疾患詳細

疾患詳細





#183086
Spinocerebellar ataxia 6 (SCA6)

脊髄小脳性運動失調 6 (SCA6)
指定難病18 脊髄小脳変性症(多系統萎縮症を除く)
<小児慢性特定疾病> 神53 脊髄小脳変性症

責任遺伝子:601011 Calcium channel, L type, alpha-1 polypeptide, isoform 4 (CACNL1A4) <19p13>
遺伝形式:常染色体優性

(症状)
(GARD)
 <80%-99%>
 Bradyopsia (遅視症) [HP:0030511] [06011]
 Gait ataxia (歩行失調) [HP:0002066] [028]
 Gaze-evoked horizontal nystagmus (注視誘発性水平性眼振) [HP:0007979] [06609]
 Incoordination (協調運動障害) [HP:0002311] [02605]
 Intention tremor (企図振戦) [HP:0002080] [02610]
 Postural instability (姿勢不安定) [HP:0002172] [028]
 Progressive cerebellar ataxia (進行性小脳失調) [HP:0002073] [028]
 Unsteady gait (不安定歩行) [HP:0002317] [028]
 
 <30%-79%>
 Babinski sign (バビンスキー徴候) [HP:0003487] [0213]
 Choking episodes (窒息発作) [HP:0030842] [01606]
 Diplopia (複視) [HP:0000651] [06004]
 Dysphagia (嚥下障害) [HP:0002015] [01820]
 Hyperreflexia (反射亢進) [HP:0001347] [0241]
 Vertical nystagmus (垂直眼振) [HP:0010544] [06609]
 
 <5%-29%>
 Blepharospasm (眼瞼スパスム) [HP:0000643] [06806]
 Dysarthria (構音障害) [HP:0001260] [0230]
 Migraine (偏頭痛) [HP:0002076] [014141]
 
 
 Abnormal vestibulo-ocular reflex (前庭動眼反射異常) [HP:0007670]
 Autosomal dominant inheritance (常染色体優性遺伝) [HP:0000006]
 Cerebellar atrophy (小脳萎縮) [HP:0001272] [16013]
 Gaze-evoked nystagmus (注視誘発性眼振) [HP:0000640] [06609]
 Genetic anticipation (遺伝的促進) [HP:0003743] 
 Impaired smooth pursuit (円滑な追視障害) [HP:0007772] [0695]
 Progressive (進行性) [HP:0003676]
 Sensory neuropathy (感覚ニューロパチー) [HP:0000763] [025]

(UR-DBMS)
【一般】嚥下障害
【神経】小脳失調
 構音障害
 感覚ニューロパチー (永久ではない)
 前頭葉症状
 認知症
 片麻痺性片頭痛 (一部の患者で)
 小脳 Purkinje 細胞の選択的喪失
【眼】注視誘発性眼振
 円滑性追従の障害
 前庭眼反射異常(VOR)
【X線】脊髄小脳萎縮
【その他】発症年齢20-65歳
 進行性疾患
 正常アレルは4-18リピート
 病的アレルは19-33リピート
 発現促進あり

(要約) 脊髄小脳失調症6型
●脊髄小脳失調症6型 (SCA6) は, 成人発症緩徐進行性小脳失調, 構音障害および眼振が特徴である
 平均発症年齢は 43 〜 52 歳
 初発症状は, 歩行不安定, つまづき, 平衡障害 (~90%)および構音障害 (~10%) である
 それ以後全例が, 歩行失調, 上肢協調運動障害, 企図振戦, 構音障害をもつ
 嚥下障害と窒息が多い
 視力障害は, 複視, 動く対照を固定できない, 水平性注視誘発性眼振, 垂直眼振で生じうる
 反射亢進や開扇反射が 40%-50%まで生じる
 ジストニアや眼瞼スパスムなどの基底核サインが〜25%まで小異ル
 知能は一般的に保持される
●診断:CACNA1Aのイントロン47の異常CAGリピート伸長
 正常:18リピート以下
 患者:20 〜 33 CAG リピート
●遺伝:常染色体優性
●疑わせる所見:成人発症緩徐進行性小脳失調, 構音障害および眼振
●頻度:常染色体優性SCA中スペイン/フランス 1%-2%, 中国, 米国 12% , ドイツ 13%, 日本 31%
 常染色体優性運動失調の全頻度は 1:100,000
●アレリック疾患
 優性遺伝性運動失調 (p.Gly293Arg or p.Arg1664Gln) →SCA6に類似するがより重症
 エピソード性運動失調2型 (EA2)
 家族性片麻痺性偏頭痛 (2つの臨床型あり)
  純粋 FHM (80%; 間欠期は正常)と永久的小脳症状を伴う FHM

