疾患詳細

疾患詳細





#125370
Dentatorubral-pallidoluysian atrophy (DRPLA)
(Myoclonus epilepsy with choreoathetosis)
(Naito-Oyanagi disease; NOD)
(Haw river syndrome; HRS)
(Ataxia, chorea, seizures, and dementia)

歯状核赤核淡蒼球ルイ核萎縮 (DRPLA)
(ミオクローヌスてんかん-舞踏病アテトーゼ)
(Naito-Oyanagi 病)
(Haw River 症候群)
(運動失調-舞踏病-けいれん-認知症)
指定難病18 脊髄小脳変性症(多系統萎縮症を除く)

遺伝形式:常染色体優性

(症状)
(GARD)
 <80%-99%>
 Atrophy of the dentate nucleus (歯状核萎縮) [HP:0007047] [160130]
 Fetal cystic hygroma (胎児嚢胞性ヒグローマ) [HP:0010878] [1000]
 Progressive cerebellar ataxia (進行性小脳失調) [HP:0002073] [028]
 
 <30%-79%>
 Action tremor (動作振戦) [HP:0002345] [02604]
 Choreoathetosis (舞踏病アテトーゼ) [HP:0001266] [02600]
 Dementia (認知症) [HP:0000726] [0123]
 Dysarthria (構音障害) [HP:0001260] [0230]
 Dysdiadochokinesis (ジスジアドコキネーゼ) [HP:0002075] [02605]
 Dysmetria (ジスメトリア) [HP:0001310] [02605]
 Dyssynergia (協調運動障害) [HP:0010867] [02605]
 Gait ataxia (歩行失調) [HP:0002066] [028]
 Hyperintensity of cerebral white matter on MRI (MRI: 大脳白質高輝度) [HP:0030890] [160127]
 Hyporeflexia (低反射) [HP:0001265] [0242]
 Impaired proprioception (固有覚障害) [HP:0010831] [02511]
 Limb ataxia (四肢運動失調) [HP:0002070] [028]
 Myoclonus (ミオクローヌス) [HP:0001336] [02612]
 Nystagmus (眼振) [HP:0000639] [06609]
 Ophthalmoparesis (眼球運動不全麻痺) [HP:0000597] [0698]
 Optic neuropathy (視神経ニューロパチー) [HP:0001138
 Saccadic smooth pursuit (サッケード性の円滑な追視) [HP:0001152] [0695]
 Seizures (けいれん) [HP:0001250] [01405]
 Truncal ataxia (体幹失調) [HP:0002078] [028]
 
 <5%-29%>
 Blepharospasm (眼瞼スパスム) [HP:0000643] [06806]
 Memory impairment (記憶障害) [HP:0002354] [0123]
 Oromandibular dystonia (口腔下顎ジストニア) [HP:0012048] [0240]
 
 <1%-4%>
 Abnormal pyramidal sign (錐体路サイン異常) [HP:0007256] [02140][01405][0213]
 Ataxia (運動失調) [HP:0001251] [028]
 Chorea (舞踏病) [HP:0002072] [02600]
 
 
 Autosomal dominant inheritance (常染色体優性遺伝) [HP:0000006]
 Genetic anticipation (遺伝的促進) [HP:0003743]

(UR-DBMS)
【一般】けいれん
【神経】小脳性運動失調
 ミオクローヌス
 舞踏病アテトーゼ
 認知症
 歯状核/赤核/淡蒼球/ルイ核変性
【検査】歯状核の著明なニューロン喪失, 淡蒼球の微小石灰化, 薄束核の神経軸索ジストロフィー, および半卵円中心の脱髄
【その他】平均発症年齢 (10歳未満-70歳)
 表現促進
 表現型に異質性あり

【一般】肺炎
 嚥下困難
【眼】眼振
 異常な眼球運動
【X線】小脳萎縮
 脳室拡大
 (白質病変)

(要約) DRPLA (Dentatorubral-Pallidoluysian Atrophy)
●歯状核赤核淡蒼球ルイ核萎縮 (DRPLA)は, 小児での運動失調, ミオクローヌス, てんかんおよび進行性知的悪化, 成人での運動失調, 舞踏病様アテトーゼ, 認知症または性格変化の進行性疾患である
 発症は1歳〜72歳で, 平均31.5歳である
 臨床像は, 発症年齢により変化がみられる
 成人での主要症状は, 運動失調, 舞踏病様アテトーゼおよび認知症候群である
 小児での主要症状は, 進行性知的悪化, 行動異常, ミオクローヌスおよびてんかんである
●診断:臨床所見, 家族歴および ATN1 のヘテロ接合病的 CAG 伸長の証明による
 患者:48-93リピート
 正常:6-35リピート
 変異可能な正常アレル:20-35リピート→不安定で次世代に症状が生じうる
●遺伝:常染色体優性
●示唆する臨床所見
○臨床症状
 20歳未満:運動失調, ミオクローヌス, けいれん, 進行性知的悪化
 20歳以上:運動失調, 舞踏病様アテトーゼ, 認知症, 精神障害
○脳MRI: 小脳および脳幹萎縮
○家族歴:常染色体優性と主に日本人 (アジア人)
●表現促進あり
●頻度:日本人 0.48:100,000

