疾患詳細

疾患詳細





#208920
Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (EAOH)
(Ataxia-oculomotor apraxia syndrome; AOA)
(Ataxia-oculomotor apraxia 1; AOA1)
(Ataxia-telangiectasia-like syndrome)
(Cerebellar ataxia, early-onset, with hypoalbuminemia; EOCA-HA)
(Ataxia, adult-onset, with oculomotor apraxia, included)

運動失調, 早期発症-眼球運動失行-低アルブミン血症
(運動失調-眼球運動失行症候群)
(運動失調-眼球運動失行1)
(運動失調-毛細血管拡張様症候群)
(小脳失調,早期発症-低アルブミン血症)
(運動失調, 成人発症-眼球運動失行症, 含む)
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:606350 Aprataxin (APTX) <9p21.1>
遺伝形式:常染色体劣性

(症状)
(GARD)
 <80%-99%>
 Ataxia (運動失調) [HP:0001251] [028]
 Gait disturbance (歩行障害) [HP:0001288] [028]
 Medial flaring of the eyebrow (内側眉毛フレア) [HP:0010747] [1725]
 Peripheral neuropathy (末梢ニューロパチー) [HP:0009830] [0204]
 
 <5%-29%>
 Mental deterioration (知能悪化) [HP:0001268] [0125]
 
 <1%-4%>
 Choreoathetosis (舞踏病アテトーゼ)  [HP:0001266] [0240]
 
 
 Adult onset (成人発症) [HP:0003581]
 Areflexia (無反射) [HP:0001284] [0242]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Axonal degeneration (軸索変性) [HP:0040078] [0201]
 Cerebellar atrophy (小脳萎縮 ) [HP:0001272] [16013]
 Cognitive impairment (認知症) [HP:0100543] [0123]
 Decreased number of large peripheral myelinated nerve fibers (大きな末梢髄鞘化神経線維の減少)  [HP:0003387]
 Dementia (認知症) [HP:0000726] [0123]
 Distal amyotrophy (遠位筋萎縮) [HP:0003693] [0270]
 Distal sensory impairment (遠位感覚障害) [HP:0002936] [025]
 Dysarthria (構音障害) [HP:0001260] [0230]
 Dystonia (ジストニア) [HP:0001332] [0240]
 Gait ataxia (歩行失調) [HP:0002066] [028]
 Gaze-evoked nystagmus (注視誘発性眼振) [HP:0000640] [06609]
 Hypercholesterolemia (高コレステロール血症) [HP:0003124] [20172]
 Hypoalbuminemia (低アルブミン血症) [HP:0003073] [2083]
 Hypometric saccades (ハイポメトリックサッケード) [HP:0000571]
 Hyporeflexia (低反射)  [HP:0001265] [0242]
 Juvenile onset (若年発症) [HP:0003621]
 Limb ataxia (四肢運動失調) [HP:0002070] [028]
 Muscle weakness (筋力低下) [HP:0001324] ) [01426]
 Oculomotor apraxia (眼球運動失行) [HP:0000657] [0698]
 Peripheral axonal degeneration (末梢性軸索変性) [HP:0000764] [0201]
 Pes cavus (扁平足) [HP:0001761] [15602]
 Progressive external ophthalmoplegia (進行性外眼筋麻痺) [HP:0000590]
 Scoliosis (側弯)  [HP:0002650] [161502]
 Tremor 振戦 [HP:0001337] [02604]
 Truncal ataxia (体幹失調) [HP:0002078] [028]
 