<指定難病> 脊髄小脳変性症 (多系統萎縮症を除く)
1.概要
 脊髄小脳変性症とは, 運動失調あるいは痙性対麻痺を主症状とし, 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。遺伝性と孤発性に大別される。
 臨床的には小脳性の運動失調症候あるいは痙性対麻痺を主体とする。いずれも小脳症状のみが目立つもの(純粋小脳型)と, 小脳以外の病変, 症状が目立つもの(多系統障害型)に大別される。劣性遺伝性の一部で後索性の運動失調症候を示すものがある。同じく, 緩慢進行性の痙性対麻痺を主徴とする疾患群においては, 臨床的に痙性対麻痺を主症候とする病型(純粋型)と, 他の系統障害の症候を伴う病型(複合型)に区別される。
2.原因
 平成15年の「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)での解析結果では, 脊髄小脳変性症の67.2%が孤発性で, 27%が常染色体優性遺伝性, 1.8%が常染色体劣性遺伝性, 残りが「その他」と「痙性対麻痺」であった。
 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。残りが小脳症候のみが目立つ皮質性小脳萎縮症であり, アルコール, 薬物, 腫瘍, 炎症, 血管障害などによる2次性の小脳失調症との鑑別が重要である。
 遺伝性の場合は, 多くは優性遺伝性である。少数の常染色体劣性遺伝性, まれにX染色体遺伝性のものが存在する。このうち, 我が国で頻度が高い遺伝性脊髄小脳変性症は, SCA3(脊髄小脳失調症3型, マシャド・ジョセフ病), SCA6, SCA31, DRPLA(歯状核赤核淡蒼球萎縮症)である。
 優性遺伝性のSCA1, 2, 3, 6, 7, 17, DRPLAでは, 原因遺伝子の翻訳領域におけるCAGという3塩基の繰り返し配列が異常に伸長することにより発症する。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, 本症は異常に伸長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異常伸長を示すハンチントン病, 球脊髄性筋萎縮症と併せて, ポリグルタミン病と総称される。
 また, 優性遺伝性のSCA8, 10, 31, 36は遺伝子の非翻訳領域にある3~6塩基繰り返し配列の異常な増大によって起こる。脆弱X関連振戦/運動失調症候群(FXTAS)も同様の機序で起きる疾患で, 運動失調症を呈する。これらの疾患群は, 「非翻訳リピート病」とも呼ばれ, 繰り返し配列の部分が転写されRNAとなって病態を起こすと考えられている。
 一方, 繰り返し配列ではなく, 遺伝子の点変異や欠失などの静的変異で起きる疾患も多数同定された。優性遺伝性のSCA5, 14, 15, 劣性遺伝性の「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」などがその例である。この中に分類される疾患は多数あり, 今後も増えることが予想される。
 この他に, 発作性に運動失調症状を呈する疾患群がある。現在, 脊髄小脳変性症の研究は進んでいるが発病や進行を阻止できる根治的治療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。なお, ミトコンドリア病やプリオン病では脊髄小脳変性症と臨床診断されることがあるため注意を要する。
3.症状
 症候は失調症候を主体とするが, 付随する周辺症候は病型ごとに異なる。優性遺伝性の脊髄小脳変性症は, 症候が小脳症候に限局する型(純粋小脳型)と, パーキンソニズム, 末梢神経障害, 錐体路症候などを合併する型(多系統障害型)に臨床的に大別される。孤発性の大部分は, 前述したように多系統萎縮症であるが, 残りが純粋小脳型の皮質性小脳萎縮症である。劣性遺伝性の多くは多系統障害型であり, 後索障害を伴う場合がある。一般的に小脳症候に限局する型の方が予後は良い。またSCA6や反復発作性失調症などで, 症候の一過性の増悪と寛解を認める場合がある。SCA7は網膜黄斑変性を伴うことが多い。DRPLAの若年発症例は進行性ミオクロニー発作の病像を呈する。家族歴のない症例に対し, 遺伝子診断を行う場合は, 優性遺伝性疾患の場合は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。
4.治療法
 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, 終了後もしばらく持続する。
 薬物療法としては, 失調症状全般に甲状腺刺激ホルモン放出ホルモン(TRH)やTRH誘導体が使われる。
 疾患ごとの症状に対して対症的に使われる薬剤がある。有痛性筋痙攣に対する塩酸メキシレチン, 反復発作性の失調症状, 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, ポリグルタミン鎖又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, 現在のところ, 有効性があるものはない。
5.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。

<指定難病診断基準>
Definite, Probable を対象とする。

【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,錐体路症候,パーキンソニズム,自律神経症候,末梢神経症候,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いが,病型や時期によっては大脳基底核病変や大脳皮質の萎縮などを認めることもある。
 ⑥ 以下の原因による 2 次性脊髄小脳失調症を鑑別する:
 脳血管障害, 腫瘍, アルコール中毒, ビタミンB1・B12・葉酸欠乏, 薬剤性(フェニトインなど), 炎症[神経梅毒, 多発性硬化症, 傍腫瘍性小脳炎, 免疫介在性小脳炎(橋本脳症, シェーグレン症候群, グルテン失調症, 抗GAD抗体小脳炎)], 甲状腺機能低下症, 低セルロプラスミン血症, 脳腱黄色腫症, ミトコンドリア病, 二次性痙性対麻痺(脊柱疾患に伴うミエロパチー, 脊髄の占拠性病変に伴うミエロパチー, 多発性硬化症, 視神経脊髄炎, 脊髄炎, HTLV-I関連ミエロパチー, アルコール性ミエロパチー, 副腎ミエロニューロパチーなど。

診断のカテゴリー
 •Definite:脊髄小脳変性症・痙性対麻痺に合致する症候と経過があり, 遺伝子診断か神経病理学的診断がなされている場合。
 • Probable:
 (1)脊髄小脳変性症に合致する症候があり, 診断基準の主要項目①②⑤及び⑥を満たす場合, 若しくは痙性対麻痺に合致する症候があり, 主要項目①②及び⑥を満たす場合。
 又は
 (2)当該患者本人に脊髄小脳変性症・痙性対麻痺に合致する症状があり, かつその家系内の他の発症者と同一とみなされる場合(遺伝子診断がなされていない場合も含む。)。
 • Possible:
 脊髄小脳変性症・痙性対麻痺に合致する症候があり, 診断基準の主要項目①②⑤を満たす, 又は痙性対麻痺に合致する症候があり, 主要項目①②を満たすが, ⑥が除外できない場合。