(要約2)
●歯状核赤核淡蒼球ルイ核萎縮 (DRPLA)は, 常染色体優性の脊髄小脳変性症で, atrophin-1 atrophin-1 のポリグルタミン径路をコードする CAG リピートの伸長が原因である
 別名, Haw River 症候群や Naito-Oyanagi 病としても知られる
 本疾患はたぶん1958年 Smith らにより最初に記載されたが, 数例の散発例が西欧から報告されている
 本疾患は日本を除いて非常にまれである
●ポリグルタミン (polyQ) ストレッチをコードするCAGリピートの伸長が原因の神経変性疾患には少なくとも8つがある
 CAGリピート伸長は遺伝子産物の不利益な機能獲得変異をつくる
 これらの疾患では, DRPLA はハンチントン病に最も類似する
●DRPLA には, 思春期発症(< 20 歳), 早期成人発症 (20–40 歳), または後期成人発症 (> 40 歳)がある
 後期成人発症 DRPLA は, 運動失調, 舞踏病アテトーゼおよび認知症が特徴である
 早期成人発症 DRPLA は, さらにけいれんとミオクローヌスを含む
 若年発症 DRPLA は, 運動失調と進行性ミオクロニー発作に一致する症状をもつ (myoclonus, multiple seizure types and dementia)
 他の症状には, 頸部ジストニア, 角膜内膜変性症, 自閉症, 外科抵抗性閉塞性睡眠時無呼吸などが記載されている
●atrophin 遺伝子には2つある (1と2)
 DRPLA は, 12p13.3 にある atrophin-1 遺伝子のポリグルタミン領域の伸長と相関する
 →正常は7-34, 患者は 49-93 リピート
 DRPLA には表現促進があり, 伸長したCAGリピートサイズと発症年齢に逆相関を示す
 父伝達は26-29歳発症で, 母伝達 (14-15歳)より顕著である
●Atrophin-1 (ATN1) は, 親水性の1184アミノ酸タンパクでいくつかの繰り返しモチーフを含む
 → serine-rich 領域, 多様な長さのポリグルタミン径路, ポリプロリン径路, 交互の酸性と塩基性残基の領域
 タンパクN末に暫定的核局在シグナルと, C末に暫定的核輸出シグナルを含む
 ATN1 は全ての組織にユビキタスに発現されるが, 神経細胞ではタンパク分解的に開裂される
 ATN1 機能は不明であるが, transcriptional co-repressor だと信じられている
 ATN1 と atrophin-2 は共免疫沈降でき, 分子複合体としていっしょに何らかの機能をもつことを示す
 atrophin-1 のヌルアレルと交配したマウスは生存可能で妊孕性のある子孫をつくり, 代償性のatrophin-2のアップレギュレーションを示さないので, atrophin-1 は重要ではない, または豊富なタンパクかもしれない
●トランスジェニックマウスモデル
 Schilling マウス
●DRPLA は, 著明な全般性脳萎縮と伸長したグルタミンストレッチをもつ atrophin-1 の蓄積が特徴である
 変異 atrophin-1 タンパクはニューロン核内封入体 (NII) としてみられ, ニューロン核にびまん性に蓄積される
 NII の役割は病的か保護的か不明であるが, 変異タンパクのびまん性蓄積は毒としてみなされている
●診断
 家族歴陽性, 臨床症状および遺伝子検査による
 親戚が誤診されている場合, 若くて死亡した場合, 遅発の場合, 家族歴を得るのは困難かもしれない
 鑑別診断には, ハンチントン病と脊髄小脳失調症がある
 若年発症性では, 家族性本態性ミオクローヌスおよびてんかん (FEME), Lafora, Unverricht-Lundborg, 神経軸索ジストロフィー, Gaucher 病, シアリドーシスおよびガラクトシアリドーシスがあげられる
●疾患程度の把握には, MRI, EEG および神経心理学的検査が推奨される
 けいれんは抗けいれん剤で, 精神障害は抗精神薬で治療される
●日本人での DRPLA 有病率は 0.2-0.7/100,000と信じられている
 他の人種では比較的低頻度である
 正常 ATN1 アレル解析では, 日本人では17以上にリピート長をもつものが有意に多い

