Spinocerebellar ataxia 2 (SCA2)
(Spinocerebellar atrophy II)
(Olivopontocerebellar atrophy, Holguin type)
(Olivopontocerebellar atrophy II; OPCA2)
(Spinocerebellar ataxia, Cuban type)
(Cerebellar degeneration with slow eye movements)
(Spinocerebellar degeneration with slow eye movements; SDSEM)
(Amyotrophic lateral sclerosis, susceptibility to, 13; ALS13, included)
(オリーブ核橋小脳萎縮症, Holguin 型)
(オリーブ核橋小脳萎縮症, II 型)
小児慢性特定疾病 神53 脊髄小脳変性症
責任遺伝子：601517 Ataxin-2 (ATXN2) <12q24.12>
Abnormality of the substantia nigra (黒質異常) [HP:0045007] 
Progressive cerebellar ataxia (進行性小脳失調) [HP:0002073] 
Abnormal cell morphology (細胞形態異常) [HP:0025461]
Abnormality of the spinocerebellar tracts (脊髄小脳路異常) [HP:0003133]  
Cerebellar Purkinje layer atrophy (小脳 Purkinje 層萎縮) [HP:0012082] 
Chorea (舞踏病) [HP:0002072] 
Dementia (認知症) [HP:0000726] 
Dysarthria (構音障害) [HP:0001260] 
Dystonia (ジストニア) [HP:0001332] 
Fasciculations (攣縮) [HP:0002380] 
Gait ataxia (歩行失調) [HP:0002066] 
Generalized hypotonia (全身性筋緊張低下) [HP:0001290] 
Hyporeflexia (低反射) [HP:0001265] 
Kinetic tremor (運動性振戦) [HP:0030186] 
Muscle spasm (筋スパスム) [HP:0003394] 
Nystagmus (眼振) [HP:0000639] 
Olivopontocerebellar hypoplasia (オリーブ核橋小脳低形成) [HP:0006955]   
Postural tremor (姿勢振戦) [HP:0002174] 
Slow saccadic eye movements (遅い衝動性眼球運動) [HP:0000514] 
Spinal cord posterior columns myelin loss (脊髄後柱ミエリン喪失) [HP:0008311] 
Supranuclear ophthalmoplegia (核上性眼球運動麻痺) [HP:0000623] 
Abnormal cortical gyration (異常な皮質脳回) [HP:0002536] 
Cerebral cortical atrophy (大脳皮質萎縮) [HP:0002120] 
Cerebral white matter atrophy (大脳白質萎縮) [HP:0012762] 
Hyperactive deep tendon reflexes (深部腱反射亢進) [HP:0006801] 
Parkinsonism (パーキンソニズム) [HP:0001300] 
Autosomal dominant inheritance (常染色体優性遺伝) [HP:0000006]
Bradykinesia (寡動) [HP:0002067] 
Dilated fourth ventricle (第4脳室拡大) [HP:0002198] 
Distal amyotrophy (遠位筋萎縮) [HP:0003693] 
Dysdiadochokinesis (ジスジアドコキネーゼ) [HP:0002075] 
Dysmetria (ジスメトリア) [HP:0001310] 
Dysmetric saccades (ジスメトリア性サッカード) [HP:0000641] 
Dysphagia (嚥下障害) [HP:0002015] 
Gaze-evoked nystagmus (注視誘発性眼振) [HP:0000640] 
Genetic anticipation (遺伝的促進) [HP:0003743]
Impaired horizontal smooth pursuit (水平のスムーズな追視障害) [HP:0001151] 
Impaired vibratory sensation (振動覚障害) [HP:0002495] 
Limb ataxia (四肢運動失調) [HP:0002070] 
Muscular hypotonia (筋緊張低下) [HP:0001252] 
Myoclonus (ミオクローヌス) [HP:0001336] 
Oculomotor apraxia (眼球運動失行) [HP:0000657] 
Olivopontocerebellar atrophy (オリーブ核橋小脳萎縮) [HP:0002542]   
Ophthalmoplegia (眼球運動麻痺) [HP:0000602] 
Postural instability (姿勢不安定) [HP:0002172] 
Rigidity (固縮) [HP:0002063] 
Rod-cone dystrophy (杆体-錐体ジストロフィー) [HP:0000510] 
Spasticity (痙縮) [HP:0001257] 
Spinocerebellar tract degeneration (脊髄小脳路変性) [HP:0002503]
Urinary bladder sphincter dysfunction (膀胱括約筋機能障害) [HP:0002839] 
キューバの Holguin 州に多い
(要約) 脊髄小脳失調症2型 (SCA2)
●脊髄小脳失調症1型 (SCA2) は．眼振, 緩徐な断続的眼球運動, 一部の患者では眼球運動不全麻痺またはパーキンソン症候群を含む, 進行性小脳失調が特徴である
●診断：ATXN2 遺伝子の異常な CAG 伸長の検出による
正常：30以下 CAG トリヌクレオチドリピート
患者→33以上の CAG リピートをもつ (30/39リピートが最も多い; 200以上の報告もある)
●遺伝子診断された患者：運動失調やサッケード眼球運動以外に, ジストニアまたは舞踏病 (38%)や痴呆症 (37%)がみられた
ジストニア, ミオクローヌス, ミオキミアをもつ患者ではCAGリピートサイズが大きい
●頻度：UCLAの常染色体優性小脳失調症で SCA2 13%, SCA1 (6%), SCA3
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。
●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)
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
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。
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。
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。
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。
Probable MSA, Definite MSA を対象とする。
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。
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。
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
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。）
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。
国際的 Consensus criteria による分類
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。）。
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
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。
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。
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。
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。
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。
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。
2) SCA2 (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)
（ア） 3成年期の発症が多いが, CAG伸長数により発症年齢はさまざまである。
② dystonia, myoclonus, tremor (進行期やCAG伸長数の長い症例)
③ fasciculation, myokymia (進行期やCAG伸長数の長い症例)
④ 認知機能の低下 (中等度)
注）20才以前の若年発症者（CAG repeat>45）では, 症状の進行が早い傾向がある。
（イ）電気生理検査: sensory ganglionopathy
（補） Aaxin-2における 27?33 repeat のCAG反復配列（intermediate-length）は, 孤発性のALSの発症リスク因子として報告されている。
（エ）他の脊髄小脳変性症（SCA1, SCA3等）との症候の相同性があり, 臨床症候のみで本症を診断することは困難である。
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。
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）
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。