<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
5) SCA6 (新潟大学脳研究所 生命科学リソース研究センター 他田正義,小野寺理同 神経内科 西澤正豊)
(1)発症年齢
(ア)19~71歳(平均43~52歳)
(2)臨床症状
(ア)初発症状は歩行のふらつき, 躓き, 構音障害が多い。
(イ)ほぼ純粋な小脳失調症を呈する。すなわち, 小脳性失調性歩行, 四肢の運動失調, 構音障害, 注視方向性眼振(水平性, 下眼瞼向き)を認める。
(ウ)頭位変換時のめまい感や動揺視などの症状を伴うことがある。
(エ)腱反射異常(亢進または低下), 足底反射陽性, 痙性, 深部覚低下, ジストニアなどの不随意運動, 外眼筋麻痺, 凹足変形などを伴うことがある。
(3)検査所見
(ア)頭部MRI:小脳に限局した萎縮を認める。小脳萎縮は虫部上面に強く, 半球で軽度である。脳幹や大脳は保たれる。
(4)診断方法
(ア)CACNA1A遺伝子におけるCAGリピート異常伸長の解析
(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家族歴。
(イ)発症年齢は20~66歳, 45歳前後。 
(ウ)緩徐進行性の純粋小脳失調症。ただし, 腱反射異常, 病的反射陽性, 軽度の深部感覚障害などは本疾患を否定する根拠にはならない。一方, 感覚障害, レストレスレッグ症候群, 視力異常, 筋萎縮は来しにくい。
(エ)頭位変換時のめまい感や動揺視, 下眼瞼向き眼振は本症を支持する所見。
(オ)MRIで小脳に限局した萎縮。

(Responsible gene) *601011 Calcium channel, L type, alpha-1 polypeptide, isoform 4 (CACNL1A4) <19p13.2>
(1) Migraine, familial hemiplegic, 1 (141500)
.0001 Migraine, familial hemiplegic, 1 [CACNA1A, ARG192GLN] (rs121908211) (RCV000009008) (Ophoff et al. 1996)
.0002 Migraine, familial hemiplegic, 1 (Migraine, familial hemiplegic, with progressive cerebellar ataxia) (Migraine, sporadic hemiplegic, with progressive cerebellar ataxia) [CACNA1A, THR666MET] (rs121908212) (RCV000516650...) (Ophoff et al. 1996; Ducros et al. 1999; Terwindt et al. 2002; Kors et al. 2003)
.0003 Migraine, familial hemiplegic, 1 [CACNA1A, VAL714ALA] (rs121908213) (RCV000009011) (Ophoff et al. 1996)
.0004 Migraine, familial hemiplegic, 1 [CACNA1A, ILE1811LEU] (rs121908214) (RCV000009012) (Ophoff et al. 1996)
.0010 Migraine, familial hemiplegic 1, with progressive cerebellar ataxia (Migraine, familial hemiplegic, 1) [CACNA1A, ASP715GLU] (rs121909315) (RCV000009020) (Ducros et al. 1999)
.0013 Migraine, familial hemiplegic, 1 [CACNA1A, TYR1385CYS] (rs121908219) (RCV000009022) (Vahedi et al. 2000)
.0017 Migraine, familial hemiplegic 1, with progressive cerebellar ataxia [CACNA1A, SER218LEU] (rs121908225) (RCV000502832...) (Kors et al. 2001; Chan et al. 2008)
Early Infantile Epileptic Encephalopathy 42 (617106) (the Epi4K Consortium 2016)
.0018 Migraine, familial hemiplegic, 1 (Migraine, familial hemiplegic 1, with progressive cerebellar ataxia) (Migraine, sporadic hemiplegic) [CACNA1A, ARG583GLN] (rs121908217) (gnomAD:rs121908217) (RCV000009030...) (Battistini et al. 1999; Terwindt et al. 2002)
.0019 Migraine, familial hemiplegic, 1 [CACNA1A, VAL1457LEU] (rs121908237) (RCV000009026) (Carrera et al. 1999)
.0024 Migraine, familial hemiplegic, 1 [CACNA1A, ILE1710THR] (rs121909326) (RCV000157056...) (Spinocerebellar ataxia 6) (Kors et al. 2004)
.0027 Migraine, familial hemiplegic, 1 [CACNA1A, ARG1347GLN] (rs121908230) (RCV000009039...) (Stam et al. 2008)
.0034 Migraine, familial hemiplegic, 1 [CACNA1A, 18.2-Kb DEL] (RCV000009046) (Labrum et al. 2009)
(2) Episodic ataxia, type 2 (108500)
.0005 Episodic ataxia, type 2 [CACNA1A, 1-BP DEL, 4073C] (rs587776692) (RCV000009013) (Ophoff et al. 1996)
.0006 Episodic ataxia, type 2 [CACNA1A, IVS24DS, G-A, +1] (rs587776693) (RCV000009014) (Ophoff et al. 1996)
.0008 Episodic ataxia, type 2 [CACNA1A, (CAG)n EXPANSION] (RCV000030866...) (Jodice et al. 1997)
.0011 Episodic ataxia, type 2 [CACNA1A, ARG1666HIS] (rs121908216) (RCV000009017...) (Friend et al. 1999)
.0012 Episodic ataxia, type 2 [CACNA1A, PHE1491SER] (rs121908233) (RCV000009021) (Guida et al. 2001)
.0014 Episodic ataxia, type 2 [CACNA1A, GLU1757LYS] (rs121908226) (RCV000009023) (Denier et al. 2001)
.0015 Episodic ataxia, type 2 [CACNA1A, 1-BP INS, 3091G [rs587776694] (RCV000009024) (Scoggan et al. 2001)
.0016 Episodic ataxia, type 2 [CACNA1A, 1-BP DEL, 5123G [rs587776695] (RCV000009025) (Scoggan et al. 2001)
.0020 Episodic ataxia, type 2 [CACNA1A, ARG1281TER] (rs121909323) (RCV000009031) (Yue et al. 1998; Jen et al. 2001)
.0021 Episodic ataxia, type 2 [CACNA1A, ARG1549TER] (rs121909324) (RCV000622947...) (Jen et al. 1999)
.0022 Episodic ataxia, type 2 [CACNA1A, PHE1406CYS] (rs121908227) (RCV000009033) (Jen et al. 2001)
.0023 Episodic ataxia, type 2, and absence epilepsy [CACNA1A, ARG1820TER] (rs267606696) (gnomAD:rs267606696) (RCV000009034) (Jouvenceau et al. 2001; Holtmann et al. 2002)
.0025 Episodic ataxia, type 2 [CACNA1A, CYS287TYR] (rs121908236) (RCV000009037) (Wan et al. 2005)
.0026 Episodic ataxia, type 2 [CACNA1A, 39.5-KB DEL] (RCV000009038) (Riant et al. 2008)
.0028 Episodic ataxia, type 2 [CACNA1A, 146.1-KB DEL] (RCV000009040) (Labrum et al. 2009)
.0029 Episodic ataxia, type 2 [CACNA1A, 35.7-KB DEL] (RCV000009041) (Labrum et al. 2009)
.0030 Episodic ataxia, type 2 [CACNA1A, 35.7-KB DUP] (RCV000009042) (Labrum et al. 2009)
.0031 Episodic ataxia, type 2 [CACNA1A, 7.4-KB DEL] (RCV000009043) (Labrum et al. 2009)
.0032 Episodic ataxia, type 2 [CACNA1A, 86.1-KB DEL] (RCV000009044) (Labrum et al. 2009)
.0033 Episodic ataxia, type 2 [CACNA1A, 18.2-Kb DEL] (RCV000009045)(Labrum et al. 2009)
(3) Spinocerebellar ataxia 6 (183086)
.0007 Spinocerebellar ataxia 6 [CACNA1A, (CAG)n EXPANSION] (RCV000030866...) (Zhuchenko et al. 1997; Matsuyama et al. 1997; Riess et al. 1997; Sasaki et al. 1998; Craig et al. 2008)
.0009 Spinocerebellar ataxia 6 [CACNA1A, GLY293ARG] (rs121908215) (RCV000009018...) (Yue et al. 1997; Wan et al. 2005)
(4) Epileptic encephalopathy, early infantile, 42 (617106)
.0035 Epileptic encephalopathy, early infantile, 42 [CACNA1A, GLU101GLN] (rs886037944) (RCV000240952) (the Epi4K Consortium 2016)
.0036 Epileptic encephalopathy, early infantile, 42 [CACNA1A, ALA713THR] (rs886037945) (RCV000255263...) (the Epi4K Consortium 2016)
.0037 Epileptic encephalopathy, early infantile, 42 [CACNA1A, ALA1511SER] (rs886037946) (RCV000240915) (the Epi4K Consortium 2016)