<指定難病> 脊髄小脳変性症 (多系統萎縮症を除く)
1.概要
 脊髄小脳変性症とは, 運動失調あるいは痙性対麻痺を主症状とし, 原因が, 感染症, 中毒, 腫瘍, 栄養素の欠乏, 奇形, 血管障害, 自己免疫性疾患等によらない疾患の総称である。遺伝性と孤発性に大別される。
 臨床的には小脳性の運動失調症候あるいは痙性対麻痺を主体とする。いずれも小脳症状のみが目立つもの(純粋小脳型)と, 小脳以外の病変, 症状が目立つもの(多系統障害型)に大別される。劣性遺伝性の一部で後索性の運動失調症候を示すものがある。同じく, 緩慢進行性の痙性対麻痺を主徴とする疾患群においては, 臨床的に痙性対麻痺を主症候とする病型(純粋型)と, 他の系統障害の症候を伴う病型(複合型)に区別される。
2.原因
 平成15年の「運動失調に関する調査及び病態機序に関する研究班」(研究代表者, 辻省次)での解析結果では, 脊髄小脳変性症の67.2%が孤発性で, 27%が常染色体優性遺伝性, 1.8%が常染色体劣性遺伝性, 残りが「その他」と「痙性対麻痺」であった。
 孤発性のものの大多数は多系統萎縮症であり, その詳細は多系統萎縮症の項目を参照されたい。残りが小脳症候のみが目立つ皮質性小脳萎縮症であり, アルコール, 薬物, 腫瘍, 炎症, 血管障害などによる2次性の小脳失調症との鑑別が重要である。
 遺伝性の場合は, 多くは優性遺伝性である。少数の常染色体劣性遺伝性, まれにX染色体遺伝性のものが存在する。このうち, 我が国で頻度が高い遺伝性脊髄小脳変性症は, SCA3(脊髄小脳失調症3型, マシャド・ジョセフ病), SCA6, SCA31, DRPLA(歯状核赤核淡蒼球萎縮症)である。
 優性遺伝性のSCA1, 2, 3, 6, 7, 17, DRPLAでは, 原因遺伝子の翻訳領域におけるCAGという3塩基の繰り返し配列が異常に伸長することにより発症する。CAG繰り返し配列は, アミノ酸としてはグルタミンとなるため, 本症は異常に伸長したグルタミン鎖が原因であると考えられる。他に同様にグルタミン鎖の異常伸長を示すハンチントン病, 球脊髄性筋萎縮症と併せて, ポリグルタミン病と総称される。
 また, 優性遺伝性のSCA8, 10, 31, 36は遺伝子の非翻訳領域にある3~6塩基繰り返し配列の異常な増大によって起こる。脆弱X関連振戦/運動失調症候群(FXTAS)も同様の機序で起きる疾患で, 運動失調症を呈する。これらの疾患群は, 「非翻訳リピート病」とも呼ばれ, 繰り返し配列の部分が転写されRNAとなって病態を起こすと考えられている。
 一方, 繰り返し配列ではなく, 遺伝子の点変異や欠失などの静的変異で起きる疾患も多数同定された。優性遺伝性のSCA5, 14, 15, 劣性遺伝性の「眼球運動失行と低アルブミン血症を伴う早発性運動失調症」などがその例である。この中に分類される疾患は多数あり, 今後も増えることが予想される。
 この他に, 発作性に運動失調症状を呈する疾患群がある。現在, 脊髄小脳変性症の研究は進んでいるが発病や進行を阻止できる根治的治療法の開発につながる病態機序はまだ明らかになっていない。なお, ミトコンドリア病やプリオン病では脊髄小脳変性症と臨床診断されることがあるため注意を要する。
3.症状
 症候は失調症候を主体とするが, 付随する周辺症候は病型ごとに異なる。優性遺伝性の脊髄小脳変性症は, 症候が小脳症候に限局する型(純粋小脳型)と, パーキンソニズム, 末梢神経障害, 錐体路症候などを合併する型(多系統障害型)に臨床的に大別される。孤発性の大部分は, 前述したように多系統萎縮症であるが, 残りが純粋小脳型の皮質性小脳萎縮症である。劣性遺伝性の多くは多系統障害型であり, 後索障害を伴う場合がある。一般的に小脳症候に限局する型の方が予後は良い。またSCA6や反復発作性失調症などで, 症候の一過性の増悪と寛解を認める場合がある。SCA7は網膜黄斑変性を伴うことが多い。DRPLAの若年発症例は進行性ミオクロニー発作の病像を呈する。家族歴のない症例に対し, 遺伝子診断を行う場合は, 優性遺伝性疾患の場合は本人の結果が未発症の血縁者にも影響を与えることから, 特に十分な説明と同意が必要である。
4.治療法
 純粋小脳型では, 小脳性運動失調に対しても, 集中的なリハビリテーションの効果があることが示唆されている。バランス, 歩行など, 個々人のADLに添ったリハビリテーションメニューを組む必要がある。リハビリテーションの効果は, 終了後もしばらく持続する。
 薬物療法としては, 失調症状全般に甲状腺刺激ホルモン放出ホルモン(TRH)やTRH誘導体が使われる。
 疾患ごとの症状に対して対症的に使われる薬剤がある。有痛性筋痙攣に対する塩酸メキシレチン, 反復発作性の失調症状, めまい症状に対するアセタゾラミド等が挙げられる。
 ポリグルタミン病に関しては, ポリグルタミン鎖又はそれが影響を及ぼす蛋白質や細胞機能不全をターゲットとした治療薬の開発が試みられているが, 現在のところ, 有効性があるものはない。
5.予後
予後は, 病型により大きく異なる。またポリグルタミン病は症例の遺伝子型の影響を受ける。