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。
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
●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
オリジナルは Joseph Jules Dejerine と André Thomas (1900) である
OPCA type 2 (258300) Fickler-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
散発例→ 現在は multiple system atrophy 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
(Responsible gene) *601517 Ataxin-2 (ATXN2) <12q24.12>
.0001 Spinocerebellar ataxia 2 (183090) (Parkinson disease, late-onset, susceptibility to, included) [ATXN2, (CAG)n expansion, long] (RCV000055892...) (Pulst et al. 1996; Sanpei et al. 1996)
Susceptibility to Late-Onset Parkinson Disease (Gwinn-Hardy et al. 2000; Charles et al. 2007)
.0002 Amyotrophic lateral sclerosis, susceptibility to, 13 (183090) [ATXN2, (CAG)n expansion, intermediate] (RCV000008583) (Elden et al. 2010; Daoud et al. 2011; Van Damme et al. 2011; Corrado et al. 2011; Ross et al. 2011)
A number sign (#) is used with this entry because spinocerebellar ataxia-2 is caused by an expanded (CAG)n trinucleotide repeat in the gene encoding ataxin-2 (ATXN2; 601517). Unaffected individuals have 13 to 31 CAG repeats, whereas affected individuals have 32 to 79 repeats, with some in the range of 500 repeats (summary by Almaguer-Mederosa et al., 2010).
There is also an association between 29 or more CAG repeats and the development of amyotrophic lateral sclerosis-13 (ALS13). For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of disorders that were classified clinically by Harding (1983). Progressive cerebellar ataxia is the primary feature. In ADCA I, cerebellar ataxia of gait and limbs is invariably associated with supranuclear ophthalmoplegia, pyramidal or extrapyramidal signs, mild dementia, and peripheral neuropathy. In ADCA II, macular and retinal degeneration are added to the features. ADCA III is a pure form of late-onset cerebellar ataxia. ADCA I includes SCA1 (164400), SCA2, and SCA3, or Machado-Joseph disease (109150). These 3 are characterized at the molecular level by CAG repeat expansions on 6p24-p23, 12q24.1, and 14q32.1, respectively.
For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Boller and Segarra (1969) reported the clinical and postmortem findings in a father (E.W.) and son (R.W.) with adult-onset ataxia. The pedigree of the 'W' family, extending through 5 generations, indicated autosomal dominant inheritance. Pogacar et al. (1978) reported 2 additional affected members of the family, R.W.'s daughter (S.W.), and a third cousin who was studied postmortem. Boller and Segarra (1969) had described the condition under the designation 'spinopontine degeneration.' When the family (of Anglo-Saxon extraction living in northern Rhode Island for over 300 years) was followed up by Pogacar et al. (1978), they questioned the separation from olivopontocerebellar ataxia (OPCA), because they found abolished tendon reflexes and flexion contractures of the legs in 1 patient, and onset at 18 years of age, palatal myoclonus, and optic atrophy in the second. Dementia developed in both. Pathologic findings, in contrast to earlier reports, showed involvement of the cerebellum and inferior olivary nuclei. Lazzarini et al. (1992) encountered a large, previously unreported branch of the 'W' family that shared a common ancestor 8 generations removed from the patients reported by Boller and Segarra (1969). Although phenotypically the disorder was similar to that in families with spinocerebellar ataxia-1, the disorder was not linked to HLA on chromosome 6p.
Wadia and Swami (1971) reported the association of spinocerebellar degeneration and abnormal eye movements, specifically, absent rapid saccades and abnormally slow tracking. They described 37 patients in 12 families in India. Some of the patients were 'mentally backward.' Starkman et al. (1972) described the syndrome in a U.S. family. Whyte and Dekaban (1976) described a family with cerebellar degeneration and slow pursuit without nystagmus. Age at onset ranged from 10 to 31 years with earlier onset in successive generations, and a rapidly progressive course. Three individuals showed progressive mental deterioration. The proband had nevus of Ota, which was considered to be unrelated. Whyte and Dekaban (1976) suggested that the eye signs were due to a brainstem lesion of the paramedian pontine reticular formation. They noted that it may be the most frequent form of spinocerebellar degeneration in India. See 271322 for a possible recessive form of the Wadia-Swami syndrome.
Wadia et al. (1998) reported reevaluation and genetic analysis of 6 Indian pedigrees with autosomal dominant spinocerebellar ataxia, some of whom had been reported by Wadia and Swami (1971). Genetic analysis confirmed SCA2. Saccadic velocity was reduced even in early stages of the disease, and the authors emphasized that it was an important diagnostic feature.
