was not limited to photoreceptors, and secondary alterations were seen in postsynaptic neurons. The authors suggested that proteolytic cleavage of mutant ataxin-7 and transneuronal responses are implicated in the pathogenesis of SCA7.

To study the mechanism of polyglutamine neurotoxicity in SCA7, La Spada et al. (2001) generated a transgenic mouse model of SCA7 that expressed ataxin-7 with 92 glutamines in the CNS and retina. They observed a cone-rod dystrophy type of retinal degeneration. Using yeast 2-hybrid studies, La Spada et al. (2001) demonstrated that ataxin-7 interacts with CRX (602225), a nuclear transcription factor predominantly expressed in retinal photoreceptor cells. Mutations in the CRX gene cause cone-rod dystrophy-2 (120970) in humans. Coimmunoprecipitation experiments colocalized ataxin-7 with CRX in nuclear aggregates. Using a rhodopsin promoter-reporter construct, La Spada et al. (2001) observed that polyglutamine-expanded ataxin-7 suppressed CRX transactivation. With electrophoretic mobility shift assays and RT-PCR analysis, they observed a reduction in CRX binding activity and reductions in CRX-regulated genes in SCA7 transgenic retinas. The data suggested that the SCA7 transgenic mice faithfully recapitulated the process of retinal degeneration observed in human SCA7 patients. The authors hypothesized that ataxin-7-mediated transcription interference of photoreceptor-specific genes may account for the retinal degeneration in SCA7, and thus may provide an explanation for how cell-type specificity is achieved in this polyglutamine repeat disorder. By coimmunoprecipitation analysis of CRX and ATXN7 truncation and point mutants, Chen et al. (2004) determined that the ATXN7-interacting domain of CRX localized to its glutamine-rich region and that the CRX-interacting domain of ATXN7 localized to its glutamine tract. Nuclear localization of ataxin-7 was required to repress Crx transactivation, and the likely nuclear localization signals were mapped to the C-terminal region of ataxin-7. Using chromatin immunoprecipitation, the authors showed that both Crx and ataxin-7 occupied the promoter and enhancer regions of Crx-regulated retinal genes in vivo. Chen et al. (2004) suggested that one mechanism of SCA7 disease pathogenesis may be transcription dysregulation, and that CRX transcription interference may be a predominant factor in SCA7 cone-rod dystrophy retinal degeneration.

Yoo et al. (2003) generated a transgenic mouse model of severe infantile SCA7 with 266 CAG repeats. At 5 weeks of age, the mice demonstrated progressive weight loss, ptosis, ataxia, muscle wasting, kyphosis, and tremor. Electroretinogram (ERG) studies showed cone and rod photoreceptor defects, and there was progressive shortening of the outer segments of the retina with accumulation of mutant ataxin-7. Mutant ataxin-7 accumulated in various neuronal subtypes throughout the brain, suggesting that polyglutamine expansion stabilizes mutant ataxin-7. The authors suggested that accumulation of the mutant protein may cause downstream molecular events that hinder cell function and survival.

Bowman et al. (2005) assessed the ubiquitin-proteasome system (UPS) using transgenic mice with 266 CAG repeats and a ubiquitin (191339) reporter gene. Reporter levels were low during the initial phase of disease, suggesting that neuronal dysfunction occurs in the presence of a functional UPS. Late in disease, there was a significant increase in reporter levels specific to the most vulnerable neurons, resulting from increase in ubiquitin reporter mRNA. No evidence for general UPS impairment or reduction of proteasome activity was seen. The differential increase of ubiquitin reporter among individual neurons directly correlated with the downregulation of a marker of selective pathology and neuronal dysfunction in SCA7. There was an inverse correlation between the neuropathology revealed by the reporter and ataxin-7 nuclear inclusions in the vulnerable neurons. Bowman et al. (2005) proposed a protective role for polyglutamine nuclear inclusions against neuronal dysfunction and excluded significant impairment of the UPS in polyglutamine neuropathology.

Using gene profiling and other techniques, Abou-Sleymane et al. (2006) showed that polyQ expansion caused retinal degeneration in animal models of Huntington disease (HD; 143100) and SCA7 by downregulating a large cohort of genes involved in phototransduction function and morphogenesis of differentiated rod photoreceptors and in rod photoreceptor differentiation. Transcription factors that inhibit photoreceptor differentiation were also aberrantly reactivated.

Using microarray analysis of the cerebellum in mouse models of SCA1 and SCA7, Gatchel et al. (2008) found that both disorders were associated with significant downregulation of Igfbp5 (146734) in the granular cell layer. Further analysis showed additional misregulation in both models, including activation of the IGF pathway and the Igf1 receptor (IGF1R; 147370) in Purkinje cells.

Janer et al. (2010) identified ATXN7 as target for sumoylation in vitro and in vivo. Sumoylation did not influence the subcellular localization of ATXN7 nor its interaction with components of the TFTC/STAGA complex. Expansion of the polyglutamine stretch did not impair the sumoylation of ATXN7. SUMO1 (601912) and SUMO2 (603042) colocalized with ATXN7 in a subset of neuronal intranuclear inclusions in the brain of SCA7 patients and Atxn7 knockin mice. In a COS-7 cellular model of SCA7, there were 2 populations of extranuclear inclusions: homogeneous and nonhomogeneous. Nonhomogeneous inclusions showed significantly reduced colocalization with SUMO1 and SUMO2, but were highly enriched in Hsp70 (HSPA1A; 140550), 19S proteasome, and ubiquitin. These were characterized by increased staining with the apoptotic marker caspase-3 (CASP3; 600636) and by disruption of PML nuclear bodies. Preventing the sumoylation of expanded ATXN7 by mutating the SUMO site increased both the amount of SDS-insoluble aggregates and of CASP3-positive nonhomogeneous inclusions, which are toxic to the cells. Janer et al. (2010) concluded that sumoylation influences the multistep aggregation process of ATXN7, and they implicated a role for ATXN7 sumoylation in SCA7 pathogenesis.

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