<指定難病診断基準>
Definite, Probable を対象とする。

【主要項目】
脊髄小脳変性症は,運動失調を主要症候とする神経変性疾患の総称であり, 臨床,病理あるいは遺伝子的に異なるいくつかの病型が含まれる。臨床的には以下の特徴を有する。
 ① 小脳性ないしは後索性の運動失調を主要症候とする。
 ② 徐々に発病し,経過は緩徐進行性である。
 ③ 病型によっては遺伝性を示す。その場合,常染色体優性遺伝性であることが多いが,常染色体劣性遺伝性の場合もある。
 ④ その他の症候として,錐体路症候,パーキンソニズム,自律神経症候,末梢神経症候,高次脳機能障害などを示すものがある。
 ⑤ 頭部の MRI や X 線 CT にて,小脳や脳幹の萎縮を認めることが多いが,病型や時期によっては大脳基底核病変や大脳皮質の萎縮などを認めることもある。
 ⑥ 以下の原因による 2 次性脊髄小脳失調症を鑑別する:
 脳血管障害, 腫瘍, アルコール中毒, ビタミンB1・B12・葉酸欠乏, 薬剤性(フェニトインなど), 炎症[神経梅毒, 多発性硬化症, 傍腫瘍性小脳炎, 免疫介在性小脳炎(橋本脳症, シェーグレン症候群, グルテン失調症, 抗GAD抗体小脳炎)], 甲状腺機能低下症, 低セルロプラスミン血症, 脳腱黄色腫症, ミトコンドリア病, 二次性痙性対麻痺(脊柱疾患に伴うミエロパチー, 脊髄の占拠性病変に伴うミエロパチー, 多発性硬化症, 視神経脊髄炎, 脊髄炎, HTLV-I関連ミエロパチー, アルコール性ミエロパチー, 副腎ミエロニューロパチーなど。

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

(Occurrence) 25 Japanese families
(Responsible gene) *607462 Atrophin 1 (ATN1) <12p13.31>
(1) Dentatorubral-pallidoluysian atrophy (125370)
.0001 Dentatorubral-pallidoluysian atrophy [ATN1, (CAG)n expansion] (RCV000003333) (Koide et al. 1994; Burke et al. 1994, 1994)
(2) Congenital hypotonia, epilepsy, developmental delay, and digital anomalies (618494)
.0002 Congenital hypotonia, epilepsy, developmental delay, and digital anomalies [ATN1, HIS1054ASN] (rs1555144357) (RCV000787317...) (Palmer et al. 2019)
.0003 Congenital hypotonia, epilepsy, developmental delay, and digital anomalies [ATN1, HIS1058TYR] (rs1555144358) (RCV000787318...) (Palmer et al. 2019)
.0004 Congenital hypotonia, epilepsy, developmental delay, and digital anomalies [ATN1, 6-BP INS, 3177AACCTG] (rs1064795494) (RCV000482562...) (Palmer et al. 2019)
.0005 Congenital hypotonia, epilepsy, developmental delay, and digital anomalies [ATN1, HIS1060TYR] (rs797044566) (RCV000171467...) (Palmer et al. 2019)
.0006 Congenital hypotonia, epilepsy, developmental delay, and digital anomalies [ATN1, HIS1062ARG] (rs1565569158) (RCV000779621...) (Palmer et al. 2019)