(UR-DBMS)
【一般】知能退行 (一部の患者で)
 認知症 (一部の患者で)
 けいれん
【神経】末梢神経障害による遠位筋萎縮
 筋力低下
 筋 coenzyme Q 欠損 (1家系)
 小脳性運動失調, 重度
 歩行失調
 四肢失調
 体幹運動失調
 大多数の患者は10歳以後車椅子生活となる
 舞踏病性アテトーゼ (79%), 疾患発症時に最も多い
 振戦
 ジストニア
 構音障害
 軸索感覚および運動性末梢神経障害, 重度
 遠位感覚喪失
 反射低下
 無反射
 神経生検は軸索変性と軸索新芽を示す
 大きな有髄線維欠乏
【眼】眼球運動失行症 (86%)
 ハイポメトリックサッケード (衝動運動)
 注視誘発性眼振
 進行性外眼筋麻痺
【四肢】凹足
【X線】側弯
 小脳萎縮
【毛髪】前頭部毛髪線低位
【皮膚】正常
【血液】免疫グロブリン正常
【検査】低アルブミン血症 (83%)
 高コレステロール血症 (75%)
 染色体正常
 AFP 正常
 T細胞およびB細胞のマーカー正常
 7番および14番染色体正常
【その他】発症は通常小児期または思春期 (2 - 18 歳)
 成人発症が報告されている
 眼球運動失行は常にみられるわけではない

(要約) 運動失調-眼球運動失行1型 (AOA1)
●運動失調-眼球運動失行1型 (AOA1)は, 緩徐進行性小脳失調の小児期発症と続く眼球運動失行および重度の原発性末梢性軸索運動性ニューロパチーが特徴である
 初発症状は, 進行性歩行障害 (平均発症年齢4.3歳, 2-10歳)で.構音障害が続き, その後軽度の企図振戦を伴う上肢ジスメトリアが続く
 眼球運動失行症は通常運動失調発症後2-3年で気付き, 外眼筋麻痺へと進行する
 全患者は全身性無反射をもち, 発症後7-10年で移動喪失となる末梢神経障害と四肢麻痺が続く
 手足は短く萎縮性である
 舞踏病や上肢ジストニアが多い
 知能は一部の患者では正常を維持するが, 他ではいろんな程度の認知障害がみられる
●診断:臨床所見 (家族歴を含む) と運動失調-毛細血管拡張症の除外による
 全例のMRIで小脳萎縮がみられる
 EMG は, 100%で軸索性ニューロパチーを明らかにする
 APTX が原因遺伝子である

<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
16) EAOH/AOA1 (新潟大学脳研究所 神経内科 横関明男,西澤正豊同 生命科学リソース研究センター 小野寺理)
(1)発症年齢  
(ア)1歳前後~20歳代(最軽症例は40歳発症例がある)
(イ)初発症状は歩行障害 (不随意運動や知能障害の合併に気づくこともある)
(2)臨床症状
(ア)知能 
 ①ナンセンス変異症例は, 知能障害を認める
 ②ミスセンス変異症例は, 知能は正常
(イ)小脳失調
(ウ)歩行障害
 ①ナンセンス変異症例は, 20歳代までにほぼ歩行不可となる
 ②ミスセンス変異症例は, 30歳以降に歩行不可となる 
注)本邦での軽症例は40歳で歩行不可
(エ)構音障害 全例で合併
(オ)腱反射消失(20歳代では, いずれも消失)
(カ)眼球運動失行 (幼小児期では陽性率が高いが, 加齢とともに減少)
(キ)不随意運動 (tremor, choreaの頻度が高い, athetosis, dystonia, myoclonusも合併する)
(3)検査所見
(ア)血清アルブミン
 ①ナンセンス変異症例は, 20歳以降で3g/dl以下に低下
 ②ミスセンス変異症例は, 全経過で3g/dlまでの低下
(イ)神経伝導速度
 ①上肢より下肢が障害されやすい
 ②脛骨神経CMAP, 腓腹神経SNAPは20歳以降では導出されない
 ③感覚神経は, 運動神経より障害されやすい
(ウ)頭部MRI  発症時より小脳萎縮を認める
(4)診断確定
(ア)APTXの遺伝子変異の確認
(5)いままでに報告のない症状 
(ア)てんかんの合併
(イ)出生直後の発症 (Floppy infantの報告はない)
(ウ)腱反射亢進 ※Babinski反射が陽性になる例は少数例存在する 
(6)本疾患を疑うポイント 
(ア)両親に血族婚または出身地が近く, 処女歩行の遅れや幼小児期に歩行の異常を認める場合
(イ)眼球運動失行は患者の自覚症状に乏しく, 他覚的には「よく首をふる」などの症状である
(ウ)遅発性の発症例では, 腱反射はすでに消失しているが, 知能は保たれている場合が多い
治療
純粋小脳型では, 小脳性運動失調に対しても, 集中的なリハビリテーションの効果があることが示唆されている。バランス, 歩行など, 個々人のADLに添ったリハビリテーションメニューを組む必要がある。リハビリテーションの効果は, 終了後しばらく持続する。

