疾患詳細

疾患詳細





#143100
Huntington disease (HD)
(Huntington chorea)

Huntington 病
(Huntington 舞踏病)
指定難病8 ハンチントン病

責任遺伝子:613004 Huntingtin (HTT) <4p16.3>
遺伝形式:常染色体優性

(症状)
(GARD)
 <30%-79%>
 Abnormality of movement (運動異常) [HP:0100022] [026]
 Abnormality of the voice (声異常) [HP:0001608] [023]
 Behavioral abnormality (行動異常) [HP:0000708] [022]
 Cerebral cortical atrophy (大脳皮質萎縮) [HP:0002120] [160121]
 Dementia (認知症) [HP:0000726] [0123]
 Developmental regression (発達退行) [HP:0002376] [0125]
 EEG abnormality (脳波異常) [HP:0002353] [01405]
 Spasticity (痙縮) [HP:0001257] [0241]
 
 <5%-29%>
 Rigidity (固縮) [HP:0002063] [0240]
 
 
 Abnormality of eye movement (異常眼球運動) [HP:0000496] [0695]
 Autosomal dominant inheritance (常染色体優性遺伝) [HP:0000006]
 Bradykinesia (寡動) [HP:0002067] [02608]
 Cerebellar atrophy (小脳萎縮) [HP:0001272] [16013]
 Chorea (舞踏病) [HP:0002072] [02600]
 Depressivity (うつ) [HP:0000716] [0206]
 Gait ataxia (歩行失調) [HP:0002066] [028]
 Gliosis (グリオーシス) [HP:0002171]  [160127]
 Hyperreflexia (反射亢進) [HP:0001347] [0241]
 Neuronal loss in central nervous system (中枢神経系ニューロン喪失) [HP:0002529]
 Personality changes (性格変化) [HP:0000751] [02217]
 Seizures (けいれん) [HP:0001250] [01405]

(UR-DBMS)
【一般】*認知症
【神経】反射亢進
 *進行性の舞踏病 (四肢, 体幹, 顔)
 動作緩慢
 けいれん (若年型)
 固縮(若年型)
 失調歩行 (若年型)
 歯状核と被殻でニューロン喪失とグリオーシス
 小脳萎縮 (若年型)
 うつ
 性格変化
【顏】口腔運動機能障害 (若年型)
【眼】異常な眼球運動
【その他】小児期ないし60歳代発症 (中央値 35-40)
 黒人より白人に多い
 若年性の固縮性早期発症型は父から遺伝したものが多い
 リピート伸長 (正常) 9-29 (HD) 36-121
 完全浸透

【一般】**家族歴陽性
 (肺炎, 尿路感染症, 褥瘡, 心不全)
【神経】失調歩行
 (捻転ジストニア)
 不明瞭な会話
 舌 / 口蓋運動異常
 (情緒不安定, パラノイア)
 (若年発症患者では痙縮
固縮)
【X線】尾状核萎縮 (進行例で) → neuroacanthosis / Hallervorden-Spatz 病などでみられる
【皮膚】皮膚潰瘍

