疾患詳細

疾患詳細





#164400
Spinocerebellar ataxia 1 (SCA1)
(Spinocerebellar atrophy I)
(Olivopontocerebellar atrophy I; OPCA I; OPCA1)
(Cerebelloparenchimal disorder I; CPD1)
(Menzel type OPCA)
(Olivopontocerebellar atrophy IV; OPCA IV; OPCA4)
(Schut-Haymaker type OPCA)

脊髄小脳失調症 1 (SCA1)
(脊髄小脳萎縮症 I)
(オリーブ核橋小脳萎縮症 I; OPCA I, OPCA1)
(Menzel 型オリーブ核橋小脳萎縮症)
指定難病17 多系統萎縮症
小児慢性特定疾病 神53 脊髄小脳変性症

責任遺伝子:601556 Ataxin 1 (ATXN1) <6p22.3>
遺伝形式:常染色体優性

(症状)
(GARD)
 <80%-99%>
 Progressive cerebellar ataxia (進行性小脳失調) [HP:0002073] [028]
 
 <30%-79%>
 Abnormal flash visual evoked potentials (フラッシュ視覚誘発電位異常) [HP:0007928] [0690]
 Abnormal nerve conduction velocity (神経伝導速度異常) [HP:0040129]
 Abnormality of somatosensory evoked potentials (体性感覚誘発電位) [HP:0007377]
 Atrophy/Degeneration affecting the brainstem (脳幹萎縮/変性) [HP:0007366] [16013]
 Bradykinesia (寡動) [HP:0002067] [02608]
 Bulbar signs (球症状) [HP:0002483] [02620]
 Cerebellar atrophy (小脳萎縮) [HP:0001272] [16013]
 Chorea (舞踏病) [HP:0002072] [02600]
 Dysarthria (構音障害) [HP:0001260] [0230]
 Dysphagia (嚥下障害) [HP:0002015] [01820]
 Dystonia (ジストニア) [HP:0001332] [0240]
 Inertia (無力症) [HP:0030216] [0403]
 Loss of Purkinje cells in the cerebellar vermis (小脳虫部の Purkinje 細胞喪失) [HP:0007001]
 Memory impairment (記憶障害) [HP:0002354] [0123]
 Slow saccadic eye movements (遅い衝動性眼球運動) [HP:0000514] [0695]
 Slurred speech (不明瞭発語) [HP:0001350] [0230]
 Staring gaze (凝視) [HP:0025401] [0424]
 Upgaze palsy (上方視麻痺) [HP:0025331] [0698]
 
 <5%-29%>
 Abnormality of masticatory muscle (咀嚼筋異常) [HP:0410011] [027]
 Dysdiadochokinesis (ジスジアドコキネーゼ) [HP:0002075] [02605]
 Dysmetria (ジスメトリア) [HP:0001310] [02605]
 Fasciculations (攣縮) [HP:0002380] [02604]
 Gait imbalance (歩行不均衡) [HP:0002141] [028]
 Generalized hypotonia (全身性筋緊張低下) [HP:0001290] [0242]
 Hyperactive deep tendon reflexes (深部腱反射亢進) [HP:0006801] [0241]
 Hypermetric saccades (ハイパーメトリックサッカード) [HP:0007338] [0695]
 Hyporeflexia (低反射) [HP:0001265] [0242]
 Impaired proprioception (固有覚障害) [HP:0010831] [02511]
 Nystagmus (眼振) [HP:0000639] [06609]
 Ophthalmoparesis (眼球運動不全麻痺) [HP:0000597] [0698]
 Optic atrophy (視神経萎縮) [HP:0000648] [06522]
 Postural tremor (姿勢振戦) [HP:0002174] [02604]
 Respiratory failure (呼吸不全) [HP:0002878] [01606]
 Skeletal muscle atrophy (骨格筋萎縮) [HP:0003202] [0270]
 
 <1%-4%>
 Decreased amplitude of sensory action potentials (感覚活動電位振幅減少) [HP:0007078]
 Decreased motor nerve conduction velocity (運動神経伝導速度減少) [HP:0003431]
 Decreased sensory nerve conduction velocity (感覚神経伝導速度減少) [HP:0003448]
 
 
 Abnormality of extrapyramidal motor function (錐体外路運動機能異常) [HP:0002071] [02141]
 Adult onset (成人発症) [HP:0003581]
 Areflexia (無反射) [HP:0001284] [0242]
 Autosomal dominant inheritance (常染色体優性遺伝) [HP:0000006]
 Babinski sign (バビンスキー徴候) [HP:0003487] [0213]
 Bulbar palsy (球麻痺) [HP:0001283] [02620]
 Cognitive impairment (認知障害) [HP:0100543] [0123]
 Dilated fourth ventricle (第4脳室拡大) [HP:0002198] [03010]
 Distal amyotrophy (遠位筋萎縮) [HP:0003693] [0270]
 Dorsal column degeneration (後柱変性) [HP:0007006] [16014]
 Dysmetric saccades (ジスメトリア性サッカード) [HP:0000641] [0695]
 Gaze-evoked nystagmus (注視誘発性眼振) [HP:0000640] [06609]
 Genetic anticipation with paternal anticipation bias (父方促進を伴う遺伝的促進) [HP:0003744]
 Hyperreflexia (反射亢進) [HP:0001347] [0241]
 Impaired horizontal smooth pursuit (水平のスムーズな追視障害) [HP:0001151] [0695]
 Impaired vibratory sensation (振動覚障害) [HP:0002495] [02511]
 Limb ataxia (四肢運動失調) [HP:0002070] [028]
 Muscular hypotonia (筋緊張低下) [HP:0001252] [0242]
 Olivopontocerebellar atrophy (オリーブ核橋小脳萎縮) [HP:0002542] [16013] [160133] [160134]
 Optic disc pallor (乳頭蒼白) [HP:0000543] [06522]
 Scanning speech (断綴言語[だんてつ]) [HP:0002168] [0230]
 Spasticity (痙縮) [HP:0001257] [0241]
 Spinocerebellar atrophy (脊髄小脳萎縮) [HP:0007263] [16013] [16014]
 Spinocerebellar tract degeneration (脊髄小脳路変性) [HP:0002503]
 Supranuclear ophthalmoplegia (核上性眼球運動麻痺) [HP:0000623] [0698]
 Truncal ataxia (体幹失調) [HP:0002078] [028]
 Urinary bladder sphincter dysfunction (膀胱括約筋機能障害) [HP:0002839] [131]

(UR-DBMS)
【一般】嚥下障害
 認知障害, 軽度の
【神経】小脳失調, 進行性
 反射亢進 (早期)
 痙縮
 断節言語
 四肢失調
 体幹失調
 構音障害
 ジスメトリ
 筋緊張低下
 深部腱反射喪失 (後半)
 開扇反射
 錐体外路サイン
 皮質精髄サイン
 舞踏病
 球麻痺
 変換運動障害 (dysdiadochokinesis)
 攣縮様運動
 オリーブ核橋小脳萎縮
 第4脳室拡大
 脊髄小脳路変性
 後索変性
 末梢神経障害
 振動覚減少
 遠位筋萎縮
【眼】核上性眼筋麻痺
 注視誘発性眼振
 ハイポメトリックサッケード (衝動運動) (多くはない)
 ジスメトリア性サッケード (衝動運動)
 水平のスムースな追跡眼球運動障害
 視神経萎縮
 蒼白の視神経乳頭
【腎】括約筋障害
【その他】20-30歳代発症
 遺伝的促進あり
 父方促進バイアスあり

(要約) 脊髄小脳失調症1型 (SCA1)
●脊髄小脳失調症1型 (SCA1)は, 進行性小脳失調, 構音障害, および球機能のその後の悪化が特徴である
 疾患の早期には, 患者は歩行障害, 不明瞭言語, 平衡障害, 短い深部腱反射, 過剰なサッケード, 眼振および軽度の嚥下障害をもつかもしれない
 後半のサインには, サッケード速度の遅延, 上方視麻痺の発生, ジスメトリア, ジスアジアドコキネージア, および筋緊張低下がある
 進行期には, 筋萎縮, 深部腱反射減退, 固有覚喪失, 認知障害 (例, 前頭葉実行機能障害, 言語記憶障害), 舞踏病, ジストニア, 球機能障害がみられる
 発症は, 典型的には20または30歳代であるが, 小児期発症や成人後半発症が報告されている
 60歳以上での発症患者は, 純粋小脳表現型を示すかも
 発症から死亡までの間隔は10~30年である
 若年発症の患者は, より急速な進行やより重症疾患を示す
 表現促進がみられている
 電気生理学的検査で検出される軸索性感覚ニューロパチーが多い
 脳画像は, 典型的には小脳および脳幹萎縮を示す
●診断:ATXN1 の異常なCAG伸展の証明による
 患者 >39リピート
 正常 6-44リピート; 正常アレルは CAT トリヌクレオチドリピートの介在があり変異できない
  36-44リピートアレルの病原性は, CAGリピートを中断するCATがあるかないかによる (CATリピートがあれば正常と判定, なければ変異可能な正常 (36-38)またはフル浸透 (>39の場合)と判定)
●遺伝:常染色体優性
●疑わせる所見
 進行性小脳失調
 構音障害
 球機能の悪化
 常染色体優性の家族歴
●MRI: 橋小脳萎縮
●SCA1 はSCA2 や SCA3より進行が速い (2.18±0.17 ポイント/年対1.40±0.11 および 1.61±0.12 /年)
●遺伝子型-表現型相関
 CAGリピート数と重症度に強い相関あり (早期発症かつより重症)
●表現促進あり
●頻度:1-2/100,000
 韓国では報告なし