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

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

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

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

診断方法
成人に準じる

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

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

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

(Responsible gene) *606350 Aprataxin (APTX) <9p21.1>
.0001 Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (208920) [APTX, 1-BP INS, 167T [dbSNP:rs587776593] (Date et al. 2001)
.0002 Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia [APTX, PRO32LEU] (dbSNP:rs121908131) (Date et al. 2001)
.0003 Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia [APTX, 1-BP DEL, 318T [dbSNP:rs587776594] (Date et al. 2001)
.0004 Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia [APTX, VAL89GLY] (dbSNP:rs121908132) (Date et al. 2001)
.0005 Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia [APTX, HIS27ARG] (dbSNP:rs121908133) (Shimazaki et al. 2002)
.0006 Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia [APTX, TRP279TER] (dbSNP:rs104894103) (Coenzyme Q10 deficiency, included) (Moreira et al. 2001; Tranchant et al. 2003; Quinzii et al. 2005; Le Ber et al. 2007; Castellotti et al. 2011)
.0007 Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia [APTX, DEL] (Amouri et al. 2004)
.0008 Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia [APTX, IVS7AS, G-A, -1] (Amouri et al. 2004)
.0009 Ataxia, adult-onset, with oculomotor apraxia [APTX, LEU223PRO [dbSNP:rs267606665] (Criscuolo et al. 2005)

(Note)
A number sign (#) is used with this entry because the early-onset ataxia with oculomotor aproxia and hypoalbuminemia is caused by homozygous or compound heterozygous mutation in the gene encoding aprataxin (APTX; 606350) on chromosome 9p13. Adult-onset ataxia with oculomotor aproxia is also caused by mutation in the APTX gene.

Ataxia-oculomotor apraxia syndrome is an early-onset autosomal recessive cerebellar ataxia with peripheral axonal neuropathy, oculomotor apraxia (defined as the limitation of ocular movements on command), and hypoalbuminemia (Moreira et al., 2001).

Genetic Heterogeneity of Ataxia-Oculomotor Apraxia

See also AOA2 (606002), caused by mutation in the SETX gene (608465) on chromosome 9q34; AOA3 (615217), caused by mutation in the PIK3R5 gene (611317) on chromosome 17p; and AOA4 (616267), caused by mutation in the PNKP gene (605610) on chromosome 19q13.

Clinical Features
Aicardi et al. (1988) described an autosomal recessive syndrome that closely resembled ataxia-telangiectasia (AT; 208900) but differed in important respects. They reported 14 patients in 10 families with a neurologic syndrome of oculomotor apraxia, ataxia, and choreoathetosis who had none of the extraneurologic features of AT. Although the neurologic signs were indistinguishable from those of AT, the onset tended to be later and none of the patients had a tendency to frequent infections; further, immunoglobulins, alpha-fetoprotein, T- and B-lymphocyte markers, and chromosomes 7 and 14 were normal in all patients tested.