Eto et al. (1990) described a family of German extraction with progressive ataxia, eye movement abnormalities, peripheral sensory loss, and spinal muscular atrophy of adult onset. The pedigree pattern in 4 generations was consistent with autosomal dominant inheritance. Eto et al. (1990) suggested that the form of spinopontine atrophy might be different from Machado-Joseph disease (SCA3): the eyes were not protuberant, extraocular movements were abnormal to a minor degree, and neuropathologically the substantia nigra and dentate nucleus were spared. Eto et al. (1990) considered their family to resemble most that reported by Boller and Segarra (1969).
Bale et al. (1987) studied a 3-generation kindred in which several persons had dominantly inherited spinopontine atrophy. Linkage analysis gave negative lod scores with both HLA and GLO1. Bale et al. (1987) also reviewed 4 published kindreds with adequate clinical and neuropathologic descriptions in addition to HLA linkage studies. Persons in the 3 families showing evidence for HLA linkage had clinical and pathologic changes consistent with OPCA type 1. The conditions in the 2 'unlinked' families were phenotypically distinct with respect to extraocular movements and peripheral sensory nervous system signs. They differed markedly from each other in neuropathologic changes.
Auburger et al. (1990) could find no evidence of linkage to HLA in over 100 affected members of a Cuban kindred of Spanish ancestry, first reported by Orozco et al. (1989). The diagnosis of spinocerebellar ataxia was confirmed at autopsy in 11 cases. Points of differentiation from Machado-Joseph disease (SCA3), including absence of the limitation of upward gaze, were outlined. The origins of the family group in Spain could not be traced. Age of onset varied from 2 to 65 years, with 40% of patients presenting before 25 years of age. Optic atrophy, retinopathy, dementia, spasticity, and rigidity were not part of the phenotype. Auburger et al. (1990) stated that 'the 300 patients already receiving medical attention constitute a severe problem for the regional health authorities in Holguin.'
Spadaro et al. (1992) were unable to demonstrate linkage to HLA on chromosome 6 in 3 of 5 Italian families with late-onset autosomal dominant SCA. They reported clinical studies of 26 patients and neuropathologic study of 1. The disease was characterized by cerebellar and pyramidal involvement, variably associated with cranial nerve and peripheral nervous system disorders. MRI of a 53-year-old man with symptoms for 7 years showed marked atrophy of the cerebellar hemispheres and vermis as well as of the pons and medulla oblongata.
Ueyama et al. (1998) studied 2 Japanese kindreds with spinocerebellar ataxia-2, for a total of 25 patients, 19 patients in 1 family and 6 patients in the other. Thirteen patients were fully evaluated, including a neurologic evaluation. The mean age of onset of symptoms was 43.5 years. The most common neurologic finding was cerebellar ataxia with deep sensory disturbance. Slow saccades were found only in patients younger than age 35 years. Brain MRI showed pontocerebellar atrophy, and PCR analysis showed that all patients had an expanded CAG allele in the ataxin-2 gene.
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 patients frequently developed diplopia, severe spasticity or pronounced peripheral neuropathy, and impaired temperature discrimination, apart from ataxia. SCA6 (183086) 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.
Giuffrida et al. (1999) performed brain MRI on 20 SCA2 patients, from 11 Sicilian families, and 20 age-matched control subjects. The findings confirmed that olivopontocerebellar atrophy is a typical pattern in SCA2. No significant correlation was found between infratentorial atrophy, disease duration, or the number of CAG repeats, but there was a significant correlation between supratentorial atrophy, which was found in 12 patients, and disease duration. OPCA appeared to represent the 'core' abnormality of SCA2; however, central nervous system involvement was not limited to pontocerebellar structures. Giuffrida et al. (1999) concluded that central nervous system degeneration in SCA2 is a widespread atrophy.
In 19 of 27 (70%) patients with confirmed SCA types 1, 2, 3, 6, or 7 (164500), 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. All 3 patients with SCA2 had a neuronopathy.
Velazquez-Perez et al. (2004) found that maximal horizontal saccade velocity (MSV) was significantly decreased in 82 SCA2 patients compared to controls (60-degree MSV range of 17 to 464 degrees per second and 277 to 678 degree per second, respectively). MSV was negatively correlated with polyglutamine expansion size and ataxia score; ataxia score was positively correlated with disease duration, and less so with polyglutamine expansion. Slowing of MSV was detected as early as 1 year after onset of ataxia. Velazquez-Perez et al. (2004) concluded that MSV is a sensitive and specific endophenotype useful for the identification of modifier genes in SCA2.
Using high-resolution volumetric MRI to examine 8 SCA2 patients, Ying et al. (2006) found a significant correlation between region-specific cerebellar and pontine atrophy and a global measure of clinical dysfunction. Atrophy was also highly correlated with disease duration.
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.
Babovic-Vuksanovic et al. (1998) reported an infant who presented with neonatal hypotonia, developmental delay, and dysphagia. Ocular findings of retinitis pigmentosa (RP) were noted at 10 months of age. Her father had mild SCA2 first noted at 22 years of age. Molecular studies showed that the father had a SCA2 CAG repeat expansion of 43 repeats, whereas the baby had an extreme expansion of more than 200 repeats. Babovic-Vuksanovic et al. (1998) noted the variable phenotype and genotype of SCA2.
Moretti et al. (2004) reported a Mexican-American child who developed abnormal eye movements at 2 months of age. Motor and language development were delayed. At age 6 years, poor coordination, arm tremor, and cognitive deficits were noted. The clinical course slowly progressed, and he had difficulty walking, incontinence, drooling, and worsening tremor by age 9 years. MRI showed cerebellar atrophy and mild cerebral atrophy, and mutation analysis identified a 62 CAG repeat expansion of the ATXN2 gene. Moretti et al. (2004) emphasized that SCA2 can have rare infantile or childhood onset, that earlier onset is associated with a higher number of CAG repeats, and that the SCA2 phenotype is clinically heterogeneous.