<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。

<小児慢性特定疾病> 神53 脊髄小脳変性症
概念・定義
脊髄小脳変性症とは, 運動失調を主症状とし, 原因が, 感染症, 中毒, 腫瘍, 栄養素の欠乏, 奇形, 血管障害, 自己免疫性疾患等によらない疾患の総称である。

臨床的には小脳性の運動失調症状を主体とする。遺伝性と孤発性に大別され, 何れも小脳症状のみがめだつもの(純粋小脳型)と, 小脳以外の病変, 症状が目立つ物(非純粋小脳型)に大別される。劣性遺伝性の一部で後索性の運動失調症状を示すものがある。
疫学
全国で約3万人の患者がいると推定される。その2/3が孤発性, 1/3が遺伝性である。遺伝性の中ではMachado-Joseph病(MJD/SCA3), SCA6, SCA31, DRPLAの頻度が高い。その他, SCA1, 2, 7, 8, 14, 15等が知られている。(下図 平成15年 日本神経学会総会 本邦に於ける脊髄小脳変性症のpopulation based 前向き臨床研究による自然歴の把握 運動失調に関する調査及び病態機序に関する研究班 研究代表者 辻省次 より)。

下に示す遺伝性SCDの内訳(図 我が国における脊髄小脳変性症の疫学) はSCA31の遺伝子が同定される以前の物で, 遺伝性の「その他」の多くはSCA31と考えられる。しかし, まだ原因遺伝子が未同定の遺伝性SCAが10~20%内外存在すると考えられる。劣性遺伝性の脊髄小脳変性症は本邦では少ない。その中では“眼球運動失行と低アルブミン血症を伴う早発性運動失調症(EAOH/AOA1)の頻度が比較的高い。小児発症型の劣性遺伝性では純粋小脳型を示すことは少なく, 他の随伴症状を伴うことが多い。欧米ではこの範疇に入る疾患としてフルードライヒ失調症の頻度が高く有名であるが, 本邦では本疾患の患者さんはいらっしゃらない。本邦でフリードライヒ失調症と考えられていたものの多くはEAOH/AOA1と考えられている。一方, 成人発症例の劣性遺伝性では純粋小脳型を示す例がある。
病因
孤発性のものの大多数は多系統萎縮症であり, その詳細は多系統萎縮症の項目を参照されたい。一部小脳症状に限局した小脳皮質萎縮症がある。アルコール多飲や, 腫瘍に伴って失調症状を示すことがある。若年者で一過性の小脳炎の存在も知られている。
遺伝性の場合は, 多くは優性遺伝性である。一部劣性遺伝性, 母系遺伝性, 希にX染色体遺伝性の物が存在する。

優性遺伝性のSCA1, 2, 3, 6, 7, 17, DRPLAでは, 原因遺伝子の中のCAGという3塩基の繰り返し配列が増大することによりおこる。本症の遺伝子診断は, この繰り返し数の長さにて診断している。各々の正常繰り返し数の上限の目安はSCA1 39, SCA2 32, MJD/SCA3 40, SCA6 18, SCA17 42, DRPLA 36 である。これを超えた場合, 疾患の可能性を考えるが, この周辺のリピート長の場合, 真に現在の病態に寄与しているかについては, 臨床症状を加味し, 慎重に診断する。

CAG繰り返し配列は, アミノ酸としてはグルタミンとなるため, 本症は異常に増大したグルタミン鎖が原因であると考えられる。他に同様にグルタミン鎖の増大を示す, ハンチントン舞踏病, 球脊髄性筋萎縮症と併せて, ポリグルタミン病と総称する。

増大したポリグルタミン鎖によって作られる凝集体が, 細胞内に認められる。この事から増大ポリグルタミン鎖の凝集体の易形成性が, 直接, もしくは間接的に細胞毒性を持つと考えられている。現在は, 凝集体そのものは, むしろ防御的で, それが形成される前の多量体が神経細胞への毒性を持つとする説が強い。
細胞毒性は増大ポリグルタミン鎖により, 他の蛋白質の機能が障害され引き起こされるという機序が唱えられている。しかし, その詳しい機序については諸説があり結論がついていない。発病や進行を阻止できる根治的な治療方法の開発につながる病態機序はまだ明らかになっていない。しかし, 病態機序に基づいた疾患の根本治療を目指す研究が活発に行われている
症状
症状は失調症状を認めるが, 周辺症状は各病型毎に異なる。優性遺伝性の脊髄小脳変性症は, 症状が小脳症状に限局する型(純粋小脳型,autosomal dominant cerebellar ataxia type III : ADCA type III)と, その他の錐体外路症状, 末梢神経障害, 錐体路症状などを合併する型(非純粋小脳型,ADCA type I)に臨床的に大別される。孤発性の物は, 前述したように大多数が多系統萎縮症であるが, 一部純粋小脳型の小脳皮質萎縮症がある。劣性遺伝性の多くは非純粋小脳型で有り, 後索障害を伴う場合が多い。一般的に小脳症状に限局する型の方が予後は良い。またSCA6や周期性失調症などで, 症状の一過性の増悪と寛解を認める場合がある。

非純粋小脳型では, 画像状の萎縮と症状に乖離が認められる場合もある。一般に非純粋小脳型のポリグルタミン病では, 高齢であるほど, リピート長が長いほど画像上の萎縮が目立つ。またその変化も小脳に限局せず脳幹にも及ぶ。このため, 若年者で発症時に, 画像上の変化が目立たない例や, 高齢者で症状に比して萎縮が強い場合などもあることもある。特にMJD/SCA3の高齢発症者は, 一見, 症状が小脳に限局している印象を与えることがある。

非純粋小脳型では頻度からMJD/SCA3, 1, 2を考える。SCA2はゆっくりとした滑動性眼球運動, MJD/SCA3は初期から目立つ姿勢反射障害や, 上方視制限が特徴である。しかし, リピートの長さや, 年齢により症状は多様である。若年発症例および進行例において, 各々の疾患に特徴的な症候が現れやすい。

純粋小脳型ではSCA6, 31を中心に考える。これらは画像上も初期から小脳に限局した萎縮を認める。

SCA7は網膜色素変性症を伴うことが多い。SCA8,SCA17 は極めて臨床症状が多様で有る。

下記に, 遺伝性のSCAの診断フローチャートを提示する (図あり)。家族歴が明瞭で無い場合でもSCA31, SCA8, MJD/SCA3等は可能性がある。この様な家族歴のない症例に対し, 遺伝子診断を行う場合は, 優性遺伝性疾患で有り, 本人の結果が未発症の血縁者にも影響を与えることから, 特に十分な説明と同意が必要である。

各疾患について病型毎の診断基準案を本稿の終わりに列挙する。またより詳しい情報はGenereviews(http://www.ncbi.nlm.nih.gov/books/NBK1116/)にて入手可能である。

ポリグルタミン病では, CAG繰り返し配列の長さと, 発症年齢に負の相関があり, 一般にリピート数が長いほど若年で発症し, 重症となる傾向にある。ポリグルタミン病は, SCA6を除き, 家系内でも症状が多彩で有り, 世代を経る毎に重症化する傾向(表現促進現象)を認める。

脊髄小脳変性症の遺伝子診断は保険適応となっていない。ポリグルタミン鎖の増大に関する遺伝子診断は, 民間検査機関, もしくは一部の大学病院などで行っている。塩基配列解析を必要とするような疾患の遺伝子診断は行っているところが極めて少ない。これらの診断は, 各研究機関(Gentests http://www.ncbi.nlm.nih.gov/sites/GeneTests/ で海外の研究機関を紹介している)に問い合わせる。

失調症状の変遷の記載方法としてはICARS, SARA, UMSARSというスケールが用いられる(SARA日本語版PDF, UMSARS日本語版PDF)。またMSAのQOLのスケールもある(MSAのQOL PDF)。ICARASの抜粋が臨床調査個人票に用いられており, この項目のみでも, 経過をよく反映する。

SCA7は網膜色素変性症を伴うことが多い。SCA8,SCA17 は極めて臨床症状が多様で有る。

下記に, 遺伝性のSCAの診断フローチャートを提示する。家族歴が明瞭で無い場合でもSCA31, SCA8, MJD/SCA3等は可能性がある。この様な家族歴のない症例に対し, 遺伝子診断を行う場合は, 優性遺伝性疾患で有り, 本人の結果が未発症の血縁者にも影響を与えることから, 特に十分な説明と同意が必要である。

SCA病型の特徴
1) SCA1 (新潟大学医学部保健学科 高橋俊昭新潟大学脳研究所 小野寺理,西澤正豊)
(1)発症年齢
(ア) 30才代ないし40才代の発症が多い。
   CAG伸長の程度により4才から74才まで報告がある。
(イ) 同一家系内においては, 表現促進現象を認める。