Barbot et al. (2001) reported 22 Portuguese patients with autosomal recessive cerebellar ataxia, ocular apraxia, and peripheral neuropathy with a mean age of onset of 4.7 years. There was no associated mental retardation, telangiectasia, or immunodeficiency. Barbot et al. (2001) concluded that ataxia with oculomotor apraxia may be more frequent than previously believed. Koeppen (2002) suggested that the patients reported by Barbot et al. (2001) may have exhibited supranuclear pseudoophthalmoplegia, which may be due to lesions in the nucleus pontis centralis caudalis of the paramedian pontine reticular formation.

Shimazaki et al. (2002) reported 5 Japanese patients with autosomal recessive EAOH from 3 families and 1 sporadic case. Clinical features included age of onset from 3 to 12 years, cerebellar ataxia, peripheral neuropathy, oculomotor apraxia and external ophthalmoplegia, choreiform movements of the limbs, facial grimacing, mental deterioration, cerebellar atrophy, hypoalbuminemia, and hypercholesterolemia.

Amouri et al. (2004) reported 3 unrelated Tunisian families with AOA, confirmed by mutation in the APTX gene (606350.0007; 606350.0008). The mean age at onset was 5 years with gait ataxia as the presenting symptom. Cerebellar ataxia affecting all 4 limbs and the trunk developed soon thereafter. Other features included dysarthria, ocular apraxia, distal sensory axonal neuropathy, and marked cerebellar atrophy by brain imaging. Hypoalbuminemia and hypercholesterolemia were also present. Affected members of 1 of the families had a somewhat atypical phenotype with absence of oculomotor apraxia, except in 1 patient, and preservation of knee reflexes. None of the patients had mental impairment.

Criscuolo et al. (2004) reported 3 unrelated Italian patients with AOA confirmed by genetic analysis. Two of the patients had adult onset at ages 28 and 29, respectively.

Criscuolo et al. (2005) reported a patient with adult-onset AOA confirmed by genetic analysis (606350.0009). The patient had onset of gait ataxia and dysarthria at age 40 years. Physical examination showed normal ocular movements, tongue and limb fasciculations, areflexia, and decreased vibration sense at the external malleoli. MRI showed cerebellar atrophy. Serum albumin was normal. Criscuolo et al. (2005) emphasized that milder phenotypes of AOA may occur in adults.

Castellotti et al. (2011) identified APTX mutations in 13 (6.4%) of 204 Italian patients with progressive cerebellar ataxia. The patients had onset between ages 3 and 7 years, but most were examined as adults. The phenotype was homogeneous, characterized mainly by gait and limb ataxia, dysarthria, nystagmus, lower limb areflexia, sensory neuropathy, cognitive decline, dysarthria, and oculomotor deficits. Some had choreic movements of the upper limbs and face, and many had distal muscle weakness and atrophy affecting both upper and lower limbs. Six patients were wheelchair-bound in young adulthood. Six patients had mental retardation since early childhood, whereas 5 showed cognitive decline later in life. Hypoalbuminemia was found in 58%, and hypercholesterolemia in 69%. Three patients had increased alpha-fetoprotein (AFP; 104150). Analyses of coenzyme Q10 in muscle, fibroblasts, and plasma demonstrated normal levels of coenzyme in 5 of 6 patients. There were no genotype/phenotype correlations.

Biochemical Features
Hannan et al. (1994) studied cultured fibroblasts from 3 patients with ataxia-oculomotor apraxia and their asymptomatic relatives in comparison with fibroblasts from a classic AT homozygote, an AT heterozygote, and 4 healthy subjects. Cell survival after acute and chronic irradiation was investigated. While a moderately increased cellular sensitivity (compared to normal) was observed in 2 AOA patients and most of their relatives, the degree of their radiosensitivity was quite different from that of the AT homozygote after both acute and chronic irradiation. A comparison of peripheral blood lymphocytes from spontaneous and acute radiation-induced chromosomal breaks also failed to show similarity between AOA and AT. The data were interpreted as indicating either that AOA and AT are distinct disease entities controlled by separate genes or that AOA is due to compound heterozygosity involving different AT genes that promote the manifestation of AOA characteristics.