*ATN1 (Atrophin 1)
 Genome size 17,859 bp, 1190 aa, 125414 Da
 Exons: 10, Coding exons: 9, Transcript length: 4,351 bps, Translation length: 1,190 residues
● DRPLA はまれな神経変性疾患で, 小脳失調, ミオクロニーてんかん, 舞踏病アテトーゼおよび認知症が特徴である
 →ATN1 遺伝子内のtrinucleotide repeat (CAG/CAA) の 735コピーから49-93コピーへの伸長と関係する
 ATN1タンパクは1つのセリンリピートと1つの選択的酸性および塩基性アミノ酸領域と多様なグルタミンリピートを含む
 同じタンパクをコードする2つの転写産物がある
 転写 corepressor である
 転写を抑制するためNR2E1をリクルートする
 血管平滑筋細胞(VSMC)の移動と方向性を促進する
 MTG8 転写抑制の corepressor である
 poly-Gln (polyQ) の数から独立するいくらかの内在性抑制活性をもつ

(Note)
A number sign (#) is used with this entry because dentatorubral-pallidoluysian atrophy (DRPLA) is caused by a heterozygous expanded trinucleotide repeat in the ATN1 gene (607462) on chromosome 12p13.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder with protean clinical manifestations consisting of various combinations of myoclonus, seizures, ataxia, choreoathetosis, and dementia. The clinical presentation correlates with the size of the causative CAG repeats, and as such, affected family members can present with very different patterns of the disorder (summary by Vinton et al., 2005).

▼ Clinical Features
In 5 families, Naito and Oyanagi (1982) reported a syndrome of myoclonic epilepsy, dementia, ataxia, and choreoathetosis. At autopsy, major neuropathologic changes consisted of combined degeneration of the dentatorubral and pallidoluysian systems. Inheritance was autosomal dominant. Onset was usually in the twenties and death in the forties. Although this condition was perhaps first described by Smith et al. (1958) and several sporadic cases have been reported from Western countries, this disorder seems to be very rare except in Japan where other hereditary cases have been described (Iizuka et al., 1984; Iwabuchi et al., 1985; Takahashi et al., 1988). Hirayama et al. (1981) classified 3 clinical forms of DRPLA: the ataxo-choreoathetoid form, the pseudo-Huntington form, and the myoclonic epilepsy form.

Tomoda et al. (1991) described a Japanese family with 12 affected individuals in 3 generations. They emphasized that patients with onset in childhood usually have the progressive myoclonic epilepsy (PME) syndrome (254800).

Warner et al. (1994) described 1 family in the United Kingdom in which the DRPLA repeat expansion was demonstrated in 3 affected sibs. In the course of studying Huntington disease (HD; 143100) in Wessex in the U.K., Connarty et al. (1996) found a second family with DRPLA. A father and daughter were affected.

In a single Japanese family, Saitoh et al. (1998) observed 5 different clinical types of DRPLA. Two sibs and their paternal uncle manifested the juvenile type, the father of the sibs had the late-adult type, and another paternal uncle had the early-adult type. Gene analysis confirmed the diagnosis for the proband and her sib. By following the clinical courses and electroencephalographic changes, they found that the types of epileptic seizures and the EEGs of the juvenile DRPLA patients changed as the course progressed. The sibs exhibited different levels of clinical severity despite the similar DNA expansion detected in their lymphocytes (see GENOTYPE/PHENOTYPE CORRELATIONS).

Shimojo et al. (2001) reported 2 unrelated patients with infantile DRPLA. Both patients developed normally until about 6 months of age, when motor signs, such as difficulty controlling the head, choreoathetosis, hyperkinetic movements, involuntary movements, and seizures developed. MRI of both patients showed cerebral atrophy and delayed myelination. CAG repeat sizes were 93 and 90, representing extreme repeat expansion. Although the parents refused DNA analysis, Shimojo et al. (2001) suggested that the early onset and severe clinical courses were related to the long repeats.

Haw River Syndrome
Farmer et al. (1989) described a family, with ancestors born in Haw River, North Carolina, that contained members in 5 generations with an autosomal dominant neurologic disorder. It was characterized by the development between 15 and 30 years of age of ataxia, seizures, choreiform movements, progressive dementia, and death after 15 to 25 years of illness. Neuropathologic findings in 2 deceased family members demonstrated remarkably similar findings, including marked neuronal loss of the dentate nucleus, microcalcification of the globus pallidus, neuroaxonal dystrophy of the nucleus gracilis, and demyelination of the centrum semiovale. The clinical and pathologic findings were closely correlated: ataxia and chorea were related to severe neuronal loss in the dentate nucleus with calcification in the globus pallidus. Dementia occurred from progressive demyelination of the centrum semiovale, and loss of posterior column function occurred from neuroaxonal dystrophy of the nucleus gracilis and nucleus cuneatus.