Vinther-Jensen et al. (2013) reported a family in which a father was diagnosed with SCA2 at age 49 years, after which it was discovered that his daughter, who had died 13 years earlier of multiorgan failure at age 19 months, had had infantile-onset SCA2. The father presented with classic adult-onset progressive SCA2, including gait ataxia, imbalance, dysarthria, fasciculations, abnormal saccades, and mild cognitive impairment. Brain MRI showed cerebellar atrophy. The daughter presented at age 3 months with delayed motor development, myoclonic jerks, and visual impairment. She later showed uncoordinated eye movements, pallor of the optic nerves, dystrophic retinas, poor head control, hypotonia, and dyskinetic movements. Molecular genetic analysis showed that the father carried an expanded ATXN2 allele of 45 CAG repeats, and the daughter carried an expanded allele of 124 repeats inherited from the father. Analysis of the father's spermatozoa showed that 4 (22%) had an expansion beyond the 45 CAG repeats detected in somatic cells, including 2 with repeat lengths of at least 92 and 116, respectively. Study of spermatozoa from another man with SCA2 showed similar meiotic instability of the expanded repeat allele. Vinther-Jensen et al. (2013) suggested that meiotic instability may be a general feature of SCA2, and noted that rare genetic disorders should be considered during diagnosis of infants and children even without a family history of a neurodegenerative disorder.
Gwinn-Hardy et al. (2000) described 4 patients from a Chinese kindred with parkinsonian features and CAG expansions at the SCA2 locus. The youngest patient had findings typical for the SCA2 ataxic phenotype with decreased saccadic velocity, limb and truncal ataxia, and a subclinical sensory neuropathy, but also had parkinsonian features such as markedly reduced blink rate, bradykinesia, and asymmetry. His SCA2 CAG repeat length was 43. Three patients from earlier generations had mildly elevated CAG repeat lengths of 33 to 36 with varying phenotypes, but all predominantly parkinsonian features, including masked facies, diminished blink rate, and bradykinesia in addition to mild cerebellar findings such as broad-based gait. Two benefited from carbidopa-levodopa therapy, reminiscent of typical late-onset Parkinson disease (PD; 168600). The third patient, with a phenotype reminiscent of progressive supranuclear palsy, did not show a response to treatment. None of the patients had cognitive disturbance or resting tremor. The authors suggested that some cases of familial parkinsonism may be due to SCA2 mutations.
Among 23 Chinese patients with familial parkinsonism, Shan et al. (2001) identified 2 patients who had expanded trinucleotide repeats (mildly elevated at 36 and 37 repeats) in the ATXN2 gene. Both patients had onset of leg tremor at age 50 years, followed by gait difficulty, rigidity, and slow, hypometric saccades. L-dopa produced marked improvement in symptoms in both patients. In addition, PET scan showed reduced dopamine distribution in the caudate and putamen in both patients. Shan et al. (2001) noted that these 2 patients represented approximately one-tenth of their population with familial parkinsonism.
In commenting on the paper by Shan et al. (2001), Kock et al. (2002) stated that in a study of 270 unrelated patients of mixed ethnic background with dopa-responsive parkinsonism, including 64 cases of early onset (age of onset less than 50 years) with a family history, 174 cases of early onset with no family history, and 32 cases of late onset with a family history, they found no expanded SCA2 alleles. Parkin (PARK2; 602544) mutations were found in 31 (18%) of 173 screened early-onset patients. In a reply, Shan and Soong (2002) suggested that SCA2-related parkinsonism is more likely to be found in late-onset cases, which tend to have lower numbers of repeats, and likely accounts for no more than one-tenth of familial parkinsonism.
Furtado et al. (2002) reported a family in which 10 members over 5 generations were affected with dopa-responsive parkinsonism, without cerebellar abnormalities, transmitted in an autosomal dominant pattern. Average age of onset was 59 years (range, 31 to 86). Three patients exhibited dystonia. Genetic analysis showed identical expanded repeats for SCA2 in all affected individuals tested (22 and 39 repeats on each allele), which were stable between generations despite a clinical suggestion of anticipation. Furtado et al. (2002) emphasized that the genetic findings were unexpected because the family's presentation was consistent with typical cases of Parkinson disease (168600).
Lu et al. (2004) stated that the normal range of SCA2 CAG repeats is 14 to 31, and that it ranges from 34 to more than 200 in affected patients. A range of 32 to 33 repeats is considered indeterminate. In 7 Taiwanese patients from 4 families with parkinsonism (representing approximately 10% of the initial group), Lu et al. (2004) found expanded CAG repeats in the ATXN2 gene. The phenotype was characterized by tremor, rigidity, and bradykinesia, and response to L-dopa. A control group of 8 patients from 6 families had the ataxic SCA2 phenotype, characterized by cerebellar gait, slow saccades, ataxic dysarthria, hypotonia, and tendency to fall, without any parkinsonian features. Patients with the parkinsonism phenotype had an older mean age at onset (45.8 years) and shorter CAG repeats (36.2 repeats) compared to those with the ataxic phenotype (26.9 years) caused by SCA2 repeats (43.1 repeats). Lu et al. (2004) noted that there were a few overlapping features between the 2 groups, including dysarthria and postural instability, but emphasized the otherwise clear phenotypic distinction.