(小児) 進行性の知能退化, けいれん, 言語困難, 行動異常はあまり明らかではない

(要約) Huntington 病 (2018.7.5)
(Huntington 舞踏病)
●Huntington 病は, 運動, 認知および精神障害の進行性疾患である
 平均発症年齢は 35 〜 44 歳で, 平均生存期間は発症から 15 〜 18 年である
 約2/3は神経症状で初発, 残りは精神症状が初発
  早期の症状:眼球運動の軽微な変化, 協同運動障害, 軽微な不随意運動, 計画できない, うつまたは不穏がみられる
 →通常活動の大部分が可能で, 仕事を継続できる
 →舞踏病が明白となり, 随意運動ができなくなり, 構音障害と嚥下障害が悪化する
  仕事を諦め, 介助を必要とする
 発症後の中央生存期間は15~18年
 平均死亡年r寧は54~55歳
●診断:家族歴陽性, 特徴的臨床症状, HTT の36以上の CAGリピートの伸長検出
●治療
 舞踏病→haloperidol, olanzapine, benzodiazepines, tetrabenazine
 寡動と固縮→抗パーキンソン病剤
 精神障害 (うつ, 精神症状, 攻撃性)→抗てんかん薬
 ミオクローヌス性多動→ valproic acid
・L-dopa→舞踏病を増加させるかも
●遺伝:常染色体優性
●示唆する所見
 舞踏病の特徴をもつ進行性運動障害 (随意運動も障害されうる)
 知的障害 (認知低下, 性格変化+/-うつ)
 常染色体優性に一致する家族歴
●遺伝子診断:HTT 遺伝子
 エクソン1の CAG リピート数の増加
 正常アレル [p.Gln18(<26)]: 26以下 CAG リピート
 中間アレル [p.Gln18(27_35): 27-35 CAG リピート→症状発症のリスクはないが, HD範囲の子供をもつ可能性あり ( "mutable normal alleles")
 HD-原因アレル [p.Gln18(>36): 以上 CAG リピート
  浸透度減少 HD-原因アレル [ p.Gln18(36_39)]: 36-39 CAG リピート→HDのリスクをもつが症状を生じないかも
  完全浸透HD-原因アレル [p.Gln18(>40)]: 40以上 CAG リピート→HDを発症する
●分類
1) Presymptomatic HD [遺伝子確定] (Clinically at risk for HD [遺伝子未確定])
 臨床的運動サインなし (motor DCL = 0 or 1)
 認知サインなし
 画像, 運動評価などの変化+/-
 治療の必要性なし
 安全な場合は疾患修飾療法
2) Prodromal HD [遺伝子確定] (Clinically prodromal HD [遺伝子未確定])
 軽微な運動サイン (motor DCL = 2) +/-軽微な認知サイン
 軽微な機能の低下
 無気力またはうつなど+/-
 画像や運動ひょかで変化あり
 治療の必要性+/-
 適切な疾患修飾療法
3) 顕性 HD [遺伝子確定] (臨床症状 HD [遺伝子未確定])
 臨床的運動+/-認知サインあり
 機能変化 (全機能低下)
 Motor DCL = 3 または 4
 適切な対症および疾患修飾療法
●臨床症状
1) 早期:不器用, 動揺, 不穏, 不安, 脱抑制, 幻覚, 異常眼球運動, うつ, 嗅覚鳥害
2) 中期:ジストニア, 不随意運動, 平衡/歩行障害, 舞踏病, 捩れおよびもがき運動 (twisting & writhing motions), 反射運動, よろめき (staggering), 揺れ (swaying), ばらばら歩行 (disjointed gait), 巧緻障害, 緩徐な随意運動, 運動速度や強さを変えられない, 反応時間が遅い, 全身筋力低下, 発語困難, 頑固
3) 後期:固縮, 寡動, 重度の舞踏病, 重度の体重減少, 歩行不能, 発語不能, 嚥下障害, 窒息,
●病理学:尾状核と被殻ニューロンの選択的変性
 ニューロン内の huntingtin を含む封入体
●若年齢 HD: 20歳以前に症状あり, HDの 5%-10%
 重度精神遅滞, 目立つ運動および小脳症状, 発語および言語遅滞, 急激な悪化
 てんかん性けいれんは10歳以前の HDの 30%-50% にみられる
 10歳代では症状は成人HDにより似てくる
●遺伝子型-表現型相関
 成人発症→36-55リピート
 若年発症→ 60 以上のリピート
 中間アレル (27 〜 35 CAG repeats) は通常は症状なし
 小さなCAGサイズ→遅発
 CAGサイズは発症年齢の多様性の70%を説明し, 10-20%はその他の遺伝因子による
●表現促進あり
●頻度:3-7/100,000 西欧人
 日本, 中国, フィンランド, アフリカ人では少ない
 日本:0.1 〜 0.38/100,000人
●鑑別診断
1) Huntington disease-like 1 (HDL1) (OMIM 603218)
 早期発症の緩徐進行性プリオン病で, 常染色体優性し, HDとオーバーラップする幅広い症状をもつ
 PRNPの 8 extra octapeptide repeats が原因
 同じ遺伝子は Creutzfeldt-Jakob 病も生じうる
2) Huntington disease-like 2 (HDL2)
 HDと臨床的に区別できない
 運動, 情緒, 認知障害が進行し, 10-20年で死亡する
 JPH3遺伝子の CTG/CAG リピート伸長が原因
 アフリカ人にみられる
 常染色体優性
3) Chorea-acanthocytosis (ChAc)
 進行性運動障害, 認知および行動変化, サブクリニカルなミオパチー, 慢性高CK血症
 有棘赤血球症は多様 (5%-50%)
 VPS13A遺伝子変異が原因
 常染色体劣性
4) McLeod neuroacanthocytosis syndrome (MLS)
 男性での中枢神経系, 神経筋および造血器障害
 基底核変性, 認知障害, 精神症状あり
 有棘赤血球, 代償性溶血, McLeod 血液型
 XK 遺伝子変異が原因
 X連鎖性
5) Spinocerebellar ataxia type 17 (SCA17)
 舞踏病, 認知症, 精神障害, 小脳失調
 常染色体優性
6) Dentatorubral-pallidoluysian atrophy (DRPLA)
7) Benign hereditary chorea (OMIM 118700)
8) Hereditary cerebellar ataxia
9) Creutzfeld-Jakob disease
10) Early-onset familial Alzheimer disease
11) Familial frontotemporal dementia with parkinsonism-17 (FTDP-17)