(Note)
A number sign (#) is used with this entry because spinocerebellar ataxia-6 (SCA6) is caused by heterozygous mutation in the CACNA1A gene (601011) on chromosome 19p13.

The most common mutation is an expanded CAG(n) repeat in exon 47 of the CACNA1A gene (601011.0007). Normal alleles contain 4 to 18 repeats, whereas pathogenic alleles contain 19 to 33 repeats (Li et al., 2009).

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

Clinical Features
Subramony et al. (1996) described a family segregating late-onset progressive cerebellar ataxia with onset of gait difficulties at age 50. There was no pontine atrophy at autopsy nor was there evidence of hypogonadism. The segregation appeared to be autosomal dominant with multiple instances of male-to-male transmission. Direct DNA analysis excluded expansions at the SCA1 (164400), Machado-Joseph (607047), and DRPLA (125370) loci.

Zhuchenko et al. (1997) reported 8 unrelated families who showed a very similar clinical picture consisting predominantly of mild but slowly progressive cerebellar ataxia of the limbs and gait, dysarthria, nystagmus, and mild vibratory and proprioceptive sensory loss. The disease is insidious and most patients do not realize they are affected initially but do describe a sense of momentary imbalance and 'wooziness' when they make a quick turn or a rapid movement. Typically, it is years after this initial sensation when the patients realize they have developed balance and coordination difficulties. The disease usually progresses over 20 to 30 years, leading to impairment of gait and causing the patient to become wheelchair-bound. In a few older patients, choking has been observed, suggesting involvement of the brainstem. The disease was the cause of death in several members of 2 kindreds. Magnetic resonance imaging (MRI) of the brain in affected individuals demonstrated isolated cerebellar atrophy. By genotype survey, Zhuchenko et al. (1997) found a CAG repeat expansion in the CACNA1A gene (see MOLECULAR GENETICS).

The clinical and genetic features of 38 genetically confirmed cases of SCA6 from 8 families were described by Ishikawa et al. (1997). Gait ataxia was invariably the initial symptom and was the chief symptom throughout the clinical course. Other symptoms were cerebellar speech, limb ataxia, decreased muscle tonus, and horizontal gaze nystagmus. Tendon reflexes were normal or slightly increased. Extracerebellar symptoms, such as pyramidal or extrapyramidal tract signs, ophthalmoparesis, or decreased sensation, were not seen. None of the patients complained of migraine. Magnetic resonance imaging demonstrated atrophy restricted to the cerebellum. The age at onset ranged from 20 to 66 years, and the average age at onset was 45 years.