(2)臨床症状
(ア)主症状
 ①小脳性運動失調(歩行障害での発症が多い。)
 ②構音障害
 ③眼振
 ④錐体路徴候;腱反射亢進
(イ)副症状
 ①嚥下障害
 ②錐体外路症候:chorea, dystonia等(進行期)
 ③認知機能の低下(中等度)
注) CAG伸長数や罹病期間により, 各症状の出現頻度や程度は変化する。
(3)検査所見
(ア)頭部画像所見:橋・小脳萎縮 
(4)診断方法
(ア)遺伝子診断:Ataxin-1遺伝子解析によりCAG反復配列の異常伸長(≧39 repeat)を証明する。 
(5)本疾患を疑う場合の重要な点 
(ア)常染色体優性遺伝性の進行性小脳性失調症。
(イ)本邦では, 東北地方において有病率が高い。
(ウ)30代ないし40代の発症が多い。
(エ)初発症状は歩行障害が多い。
(オ)SCA2, SCA3などと臨床症状の相同性がある。SCA2とは緩徐眼球運動や腱反射の減弱, SCA3とは, 錐体外路症候, 眼球運動障害の程度・頻度において異なる。
治療
純粋小脳型では, 小脳性運動失調に対しても, 集中的なリハビリテーションの効果があることが示唆されている。バランス, 歩行など, 個々人のADLに添ったリハビリテーションメニューを組む必要がある。リハビリテーションの効果は, 終了後しばらく持続する。

薬物療法としては, 失調症状全般にセレジスト®(甲状腺刺激ホルモン放出ホルモン誘導体)が使われる。本薬剤の有効性が確かめられたモデルマウスの一つはSCA6や片頭痛を伴う失調症の原因遺伝子であるカルシウムチャネル(CACNA1A)の点変異マウスである。しかし, 実際の使用経験では, 本薬剤の効果に病型毎の明確な差は報告されていない。

疾患毎の症状に対して対症的に使われる薬剤がある。MJD/SCA3の有痛性筋痙攣に対する塩酸メキシレチン, SCA6などの周期性の失調症状, めまい症状に対するアセタゾラミド等が挙げられる。
ポリグルタミン病に関しては, ポリグルタミン鎖, もしくはそれが影響を及ぼす蛋白質や細胞機能不全をターゲットとした治療薬の開発が試みられているが, 現在の所, 有効性があるものはない。 

予後
予後は, 病型により大きく異なる。またポリグルタミン病は症例の遺伝子型の影響を受ける。

下図(平成15年 日本神経学会総会 本邦に於ける脊髄小脳変性症のpopulation based 前向き臨床研究による自然歴の把握 運動失調に関する調査及び病態機序に関する研究班 研究代表者 辻省次 より)

診断方法
成人に準じる

【主要項目】
脊髄小脳変性症は, 運動失調を主要症候とする原因不明の神経変性疾患の総称であり, 臨床, 病理あるいは遺伝子的に異なるいくつかの病型が含まれる。 臨床的には以下の特徴を有する。

1. 小脳性ないしは後索性の運動失調を主要症候とする。
2. 徐々に発病し, 経過は緩徐進行性である。
3. 病型によっては遺伝性を示す。その場合, 常染色体優性遺伝性であることが多いが, 常染色体劣性遺伝性の場合もある。
4. その他の症候として, 錐体路徴候, 錐体外路徴候, 自律神経症状, 末梢神経症状, 高次脳機能障害などを示すものがある。
5. 頭部のMRI やX 線CT にて, 小脳や脳幹の萎縮を認めることが多く, 大脳基底核病変を認めることもある。
6. 脳血管障害, 炎症, 腫瘍, 多発性硬化症, 薬物中毒, 甲状腺機能低下症など二次性の運動失調症を否定できる。

当該事業における対象基準
神経A
運動障害, 知的障害, 意識障害, 自閉傾向, 行動障害(自傷行為又は多動), けいれん発作, 皮膚所見(疾病に特徴的で, 治療を要するものをいう。), 呼吸異常, 体温調節異常, 温痛覚低下, 骨折又は脱臼のうち一つ以上の症状が続く場合

(責任遺伝子) *601556 Ataxin 1 (ATXN1) <6p22.3>
.0001 Spinal cerebellar ataxia 1 (164400) [ATXN1, (CAG)n EXPANSION [dbSNP:rs193922926] (RCV000008537) (Orr et al., 1993; Banfi et al., 1994; Zuhlke et al. 2002)

*ATXN1 (Ataxin 1)
 Genome size 462,379 bp, Minus strand; 815 aa, 86923 Da
 Exons: 8, Coding exons: 2, Transcript length: 10,557 bps, Translation length: 815 residues
●常染色体優性小脳失調症 (ADCA) は神経変性疾患の異質性のあるグループで,小脳,脳幹および脊髄の進行性変性が特徴である
 臨床的に, ADCA は3つのグループに分けられる
 → ADCA types I-III
・ADCAI は遺伝的異質性があり,5つの遺伝子座があり spinocerebellar ataxia (SCA) 1, 2, 3, 4 および 6 と命名され,5つの異なる染色体に同定されている
・ADCAII は常に網膜変性を伴う (SCA7)
・ ADCAIII は `pure' cerebellar syndrome (SCA5) と呼ばれることが多く,均質性疾患の可能性が高い
 いくつかのSCA遺伝子がクローニングされ,coding 領域に CAG repeats を示すことが知られている
 ADCA は,CAG repeats の伸長が原因で,相当するタンパクの伸長したポリグルタミンを生じる
 伸長したリピートはサイズが多様で不安定である
 →通常次世代へ伝達される時サイズが増加する
 ataxins の機能は不明である
 この遺伝子座は6番染色体にマップされている
 疾患アレルは 40-83 CAG repeats を含む (正常では 6-39)→ SCA1 と連関する
 選択的スプライシングは多くの転写バリアントを生じる
 →オーバーラップする選択的リーディングフレームを使うことで ATXN1 や Alt-ATXN1を生じる
 CBF1 corepressor として作用することで Notch intracellular domain 欠損で,Notch signaling を抑制するクロマチン結合因子である
 HEY promoterと結合し,NCOR2 といっしょに RBPJ-mediated repression をアシストするかも
 in vitro で RNA と結合する
 RNA 代謝に関与するかも
 CIC や ATXN1Lと協調し,脳発生に関与する
●関係する pathways: Chks in Checkpoint Regulation; Pathways of neurodegeneration - multiple diseases

(参考)
●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

(ノート)
●(#) は、脊髄小脳失調1は、ataxin-1 遺伝子 (ATXN1; 601556)の伸長した (CAG)n トリヌクレオチドリピートが原因なため

●常染色体優性小脳変性症は、 '脊髄小脳性' は臨床サインと神経解剖学的領域をいう合成語であるが、一般的に '脊髄小脳失調症'と呼ばれる (Margolis, 2003)
 神経病理学者は、SCA を多様な脳幹と脊髄病変を伴う小脳失調と定義している
 本疾患の臨床症状は、小脳とその求心性および遠心性連結 (脳幹と脊髄を含む)の変性が原因である (Schols et al., 2004; Taroni and DiDonato, 2004).

●歴史的に、Harding (1982) は、常染色体優性小脳失調 (ADCAs)の臨床的分類を提唱した
 ADCA I:小脳失調+いろんな合併神経症状 (眼球麻痺、錐体路および錐体外路サイン、末梢神経障害、認知症など)
 ADCA II:小脳失調+神経症状+黄斑および網膜変性
 ADCA III:他の症状のない遅発性小脳失調の純粋型
 SCA1, SCA2 (183090), SCA3 または Machado-Joseph 病 (109150)は、ADCA I の型であると考えられている
 →これら3疾患は、分子レベルでは、おのおの6p24-p23, 12q24.1, 14q32.1 の CAG リピートの伸長が特徴である
 SCA7 (607640):3p13-p12 の CAG リピート伸長が原因で、ADCA II 型である
 SCA5 (600224), SCA4 (純粋日本人型; 117210), SCA6 (183086), および SCA11 (600432) は、ADCA III を最も疑わせる表現型を伴う
 しかし、Schelhaas et al. (2000) は、SCA の異なる型間には有意な表現型のオーバーラップがあり、各々のサブタイプないにも有意な表現型の多様性があると述べた

●オリーブ核小脳萎縮や一般t系な遺伝性運動失調の古典的レビューには、オリーブ核小脳萎縮の5つの型を証明したKonigsmark and Weiner (1970)、Berciano (1982), Harding (1993), Schelhaas et al. (2000), および Margolis (2003)が含まれる

Clinical Features
Symptoms of SCA1 usually begin in the third or fourth decade of life, most often around age 30. In addition to cerebellar signs, there are upper motor neuron signs and extensor plantar responses. Involuntary choreiform movements may occur. Characteristic families with autosomal dominant spinocerebellar ataxia were reported by Menzel (1890), Waggoner et al. (1938), and Destunis (1944).