Ragothaman et al. (2004) reported a consanguineous Indian family with SCA2 expansions and a complex phenotype comprising ataxia, parkinsonism, and retinitis pigmentosa, either in isolation or in combination. Two patients with homozygous SCA2 repeat expansions (35 to 39 repeats) presented with dopa-responsive parkinsonism, including tremor, rigidity, and bradykinesia. Age at onset was 15 and 22 years. Twelve other family members who were heterozygous for SCA2 repeat expansions had isolated late-onset parkinsonism (2 patients), late-onset parkinsonism and ataxia (1 patient), isolated ataxia (6 patients), ataxia and RP (2 patients), and isolated RP (1 patient). Approximately 38% of family members with expanded SCA2 repeats were asymptomatic.
Charles et al. (2007) found that 3 (2%) of 164 French families with autosomal dominant parkinsonism had SCA2 expansions ranging in size from 37 to 39 repeats that were interrupted by CAA triplets. These interrupted expansions were stable in transmission. All 9 patients had levodopa-responsive parkinsonism without cerebellar signs and had less rigidity and more symmetric signs compared to patients with other causes of PD. Two sisters with both the SCA2 expansion and the LRRK2 mutation G2019S (609007.0006) had earlier onset that their mother who had only the SCA2 expansion, suggesting an additive pathogenic effect in the sisters. As a phenotypic comparison, 53 SCA2 patients with similar-sized, uninterrupted SCA2 repeats showed predominant cerebellar ataxia with rare signs of parkinsonism. The findings suggested that the configuration of SCA2 repeat expansions plays an important role in phenotypic variability.
By polysomnography of 8 patients from 5 families with SCA2, Tuin et al. (2006) observed evidence of REM sleep behavior disorder. Patient age ranged from 14 to 55 years; disease duration ranged from 3 to 31 years. Clinically, almost all patients reported good subjective sleep quality. Four patients with early disease stage showed REM without atonia accompanied by a consistent reduction of REM density. Three patients with later stage disease had undetectable REM sleep, whereas slow wave sleep was increased at the cost of light sleep. In addition, patients showed a progressive loss of dream recall that correlated with stages of REM and theoretically corresponded to progressive brain atrophy from the pons, nigrostriatal projection, and locus ceruleus to the thalamus.
There is a wide range in the age at onset of SCA2, both between and within families, and several studies have shown a strong inverse correlation between the size of the (CAG)n repeat and the age of onset of SCA2 symptoms (Sanpei et al., 1996; Imbert et al., 1996). Almaguer-Mederosa et al. (2010) analyzed a large group of 924 Cuban individuals, including 394 presymptomatic and 530 affected individuals with 32 to 79 CAG repeats. There was a highly significant negative linear relation between mean age at onset and CAG repeat number. There was a significant increase in the probability of manifesting disease for a given age as the CAG repeat number increased from 34 to 45 units. Cumulative probability curves for disease manifestation at a particular age for each CAG repeat length in the 34 to 45 unit range were significantly different for each studied CAG repeat number, stressing the importance of expanded allele CAG repeat number as the principal factor in determining age at onset in SCA2. Overall, the mean age at onset diminished by 4.15 +/- 3.45 years for each increase in the CAG repeat number.
SCA2 is most often transmitted in an autosomal dominant pattern of inheritance, and genetic anticipation is observed (Pulst et al., 1996). However, rare patients with homozygous ATXN2 repeat expansions have been reported (Ragothaman et al., 2004).
In a Nebraska kindred with 33 affected members, of whom 12 were living, Ranum et al. (1992) excluded linkage to the highly informative GT-repeat marker D6S89, which had been located on 6p and found to be closely linked to the SCA1 locus in 5 other large kindreds. They excluded linkage to this marker for moderate to tight linkage, less than 11% recombination. The disorder was clinically indistinguishable from that in the linked kindreds. The clinical features were also identical to those in the Cuban family described by Orozco Diaz et al. (1990).
Gispert et al. (1993) found that in the large Cuban (Holguin) kindred that failed to show linkage to chromosome 6 markers, the locus, designated SCA2, could be assigned to 12q23-q24.1 by linkage analysis. Probable flanking markers were D12S58 and phospholipase A2 (PLA2A; 172410). Hernandez et al. (1995) performed further studies on 11 large pedigrees from the Holguin SCA2 family collective. Three-point analysis localized the SCA2 mutation within the 6-cM interval between D12S84 and D12S79. The microsatellite D12S105 within that interval showed a peak 2-point lod score 16.14 at theta = 0.00, as well as complete linkage disequilibrium among affected individuals. A common disease haplotype was found in all family ancestors, supporting an SCA2 founder effect in Holguin. Investigation of linkage to the interval containing SCA2 in 7 French autosomal dominant SCA families, previously excluded from linkage to SCA1, provided preliminary data suggesting the existence of a third locus, SCA3 (607047). In 2 kindreds, 1 Austrian-Canadian and 1 French-Canadian, Lopes-Cendes et al. (1994) found that an autosomal dominant form of SCA could be mapped within a region of approximately 16 cM between the microsatellite markers D12S58 and D12S84/D12S105. Silveira et al. (1993) found that Machado-Joseph disease is not linked to the phenylalanine hydroxylase locus (PAH; 612349) on chromosome 12q; MJD was subsequently mapped to chromosome 14.