Gomez et al. (1997) described clinical, genetic, neuroimaging, neuropathologic, and quantitative oculomotor studies in 4 kindreds with genotypically confirmed SCA6. The age of onset of ataxia ranged from 24 to 63 years among affected individuals. Radiographically and pathologically, there was selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In addition, clinical and quantitative measurement of extraocular movements demonstrated a characteristic pattern of oculomotor and vestibular abnormalities, including horizontal and vertical nystagmus and an abnormal vestibuloocular reflex. In 2 of the kindreds, they found strong linkage to the CACNL1A4 locus and strong association with the expanded (CAG)n alleles, which were a single size in the 2 kindreds (22 and 23 units). These studies identified a distinct phenotype associated with SCA6, just as SCA7 (164500) is associated with retinopathy and blindness, and SCA2 (183090) is associated with pronounced slowing or loss of saccadic eye movements. One of the families in which the expanded CAG repeat was identified was the family previously reported by Zee et al. (1976).

Schols et al. (1998) studied 9 German families with spinocerebellar ataxia-6 and found that the phenotype comprised predominantly cerebellar signs in accord with isolated cerebellar atrophy on MRI. Noncerebellar systems were only mildly affected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Disease onset ranged from 30 to 71 years of age and was significantly later than in other forms of autosomal dominant cerebellar ataxia. Although age at onset correlated inversely with CAG repeat length, other clinical signs and progression rate did not. By comparison with SCA1, SCA2, and SCA3, no clinical or electrophysiologic findings were specific for SCA6. Moreover, the molecular defect could not be predicted from clinical investigations.

Fukutake et al. (2002) described a 55-year-old man, the offspring of first-cousin parents, who presented not only with cerebellar ataxia and vertical antidirectional nystagmus but also with retinitis pigmentosa. The numbers of CAG repeats in the expanded alleles of the SCA6 gene were 21 on each chromosome. The retinal degeneration was thought to be secondary to a genetic disorder of either autosomal or X-linked recessive inheritance rather than SCA6. The association of retinitis pigmentosa with spinocerebellar ataxia is most characteristic of SCA7 (164500). Both parents had staggering gait and slurred speech late in life, but were not available for study.

In 7 SCA6 patients, van de Warrenburg et al. (2004) found no significant electrophysiologic evidence of peripheral nerve involvement.

Pathologic Findings

Tsuchiya et al. (1998) described a Japanese family with 2 affected sisters and an affected father. The proband developed gait disturbance at age 62 years and died at age 67 years due to subarachnoid hemorrhage. Neuropathologic examination showed severe loss of Purkinje cells in the cerebellum, predominantly in the dorsal vermis, and absence of neuronal loss in the inferior olives. The younger sister developed gait disturbance also at age 62 years. Neuroimaging at the age of 66 years showed cerebellar atrophy, predominantly in the vermis. Tsuchiya et al. (1998) performed a neuropathologic review of Japanese autopsy cases of autosomal dominant cortical cerebellar atrophy and found 2 patterns in the distribution of cerebellar cortical lesions. The distribution of cerebellar cortical lesions in genetically confirmed Japanese patients with SCA6 was more prominent in the vermis than in the hemisphere.

Takahashi et al. (1998) described a family with dominantly inherited ataxia of late adult onset with affected individuals in 4 generations. Expansion of a CAG repeat in the CACNA1A gene was identified at autopsy in 1 patient, a 65-year-old woman with a disease duration of 11 years. In this patient, pathologic changes were confined to the cerebellar cortex and inferior olivary complex. The cerebellar cortex showed severe loss of Purkinje cells with proliferation of Bergmann glia, more pronounced in the superior parts of the vermis and hemispheres. In the inferior olivary complex, a reduced neuronal cell population, which could be interpreted as a change secondary to the cerebellar cortical lesion, was evident. They concluded that the pathologic phenotype of SCA6 is cerebelloolivary atrophy, or more strictly cerebellar cortical atrophy.

Other Features
Soong et al. (2001) performed positron emission tomography using labeled glucose on 7 patients with SCA6 and 7 healthy controls to elucidate metabolic features of SCA6. They found significant hypometabolism in the patients with SCA6, ranging from 63 to 78% that of controls, in the brainstem, cerebellar hemisphere, basal ganglia, and various areas of the cortex. None of the patients manifested symptoms referable to the basal ganglia or cerebral cortices. Although Soong et al. (2001) postulated that the differences may be due to subclinical neuronal cell dysfunction, variation in regional blood flow, or metabolic dysfunction in structurally intact neurons, they suggested that the findings may indicate that SCA6 is not a purely cerebellar syndrome.

Christova et al. (2008) observed abnormal ocular motor anomalies in 4 presymptomatic SCA6 patients with CACNA1A mutations. Two patients had a low-amplitude horizontal gaze-evoked nystagmus, 1 of whom had a significantly decreased eye velocity for upward saccades and an abnormal frequency of square-wave jerks. Another had abnormal square-wave jerks, and a fourth had a reduced gain for pursuit tracking. Multivariate analysis discriminated the presymptomatic patients as a group from healthy controls and 5 manifesting SCA6 patients. Christova et al. (2008) suggested that early functional oculomotor impairments in SCA6 are caused by cellular dysfunction and/or loss in the posterior cerebellar vermis and flocculus.

Mapping
Ishikawa et al. (1997) carried out genomewide linkage analysis in 15 Japanese families with autosomal dominant pure cerebellar ataxia (ADPCA). Evidence for linkage to chromosome 19p markers was found in 8 families, all of whom showed expansion of a CAG repeat in the CACNA1A gene, and combined multipoint analysis refined the candidate region to a 13.3-cM interval in 19p13.2-p13.1. 6 families were excluded for this region and 1 family was inconclusive.