Both the clinical and the pathologic pictures in the disorder described in a large kindred, known as Vandenberg, by Schut (1950) and by Schut and Haymaker (1951) were variable. Symptoms varied from those of spinocerebellar ataxia to spastic paraplegia. Identification as a form of OPCA was based on the presence of the major pathology in the inferior olivary nucleus and cerebellum with variable pontine involvement. The spinal cord showed variable loss of anterior motor horn cells and changes in the spinocerebellar tracts and posterior funiculus. Involvement of cranial nerves IX, X and XII was another distinguishing feature.

Nino et al. (1980) reported a family in which the mean age of onset was 38.8 years. In addition to ataxia, affected persons showed lower bulbar palsies, hyperreflexia, scanning and explosive speech, incoordination, and, in some, slow motor-nerve conduction. Neuropathologic findings included atrophy of the cerebellum, pons and olives, degeneration of lower cranial nerve nuclei, and atrophy of the dorsal columns and spinocerebellar tracts. Deep tendon reflexes were increased and the Babinski sign was present. Pedersen (1980) reported an extensively affected Danish kindred. Clinical expression was highly variable so that different types of cerebellar ataxia had been diagnosed in individual members of the family. In at least 10, multiple sclerosis had been diagnosed.

Robitaille et al. (1995) compared the neuropathologic features of SCA1 with those reported for SCA2 and SCA3. Unlike the findings in SCA2 and SCA3, brains in SCA1 show almost no neuronal loss from the pars compacta of the substantia nigra or from the locus ceruleus, whereas there is severe atrophy of the dentatorubral pathways. Both SCA1 and SCA2 show severe loss of Purkinje cell and degeneration of the olivocerebellar pathways, which is not seen in SCA3. All 3 disorders share severe atrophy of the nucleus pontis, sparing of the retina and optic nerve, and marked atrophy of Clarke columns and the spinocerebellar tracts. Argyrophilic glial inclusions have not been reported in any of these disorders.

In 19 (70%) of 27 patients with confirmed SCA type 1, 2, 3, 6, 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. Four of 5 patients with SCA1 had a neuronopathy and 1 had a sensorimotor axonopathy.

▼ Biochemical Features
In autopsied brain from 2 patients with autosomal dominant OPCA, Perry et al. (1977) found markedly reduced aspartic acid and markedly elevated taurine content. The patients were from the family reported by Currier et al. (1972), in which linkage to HLA was discovered by Jackson et al. (1977).

Plaitakis et al. (1980) found deficiency of glutamate dehydrogenase (GLUD1; 138130) in 3 patients with a 'spinocerebellar syndrome.' One was a 19-year-old male with juvenile onset of spinocerebellar and extrapyramidal manifestations. The others were 2 sibs, aged 64 and 71, with adult onset of spinocerebellar symptoms. The authors were led to this work by the fact that the nicotinamide antagonist 3-acetylpyridine produces ataxia in rats and CNS changes like those of OPCA IV. Four nicotinamide-adenine dinucleotide phosphate-requiring enzymes were measured. GDH may have an important role in metabolism of glutamate, a putative neurotransmitter in cerebellum, brainstem and spinal cord.

Sorbi et al. (1986) found a 50 to 60% reduction in platelet GLUD activity in 3 patients out of 4 with a so-called nondominant, i.e., sporadic or recessive, form of adult-onset OPCA and in father and son with a dominant form of OPCA. In another family, affected members (but not unaffected members), despite normal GDH activity, showed lack of activation of GDH by ADP in either the presence or the absence of Triton.

▼ Diagnosis
Lucotte et al. (2001) demonstrated the feasibility of presymptomatic diagnosis in spinocerebellar ataxia-1. They studied a family in which the mean age of onset of the disorder was 38 years. Hitherto, presymptomatic testing for late-onset autosomal dominant disorders had largely been confined to Huntington disease, which is a genetically homogeneous entity. The same protocol could be applied to dominantly inherited ataxias, with the additional requirement that the SCA type of the disorder must be determined in the family at risk.

▼ Mapping
Jackson et al. (1977) concluded that a form of spinocerebellar atrophy is linked with HLA on chromosome 6; the lod score was 3.15 for a recombination fraction of about 12. Moller et al. (1978) found further evidence in support of this linkage. In an extensively affected Prussian family, Nino et al. (1980) also found linkage to HLA. The maximum lod score was 1.97 at a male recombination fraction of 0.18 and a female recombination fraction of 0.36. When combined with data from other families, these results yielded a lod score of 4.681 at a recombination frequency of 0.22. Morton et al. (1980) reviewed linkage data on 13 kindreds. For linkage with HLA, they found a lod score of 5.53 at recombination rates of 0.223 in males and 0.327 in females. Nine of the 13 pedigrees, which appeared to have typical OPCA I, showed recombination rates of 0.150 in males and 0.300 in females. The remaining 4 pedigrees were clinically atypical or included discrepant data and gave no evidence of linkage. They suggested that linkage evidence may be decisive in delineation of the confused category of ataxias. In addition to the typical OPCA I of Menzel, other allelic forms of ataxia may exist, e.g., that in the Danish pedigree with pyramidal lesions and dementia (Pedersen et al., 1980).

In connection with other studies of a large family, the Schut-Swier kindred (Schut, 1950), Haines et al. (1984) concluded that there was linkage with HLA (maximum lod score = 3.71 at theta = 0.18). Haines and Trofatter (1986) placed ATXN1 telomeric to HLA-A. Using a DNA marker (D6S7) to study the Schut-Swier kindred, Rich et al. (1987) demonstrated linkage between the SCA locus and HLA-A. The observed linkage indicated that the position of the gene was about 15 cM telomeric of HLA-A on 6p. Rich and Orr (1989) and Orr and Rich (1989) studied the linkage of SCA1 in 2 '7-generation kindreds' (the Schut-Swier kindred) with the conclusion that the locus is distal to HLA and proximal to F13A. Three-point linkage analysis on the 2 kindreds combined favored the gene order HLAA--ATXN1--F13A--6pter over the second most likely order ATXN1--HLAA--F13A by odds of 9 million to 1.

Zoghbi et al. (1987) demonstrated HLA linkage in a large black kindred with variable age of onset. Although the mean age of onset was 34 years, in 6 of 41 affected individuals onset was under 15 years of age and was accompanied by the unique clinical features of mental retardation and rapid progression of disease. Linkage to HLA showed a lod score of 5.83 at a recombination fraction of 0.12. Linkage to HLA-DR and HLA-DQ showed lod scores of 3.39 and 2.51 at recombination fractions of 0.15 and 0.17, respectively. This suggested that the SCA1 locus is distal to the MHC region. However, Zoghbi et al. (1988, 1989), by multilocus linkage analysis, obtained results indicating that the SCA1 gene locus is centromeric to HLA-DP, with odds of 46:1 favoring this most likely location over the second most likely location, i.e., telomeric to the HLA complex but proximal to F13A (134570). This appears to indicate localization in the 6p21.3-p21.2 region.

Wakisaka et al. (1989) and Shrimpton et al. (1989) described linkage studies in families with autosomal dominant ataxia. In 2 large Italian pedigrees with HLA-linked spinocerebellar ataxia, Frontali et al. (1991) excluded linkage with F13A at less than 5% recombination and with GLO1 at less than 10% recombination. The results favored the view that ATXN1 is distal to HLA. Thus, they favored the order cen--GLO1--HLA--ATXN1--tel.

Studies of 2 large kindreds led Ranum et al. (1991) to conclude that ATXN1 is unequivocally located distal to HLA and proximal to F13A. Furthermore, ATXN1 was found to lie centromeric and genetically very close to the highly informative D6S89 marker. In the 2 kindreds, 1 recombinant was observed between D6S89 and ATXN1, resulting in a recombination fraction of 0.014. Linkage analysis in the Schut-Swier kindred led Wilkie et al. (1991) likewise to conclude that ATXN1 is telomeric to HLA-A and lies between HLA-A and F13A. The maximum pairwise lod score for linkage between ATXN1 and HLA-A was 8.52; male theta = 0.10, female theta = 0.22. In a 5-generation American black family, Keats et al. (1991) excluded close linkage between the SCA1 locus and both HLA and F13A1; lod scores for all locations of the disease locus between these 2 loci were less than -1.4. However, the disease locus was found to be closely linked to a microsatellite polymorphism, D6S89, which is situated between HLA and F13A1; maximum lod = 4.90 at theta = 0.0, both in males and in females. The findings indicated that exclusion of close linkage to HLA and F13A1 in a kindred with spinocerebellar ataxia does not rule out the possibility that the disease locus is in fact on 6p. Accordingly, all families segregating a dominantly inherited ataxia should be evaluated for linkage to D6S89.