Pathogenesis
Aprataxin has been shown to interact with poly(ADP-ribose) polymerase-1 (PARP1; 173870), a key player in the detection of DNA single-strand breaks. Harris et al. (2009) reported reduced expression of PARP1, apurinic endonuclease-1 (APEX1; 107748) and OGG1 (601982) in AOA1 cells and demonstrated a requirement for PARP1 in the recruitment of aprataxin to sites of DNA single-strand breaks. Mouse embryonic fibroblasts (MEFs) derived from Parp1-knockout mice showed reduced levels of aprataxin and reduced DNA-adenylate hydrolysis; however, inhibition of PARP1 activity did not affect aprataxin activity in vitro. Rather, aprataxin failed to relocalize to sites of DNA single-strand breaks in Parp1-null MEFs compared to wildtype cells, and inhibition of PARP1 activity resulted in delayed recruitment of aprataxin to DNA breaks. There were elevated levels of oxidative DNA damage in AOA1 cells coupled with reduced base excision and gap filling repair efficiencies indicative of a synergy between aprataxin, PARP1, APE1 and OGG1 in the DNA damage response. Harris et al. (2009) proposed both direct and indirect modulating functions for aprataxin on base excision repair.

Garcia-Diaz et al. (2015) found that most, but not all, cell lines derived from AOA1 patient fibroblasts showed coenzyme Q10 (CoQ10) deficiency due to reduced mRNA and protein expression of PDSS1 (607429), the first committed enzyme of CoQ10 biosynthesis. Low PDSS1 was caused by reduced activity of a transcriptional regulatory pathway that included APE1, NRF1 (600879) and NRF2 (see 600609). Knockdown of APTX or APE1 in HeLa cells recapitulated CoQ10 deficiency and other mitochondrial abnormalities, and these were reversed by upregulation of NRF2. Garcia-Diaz et al. (2015) concluded that mitochondrial dysfunction in APTX-depleted cells is not due to involvement of APTX in mtDNA repair, but rather to a role for APTX in transcriptional regulation of mitochondrial function.

Mapping
9p Locus (APTX gene)

Date et al. (2001) identified a group of Japanese patients whose clinical presentation was characterized by autosomal recessive inheritance, early age at onset, Friedreich ataxia (FRDA; 229300)-like clinical presentations, and hypoalbuminemia. Linkage to the FRDA locus was excluded. They confirmed that the disorder in these patients was linked to the same locus, 9p13, as the ataxia-oculomotor apraxia syndrome.

Moreira et al. (2001) studied 13 Portuguese families with AOA and found that the 2 largest families showed linkage to 9p, with lod scores of 4.13 and 3.82, respectively, at a recombination fraction of 0.0. These and 3 smaller families, all from northern Portugal, showed homozygosity and haplotype sharing over a 2-cM region on 9p13.3, demonstrating founder effect and linkage to this locus, designated AOA1, in the 5 families. Three other families were excluded from this locus, demonstrating nonallelic heterogeneity in AOA. They also analyzed 2 unrelated Japanese families with early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA). This disorder, described only in Japan (Uekawa et al., 1992; Fukuhara et al., 1995; Sekijima et al., 1998; Tachi et al., 2000), is characterized by marked cerebellar atrophy, peripheral neuropathy, mental retardation, and occasionally oculomotor apraxia. Both families appeared to show linkage to the AOA1 locus. Subsequently, the authors found hypoalbuminemia in all 5 Portuguese families with AOA1 with a long disease duration, suggesting that AOA1 and EOCA-HA correspond to the same entity that accounts for a significant proportion of all recessive ataxias.