Pathogenesis
Expansion of repeat sequences involving the trinucleotides CAG, CTG, CGG, or GAA is the primary cause of several dominantly inherited neurologic disorders. Among them, CAG repeat expansions have been associated with Huntington disease (HD; 143100), X-linked spinobulbar muscular atrophy (313200), and several spinocerebellar ataxias. Zhuchenko et al. (1997) noted that the CAG repeat arrays in these diseases are located in the coding region of the involved gene and are translated into polyglutamine tracts in the protein product. It is postulated that an expansion of the polyglutamine tract produces a gain of function in the protein product in each disease, accounting for the dominant inheritance.

Ishikawa et al. (1999) used RT-PCR and in situ hybridization to demonstrate that the calcium channel mRNA/protein containing the CAG repeat/polyglutamine tract is most intensely expressed in Purkinje cells of normal human brains. In SCA6 brains, numerous oval or rod-shaped aggregates were seen exclusively in the cytoplasm of Purkinje cells. These cytoplasmic inclusions were not ubiquitinated, which contrasts with the neuronal intranuclear inclusions of other CAG repeat/polyglutamine diseases. In cultured cells, formation of perinuclear aggregates of the channel protein and apoptotic cell death were seen when transfected with full-length CACNA1A coding an expanded polyglutamine tract. The authors concluded that the mechanism of neurodegeneration in SCA6 is associated with cytoplasmic aggregations of the alpha-1A calcium channel protein caused by a small CAG repeat/polyglutamine expansion in CACNA1A.

Kordasiewicz et al. (2006) found that a 75-kD C-terminal fragment of CACNA1A, which is the location of the polyglutamine tract expanded in SCA6, is cleaved from the full-length protein and translocated to the nucleus, where it is toxic to cells when in the expanded state. The polyglutamine-mediated cell toxicity was dependent on nuclear localization, suggesting that specific processing and localization of the mutant protein is involved in the pathogenesis of SCA6.

Li et al. (2009) confirmed that C-terminal fragments of CACNA1A localized predominantly to the nucleus of HEK293 cells where they existed as speckle-like structures resembling promyelocytic leukemia nuclear bodies (PMLNBs). HEK293 cells expressing an expanded (24 CAG repeats) C-terminal end of CACNA1A showed decreased viability when exposed to toxic cadmium compared to cells with nonexpanded (13 CAG) repeats. However, there were no differences in viability under normal culture conditions. Cadmium treatment also disrupted the PMLNBs and enhanced aggregation of C-terminal CACNA1A fragments, particularly in CAG-expanded cells. Immunocytochemical studies showed that cadmium-induced death was caspase-3 (CASP3; 600636)-dependent, indicating apoptosis. Gene expression studies showed downregulation of the HSF1 (140580)-HSPA1A (140550) axis as an event in 24-CAG repeat cells that appeared to be critical for cellular toxicity. The findings were consistent with SCA6 pathogenesis being related to polyglutamine diseases.

Molecular Genetics
Zhuchenko et al. (1997) performed a genotyping survey using polymorphic CAG repeats and DNA samples from patients with late-onset neurogenic diseases. In the course of these studies they found an expansion of a CAG repeat in the human alpha-1A-voltage-dependent Ca(2+) channel gene (601011.0007), which maps to 19p13. They identified 6 isoforms of the human alpha-1A calcium channel subunit. The CAG repeat was within the open reading frame and was predicted to encode glutamine in 3 of the isoforms. In 8 families, the CAG repeat expansion of the Ca(2+) channel gene was the mutation mechanism for SCA6. One of the families had been reported by Subramony et al. (1996).

Analysis of CAG repeat expansion in the CACNL1A4 gene by Ishikawa et al. (1997) revealed expansion in 8 of 15 Japanese families with autosomal dominant cerebellar ataxia; all affected individuals had larger alleles (range of CAG repeats 21 to 25), compared with alleles observed in neurologically normal Japanese (range 5 to 20 repeats).

Takiyama et al. (1998) studied a Japanese family that included 13 persons with SCA6 in 5 generations. Molecular testing revealed that the patients carried the smallest known expanded CAG repeat (21 repeat units). The clinical features of these patients included predominantly cerebellar ataxia with onset late in adult life and a very slowly progressive course. In addition, this SCA6 family showed some characteristic clinical and genetic features, including (1) apparent lack of genetic anticipation, with an intergenerationally stable CAG repeat size, and (2) down-beat nystagmus and diabetes mellitus in some of the SCA6 patients. They identified 3 individuals homozygous for an expanded CAG repeat (21/21) in the CACNL1A4 gene; 2 were symptomatic and 1 was asymptomatic at age 50 years. There was no apparent difference in clinical phenotype between the homozygotes and the heterozygotes.

Fukutake et al. (2002) stated that 11 patients with genetically verified SCA6 who were homozygous or compound heterozygous for (CAG)n repeats in the CACNA1A gene (601011.0007) had previously been reported.

In a family in which multiple members had severe progressive cerebellar ataxia involving the trunk, extremities, and speech, Yue et al. (1997) identified a 1152G-A transition in exon 6 of the CACNA1A gene, resulting in a gly293-to-arg substitution (G293R; 601011.0009). The CAG(n) repeat expansion associated with SCA6 was not present in any family member.

In a large Portuguese family in which 17 patients over 4 generations were affected with hemiplegic migraine and/or progressive SCA6, Alonso et al. (2003) found that all patients shared a common haplotype and carried an arg583-to-gln mutation in the CACNA1A gene (R583Q; 601011.0018).