Zoghbi et al. (1991) tested for linkage with 2 highly informative dinucleotide repeat sequences in 3 large kindreds, 1 in Houston, Texas, and 2 in Calabria. Pairwise linkage analysis of ATXN1 and D6S89 revealed a maximum lod score of 5.86 in the Houston kindred and of 8.08 in the Calabrian kindreds, at recombination fractions of 0.050 and 0.022, respectively. A maximum pairwise lod score of 4.54 at recombination frequency of 0.100 was obtained for ATXN1 and TCTE1 (186975) in the Houston pedigree but no evidence of linkage was detected between these loci in the case of the Calabrian kindreds. Multilocus linkage analysis supported strongly localization of ATXN1 telomeric to HLA. Volz et al. (1992) studied D6S89 in mutant cell lines with cytogenetically detectable interstitial 6p deletions to map the marker to 6p24.2-p23.05. This would place ATXN1 in the 6p24-p23 segment. In 4 of 10 French families with autosomal dominant cerebellar ataxia type 1, Khati et al. (1993) found very close linkage of the neurologic disorder to the D6S89 marker, with no evidence of recombination. Linkage to D6S89 was excluded in the other 6. After the cloning of the ataxin-1 gene (601556), Volz et al. (1994) reported that it was mapped to 6p23 by in situ hybridization.

Kwiatkowski et al. (1993) reported a new marker, AM10GA, that demonstrated no recombination with ATXN1; maximum lod = 42.14 at theta = 0. Linkage analysis and analysis of recombination events confirmed that ATXN1 maps centromeric to D6S89 (which showed a maximum lod score of 67.58 at a maximum recombination fraction of 0.004 with ATXN1). They cited multipoint linkage analysis indicating that ATXN1 is telomeric to HLA.

In 7 families from a Siberian founder population with autosomal dominant SCA, Lunkes et al. (1994) demonstrated allelic association of the disease with polymorphisms known to flank the SCA1 locus on 6p. The association was absolute in the case of microsatellite D6S274, whereas an allele switch was observed for D6S89 in 2 families, suggesting a historic recombinant.

▼ Heterogeneity
Genetic Heterogeneity
Koeppen et al. (1980) found no evidence of linkage to chromosome 6 markers in 5 families with 'dominant ataxia' and 3 with 'recessive ataxia' (Friedreich disease). Kumar et al. (1986) found negative lod scores for linkage to HLA in all of 5 families in which at least 3 generations were affected with autosomal dominant SCA.

By linkage studies in families with Machado-Joseph disease (MJD; 109150), Carson et al. (1992) demonstrated conclusively that MJD cannot be allelic to SCA1. A clinically indistinguishable form of spinocerebellar ataxia, SCA2, occurs in high frequency in Cuba. Lunkes et al. (1993) excluded linkage to 6p in a 5-generation Danish family.

▼ Pathogenesis
Orr et al. (1993) demonstrated that the basic genetic defect in spinocerebellar ataxia-1 consists of expansion of a trinucleotide CAG repeat. They showed that the repeat is present not only in genomic DNA but also in a 10-kb mRNA transcript. Banfi et al. (1994) identified the gene, termed ataxin-1. This was the fifth example of a pathologic state resulting from expansion of an unstable trinucleotide repeat. The others, in chronologic order of discovery, were the fragile X syndrome (300624), myotonic dystrophy (160900), Kennedy spinal and bulbar muscular atrophy (313200), and Huntington disease (143100).

After the lesion in SCA1 was found to involve an expanded trinucleotide repeat, this lesion was demonstrated in affected members of the Schut-Swier kindred, thus proving that it was, in fact, SCA1 (Wexler, 1993).

By immunoblot analysis, Servadio et al. (1995) demonstrated that a mutant protein that varies in its electrophoretic migration properties according to the size of the CAG repeat is detected in cultured cells and tissues from SCA1 individuals along with the wildtype protein. The ataxin-1 protein has a nuclear localization in all normal and SCA1 brain regions examined, but a cytoplasmic localization of ataxin-1 was also observed in cerebellar Purkinje cells, leading to progressive degeneration of Purkinje cells. The data showed that the expanded ATXN1 alleles are also translated into proteins of apparently normal stability and distribution.

Orr and Zoghbi (1996) reviewed the work elucidating polyglutamine-induced neurologic disease in SCA1.

Cummings et al. (1998) found colocalization of the 20S proteasome (see 602175) and chaperone HSJ2 (602837), a member of the Hsp40 family, with large nuclear inclusions of ataxin-1 in brain neurons of patients with SCA1 and in mice transgenic for a mutant ATXN1 allele containing 82 glutamines. In these nuclear inclusions, there was also faint staining for Hsc70 (HSPA8; 600816), a member of the Hsp70 chaperone family. Similar colocalization was seen in HeLa cells transfected with ataxin-1. In the transfected HeLa cells, unlike in the brains, there was apparent induction of Hsc70 chaperone. Overexpression of HSJ2 in these cells reduced aggregation of ataxin-1, suggesting a possible therapeutic strategy.

Lam et al. (2006) examined soluble protein complexes from mouse cerebellum and found that the majority of wildtype and expanded Atxn1 assembles into large stable complexes containing the transcriptional repressor Capicua (CIC; 612082). Atxn1 directly bound Cic and modulated Cic repressor activity in Drosophila and mammalian cells, and its loss decreased the steady state level of Cic. Interestingly, the S776A mutation, which abrogates the neurotoxicity of expanded Atxn1 (Emamian et al., 2003), substantially reduced the association of mutant Atxn1 with Cic in vivo. Lam et al. (2006) concluded that their data provided insight into the function of Atxn1 and suggested that the neuropathology of SCA1, caused by expansion of the ATXN1 polyglutamine tract, depends on native, not novel, protein interactions. Lam et al. (2006) found that the majority of CIC associates with ATXN1 in vivo and that ATXN1 binds CIC through an 8-amino-acid sequence conserved across species.

Lim et al. (2008) demonstrated that the expanded polyglutamine tract of ATXN1 differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favors the formation of a particular protein complex containing RBM17 (606935), contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. Lim et al. (2008) concluded that their model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.

Jain and Vale (2017) showed that repeat expansions create templates for multivalent basepairing, which causes purified RNA to undergo a sol-gel transition in vitro at a similar critical repeat number as observed in Huntington disease, spinocerebellar ataxia, myotonic dystrophy, and FTDALS1 (105550). In human cells, RNA foci form by phase separation of the repeat-containing RNA and can be dissolved by agents that disrupt RNA gelation in vitro. Jain and Vale (2017) concluded that, analogous to protein aggregation disorders, their results suggested that the sequence-specific gelation of RNAs could be a contributing factor to neurologic disease.

▼ Molecular Genetics
Banfi et al. (1994) determined that the CAG trinucleotide repeat identified by Orr et al. (1993) in SCA1 occurs in the ataxin-1 gene (601556.0001).

Genetic Anticipation

Chung et al. (1993) found that 63% of paternal transmissions show an increase in repeat number, whereas 69% of maternal transmissions show no change or a decrease in repeat number. Sequence analysis showed that 98% of unexpanded alleles had an interrupted repeat configuration, whereas a contiguous repeat (CAG)n was found in expanded alleles. This indicated that the repeat instability in ATXN1 is more complex than a simple variation in repeat number and that the loss of an interruption predisposes the ATXN1 (CAG)n to expansion. Matilla et al. (1993) studied the expansion of the ATXN1 gene CAG repeat in a large family in which spinocerebellar ataxia showed the phenomenon of anticipation. There were 41 affected members with no juvenile cases of SCA1, the mean age of onset being 36 years. The family also showed the phenomenon of parental male bias; i.e., the age of onset was younger and the duration of illness before death was shorter in the members of the family who inherited the disorder from the father. In this large Spanish kindred, Matilla et al. (1993) found 9 clinically unaffected persons between ages 18 and 40 years who had expansions of the CAG repeat within the pathogenetic range. In 22 other genetically 'at risk' individuals, they found that the number of CAG repeats in the ATXN1 gene was within the normal range.

Ranum et al. (1994) examined the frequency and variability of the ATXN1 repeat expansion in 87 kindreds with diverse ethnic backgrounds and dominantly inherited ataxia. All 9 families for which linkage to the ATXN1 region of 6p had previously been established showed repeat expansion, while 3 of the remaining 78 showed a similar abnormality. For 113 patients from the families with repeat expansion, inverse correlations between CAG repeat size and both age at onset and disease duration were observed. Repeat size accounted for 66% of the variation in age at onset in these patients. After correction for repeat size, interfamilial differences in age at onset remained significant, suggesting that additional genetic factors affect the expression of the ATXN1 gene product.

Jodice et al. (1994) found trinucleotide repeat expansion in 64 subjects from 19 families: 57 patients with SCA1 and 7 subjects predicted, by haplotype analysis, to carry the mutation. Comparison with a large set of normal chromosomes showed 2 distinct distributions with a much wider variation among expanded chromosomes. The sex of the transmitting parent played a major role in the size distribution of expanded alleles, those with more than 54 repeats being transmitted by affected fathers exclusively. Alleles with 46 to 54 repeats were transmitted by affected fathers and mothers in equal proportions. On the other hand, the sex ratio of offspring receiving either more than 54 or less than 54 repeats approached the expected 50:50. If a steady-state distribution of repeat numbers is assumed to persist through the generations, this raises the question as to why affected females transmitting alleles with more than 54 repeats are lacking, while females receiving more than 54 repeats exist. This may be explained, at least in part, by reduced biologic fitness. Detailed clinical follow-up of a subset of patients by Jodice et al. (1994) demonstrated significant relationships between increasing repeat number on expanded chromosomes and earlier age at onset, faster progression of the disease, and earlier age at death.