9q Locus

Nemeth et al. (2000) identified a family with ataxia and oculomotor apraxia in which the disorder showed linkage to 9q34; see 606002. Bomont et al. (2000) performed linkage studies in the Japanese family reported by Watanabe et al. (1998) in which 4 affected sibs had spinocerebellar ataxia associated with elevated levels of serum creatine kinase, gamma-globulin, and alpha-fetoprotein. Homozygosity over a 20-cM region allowed demonstration of linkage at 9q33.3-q34.3 with a lod score of 3.0.

Koenig (2001) concluded that there are 2 recessive ataxia loci on chromosome 9: one on 9p, the site of the APTX gene, and one on 9q. The disorder that maps to 9p13 appears always to be associated with oculomotor apraxia (Barbot et al., 2001), early onset (usually between 2 and 6 years of age), and hypoalbuminemia after a long disease duration. The disorder on 9q34 is of later onset (between 11 and 22 years) and is occasionally associated with oculomotor apraxia or elevated gamma-globulin, alpha-fetoprotein, and creatine kinase. Tentatively, early-onset ataxia with oculomotor apraxia and hypoalbuminemia, which appears to map to 9p13.3 and to be caused by mutation in the aprataxin gene, will be referred to as ataxia-oculomotor apraxia-1, whereas ataxia of later onset with inconsistent association of oculomotor apraxia will be designated ataxia-oculomotor apraxia-2. Koenig (2001) suggested that the designation AOA is inappropriate for the form of ataxia mapped to 9q.

Population Genetics
By 2001, the ongoing survey initiated in 1993 of hereditary ataxias and spastic paraplegias in Portugal, a country of 9.8 million persons, had identified 107 patients with autosomal recessive ataxia (Barbot et al., 2001). Friedreich ataxia (FRDA;229300) accounted for 38% of the cases. The next most common recessive ataxia in the survey, accounting for 21% of the cases, was ataxia with oculomotor apraxia.

Anheim et al. (2010) found that AOA1 was the fourth most common form of autosomal recessive cerebellar ataxia in a cohort of 102 patients from Alsace, France. Of 57 patients for whom a molecular diagnosis could be determined, 3 were affected with AOA1. FRDA was the most common diagnosis, found in 36 of 57 patients, AOA2 (606002) was the second most common diagnosis, found in 7 patients, and ataxia-telangiectasia (AT; 208900) was the third most common diagnosis, found in 4 patients. Marinesco-Sjogren syndrome (MSS; 248800) was also found in 3 patients.

Molecular Genetics
Date et al. (2001) characterized 7 families from various regions of Japan with clinical manifestations like those of the ataxia-oculomotor apraxia syndrome and again showed mapping to 9p13 as in Europeans and people of European descent. They narrowed the candidate region and identified a novel gene encoding a member of the histidine triad (HIT, e.g., 601153, 601314) superfamily as the causative gene. They called its product aprataxin and assigned the gene symbol APTX (606350); this was the first member of the HIT superfamily to be linked to a distinct phenotype.

Moreira et al. (2001) and Date et al. (2001) demonstrated mutations in the APTX gene as the cause of AOA in their Portuguese and Japanese populations (606350.0001-606350.0004).

Castellotti et al. (2011) identified recessive APTX mutations in 13 (6.4%) of 204 Italian probands with progressive cerebellar ataxia. The most common mutation was W279X (606350.0006), which was found in homozygous state in 7 patients and in compound heterozygosity with another pathogenic APTX mutation in 1 patient. Three additional novel mutations were identified. Western blot analysis of patient lymphocytes showed severely decreased levels of APTX protein, consistent with loss of function as a disease mechanism. There were no genotype/phenotype correlations.