<指定難病8 ハンチントン病>
概要
  ハンチントン病は, 常染色体優性遺伝様式をとり, 舞踏病運動を主体とする不随意運動と精神症状, 認知症を主症状とする 慢性進行性神経変性疾患である。
 ハンチントン病はポリグルタミン病の一つで, 病因遺伝子は第4染色体 短腕 4p16.3 の HTT である。遺伝子産物は huntingtin とよばれる。
 浸透の高い遺伝病とされており, 環境による発症率の差異は報告されていない。
 ポリグルタミン病の特徴としての表現促進現象が見られる。
 主として成人に発症し, 好発年齢は 30 歳台であるが, 小児期から老齢期まで様々な年齢での発症が見られる。男女差はない。
 約10%の症例は 20 歳以下で発症し, 若年型ハンチントン病と称する。
 優性遺伝のため多くは両親のどちらかが本症に罹患しているが, 小児期発症例(特に幼児期発症例)の場合には, 表現促進現象のため小児発症者の遺伝子診断が, 両親のどちらかにとっての発症前診断とな ってしまうこともあり留意する必要がある。罹病期間は一般に 10~20 年である。
 臨床像では舞踏運動を主症状とする不随意運動と精神症状とがある。舞踏運動は早期には四肢遠位部に見られることが多いが, 次第に全身性となり, ジストニアなど他の不随意運動が加わる。運動の持続障害があり, 転倒, 手の把持持続障害の要因となる。
 精神症状には人格障害と易刺激性, うつなどの感情障害と認知機能低下を認める。進行期になると立位保持が不能となり, 臥床状態となる。てんかん発作を合併することもある。

原因
 ハンチントン病はポリグルタミン病の一つである。臨床症状と huntingtin の CAG リピート数との間には, 関連があり, リピート数が多いほうが若年に発症し, かつ重篤である。また, 世代を経るごとにリピート数は増加する傾向があり(表現促進現象), 病因遺伝子が父親由来の際に著しい。この父親由来での繰り返し数 の増大の要因として, 精母細胞での繰り返し数がより不安定であることが推定されている。huntingtin は 様々な組織で発現されているが, 現時点では huntingtin の機能は不明である。