Koefoed et al. (1998) performed single sperm analysis of (CAG)n stretches in SCA1 patients and asymptomatic carriers. A pronounced variation in the size of the expanded allele was found in sperm cells and in peripheral blood leukocytes, with a higher degree of instability in sperm cells, where an allele with 50 repeat units was contracted in 11.8%, further expanded in 63.5%, and unchanged in 24.6% of the single sperm analyzed. They also found a low instability of the normal alleles; the normal alleles from the individuals carrying a CAG repeat expansion was significantly more unstable than the normal alleles from control individuals (P less than 0.001), indicating an interallelic interaction between the expanded and the normal alleles.

Matsuyama et al. (1999) studied 17 patients with SCA1. In one of these patients the expanded ATXN1 allele was interrupted by a CAT trinucleotide. The total number of CAG repeats was 58, predicting an age at onset of 22.0 years, in contrast to the actual age at onset of 50 years. In addition, brainstem atrophy was mild compared to that of a patient with 52 CAG repeats. Sequence analysis showed the repeat portion of the ATXN1 allele contained 45 uninterrupted CAG repeats with 2 interspersed CAT repeats in the subsequent 12 trinucleotides. Matsuyama et al. (1999) concluded that the age at onset of SCA1 is not determined by the total number of CAG repeats, but rather by the total number of uninterrupted CAG repeats.

Zuhlke et al. (2002) performed genotype-phenotype correlation in intermediate alleles from 36 to 43 CAG repeats in the ATXN1 gene with respect to the presence of interrupting CAT trinucleotides. Alleles with 36 to 38 triplets were present in individuals with ataxia but without additional characteristic features of SCA1. SCA1 phenotypes were found for patients with 41 and 43 triplets. The 39 triplet allele missing CAT interruptions was associated with symptoms characteristic for SCA1 in 4 patients, whereas the interrupted allele with 39 triplets did not cause characteristic SCA1 features in 1 individual. These findings suggested a change from normal to pathologic alleles at 39 triplets depending on the presence of CAT interruptions in the CAG repeat. Stable inheritance of the uninterrupted 39 triplet allele was observed in 1 familial case of SCA1.

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.

Associations Pending Confirmation

For discussion of a possible association between autosomal dominant SCA and variation in the ZFYVE27 gene, see 610243.0002.

For discussion of a possible association between autosomal dominant SCA and variation in the KIF26B gene, see 614026.0001.

For discussion of a possible association between autosomal dominant SCA and variation in the EP300 gene, see 602700.

▼ Genotype/Phenotype Correlations
Schols et al. (1997) compared clinical, electrophysiologic, and magnetic resonance imaging (MRI) findings to identify phenotypic characteristics of genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and action tremor suggested SCA2. SCA3 patients frequently developed diplopia, severe spasticity or pronounced peripheral neuropathy, and impaired temperature discrimination, apart from ataxia. SCA6 presented with a predominantly cerebellar syndrome, and patients often had onset after 55 years of age. SCA1 was characterized by markedly prolonged peripheral and central motor conduction times in motor evoked potentials. MRI scans showed pontine and cerebellar atrophy in SCA1 and SCA2. In SCA3, enlargement of the fourth ventricle was the main sequel of atrophy. SCA6 presented with pure cerebellar atrophy on MRI. Overlap between the 4 SCA subtypes was broad, however.

Among 65 patients with SCA1, SCA2, or SCA3, Burk et al. (1996) found reduced saccade velocity in 56%, 100%, and 30% of patients, respectively. MRI showed severe olivopontocerebellar atrophy in SCA2, similar but milder changes in SCA1, and very mild atrophy with sparing of the olives in SCA3. Careful examination of 3 major criteria of eye movements, saccade amplitude, saccade velocity, and presence of gaze-evoked nystagmus, permitted Rivaud-Pechoux et al. (1998) to assign over 90% of patients with SCA1, SCA2, or SCA3 to their genetically confirmed patient group. In SCA1, saccade amplitude was significantly increased, resulting in hypermetria. In SCA2, saccade velocity was markedly decreased. In SCA3, the most characteristic finding was the presence of gaze-evoked nystagmus.

In an investigation of oculomotor function, Buttner et al. (1998) found that all 3 patients with SCA1, all 7 patients with SCA3, and all 5 patients with SCA6 had gaze-evoked nystagmus. Three of 5 patients with SCA2 did not have gaze-evoked nystagmus, perhaps because they could not generate corrective fast components. Rebound nystagmus occurred in all SCA3 patients, 33% of SCA1 patients, 40% of SCA6 patients, and none of SCA2. Spontaneous downbeat nystagmus only occurred in SCA6. Peak saccade velocity was decreased in 100% of patients with SCA2, 1 patient with SCA1, and no patients with SCA3 or SCA6. Saccade hypermetria was found in all types, but was most common in SCA3. Burk et al. (1999) found that gaze-evoked nystagmus was not associated with SCA2. However, severe saccade slowing was highly characteristic of SCA2. Saccade velocity in SCA3 was normal to mildly reduced. The gain in vestibuloocular reflex was significantly impaired in SCA3 and SCA1. Eye movement disorders of SCA1 overlapped with both SCA2 and SCA3.

The reticulotegmental nucleus of the pons (RTTG), also known as the nucleus of Bechterew, is a precerebellar nucleus important in the premotor oculomotor circuits crucial for the accuracy of horizontal saccades and the generation of horizontal smooth pursuit. By postmortem examination, Rub et al. (2004) identified neuronal loss and astrogliosis in the RTTG in 1 of 2 SCA1 patients, 2 of 4 SCA2 patients, and 4 of 4 SCA3 patients that correlated with clinical findings of hypometric saccades and slowed and saccadic smooth pursuits. The 3 patients without these specific oculomotor findings had intact RTTG regions. The authors concluded that the neurodegeneration associated with SCA1, SCA2, and SCA3 affects premotor networks in addition to motor nuclei in a subset of patients.

Using an analysis of covariance and multivariate models to examine symptom severity in 526 patients with SCA1, SCA2, SCA3, or SCA6, Schmitz-Hubsch et al. (2008) found that repeat length of the expanded allele, age at onset, and disease duration explained 60.4% of the ataxia score in SCA1, 45.4% in SCA2, 46.8% in SCA3. However, only age at onset and disease duration appeared to explain 33.7% of the score in SCA6. Similar findings were obtained for nonataxic symptoms. The study suggested that SCA1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors.

▼ Population Genetics
Giunti et al. (1994) examined members of 73 families who were affected with a variety of autosomal dominant late-onset cerebellar ataxias for the trinucleotide repeat expansion associated with the SCA1 locus. The mutation was found in 19 of 38 kindreds with the SCA1 phenotype. However, it was not found in any of 8 families with olivopontocerebellar atrophy with maculopathy (164500), or in 24 kindreds with pure adult-onset cerebellar ataxia (SCA31; 117210), or in 12 patients with sporadic degenerative ataxia. The patients with the expansion were Italian, British, Malaysian, Bangladeshi, and Jamaican.

Ranum et al. (1995) made use of the fact that the genes involved in 2 forms of autosomal dominant ataxia, that for Machado-Joseph disease (109150) and that for SCA1, have been isolated to assess the frequency of trinucleotide repeat expansions among individuals diagnosed with ataxia. They collected and analyzed DNA from individuals with both disorders. In both cases, the genes responsible for the disorder were found to have an expansion of an unstable CAG trinucleotide repeat. These individuals represented 311 families with adult-onset ataxia of unknown etiology, of which 149 families had dominantly inherited ataxia. Ranum et al. (1995) found that of these, 3% had SCA1 trinucleotide repeat expansions, whereas 21% were positive for the MJD trinucleotide expansion. For the 57 patients with MJD trinucleotide repeat expansions, strong inverse correlation between CAG repeat size and age at onset was observed (r = -0.838). Among the MJD patients, the normal and affected ranges of CAG repeat size were 14 to 40 and 68 to 82 repeats, respectively. For SCA1, the normal and affected ranges were much closer, namely 19 to 38 and 40 to 81 CAG repeats, respectively.

In a nationwide survey of Japanese patients, Hirayama et al. (1994) found an estimated prevalence of the various forms of spinocerebellar degeneration to be 4.53 per 100,000. Of these, 12.6% were thought to have the Menzel type of spinocerebellar atrophy (SCA1). However, it was not clear how they distinguished this disorder from the other forms of OPCA. In Japan, Suzuki et al. (1995) found that all affected and presymptomatic individuals in 12 pedigrees with SCA1 (determined by haplotype per segregation analyses) carried an abnormally expanded allele with a range of 39 to 63 repeat units. This repeat size inversely correlated with the age of onset. However, contrary to previous reports, the size of the repeat did not correlate with gender of the transmitting parent. CAG triplet repeat instability on paternal transmission was not observed.