Genotype/Phenotype Correlations
Quinzii et al. (2005) found that 3 sibs originally reported by Musumeci et al. (2001) as having familial cerebellar ataxia with muscle coenzyme Q10 (CoQ10) deficiency (see 607426) actually had AOA1 due to a homozygous mutation in the APTX gene (W279X; 606350.0006). All 3 patients responded well to CoQ10 supplementation. Thirteen additional patients with coenzyme Q deficiency did not have APTX mutations. Quinzii et al. (2005) noted that CoQ10 deficiency has been associated with 3 major clinical phenotypes and remarked that the finding of mutation in the APTX gene in these sibs supports the hypothesis that the ataxic form of CoQ10 deficiency is a genetically heterogeneous entity in which deficiency of CoQ10 can be secondary.

Le Ber et al. (2007) found decreased muscle CoQ10 in 5 of 6 patients with AOA1. Three patients who were homozygous for the W279X mutation had the lowest values. The CoQ10 deficiency did not correlate with disease duration, severity, or other blood parameters, and mitochondrial morphology and respiratory function were normal.

Nomenclature
Date et al. (2001) suggested that the best name for this disorder is 'early-onset ataxia with oculomotor apraxia and hypoalbuminemia' (EAOH).

According to Dawson (2001), the syndrome of ataxia with oculomotor apraxia is sometimes referred to as Aicardi syndrome; this runs the risk of confusion with the other Aicardi syndrome, agenesis of the corpus callosum with chorioretinal abnormalities (304050).