症状
 多くの症例で舞踏運動を中心とする不随意運動, 運動の持続障害, 精神症状を様々な程度で認める。臨床像は家系内でも一定ではない。発症早期には巧緻運動障害と軽微な不随意運動, 遂行運動の障害, うつ状態もしくは易刺激性などを認めるのみである。やや進行すると舞踏運動などの不随意運動が明らかとなり, 随意運動も障害される。不随意運動はジストニアやアテトーゼ, ミオクローヌス, 振戦であることもある。 さらに進行すると構音, 構語障害が目立つようになり, 人格の障害や認知障害が明らかとなる。最終的に は日常生活全てに要介助, 次いで失外套状態となる。

治療法
 現時点では根治治療はない。舞踏運動など不随意運動および精神症状に対して対症療法を行う。
 主としてドパミン受容体遮断作用を示す抗精神病薬を使用する。その他, クレアチン, CoQ10, リルゾール, 胆汁酸誘導体, 多糖体などの投与が試みられているが, 現在のところ有効性は確立されていない。

予後
 慢性進行性に増悪し, 罹病期間は 10~20 年である。死因は低位栄養, 感染症, 窒息, 外傷が多い。

<指定難病診断基準>
1 遺伝性
 常染色体優性遺伝の家族歴
2 神経所見
 (1) 舞踏運動(chorea)を中心とした不随意運動と運動持続障害。ただし若年発症例では仮面様顔貌,筋固縮,無動などのパーキンソニズム症状を呈することがある。
 (2) 易怒性,無頓着,攻撃性などの性格変化・精神症状
 (3) 記銘力低下,判断力低下などの知的障害(認知症)
3 臨床検査所見
 脳画像検査(CT,MRI)で尾状核萎縮を伴う両側の側脳室拡大
4 遺伝子診断
 DNA 解析によりハンチントン病遺伝子に CAG リピートの伸長がある。 →SRLなど
5 鑑別診断
(1) 症候性舞踏病
 小舞踏病,妊娠性舞踏病,脳血管障害
(2) 薬剤性舞踏病
 抗精神病薬による遅発性ジスキネジア その他の薬剤性ジスキネジア
(3) 代謝性疾患
 ウイルソン病,脂質症
(4) 他の神経変性疾患
 歯状核赤核淡蒼球ルイ体萎縮症
 有棘赤血球症を伴う舞踏病
6 診断の判定
 次の①~⑤のすべてを満たすもの,あるいは③及び⑥を満たすものを,ハンチントン病と診断する。
 ① 経過が進行性である。
 ② 常染色体優性遺伝の家族歴がある。
 ③ 神経所見で,(1)~(3)のいずれか1つ以上がみられる。
 ④ 臨床検査所見で,上記の所見がみられる。
 ⑤ 鑑別診断で,上記のいずれでもない。
 ⑥ 遺伝子診断で,上記の所見がみられる。
7 参考事項
(1) 遺伝子検査を行う場合の注意
 ① 発症者については,本人又は保護者の同意を必要とする。
 ② 未発症者の遺伝子診断に際しては,所属機関の倫理委員会の承認を得て行う。また以下の条件を満 たすことを必要とする。
 (a) 被検者の年齢が 20 歳以上である。
 (b) 確実にハンチントン病の家系の一員である。
 (c) 本人又は保護者が,ハンチントン病の遺伝について正確で十分な知識を有する。
 (d) 本人の自発的な申し出がある。
 (e) 結果の告知方法はあらかじめ取り決めておき,陽性であった場合のサポート体制の見通しを明らか にしておく。
(2) 歯状核赤核淡蒼球ルイ体萎縮症は,臨床事項がハンチントン病によく似る場合があるので,両者の鑑別 は慎重に行わなければならない。なお両疾患の遺伝子異常は異なり,その検査法は確立している。