Genetic Anticipation

In his studies of families with SCA6, Zhuchenko et al. (1997) noted that there seemed to be a correlation between the repeat number and earlier onset of the disorder. Matsuyama et al. (1997) analyzed 60 SCA6 individuals from 39 independent Japanese SCA6 families and found that the CAG repeat length in the CACNL1A4 gene was inversely correlated with age of onset. SCA6 chromosomes contained 21 to 30 repeat units, whereas normal chromosomes displayed 6 to 17 repeats. There was no overlap between the normal and affected CAG repeat number. Anticipation was observed clinically in all 8 parent-child pairs examined; the mean age of onset was significantly lower (P = 0.0042) in children than in parents. However, a parent-child analysis showed an increase in the expansion of CAG repeats only in 1 pair and no diminution in any affected cases. The results suggested that factors other than CAG repeats may produce the clinical anticipation. A homozygotic case could not demonstrate unequivocal gene dosage effect on the age of onset.

In the 8 families with SCA6 reported by Ishikawa et al. (1997), inverse correlation between the CAG-repeat number and the age of onset was found in affected individuals with expansion. The number of CAG repeats in expanded chromosomes was completely stable within each family, which was consistent with the fact that anticipation was not statistically proven in these SCA6 families.

Riess et al. (1997) observed the trinucleotide expansion in 4 ataxia patients without obvious family history of the disease, indicating the necessity to search for the SCA6 (CAG)n expansion even in sporadic patients. In their series of 32 patients, onset was usually late and the (CAG)n stretch varied between 22 and 28 trinucleotide units, the shortest trinucleotide repeat expansion causing spinocerebellar ataxia. Analyzing 248 apparently healthy octogenarians, Riess et al. (1997) found 1 allele of 18 repeats, the longest normal CAG repeat in the CACNL1A4 gene reported to that time. They could demonstrate no repeat instability of the expanded allele on transmission and no repeat instability was found for the normal allele in 431 meioses in the CEPH families.

Mariotti et al. (2001) described an Italian family in which 1 member carried a fully expanded SCA6 allele with 26 CAG repeats, whereas the other affected family member was homozygous for an intermediate allele of 19 CAG repeats. Three family members, heterozygous for the intermediate allele, were clinically unaffected. The findings demonstrated a dose-dependent pathogenic effect of an intermediate CAG expansion in the SCA6 gene.

Takahashi et al. (2004) retrospectively analyzed 140 patients with SCA6. They observed an inverse correlation between the age at onset and the length of the expanded allele, and also between the age at onset and the sum of CAG repeats in the normal and the expanded alleles. The ages at onset of 4 homozygous patients correlated better with the sum of CAG repeats in both alleles than with the expanded allele calculated from heterozygous SCA6 patients. Clinically, unsteadiness of gait was the main initial symptom, followed by vertigo and oscillopsia, and cerebellar signs were detected in nearly 100% of the patients. In contrast, extracerebellar signs were relatively mild and infrequent. Neuro-otologic examination performed in 22 patients suggested that the abnormalities of ocular movements were purely cerebellar in nature. There was a close relationship between down-beat positioning nystagmus and positioning vertigo, which became more common in the later stage. Takahashi et al. (2004) concluded that total number of CAG repeat units in both alleles is a good parameter for assessment of age at onset in SCA6, including in homozygous patients. In addition, clinical and neuro-otologic examination suggested that SCA6 is a disease with predominantly cerebellar dysfunction.

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.

Genotype/Phenotype Correlations
Schols et al. (1997) compared clinical, electrophysiologic, and MRI findings to identify phenotypic characteristics of genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and action tremor suggested SCA2. SCA3 (109150) 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 (164400) 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 among the 4 SCA subtypes was broad, however.

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.

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.

Heterogeneity
In a family initially classified as autosomal dominant cerebellar ataxia of unknown type, Jodice et al. (1997) found an intergenerational allele size change in the CACNA1A gene, showing that a (CAG)20 allele (601011.0008) was associated with the phenotype of episodic ataxia type 2 (EA2; 108500) and a (CAG)25 allele with progressive cerebellar ataxia. These results suggested that EA2 and SCA6 are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggested that the small expansions may not be as stable as previously reported.

Sinke et al. (2001) described a study of 24 Dutch families with SCA6. Clinical analysis identified SCA6 as a late-onset ataxia in which eye movement abnormalities are prominent and consistent early manifestations. Some patients had ataxia combined with episodic headaches or nausea, suggesting an overlap among SCA6, episodic ataxia type 2, and familial hemiplegic migraine (141500).

In a large Portuguese family in which 17 patients over 4 generations were affected with hemiplegic migraine and/or progressive SCA6, Alonso et al. (2003) found that all patients shared a common haplotype and carried an arg583-to-gln mutation in the CACNA1A gene (R583Q; 601011.0018). Four patients, all under the age of 18 years, had only hemiplegic migraine, 8 patients had isolated progressive cerebellar ataxia, and 5 patients had both hemiplegic migraine and cerebellar ataxia. Several patients reported symptoms triggered by minor head trauma. Alonso et al. (2003) suggested that EA2, SCA6, and familial hemiplegic migraine are not only allelic disorders, but may be the same disorder with great phenotypic variability.

Population Genetics
Riess et al. (1997) found that the SCA6 mutation accounts for approximately 10% of autosomal dominant SCA 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. Schols et al. (1998) investigated the SCA6 mutation (expanded repeat in the CACNA1A gene) in 69 German families with autosomal dominant cerebellar ataxia and 61 patients with idiopathic sporadic cerebellar ataxia. The expanded CAG repeat was found in 9 of 69 families, as well as in 4 patients with sporadic disease. Schols et al. (1998) noted that in Germany, SCA6 accounts for about 13% of families with autosomal dominant cerebellar ataxia. However, up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadic disease due to late manifestation in apparently healthy parents. Genetic testing was therefore recommended for the SCA6 mutation also in patients with putative sporadic ataxia. In a study of apparently idiopathic sporadic cerebellar ataxia involving 124 patients, Schols et al. (2000) found the SCA6 mutation in 9 patients with disease onset between 47 and 68 years of age.