(文献)
(1) Aicardi J et al. Ataxia-ocular motor apraxia: a syndrome mimicking ataxia-telangiectasia. Ann Neurol 24: 497-502, 1988
(2) Uekawa K et al. A hereditary ataxia associated with hypoalbuminemia and hyperlipidemia--a variant form of Friedreich's disease or a new clinical entity? Clin. Neurol. 32: 1067-1074, 1992
(3) Hannan MA et al. Ataxia-ocular motor apraxia syndrome: an investigation of cellular radiosensitivity of patients and their families. J. Med. Genet. 31: 953-956, 1994
(4) Fukuhara N et al. Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): a new disease. J. Neurol. Sci. 133: 140-151, 1995
(5) Sekijima Y et al. Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): clinical and neuropathological features of a Japanese family. J. Neurol. Sci. 158: 30-37, 1998
(6) Watanabe M et al. Familial spinocerebellar ataxia with cerebellar atrophy, peripheral neuropathy, and elevated level of serum creatine kinase, gamma-globulin, and alpha-fetoprotein. Ann. Neurol. 44: 265-269, 1998
(7) Bomont P et al. Homozygosity mapping of spinocerebellar ataxia with cerebellar atrophy and peripheral neuropathy to 9q33-34, and with hearing impairment and optic atrophy to 6p21-23. Europ. J. Hum. Genet. 8: 986-990, 2000
(8) Nemeth AH et al. Autosomal recessive cerebellar ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome) is linked to chromosome 9q34. Am. J. Hum. Genet. 67: 1320-1326, 2000
(9) Tachi N et al. Hereditary cerebellar ataxia with peripheral neuropathy and mental retardation. Europ. Neurol. 43: 82-87, 2000
(10) Barbot C et al. Recessive ataxia with ocular apraxia: review of 22 Portuguese patients. Arch. Neurol. 58: 201-205, 2001
(11) Date H et al. Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene. Nature Genet. 29: 184-188, 2001
(12) Dawson DM: Recessive ataxia with ocular motor apraxia. (Editorial) Arch. Neurol. 58: 173-174, 2001
(13) Moreira MC et al. Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13, and evidence for genetic heterogeneity. Am. J. Hum. Genet. 68: 501-508, 2001
(14) Moreira M-C et al. The gene mutated in ataxia-oculomotor apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nature Genet. 29: 189-193, 2001
(15) Musumeci, O.; Naini, A.; Slonim, A. E.; Skavin, N.; Hadjigeorgiou, G. L.; Krawiecki, N.; Weissman, B. M.; Tsao, C.-Y.; Mendell, J. R.; Shanske, S.; De Vivo, D. C.; Hirano, M.; DiMauro, S. : Familial cerebellar ataxia with muscle coenzyme Q10 deficiency. Neurology 56: 849-855, 2001
(16) Koeppen, A. H. : Ocular apraxia in recessive ataxia. (Letter) Arch. Neurol. 59: 874 only, 2002
(17) Shimazaki, H.; Takiyama, Y.; Sakoe, K.; Ikeguchi, K.; Niijima, K.; Kaneko, J.; Namekawa, M.; Ogawa, T.; Date, H.; Tsuji, S.; Nakano, I.; Nishizawa, M. : Early-onset ataxia with ocular motor apraxia and hypoalbuminemia: the aprataxin gene mutations. Neurology 59: 590-595, 2002
(18) Amouri, R.; Moreira, M.-C.; Zouari, M.; El Euch, G.; Barhoumi, C.; Kefi, M.; Belal, S.; Koenig, M.; Hentati, F. : Aprataxin gene mutations in Tunisian families Neurology 63: 928-929, 2004
(19) Criscuolo, C.; Mancini, P.; Sacca, F.; De Michele, G.; Monticelli, A.; Santoro, L.; Scarano, V.; Banfi, S.; Filla, A. : Ataxia with oculomotor apraxia type 1 in southern Italy: late onset and variable phenotype. Neurology 63: 2173-2175, 2004
(20) Criscuolo, C.; Mancini, P.; Menchise, V.; Sacca, F.; De Michele, G.; Banfi, S.; Filla, A. Very late onset in ataxia oculomotor apraxia type I. (Letter) Ann. Neurol. 57: 777 only, 2005
(21) Quinzii, C. M.; Kattah, A. G.; Naini, A.; Akman, H. O.; Mootha, V. K.; DiMauro, S.; Hirano, M. : Coenzyme Q deficiency and cerebellar ataxia associated with an aprataxin mutation. Neurology 64: 539-541, 2005
(22) Le Ber, I.; Dubourg, O.; Benoist, J.-F.; Jardel, C.; Mochel, F.; Koenig, M.; Brice, A.; Lombes, A.; Durr, A. Muscle coenzyme Q10 deficiencies in ataxia with oculomotor apraxia 1. Neurology 68: 295-297, 2007
(23) Harris, J. L., Jakob, B., Taucher-Scholz, G., Dianov, G. L., Becherel, O. J., Lavin, M. F. Aprataxin, poly-ADP ribose polymerase 1 (PARP-1) and apurinic endonuclease 1 (APE1) function together to protect the genome against oxidative damage. Hum. Molec. Genet. 18: 4102-4117, 2009
(24) Anheim, M., Fleury, M., Monga, B., Laugel, V., Chaigne, D., Rodier, G., Ginglinger, E., Boulay, C., Courtois, S., Drouot, N., Fritsch, M., Delaunoy, J. P., Stoppa-Lyonnet, D., Tranchant, C., Koenig, M. Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management. Neurogenetics 11: 1-12, 2010
(25) Castellotti, B., Mariotti, C., Rimoldi, M., Fancellu, R., Plumari, M., Caimi, S., Uziel, G., Nardocci, N., Moroni, I., Zorzi, G., Pareyson, D., Di Bella, D., Di Donato, S., Taroni, F., Gellera, C. Ataxia with oculomotor apraxia type 1 (AOA1): novel and recurrent aprataxin mutations, coenzyme Q10 analyses, and clinical findings in Italian patients. Neurogenetics 12: 193-201, 2011
(26) Garcia-Diaz, B., Barca, E., Balreira, A., Lopez, L. C., Tadesse, S., Krishna, S., Naini, A., Mariotti, C., Castellotti, B., Quinzii, C. M. Lack of aprataxin impairs mitochondrial functions via downregulation of the APE1/NRF1/NRF2 pathway. Hum. Molec. Genet. 24: 4516-4529, 2015

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2015/03/21 ノート追加
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