Gispert et al. (1995) reported that complete allelic association was established with the microsatellite marker D12S105. The D12S105 sequence, including 342 basepairs representing the region of maximal allelic association in the Cuban SCA2 founder effect, was subjected to sequence homology analysis at the European Molecular Biology Laboratories database and yielded an almost perfect match (99.7% similarity) with intron 1 of the human D-amino acid oxidase gene (DAO; 124050), which had previously been shown to be linked to all SCA2 pedigrees worldwide with no recombination (Hernandez et al., 1995). The small sequence differences were the result of length variations in the 4 primitive repeat motifs contained in this intron. The authors stated that a mutation in the DAO gene could fit well with previous hypotheses on the pathologic mechanism of spinocerebellar degeneration, since oral loading tests with glutamate in such patients have demonstrated a decreased metabolism of glutamic acid and aspartic acid, and since accumulation of the excitotoxic neurotransmitter glutamate is known to lead to cerebellar Purkinje neuron death. However, Gispert et al. (1995) found recombinants between SCA2 and a second microsatellite marker within intron 1 of the DAO gene. These and other recombination data of Gispert et al. (1995) excluded the DAO gene from the SCA2 region.
Belal et al. (1994) described an affected Tunisian family that showed linkage to the SCA2 locus. Multipoint linkage analysis, including markers D12S78, D12S79, and D12S105, generated a peak lod score of 3.46 at the D12S105 locus. By this analysis the SCA2 gene was localized to a 12.8-cM interval between D12S78 and D12S79. The members of the Tunisian pedigree exhibited progressive cerebellar ataxia and dysarthria with or without ophthalmoplegia, optic atrophy, pyramidal signs, sensory loss, dementia, or extrapyramidal features. Extrapyramidal signs were found in 23% of the Tunisians but in none of the Cubans. Ihara et al. (1994) identified Japanese families with OPCA showing linkage to a 6.2-cM interval between IGF1 (147440) and D12S84/D12S85 on chromosome 12.
Pulst et al. (1993) identified a pedigree with linkage to 12q and established closer flanking markers for SCA2 than had been achieved in the Cuban pedigree. The second family was of southern Italian descent and showed segregation for SCA in 5 generations. All affected persons showed marked appendicular and gait ataxia as well as slow saccadic eye movements (Starkman et al., 1972). Mean age of onset in 19 affecteds was 26.9 +/- 12.5. Anticipation was demonstrated in this family; in 14 of 15 parent-child pairs, onset of the disease in the offspring occurred earlier than in the parent by 14.4 +/- 7.9 years. Pulst et al. (1993) suggested that this indicates that an expanded triplet repeat underlies SCA2 as it does in SCA1.
Using a monoclonal antibody that recognizes expanded polyglutamine stretches in TATA box-binding protein (600075), mutant huntingtin (613004), mutant ataxin-1 (164400), and glutamine expanded proteins in patients with SCA3 (109150), Trottier et al. (1995) used Western blotting to detect a 150-kD protein in a patient with SCA2, but not his normal relative. By analogy to other disorders associated with anticipation in expanded triplet repeats, they suggested that this may be the protein encoded by the mutant gene responsible for this disorder.
Proteins with long polyQ tracts have an increased tendency to aggregate, often as truncated fragments forming ubiquitinated intranuclear inclusion bodies. In SCA2 brains, Huynh et al. (2000) found cytoplasmic, but not nuclear, microaggregates. Mice expressing ataxin-2 with Q58 (58 CAG repeats) showed progressive functional deficits accompanied by loss of the Purkinje cell dendritic arbor and finally loss of Purkinje cells. Despite similar functional deficits and anatomic changes observed in ataxin-1(Q80) transgenic lines, ataxin-2(Q58) remained cytoplasmic without detectable ubiquitination.
Sisodia (1998) reviewed the significance of nuclear inclusions in glutamine repeat disorders.
The ATXN2 promoter is located exon 1 of the ATXN2 gene in a typical CpG island devoid of a TATA box and is usually partially methylated. Using a methyl-specific PCR protocol, Laffita-Mesa et al. (2012) found differences in the methylation levels of the ATXN2 promoter in a family in which anticipation was observed without CAG repeat expansion. Specifically, the promoter was hypomethylated in an affected son with earlier onset of SCA2 compared to that of his affected mother with later onset of the disorder, even though both patients carried CAG expansions of 39 repeats on the pathogenic allele. In 9 SCA2 patients, quantitative analysis indicated that hypermethylation at the promoter, leading to partial or complete epigenetic silencing, was associated with longer expansions of the ATXN2 repeat and that alleles with pathogenic CAG expansions were preferentially hypermethylated. These findings may represent part of the cellular defense mechanism to reduce the burden of cytotoxic mutant ATXN2. Study of 2 patients with homozygous expansions of 43 and 39 CAG repeats, respectively, found an association between hypermethylation at the ATXN2 promoter and delayed age at onset. SCA3 (109150) is caused by a similar CAG repeat expansion in the ATXN3 gene (607047), which is closely connected to ATXN2. Laffita-Mesa et al. (2012) also found that hypermethylation at the ATXN2 promoter was associated with lower age of onset of SCA3, although methylation at the ATXN3 promoter had no effect on age at onset of SCA3. These findings suggested that the development of SCA3 may involve physiologic functions of ATXN2. Overall, the report of Laffita-Mesa et al. (2012) showed that methylation of the ATXN2 promoter can occur, consistent with epigenetic control of ATXN2 expression, and that differences in methylation may affect disease course.
Spinocerebellar Ataxia 2
In patients with spinocerebellar ataxia-2, Pulst et al. (1996) identified a (CAG)n repeat located in the 5-prime end of the coding region of the ATXN2 gene (601517.0001). They detected expansions of 36 to 52 repeats in affected individuals; the most common allele contained 37 repeats. They noted that the SCA2 repeat is unusual in that only 2 alleles were demonstrated in the normal population. A common allele with 22 repeats was found in people of European descent. Using RT-PCR, Pulst et al. (1996) determined that the SCA2 (CAG)n repeat is transcribed in lymphoblastoid cell lines and that the cells could be used to express the expanded repeat genes from patients with SCA2.