<重症度分類>
機能的評価:Barthel Index :85 点以下を対象とする。
障害者総合支援法における障害支援区分における「精神症状・能力障害二軸評価」を用いて精神症状評価2以上若しくは能力障害評価2以上を対象とする。


(参照) *600947 Huntingtin-associated protein (HAP1) (変異 HD タンパクと結合するラット脳タンパク): その他の (CAG)n リピートをもつ疾患 = Spinocerebellar ataxia type 1 (164400), Machado-Joseph 病 (109150), Spinobulbar muscular atrophy (313700.0014)
(責任遺伝子) *613004 Huntingtin (HTT) <4p16.3>
(1) Huntington disease (143100)
.0001 Huntington disease [HTT, (CAG)n expansion] (rs71180116) (RCV000030659) (Gellera et al. 1996)
・gene is a polymorphic expanded unstable trinucleotide (CAG)n repeat.
Normal range 9-37 repeats (mean 18.29-19.71).
HD range 37-86 (mean 46.42)
(2) Lopes-Maciel-Rodan syndrome (617435)
.0002  Lopes-Maciel-Rodan syndrome [HTT, PRO703LEU] (rs768047421) (gnomAD:rs768047421) (RCV000477706) (Lopes et al. 2016)
.0003  Lopes-Maciel-Rodan syndrome [HTT, THR1260MET] (rs34315806) (gnomAD:rs34315806) (RCV000477735) (Lopes et al. 2016)
.0004  Lopes-Maciel-Rodan syndrome [HTT, IVS34DS, G-A, +1] (rs1060505027) (RCV000490292...) (Rodan et al. 2016)
.0005  Lopes-Maciel-Rodan syndrome [HTT, PHE2719LEU] (rs1060505028) (RCV000477714) (Lopes et al. 2016)

*HTT (Huntingtin): genome 169,451 bp, Plus strand; 3142 aa, 347603 Da
 Exons: 67, Coding exons: 67, Transcript length: 13,475 bps, Translation length: 3,142 residues
 Exons: 3, Coding exons: 3, Transcript length: 429 bps, Translation length: 112 residues
●Huntingtin は線条体ニューロンの喪失が特長の Huntingtin 病に連鎖する遺伝子である
 →huntingtin 遺伝子のエクソン1にある不安定なトリヌクレオチドリピート (タンパクの polyglutamine リピートとして翻訳される) の拡大が原因である
 正常者では幅広い範囲のリピート数がみられ, 40リピート以上が病的である
・huntingtin座は大きく 180 kb にスパンし67のエクソンからなる
・huntingtin 遺伝子は幅広く発現され, 正常な発生に必要である
・2つの選択的ポリアデニル化型で発現され, 組織で異なる多さで分布する
 大きな転写産物は約 13.7 kb で主に成人と胎児の脳で発現される
 小さな転写産物は約 10.3 kb でより幅広く発現される
・Huntington 病を生じる遺伝子障害は, 転写産物の除去である必要はない
 →mRNA に新しい特性を与える, またはタンパクの機能を変化させる
・huntingtin-associated protein-1 は脳で多く発現され, ポリグルタミンリピートの拡大をもつhuntingtinタンパクへの親和性の増加をもつ
 この遺伝子は, 翻訳抑制を通して huntingtin 遺伝子産物の発現を抑制する 5' UTR の上流 ORF を含む
●関係する pathway: Mesodermal Commitment Pathway, Direct p53 effectors
●微小管仲介による輸送または小水疱機能で役割をもつ

(ノート)
●Huntington 病 (HD) は常染色体優性疾患である
 進行性の選択的 (限局性) の神経細胞死と精神運動技術の減少, 舞踏病運動および認知症を伴う
 疾患は'huntingtin'と呼ばれ, 4p16.3 に座をもつ遺伝子内にある CAG triplet (または '多グルタミン') リピートの増加を伴う
 疾患変異は十分に優性で, ホモはヘテロ接合体よりさらに重症ではない (Wexler ら, 1987)
 長い間, 父からの伝達は重症度が増加し (例, 硬縮), 早期発症で (anticipation), 母からの伝達より進行が早いことが分かっていた (van Dijk ら, 1986)