Burke et al. (1994) noted that the phenotypic differences between Haw River syndrome and DRPLA include the absence of myoclonic seizures in HRS as well as the presence of extensive demyelinization of the subcortical white matter, basal ganglia calcifications, and neuroaxonal dystrophy which are not seen in DRPLA.

▼ Inheritance
The pattern of inheritance of DRPLA in the families studied by Naito and Oyanagi (1982), Tomoda et al. (1991), and others was consistent with autosomal dominant inheritance.

▼ Mapping
Kondo et al. (1990) demonstrated that the mutant gene in this disorder is not an allele of the Huntington disease locus (143100), even though there is sufficient phenotypic overlap to lead to confusion of diagnosis; they found that in 4 families there were negative lod scores for DRPLA and D4S10, the locus first linked to HD.

Nagafuchi et al. (1994) cited linkage analyses using polymorphic markers in DRPLA families that localized the responsible gene locus to chromosome 12p. The DRPLA locus segregated with CD4 (186940), with maximum lod = 3.61 at theta = 0.00, and also with VWF (613160), with maximum lod = 3.32 at theta = 0.06. Both CD4 and VWF are located on chromosome 12pter-p12. To define the precise location of the DRPLA gene, Kuwano et al. (1996) studied genotypes of 4 patients, each with a different deletion of 12p. The gene for DRPLA was assigned to 12p13.1-p12.3.

Burke et al. (1994) found that HRS locus is tightly linked to the region of DRPLA on 12p.

Cancel et al. (1994) studied a large French kindred in which the disorder in 11 affected individuals was considered consistent with DRPLA. A suggestion of linkage was found, however, to the region of chromosome 14 (q24.3-qter) where the gene for spinocerebellar ataxia-3 (SCA3)/Machado-Joseph disease (607047) has been mapped.

▼ Molecular Genetics
DRPLA is one of several examples of disorders related to expansion of a trinucleotide repeat. Koide et al. (1994) searched a catalog of genes identified by Li et al. (1993) that contained trinucleotide repeats expressed in human brain. One of these cDNAs, B37 (ATN1), known to map to chromosome 12, was examined and found to show CAG repeat expansion (607462.0001) in 22 individuals with DRPLA. Fragile X syndrome (300624), myotonic dystrophy (see 160900), Kennedy disease (313200), Huntington disease, spinocerebellar ataxia-1 (SCA1; 164400), and fragile XE mental retardation (see 309548) were the previously identified disorders due to expanded trinucleotide repeats.

Burke et al. (1994, 1994) demonstrated that despite their distinct cultural origins and clinical and pathologic differences, Haw River syndrome and DRPLA are is caused by the same expanded CAG repeat in the ATN1 gene (607462.0001).

▼ Genotype/Phenotype Correlations
Burke et al. (1994) suggested that the difference in racial frequency of DRPLA is probably due to differences in the repeat size. The frequency of the repeat allele of intermediate size was very low in Europeans, somewhat higher in African Americans, and relatively high (5-10%) in Japanese. This is a situation comparable to the virtual absence of myotonic dystrophy (DM; 160900) in South African blacks, in whom the frequency of large-length CTG repeats is much lower than in white and Japanese populations (Goldman et al., 1994). See the graphs of the distribution of CAG trinucleotide repeat frequencies in 3 populations presented by Burke et al. (1994), including Japanese colleagues.

Genetic Anticipation
Koide et al. (1994) found a good correlation between the size of the (CAG)n repeat expansion and the age of onset. Patients with earlier onset tended to have a phenotype of progressive myoclonic epilepsy and larger expansions. They proposed that the wide variety of clinical manifestations of DRPLA can be explained by the variable unstable expansion of the CAG repeat. Although only 5 cases of paternal transmission and 2 cases of maternal transmission were analyzed, the length of the repeat unit was altered in all cases: the average change in repeat length for paternal transmission was an increase of 4.2 repeats, while that of maternal transmission was a decrease of 1.0 repeat.