Wakisaka et al. (1995) determined the haplotype cosegregating with SCA1 in 12 Japanese pedigrees. Although the alleles of the ATXN1 haplotype varied from pedigree to pedigree depending on the distance from the SCA1 locus, the affected and presymptomatic subjects carried the same alleles at 2 loci, D6S288 and D6S274. All the families with SCA1 had migrated from either the Miyagi or Yamagata Prefectures, neighboring areas in the Tokohu District, the northern part of Honshu, which is the main island of Japan. The findings suggested to the authors that SCA1 in the Japanese, at least those residing in Hokkaido, derived from a single common ancestry. Goldfarb et al. (1996) studied 78 SCA1 patients from a large Siberian kindred which included 1,484 individuals, 225 of whom are known to be affected and 656 of whom were at risk. Normal alleles had 25 to 37 trinucleotide repeats, whereas expanded alleles contained 40 to 55 repeats. The disease was not fully penetrant inasmuch as there was one 66-year-old woman with 44 CAG repeats who was asymptomatic. Of her 7 children, 4 were affected, including a homozygous daughter and another child with 44 repeats. Two symptomatic individuals who had expansions on both chromosomes demonstrated clinical manifestations that corresponded to the size of the larger allele.

In Catalonia, Genis et al. (1995) found a large kindred traced to a common ancestor born in 1735 that segregated spinocerebellar ataxia-1. Affected individuals all had 1 allele with between 41 in 59 repeats, whereas asymptomatic individuals for the most part fell in the range of 6 to 39 repeats. Two asymptomatic individuals, an 18-year-old female and a 25-year-old male, had 41 repeats.

Klockgether et al. (1994) analyzed DNA from 19 German families with autosomal dominant cerebellar ataxia and 61 unrelated individuals with idiopathic cerebellar ataxia with a mean age of onset of 53.6 years. Heterozygosity for the ATXN1 triplet repeat expansion was diagnosed in 5 out of 19 of the autosomal dominant kindreds. In contrast, none of the 61 cases of idiopathic adult-onset cerebellar ataxia showed this expansion. This suggested that SCA1 is not a significant cause of idiopathic cerebellar ataxia in Germany. Studying 77 German families with autosomal dominant cerebellar ataxia of SCA types 1, 2, 3, and 6, Schols et al. (1997) found that the SCA1 mutation accounted for 9%, SCA2 for 10%, SCA3 for 42%, and SCA6 for 22%. There was no family history of ataxia in 7 of 27 SCA6 patients. Age at onset correlated inversely with repeat length in all subtypes. Yet the average effect of 1 CAG unit on age of onset was different for each SCA subtype. Riess et al. (1997) found that in both SCA1 and SCA3 patients in German families there was distortion of the mendelian 1:1 segregation of the disease. They noted that mutations in the ataxin-1 gene are responsible for autosomal dominant spinocerebellar ataxia in about 10% of all families, whereas SCA3 is the most common cause in Germany, accounting for up to 50% of cases.

Ramesar et al. (1997) investigated 14 South African kindreds and 22 sporadic individuals with SCA for expanded ATXN1 (601556.0001) and ATXN3 (607047.0001) repeats. The authors stated that, in the present study, ATXN1 mutations accounted for 43% of known ataxia families in the Western Cape region. They found that expanded ATXN1 and CAG repeats cosegregated with the disorder in 6 of the families, 5 of mixed ancestry and 1 Caucasian, and were also observed in a sporadic case from the indigenous Black African population. The use of the microsatellite markers D6S260, D6S89, and D6S274 provided evidence that the expanded ATXN1 repeats segregated with 3 distinct haplotypes in the 6 families. None of the families nor the sporadic individuals showed expansion of the MJD repeat.

Among 202 Japanese and 177 Caucasian families with autosomal dominant SCA, Takano et al. (1998) found that the prevalence of SCA1 was significantly higher in the Caucasian population (15%) compared to the Japanese population (3%). This corresponded to higher frequencies of large normal ATXN1 CAG repeat alleles (greater than 30 repeats) in Caucasian controls compared to Japanese controls. The findings suggested that large normal alleles contribute to the generation of expanded alleles that lead to dominant SCA.

In Spain, Pujana et al. (1999) performed molecular analysis on 87 unrelated familial and 60 sporadic cases of spinocerebellar ataxia of autosomal dominant type. For the familial cases of ADCA, 6% were SCA1, 15% were SCA2, 15% were SCA3, 1% represented SCA6, 3% were SCA7, and, in 1%, the diagnosis was DRPLA (125370), an extremely rare mutation in Caucasoid populations. About 58% of ADCA cases remained genetically unclassified. All the SCA1 cases belonged to the same geographic area and shared a common haplotype for the SCA1 mutation. The expanded alleles ranged from 41 to 59 repeats for SCA1, 35 to 46 for SCA2, 67 to 77 for SCA3, and 38 to 113 for SCA7. The 1 SCA6 case had 25 repeats and the 1 DRPLA case had 63 repeats. The highest CAG repeat variation in meiotic transmission of expanded alleles was detected in SCA7, this being an expansion of 67 units in one paternal transmission, giving rise to a 113 CAG repeat allele in a patient who died at 3 years of age. Meiotic transmissions showed a tendency to more frequent paternal transmission of expanded alleles in SCA1 and maternal in SCA7. All SCA1 and SCA2 expanded alleles analyzed consisted of pure CAG repeats, whereas normal alleles were interrupted by 1 to 2 CAT trinucleotides in SCA1, except for 3 alleles of 6, 14, and 21 CAG repeats, and by 1 to 3 CAA trinucleotides in SCA2. The failure to find SCA or DRPLA mutations in the 60 sporadic cases of spinocerebellar ataxia is consistent with the lack of evidence of de novo mutations noted by Andrew et al. (1997).

Pareyson et al. (1999) evaluated 73 Italian families with type I ADCA. SCA1 was the most common genotype, accounting for 41% of cases (30 families); SCA2 was slightly less frequent (29%, 21 families), and the remaining families were negative for the SCA1, SCA2, and SCA3 mutations. Among the positively genotyped families, SCA1 was found most frequently in families from northern Italy (50%), while SCA2 was the most common mutation in families from the southern part of the country (56%). Slow saccades and decreased deep tendon reflexes were observed significantly more frequently in SCA2 patients, while increased deep tendon reflexes and nystagmus were more common in SCA1.

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.

Zhou et al. (2001) performed molecular analysis of 109 patients in 75 Chinese families with autosomal dominant SCA and 16 patients with sporadic SCA or spastic paraplegia. SCA type 1 was found in 5 families (7%), and all patients with the SCA1 phenotype were heterozygous for alleles with CAG repeat numbers ranging from 51 to 64 (control groups, 26-35). There was a significant negative correlation between age of disease onset and number of CAG repeat units. SCA3/MJD was found in 26 families, SCA2 in 9 families, SCA6 in 2 families, and SCA7 in 2 families. The combined frequency of SCA1, SCA2, and SCA3/MJD was 53%. None of the 16 sporadic cases was positive for the mutations tested, and no patients were positive for SCA8 (608768), SCA12, or DRPLA. Clinically, the authors noted that SCA3/MJD tended to manifest more frequently with ophthalmoparesis, eyelid retraction, facial myokymia, ataxia, spasticity, and amyotrophy. The frequency of single CAT interruptions in the ATXN1 gene was higher in the Siberian Sakha control group, which also had a higher prevalence of SCA1 than the Chinese population, suggesting that a substitution of CAT for CAG may be the initial event contributing to the generation of expanded alleles.

Of 253 unrelated Korean patients with progressive cerebellar ataxia, Lee et al. (2003) identified 52 (20.6%) with expanded CAG repeats. The most frequent SCA type was SCA2 (33%), followed by SCA3 (29%), SCA6 (19%), SCA1 (12%), and SCA7 (8%). There were characteristic clinical features, such as hypotonia and optic atrophy for SCA1, hyporeflexia for SCA2, nystagmus, bulging eye, and dystonia for SCA3, and macular degeneration for SCA7.

Mittal et al. (2005) found SCA1 in 37 (22%) of 167 Indian families with ADCA. The frequency of SCA1 in the south Indian population was twice (33%) that of the north Indian population (16%). The nonaffected repeat length ranged from 21 to 39 triplets. Haplotype analysis identified an ancestral C-4-C haplotype (rs1476464, D6S288, and rs2075974) that was mostly present in the affected individuals, suggesting that this background might have been predisposed for repeat expansion. This haplotype, when present in the nonaffected chromosomes, had multiple interruptions in the repeat tract, which the authors hypothesized would provide genetic stability. However, in disease chromosomes, this haplotype showed large normal (greater than 30 repeats) expansions and was associated with the expanded chromosomes in about 44% of SCA1 families.

Among 113 Japanese families from the island of Hokkaido with autosomal dominant SCA, Basri et al. (2007) found that SCA6 was the most common form of the disorder, identified in 35 (31%) families. Thirty (27%) families had SCA3, 11 (10%) had SCA1, 5 (4%) had SCA2, 5 (4%) had DRPLA, 10 (9%) had 16q22-linked SCA, and 1 (1%) had SCA14 (605361). The specific disorder could not be identified in 16 (14%) families.