●Huntington 病の古典的徴候は, 進行性舞踏病, 硬縮および認知症で, しばしば痙攣を伴う
 典型的には, 軽度の精神的および行動的症状の潜伏期があるが, うつと精神疾患は疾患遺伝子の発現の前神経症状の示唆より, リスクがあることの不確かさによるストレスとより奸計しているようだ (Giordani ら, 1995)
 しかし, 重度の精神疾患は数家系では神経兆候に先行しうる (Lovestone ら, 1996)
  数家系は舞踏病のない認知症が先行しうる (Behan and Bone, 1977)
 精神運動技術の減退が早期に生じる (Bamford ら, 1995)
  有意に低い認知機能, 主に注意, 学習および計画機能が臨床診断以前に神経精神試験により遺伝子保因者で明らかになりうる (Rosenberg ら, 1995)
 発症年齢は非常に差異があり, 10歳以前から60歳代まであり, 中央は30-40歳である (Chandler ら, 1960)
 臨床症状は重度の舞踏病運動と認知症の増加を伴い進行性に発達する
  最初の症状が出現後平均17年で死亡する
 PET による尾状核でのブドウ糖取り込みの減少の証明が組織喪失に先行し, 前症状筋緊張低下の疾患の示唆かもしれない (Hayden ら, 1986)
 Huntington 病の患者の尾状核ではミトコンドリア呼吸鎖の著明な欠乏がある (Gu ら, 1996)

●ベネズエラ人大家系と小さな米国人家系の研究の結果から, 4番染色体短腕にマップされていた無名DNA断片との連鎖が発見された (Gusella ら, 1983)
 その後の研究は原因遺伝子を 4p16.3 にマップした(Buetow ら, 1991)
●Huntington's Disease Collaborative Research Group (1993) は標的領域の遺伝子 (彼らは IT15 と命名) は多型の trinucleotide リピート, (CAG)n を含んでいることを発見した
 伸展し HD 染色体で不安定であった
 予測されたタンパク, huntingtin, はニューロンを含む多くの細胞の細胞質と核に幅広く発現されている (Hoogeveen ら, 1993; Dure ら, 1994; De Rooij ら, 1996)
 HD のヘテロ接合体は正常と変異体 RNA を発現する(Ambrose ら, 1994)
 ヒト線条体では, huntingtin はパッチ様分布で, 潜在的に HD で侵される最初の領域に相当する
 huntingtin の細胞での局在は somatodendritic 領域で主にみられる cytosolic タンパクに一致し, 特に microtubules と連関する (Gutekunst ら, 1995)

●脳から抽出された細胞質タンパクの解析は, CAGリピート配列と特異的に相互作用するRNA 結合タンパクを明らかにした
 より長いリピートは実質的により多くのタンパクと結合する (McLaughlin ら, 1996)
 そのようなタンパクは酵素 glyceraldehyde-3-phosphate dehydrogenase (GAPD; 138400)で, ポリグルタミン経路をもつもう一つのタンパクとも結合する
  すなわちdentatorubral-pallidoluysian atrophy の DRPLA タンパク (125370) (Burke ら, 1996)
 このことは RNA 結合タンパクが trinucleotide-連関神経疾患の機序に含まれるメカニズムを示唆する
●Roses (1996) のレビューを参照
●Huntingtin は apopain (CASP3; 600636)により分割される
 HD は不適当なアポトーシスの疾患かもしれないと示唆する(Goldberg ら, 1996)