Nagafuchi et al. (1994) found that the repeat size varied from 7 to 23 in normal individuals. In patients, one allele was expanded to between 49 and 75 repeats or occasionally even more. Expansion was usually associated with paternal transmission. Like Koide et al. (1994), they found that repeat size correlated closely with age of onset of symptoms and with disease severity. Komure et al. (1995) analyzed CAG trinucleotide repeats in 71 individuals from 12 Japanese DRPLA pedigrees that included 38 affected individuals. Normal alleles varied from 7 to 23 repeats, whereas affected individuals had from 53 to 88 repeats. Like Koide et al. (1994) and Nagafuchi et al. (1994), they found a significant negative correlation between CAG repeat length and age of onset. In 80% of the paternal transmissions, there was an increase of more than 5 repeats, whereas all the maternal transmissions showed either a decrease or an increase of fewer than 5 repeats.

Aoki et al. (1994) demonstrated that anticipation with expansion of the CAG repeat can occur through mothers as well as through fathers. They investigated 2 families in which offspring showed progressive myoclonic epilepsy with onset in childhood. In 1 family, patients of the first generation showed mild cerebellar ataxia with onset at 52 to 60 years. A patient of the second generation, the mother, showed severe ataxia with onset in the early thirties. The offspring in the third generation showed mental retardation, convulsions and myoclonus beginning at age 8. Sano et al. (1994) studied 4 families and also demonstrated anticipation. Older-onset patients suffered from cerebellar ataxia with or without dementia, whereas younger-onset patients presented as progressive myoclonus epilepsy syndrome, consisting of mental retardation, dementia, and cerebellar ataxia as well as epilepsy and myoclonus. Anticipation with paternal transmission was significantly greater than with maternal transmission.

Sato et al. (1995) reported homozygosity for a modest (57-repeat) triplet repeat in a man with early onset of DRPLA at age 17. His parents were first cousins and were neurologically normal at ages 73 and 71, in spite of having 57 CAG repeats in heterozygous state. Four of the proband's sibs died at age 12 with the phenotype of progressive myoclonic epilepsy. These findings supported the hypothesis that the clinical features of DRPLA, like those of Machado-Joseph disease, are influenced by the dosage of expansion of triplet repeats, unlike Huntington disease, in which the homozygous state does not appear to be different clinically from the heterozygous state.

Norremolle et al. (1995) described a Danish family in which affected persons in at least 3 generations had been thought to be suffering from Huntington disease. Because analysis of the huntingtin gene revealed normal alleles and because some of the patients had seizures, they analyzed the B37 gene and found significantly elongated CAG repeats, as had been reported in cases of DRPLA. Norremolle et al. (1995) reported that affected persons with almost identical repeat lengths presented very different symptoms. Both expansion and contraction in paternal transmission was observed.

Ikeuchi et al. (1996) analyzed the segregation patterns of 411 transmissions of 24 DRPLA pedigrees and 80 transmissions in 7 Machado-Joseph disease (MJD; 109150) pedigrees, with the diagnoses confirmed by molecular testing. Significant distortions in favor of transmission of the mutant alleles were found in male meiosis, where the mutant alleles were transmitted to 62% of all offspring in DRPLA (P less than 0.01) and 73% in MJD (P less than 0.01). The results were considered consistent with meiotic drive in both disorders. The authors commented that since more prominent meiotic instability of the length of the CAG trinucleotide repeats is observed in male meiosis than in female meiosis and since meiotic drive is observed only in male meiosis, these results raised the possibility that a common molecular mechanism underlies the meiotic drive and the meiotic instability in male meiosis.

On the basis of studies in an extensively affected Tennessee family, Potter (1996) emphasized the intrafamilial variability and lack of close correlation between age of onset and (CAG)n repeat number in this disease. The studies were done on DNA derived from leukocytes; tissue-specific instability (somatic mosaicism) has been reported in DRPLA.

Takiyama et al. (1999) determined the CAG repeat size in 427 single sperm from 2 men with DRPLA. The mean variance of the change in the CAG repeat size in sperm from the DRPLA patients (288.0) was larger than any variances of the CAG repeat size in sperm from patients with Machado-Joseph disease (38.5), Huntington disease (69.0), and spinal and bulbar muscular atrophy (16.3; 313200), which is consistent with the clinical observation that the genetic anticipation on the paternal transmission of DRPLA is the most prominent among CAG repeat diseases. The variance was different in the 2 patients (51.0 vs 524.9, P greater than 0.0001). The segregation ratio of normal to expanded allele sperm was 1:1.

Vinton et al. (2005) reported a 3-generation Caucasian family of Macedonian origin with DRPLA, manifesting as very mild elderly onset, severe young-adult onset, and severe childhood onset presentations in the 3 generations, respectively. Atrophin-1 expansion sizes of 52, 57, and 66 repeats were demonstrated in the 3 patients, respectively. Vinton et al. (2005) stated that the grandparental trinucleotide expansion size of 52 repeats was the smallest overtly pathogenic mutation yet reported.