▼ History
Weiner and Konigsmark (1971) provided a review of hereditary diseases of the cerebellum. Affected families have been described by Hall et al. (1941), Richter (1950), Weber and Greenfield (1942), and others.

▼ Animal Model
Servadio et al. (1995) mapped the mouse homolog of the ATXN1 gene to mouse chromosome 13. Although human SCA1 is characterized by progressive Purkinje cell degeneration, Servadio et al. (1995) showed that pcd (Purkinje cell degeneration) mutation in the mouse, which also maps to mouse chromosome 13, is not caused by mutation in the murine Sca1 gene since linkage studies indicated that the 2 loci are separated by 7 or more cM.

To gain insight into the pathogenesis of SCA1 and the intergenerational stability of trinucleotide repeats in mice, Burright et al. (1995) generated transgenic mice expressing the human ATXN1 gene with either a normal or an expanded CAG tract. Both transgenes were stable in parent-to-offspring transmissions. While all 6 transgenic lines expressing the unexpanded human ATXN1 allele had normal Purkinje cells, transgenic animals from 5 of 6 lines with the expanded ATXN1 allele developed ataxia and Purkinje cell degeneration. These data indicated to the authors that expanded CAG repeats expressed in Purkinje cells are sufficient to produce degeneration and ataxia and demonstrated that a mouse model can be established from neurodegeneration caused by CAG repeat expansions.

To examine genetic aspects of trinucleotide repeat instability, Kaytor et al. (1997) introduced an ATXN1 cDNA containing a CAG trinucleotide repeat tract into transgenic mice and analyzed both maternal and paternal transmission of the repeat. Intergenerational CAG repeat instability was detected only when the transgene was maternally transmitted. The intergenerational instability increased in frequency and magnitude as the transgenic mother aged. Furthermore, triplet repeat variations were detected in unfertilized oocytes and were comparable with those in the offspring. These data showed that maternal repeat instability in the transgenic mice occurs after meiotic DNA replication and before oocyte fertilization. The findings demonstrated that advanced maternal age is an important factor for instability of nucleotide repeats in mammalian DNA.

Klement et al. (1998) stated that transgenic mice carrying the Sca1 gene develop ataxia with ataxin-1 localized to aggregates within cerebellar Purkinje cell nuclei. To examine the importance of nuclear localization and aggregation in pathogenesis, mice expressing ataxin-1(82) with a mutated NLS (nuclear localization signal K772T) were established. These mice did not develop disease, demonstrating that nuclear localization is critical for pathogenesis. In another transgenic mouse colony, ataxin-1(77) containing a deletion within the self-association region (amino acid residues 472-594) was expressed within Purkinje cell nuclei. These mice developed ataxia and Purkinje cell pathology similar to the original SCA1 mice. However, no evidence of nuclear ataxin-1 aggregates was found. Thus Klement et al. (1998) concluded that although nuclear localization of ataxin-1 is necessary, nuclear aggregation of ataxin-1 is not required to initiate pathogenesis in transgenic mice.

Lorenzetti et al. (2000) generated knockin mice by inserting an expanded tract of 78 CAG repeats into the mouse Sca1 locus. Mice heterozygous for the CAG expansion showed intergenerational repeat instability (+2 to -6) at a much higher frequency in maternal transmission than in paternal transmission. Mice homozygous for mutant ataxin-1 on a C57BL/6J-129/SvEv mixed background performed significantly less well on the rotating rod than did wildtype littermates at 9 months of age, although they were not ataxic by cage behavior. Histologic examination of brain tissue from mutant mice up to 18 months of age revealed none of the neuropathologic changes observed in other transgenic models overexpressing expanded polyglutamine tracts. The authors hypothesized that, even with 78 glutamines, prolonged exposure to mutant ataxin-1 at endogenous levels is necessary to produce a neurologic phenotype reminiscent of human SCA1, and that pathogenesis may be a function of polyglutamine length, protein levels, and duration of neuronal exposure to the mutant protein.

Cummings et al. (2001) crossbred SCA1 mice with mice overexpressing the molecular chaperone inducible HSP70 (HSPA1A; 140550). Although the amount of nuclear inclusions in Purkinje cells persisted, physiologic and histopathologic analysis revealed that high levels of HSP70 appeared to afford protection against neurodegeneration and preserved dendritic arborization in the cerebellum.

Okuda et al. (2003) generated transgenic mice overexpressing human PQBP1 (300463), a polyglutamine-binding nuclear protein that interacts with ataxin-1. The mice showed a late-onset and gradually progressive motor neuron disease-like phenotype suggestive of the neurogenic muscular atrophy observed in SCA1 patients. Ataxia could not be discriminated from predominant progressive weakness. Pathologic examinations of the transgenic mice revealed loss of Purkinje and granular cells in the cerebellum as well as loss of motor neurons in the spinal anterior horn, corresponding to the pathology of human SCA1. Okuda et al. (2003) concluded that excessive action of PQBP1 causes neuronal dysfunction and that PQBP1 may be involved in the pathology of SCA1.

Watase et al. (2003) investigated the pattern of CAG repeat instability in a knockin mouse model of SCA1. Small pool (SP)-PCR analysis on DNA from various neuronal and nonneuronal tissues revealed that somatic repeat instability was highest in the striatum. In 2 SCA1-vulnerable tissues, cerebellum and spinal cord, there were substantial differences in the profile of mosaicism. Watase et al. (2003) suggested that in SCA1 there is no clear causal relationship between the degree of somatic instability and selective neuronal vulnerability. The finding that somatic instability is most pronounced in the striatum of various knockin models of polyglutamine diseases may suggest a role of trans-acting tissue- or cell-specific factors in mediating the instability.

In a mouse model of SCA1, Xia et al. (2004) performed intracerebellar delivery of viral vectors expressing short hairpin RNAs targeting ataxin-1 as a therapeutic use of RNA interference (RNAi). The treated mice showed reduced ataxin-1 expression in Purkinje cells, resolution of intracellular ataxin-1 inclusions in the cerebellum, and improved motor performance. Xia et al. (2004) noted the importance of screening multiple hairpins before identifying an appropriate one for targeted gene silencing.

By comparing previously reported genetic modifiers in 3 Drosophila models of human neurodegenerative disease, Ghosh and Feany (2004) confirmed that protein folding, histone acetylation, and apoptosis are common features of neurotoxicity. Two novel genetic modifiers, the Drosophila homolog of ATXN2 (601517) and CGI7231, were identified. Cell-type specificity was demonstrated as many, but not all, retinal modifiers also modified toxicity in postmitotic neurons. Ghosh and Feany (2004) identified nicotinamide, which has histone deacetylase-inhibiting activity, as a potent suppressor of polyglutamine toxicity.

Using a conditional transgenic mouse model of SCA1, Serra et al. (2006) showed that delaying postnatal expression of mutant human ATXN1 until completion of cerebellar maturation led to a substantial reduction in disease severity in adults compared with early postnatal expression of mutant ATXN1. Microarray analysis revealed that genes regulated by Rora (600825), a transcription factor critical for cerebellar development, were downregulated at an early stage of disease in Purkinje cells of SCA1 transgenic mice. Rora mRNA and protein levels were reduced in Purkinje cells of SCA1 transgenic mice, and the effect of mutant ATXN1 on Rora protein levels appeared to be independent of its effect on Rora mRNA levels. Partial loss of Rora enhanced the pathogenicity of mutant ATXN1 in transgenic mice. Coimmunoprecipitation and pull-down analyses suggested the existence of a complex containing Atxn1, Rora, and the Rora coactivator Tip60 (HTATIP; 601409), with Atxn1 and Tip60 interacting directly. Serra et al. (2006) concluded that RORA and TIP60 have a role in SCA1 and proposed that their findings provide a mechanism by which compromised cerebellar development contributes to the severity of neurodegeneration in an adult.

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.

To determine the long-term effects of exercise, Fryer et al. (2011) implemented a mild exercise regimen in a mouse model of SCA1 and found a considerable improvement in survival accompanied by upregulation of epidermal growth factor and consequential downregulation of Capicua (612082), which is an ATXN1 (601556) interactor. Offspring of Capicua mutant mice bred to Sca1 mice showed significant improvement of all disease phenotypes. Although polyglutamine-expanded Atxn1 caused some loss of Capicua function, further reduction of Capicua levels--either genetically or by exercise--mitigated the disease phenotypes by dampening the toxic gain of function. Fryer et al. (2011) concluded that exercise might have long-term beneficial effects in other ataxias and neurodegenerative diseases.

In Sca1 mice, Cvetanovic et al. (2011) found that mutant Atxn1 repressed transcription of Vegfa (192240), resulting in decreased Vegfa mRNA and protein levels in cerebellar Purkinje cells. Sca1 mice showed a decrease in cerebellar microvessel density and length, as well as evidence of cellular hypoxia. Inhibition of Vegfa in neuronal cell culture resulted in decreased neurite length and increased cell death. Genetic overexpression or pharmacologic infusion of Vegfa ameliorated the phenotype of Sca1 mice and improved cerebellar pathology. The findings suggested a role for VEGFA in SCA1 pathogenesis and suggested that restoration of VEGFA may be a therapeutic strategy.

(文献)
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