●変異遺伝子は (CAG)n リピートのサイズを測定することで検出される
 したがって予測試験は可能である
 リピート数の幅は正常では9-37で, HD 患者では37-86である (Read, 1993)
 不完全浸透がリピート長36-40 CAGs でみられている (Rubinsztein ら, 1996)
 Huntington 病の全変異 (遺伝子のコード領域での CAG trinucleotide リピートの増幅) はいわゆる29-35 CAG リピートを含む intermediate alleles (IAs) から生じる
 伸長されたリピートは不安定である
 精子形成での伸長のリスクが卵子形成でのリスクより大きい
  発症年齢と CAGリピート長には逆相関がある (Ranen ら, 1995)
  父伝達による anticipation を説明する
 1つの精子での HD 遺伝子の CAG triplet リピート領域の研究は, 平均サイズアレルで少数の短縮変異を示した
  30リピートの正常アレルで11% の変異率であった
  36リピートのintermediate alleleでは53%の変異率であった
 疾患アレル (38 - 51 リピート) は非常に高い変異率 (92 to 99%) を示した (Leeflang ら, 1995)
 散発性 HD 家系での intermediate alleles は同じサイズと配列をもつ一般集団より不安定であった (Chong ら, 1997)
●Brinkman ら(1997) は, CAG リピートサイズと HD 発症年齢との関係を定義した
 完全な HD の浸透はCAG リピートサイズ42以上で見られたが, 36-41リピートの少数が正常寿命内に HDの症状を示した
 彼らのデータは特別の VAGサイズと年齢による患者になりやすさに関する情報を提供した
  予測試験プログラムで有用かもしれない
  HDのリスク増加をもつヒトへの臨床試験のデザインに有用かもしれない

●DNA 解析による予測試験の試みは不幸であり恩恵でもある
 リスクのあるヒトは試験を受けるかどうか決める時, ハイリスクである時の負の効果よりローリスクである時の利益に重きをおかねばならない (Wexler, 1992; Hayes, 1992)
 予測試験に先行し, 成功させるための広範なカウンセリングプロトコールに対して多くの努力がなされた (Read, 1993)
 長い間, 予測試験は検査を受けた人の心理的健康に有益な結果をもたらした (Wiggins ら, 1992)
 リスクのある小児の予測試験は落胆させてきた (Read, 1993)
  両親が陽性の胎児の中絶を希望しなければ, 出生前診断も同様であった (Quarrell ら, 1988; Bloch and Hayden, 1990)
 両親のリスクを決めずに胎児で連鎖解析でおこなわれる除外試験も難しい問題がある (Tolmie ら, 1995)
 HDの PCR 診断は HDの(CAG)n リピートのすぐ下流の中等度多型のポリプロリン (CCG)n リピートの伸長により複雑化される
 理想的には2つの PCR反応のシリーズが HD を除外するため行われるべきである
  1つは(CAG)n 径のみを増幅する
  1つは (CCG)n 径のみを増幅する
  1つは全領域を増幅する (Gellera ら, 1996)

●多くの西欧諸国での Huntington 病の頻度は30-70/100万で, 黒人, 日本人, フィンランド人では少ない (Palo ら, 1987)
 北アイルランドでは遺伝的適合が HD患者集団で増加していたが, リスク集団では増加していなかった
 リスクのある人は家族サイズをHD発生の恐怖または遺伝相談後に制限したようだ (Morrison ら, 1995)
 ウェールズでの安定的減少傾向は遺伝相談プログラムによっていた (Quarrell ら, 1988)
 進化的考察は干渉がないとすれば, HDはまだ増加することを示すであろう (Rubinsztein ら, 1994)

●マウスモデルはHD遺伝子は着床後の分化発生に必須であり, 基底核の正常な機能に重要な役割をもつことを示唆する (Nasir ら, 1995)
 ヒトの疾患は機能獲得を含む (Duyao ら, 1995)
  huntingtin はアポトーシス経路動作の counterbalancing プロセッシングに関与する (Zeitlin ら, 1995)
  ヒトhuntingtin タンパクはマウスの遺伝的背景で機能する (Hodgson ら, 1996)
● HD 変異のトランスジェニックマウスでの (CAG)n リピートの行動については Mangiarini ら(1997) も参照のこと

(文献)
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