▼ Pathogenesis
Studying the CAG expansion in brain and other tissues from 6 unrelated DRPLA patients, Ueno et al. (1995) showed that the sizes of the CAG expansion in various regions of the brain, except the cerebellum, were generally larger by several repeats than in other peripheral tissues. Brain samples showed greater variation of the expansion compared with other tissues, but neither the size of the CAG expansion nor the degree of CAG repeat variation paralleled the detailed findings of neuropathologic involvement. They concluded that somatic instability of the CAG repeat causes tissue variability, but that other regional or cell type-specific factors must explain the selectivity of cell damage in DRPLA.

Burke et al. (1996) demonstrated that synthetic polyglutamine peptides, DRPLA protein and huntingtin (613004) from unaffected individuals with normal-sized polyglutamine tracts bind to glyceraldehyde-3-phosphate dehydrogenase (GAPD; 138400). The authors postulated that diseases characterized by the presence of an expanded CAG repeat may share a common metabolic pathogenesis involving GAPD as a functional component. Roses (1996) and Barinaga (1996) reviewed the findings.

Hayashi et al. (1998) used an antibody against ubiquitin to examine the brains and spinal cords of 7 patients with DRPLA. They found small, round immunoreactive intranuclear inclusions in both neurons and glial cells in various brain regions. Electron microscopy showed that such inclusions are composed of granular and filamentous structures. The findings strongly suggested that, in DRPLA, the occurrence of neuronal and glial inclusions is directly related to the causative expanded CAG repeat, that neurons are affected much more widely than previously recognized, and that glial cells are also involved in the disease process.

Sisodia (1998) reviewed the significance of nuclear inclusions in glutamine repeat disorders. For a comprehensive review of DRPLA, including the Japanese literature, see Kanazawa (1998).

Yamada et al. (2002) noted that some patients with DRPLA have white matter lesions characterized neuropathologically by diffuse myelin pallor. The number of lesions correlates with increasing age, being milder in degree in juveniles and more severe in older adults. In immunohistochemical studies of brains of 12 affected patients and transgenic mice with expanded (CAG)n repeats, Yamada et al. (2002) found immunoreactivity for polyQ in some glial nuclei that was increased with larger expansions of (CAG)n repeats. The authors concluded that oligodendrocytes are a target for the polyQ pathogenesis in DRPLA and may lead to white matter degeneration.

▼ Population Genetics
Since DRPLA occurs almost only in Japanese, Koide et al. (1994) suggested that there may exist a founder effect. In a nationwide survey of Japanese patients, Hirayama et al. (1994) estimated the prevalence of all forms of spinocerebellar degeneration to be 4.53 per 100,000, of which 2.5% were estimated to have DRPLA. 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. DRPLA ranked second in prevalence, accounting for 19.8% of the cases.

DRPLA has been considered to be rare in Europe. Dubourg et al. (1995) failed to find a single case in a survey of 117 French patients with cerebellar ataxia from 94 families, concluding that DRPLA is rare in the French population.

Among 202 Japanese and 177 Caucasian families with autosomal dominant SCA, Takano et al. (1998) found that the prevalence of DRPLA was significantly higher in the Japanese population (20%) compared to Caucasian population (0%). This corresponded to higher frequencies of large normal ATN1 CAG alleles (greater than 17 repeats) in Japanese controls compared to Caucasian controls. The findings suggested that large normal alleles contribute to the generation of expanded alleles that lead to dominant SCA.

Shimizu et al. (2004) estimated the prevalence of autosomal dominant cerebellar ataxia (ADCA) in the Nagano prefecture of Japan to be at least 22 per 100,000. Thirty-one of 86 families (36%) were positive for SCA disease-causing repeat expansions: SCA6 (183086) was the most common form (19%), followed by DRPLA (10%), SCA3 (109150) (3%), SCA1 (2%), and SCA2 (183090) (1%). The authors noted that the prevalence of SCA3 was lower compared to other regions in Japan, and that the number of genetically undetermined SCA families in Nagano was much higher than in other regions. Nagano is the central district of the main island of Japan, located in a mountainous area surrounded by the Japanese Alps. The restricted geography suggested that founder effects may have contributed to the high frequency of genetically undetermined ADCA families.

▼ History
DRPLA appears to have first been described by Smith et al. (1958). Smith (1975) wrote about the disorder under the designation dentatorubropallidoluysian atrophy.

(文献)
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