Using an intragenic marker, D19S1150, and 2 markers (DS19S221 and DS19S226) bracketing 3 cM on either side, Dichgans et al. (1999) found a common haplotype in 7 of 12 German families segregating SCA6. This finding, as well as a clustering of the families from Northrhine-Westfalia, strongly suggests a founder effect.

From their study of 15 families with autosomal dominant cerebellar ataxia, Ishikawa et al. (1997) concluded that more than half of Japanese cases of ADPCA map to 19p and are strongly associated with a mild CAG expansion in the SCA6/CACNL1A4 gene.

Watanabe et al. (1998) investigated 101 kindreds with spinocerebellar ataxias from the central Honshu island of Japan, using a molecular diagnostic approach with amplification of the CAG trinucleotide repeat of the causative genes. Machado-Joseph disease (109150) was the most prevalent (33.7%) form, followed by dentatorubral-pallidoluysian atrophy (125370; 19.8%), SCA6 (5.9%), and SCA2 (5.9%). All 7 SCA6 patients had expanded alleles of the CACNL1A4 gene and signs of a pure cerebellar syndrome.

Among 202 Japanese and 177 Caucasian families with autosomal dominant SCA, Takano et al. (1998) found that the prevalence of SCA6 was significantly higher in the Japanese population (11%) compared to Caucasian population (5%). This corresponded to higher frequencies of large normal CACNA1A CAG repeat alleles (greater than 13 repeats) in Japanese controls compared to Caucasian controls. The findings suggested that large normal alleles contribute to the generation of expanded alleles that lead to dominant SCA.

Yabe et al. (2001) studied 21 Japanese families with SCA6 and found one of 2 haplotypes in each family. They suggested a mechanism by which the second haplotype could have arisen from a single common haplotype, and that therefore there was evidence of a founder effect in SCA6 families in Japan.

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.

Sinke et al. (2001) determined that SCA6 accounted for approximately 11% of all Dutch families with autosomal dominant cerebellar ataxia.

Among 74 Taiwanese families with autosomal dominant cerebellar ataxia and 49 Taiwanese patients with sporadic ataxia, Soong et al. (2001) determined that SCA6 accounted for 10.8% of the familial cases and 4.1% of the sporadic cases. The prevalence of SCA3 was 47.3%, followed by SCA2 (10.8%), SCA1 (5.4%), SCA7 (2.7%), and DRPLA (1.4%). In the families with SCA6, there was significant anticipation in the absence of genetic instability. The same allele of intragenic marker D19S1150 was found in 70% of the SCA6 patients, suggesting a founder effect.

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.

By haplotype analysis of 12 Dutch SCA6 families confirmed by genotype, Verbeek et al. (2004) found that 8 families (approximately 70%) shared a region between markers D19S1165 and D19S840, including the SCA6 gene, which was not observed in 80 control chromosomes. Two additional SCA6 families shared an extended haplotype. Genealogic research showed that most of the families were clustered in North Holland. The authors noted that mutation in the SCA6 gene occurs in 23.4% of the Dutch autosomal dominant cerebellar ataxia population. Similar haplotype results were found for SCA3.

In a population-based study in Northeastern England, Craig et al. (2004) estimated that the number of people with or at risk for SCA6 was at least 5.21/100,000, or 1 in 19,210. Haplotype analysis suggested a founder effect, and 56% of affected individuals had an identical CAG repeat length (21 repeats). The clinical phenotype of this group was homogeneous.

Shimizu et al. (2004) estimated the prevalence of SCA in the Nagano prefecture of Japan to be at least 22 per 100,000. Thirty-one of 86 families (36%) were positive for SCA disease-causing repeat expansions: SCA6 was the most common form (19%), followed by DRPLA (10%), SCA3 (3%), SCA1 (2%), and SCA2 (1%). The authors noted that the prevalence of SCA3 was lower compared to other regions in Japan, and that the number of genetically undetermined SCA families in Nagano was much higher than in other regions. Nagano is the central district of the main island of Japan, located in a mountainous area surrounded by the Japanese Alps. The restricted geography suggested that founder effects may have contributed to the high frequency of genetically undetermined ADCA 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 (117210), and 1 (1%) had SCA14 (605361). The specific disorder could not be identified in 16 (14%) families.

Craig et al. (2008) identified a common core haplotype carrying the CACNA1A CAG repeat in 45 SCA6 families from different geographic regions, including Europe, Brazil, and Japan. The haplotype was also present in the unaffected father of a proven de novo Japanese patient, suggesting that the shared chromosome predisposes to the CAG repeat expansion at the SCA6 locus. The SCA6 expansion lies immediately downstream of a CpG island, which could act as a cis-acting element predisposing to repeat expansion, as observed for other CAG/CTG repeat diseases.

Animal Model
Watase et al. (2008) found that knockin mice expressing a hyperexpanded polyglutamine (84Q) Cacna1a repeat developed progressive motor impairment consistent with SCA6. Knockin mice with normal 14 CAG or expanded 30 CAG repeats did not show such defects. Electrophysiologic analysis of cerebellar Purkinje cells revealed similar calcium channel current density among the 3 mouse models, although all were decreased compared to wildtype due to decreased channel abundance. Neither voltage sensitivity of activation nor inactivation was altered in the Sca6(84Q) neurons, suggesting that the expanded CAG repeat does not per se affect the intrinsic electrophysiologic properties of the channels. Mice with the hyperexpanded polyglutamine repeat showed cytoplasmic neuronal inclusions, consistent with aggregation of mutant calcium channels. Watase et al. (2008) concluded that the pathogenesis of SCA6 is related to an age-dependent process accompanied by accumulation of mutant CACNA1A channels resulting in a toxic gain-of-function effect.

(文献)
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