Sanpei et al. (1996) analyzed 286 normal chromosomes and found that the (CAG)n repeats ranged in size from 15 to 24, with a unit of 22 repeats accounting for 94% of the alleles. In contrast, SCA2 patient chromosomes contained expanded repeats ranging in size from 35 to 59 units. Sanpei et al. (1996) reported that there was a strong inverse correlation between the size of the (CAG)n repeat and the age of onset of SCA2 symptoms.
Imbert et al. (1996) reported that normal SCA2 alleles contained 17 to 29 (CAG)n repeats and 1 to 3 (CAA)n repeats (also glutamine-encoding). Mutated alleles contained 37 to 50 repeats and appeared to be particularly unstable in maternal and paternal transmissions. Sequence analysis of expanded repeats from 3 individuals revealed pure CAG stretches. Imbert et al. (1996) reported a steep inverse correlation between the age of onset of disease and (CAG)n repeat number.
Riess et al. (1997) investigated the (CAG)n repeat length of the ATXN2 gene in 842 patients with sporadic ataxia and in 96 German patients with dominantly inherited SCA that did not harbor the SCA1 or MJD1/SCA3 mutation. The SCA2 (CAG)n expansion was identified in 71 patients from 54 families. The (CAG)n stretch of the affected allele varied between 36 and 64 trinucleotide units. Significant repeat expansions occurred most commonly during paternal transmission. Analysis of the (CAG)n repeat lengths with respect to the age of onset in 41 patients revealed an inverse correlation. They found that 241 apparently healthy octogenarians carried alleles between 16 and 31 repeats. One 50-year-old healthy individual had 34 repeats; she had transmitted an expanded allele to her child. Riess et al. (1997) commented that the small difference between 'normal' and disease alleles makes it necessary to define the extreme values of their reaches. With one exception, the trinucleotide expansion was not observed in 842 ataxia patients without a family history of the disease. The SCA2 mutation causes the disease in nearly 14% of autosomal dominant SCA in Germany.
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.
Spadafora et al. (2007) reported 2 brothers and a nephew with SCA2. Molecular analysis identified CAG repeat numbers of 35/36, 22/35, and 22/42, respectively. The brother and nephew with the 35/36 and 22/42 repeat expansions showed earlier age at onset and a more severe progressive disorder compared to the brother with the 22/35 repeat expansions. The family was from Sicily and denied consanguinity, although both deceased parents of the brothers were reportedly affected late in life. Spadafora et al. (2007) concluded that SCA2 shows gene dosage effects on phenotype.
Amyotrophic Lateral Sclerosis 13
Elden et al. (2010) demonstrated genetic, biochemical, and neuropathologic interactions between TDP43 (605078), a protein involved in amyotrophic lateral sclerosis (ALS10; 612069), and ATXN2, which raised the possibility that mutations in ATXN2 may have a causative role in ALS. The ATXN2 polyQ tract length, although variable, is most frequently 22-23, with expansions of greater than 34 causing SCA2. However, the variable nature of the polyQ repeat indicated a mechanism by which such mutations in ATXN2 could be linked to ALS: Elden et al. (2010) proposed that intermediate-length expansions greater than 23 but below the threshold for SCA2 may be associated with ALS. They studied the frequency of intermediate-length ATXN2 polyglutamine repeat in ALS, comparing 915 subjects with ALS with 980 neurologically normal controls. Among those with ALS, 4.7% (43) had repeat lengths of 27 to 33, whereas only 1.4% (14) of neurologically normal subjects had glutamine expansions. The P value for this difference was 3.6 x 10(-5) with an odds ratio (OR) of 2.80. Elden et al. (2010) analyzed ATXN2 protein levels in patient-derived lymphoblastoid cells from ALS cases harboring intermediate-length polyQ expansions, ALS cases with normal-range repeat lengths, and controls. These studies showed that whereas the steady-state levels of ATXN2 were comparable, cyclohexamide treatment, which blocks new protein synthesis, revealed an increase in stability (or decreased degradation) of ATXN2 in cells with intermediate-length polyQ repeats. Elden et al. (2010) found that polyQ expansions in ATXN2 enhance its interaction with TDP43. Both ATXN2 and TDP43 relocalize to stress granules, sites of RNA processing, under various stress situations such as heat shock and oxidative stress. Under normal conditions TDP43 localized to the nucleus and ATXN2 to the cytoplasm in both control cells and cells harboring polyQ repeat expansions. The authors proposed that intermediate-length ATXN2 polyQ repeats might confer genetic risk for ALS by making TDP43 more prone to mislocalize from the nucleus to the cytoplasm under situations of stress.
In a case-control study of 556 ALS patients and 471 controls of French or French Canadian origin, Daoud et al. (2011) found that 7.2% of patients and 5.1% of controls had 1 intermediate repeat allele (24-33 repeats), which was not significantly different. However, receiver operating characteristic curve analysis yielded a significant association between ALS and high-length ATXN2 repeat alleles (29 or more repeats). CAG repeats of 29 or more were found in only 4 controls (0.8%), whereas they were found in 25 patients (4.5%) (OR, 5.5; p = 2.4 x 10(-4)). The association was even stronger for familial cases when stratified by familial versus sporadic cases (OR for familial cases, 9.29; p = 5.2 x 10(-5)). There was no correlation between size of repeat and age of onset. In addition, 2 familial and 9 sporadic ALS cases carried SCA2-sized pathogenic alleles (more than 32 repeats), and none had features of SCA2 such as cerebellar or brainstem atrophy.
Among 1,845 sporadic and 103 familial ALS cases and 2,002 controls from Belgium and the Netherlands, Van Damme et al. (2011) found an association between ALS and an expanded repeat of 29 or more CAG repeats in the ATXN2 gene (OR, 1.92; p = 0.036). In controls, the repeat length ranged from 16 to 31, with 22 being the most abundant. Repeat sizes of 31 or less were not significantly different between patients and controls. However, receiver operating characteristic analysis showed that the greatest sensitivity and specificity of discriminating ALS from control was using a cutoff of 29 repeats: 1.5% of patients had 29 or more repeats compared to 0.8% of controls (OR, 1.92; p = 0.036). There was no correlation between repeat length and disease parameters. When combined in a metaanalysis with the data of Elden et al. (2010), the association was highly significant (OR, 2.93; p less than 0.0001). Ten patients (0.05%) with sporadic ALS had 32 or more repeats, and none of these patients had signs of SCA2. Two of 91 families with ALS (2.2%) had expanded repeats: 1 with 31 repeats and the other with 33 repeats. In the 33-repeat family, which was consanguineous, 2 affected individuals had repeat expansions on both alleles, 33:33 and 33:31, respectively, although the phenotype was not significantly different from classic ALS, except for some sensory abnormalities. Two sibs from a third family with a heterozygous repeat length of 34 and 35, respectively, had classic SCA2 with no signs of upper motor neuron involvement. The findings indicated a genetic overlap between SCA2 and ALS13.
Among 3,919 patients with various neurodegenerative diseases, including 532 with ALS, 641 with frontotemporal dementia (FTD; 600274), 1,530 with Alzheimer disease (AD; 104300), 702 with Parkinson disease (PD; 168600), and 514 with progressive supranuclear palsy (PSP;601104), and 4,877 healthy controls, Ross et al. (2011) found that ATXN2 repeat lengths greater than 30 units were significantly associated with ALS (odds ratio of 5.57; p = 0.001) and with PSP (OR of 5.83; p = 0.004). Repeat expansions were found in 8 (1.5%) ALS patients, 4 (0.8%) PSP patients, and 9 (0.2%) controls. Significant associations between repeats greater than 30 were not observed in patients with FTD, AD, or PD. The findings of expanded repeat alleles (31 to 33) in control individuals indicated that caution should be taken when attributing specific disease phenotypes to these repeat lengths. However, 6 of the controls with expanded repeats were under the mean onset age of all patient groups except PD. The findings confirmed the role of ATXN2 as an important risk factor for ALS and suggested that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.
In the vicinity of Holguin in northeastern Cuba (neighboring the Guantanamo Naval Base), Orozco et al. (1989) estimated a frequency of 41 per 100,000 for a form of dominantly inherited olivopontocerebellar atrophy occurring in persons of Spanish ancestry. The high prevalence was thought to be the result of founder effect. The clinical and biochemical features were described together with the neuropathologic findings in 7 autopsied patients.
Geschwind et al. (1997) found that SCA2 accounts for 13% of patients with autosomal dominant cerebellar ataxia (without retinal degeneration), which is intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively. Together, SCA1, SCA2, and SCA3/MJD constitute more than 40% of the mutations leading to autosomal cerebellar ataxia type I. Geschwind et al. (1997) found that no patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3. No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, was observed. Repeat length correlated inversely with age at onset, accounting for approximately 80% of the variability in onset age. Haplotype analysis provided no evidence for a single founder chromosome, and diverse ethnic origins were observed among SCA2 kindreds. In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia.
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.
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. SCA2 accounted for 5.9% of the cases.
Among 202 Japanese and 177 Caucasian families with autosomal dominant SCA, Takano et al. (1998) found that the prevalence of SCA2 was significantly higher in the Caucasian population (14%) compared to the Japanese population (5%). This corresponded to higher frequencies of large normal CACNA1A CAG repeat alleles (greater than 22 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.
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.
In an analysis of 42 Indian families, Saleem et al. (2000) found that SCA2 was the most frequent ataxia among those studied. In the SCA2 families, together with an intergenerational increase in repeat size, a horizontal increase with the birth order of the offspring was also observed, indicating an important role for parental age in repeat instability. This was strengthened by the detection in a pair of dizygotic twins of expanded alleles showing the same repeat number. Haplotype analysis indicated the presence of a common founder chromosome for the expanded allele in the Indian population. Polymorphism of CAG repeats in 135 normal individuals at the SCA loci studied showed similarity to the Caucasian population but was significantly different from the Japanese population.
Storey et al. (2000) examined the frequency of mutations for SCA types 1, 2, 3, 6, and 7 (164500) 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.
Zhao et al. (2002) found that SCA2 is relatively common in the Malay population of Singapore.
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.
In a study of ATXN2 CAG repeat alleles in about 3,000 Cuban chromosomes, Laffita-Mesa et al. (2012) found that the range of repeats was distributed continuously from 13 to 31 repeats, with 22 repeats being the most frequent allele (76%). However, the distribution was skewed toward the large CAG range and was higher compared to Caucasian, Japanese, Indian, and Polish populations. Cuban chromosomes also had a high frequency of intermediate alleles (32 and 33 CAG repeats). Examination of 81 normal chromosomes showed high variance in the CAG with CAA interruption sequence, with many normal alleles lacking the stability-mediating CAA interruptions. Alleles with 27-31 repeats were somatically unstable, suggesting that they may give rise to de novo pathogenic expansions. Statistical analysis pointed to 27 CAG repeats as being the threshold for intermediate alleles.
▼ Animal Model
Scoles et al. (2017) developed an antisense oligonucleotide, ASO7, that downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice.
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