Huntington病
正常時の不随意運動調節のメカニズム
黒質緻密部のドパミン神経細胞でドパミンが産生された後、黒質線条体神経路によって線条体に送られる。ドパミンは線条体(尾状核・被殻)の直接路ニューロンに対してはドパミンD1受容体を介して興奮性に働き、間接路ニューロンに対してはドパミンD2受容体を介して抑制性に働く。
直接路ニューロンは淡蒼球内節を抑制することで、視床を脱抑制させて大脳皮質の興奮性を高める役割を果たす。
間接路ニューロンは淡蒼球内節を促進することによって、視床を抑制して大脳皮質の興奮性を弱める役割を果たす。
正常時は間接路ニューロンと直接路ニューロンが上手くバランスの取れた働きをすることで、不随意運動調整のメカニズムを機能させている。
Huntington病の病態
Huntington病では常染色体優性遺伝性に尾状核神経細胞の間接路ニューロンが変性して脱落する。
間接路ニューロンが機能しなくなり、直接路ニューロンのみが機能するため淡蒼球内節が過剰に抑制されるようになる。
このため、淡蒼球内節(大脳基底核)から抑制性入力を受けなくなった視床は常に脱抑制された状態となる。
結果として、大脳皮質が過剰に興奮して過剰な運動が生じてしまう。
Huntington病の症状
まず、常染色体優性遺伝性のポリグルタミン病の機序で尾状核神経細胞が変性することによって間接路ニューロンが脱落してしまい舞踏運動などの不随意運動が引き起こされる。
やがて、大脳皮質の神経細胞も障害されるようになり認知機能が低下したり精神症状(易怒性・脱抑制)を呈するようになる。
舞踏運動
不規則に繰り返されるやや素早い不随意運動を指し、手先や足先が勝手に素早く動いたり顔面が不規則にしかめ面になったりする。
歩行をするとき、不随意運動によってまるで踊っているかのようにみえることがあるため舞踏運動(chorea)と呼ばれるようになった。
Huntington病の検査(頭部CT・頭部MRI)
尾状核神経細胞が変性するため尾状核は萎縮する。
これに伴って側脳室は拡大する。
尾状核は側脳室に接しているという解剖学的位置を知っておくのが重要である。
Huntington病の治療
不随意運動(舞踏運動)に対しては抗精神病薬(ハロペリドールなど)が有効となる。
また、L-dopaは直接路を亢進させて間接路を抑制するため、不随意運動(舞踏運動)を憎悪させてしまうことに注意する。
参考文献
Huntington病の診断,治療,療養の手引き:https://www.jstage.jst.go.jp/article/jsnt/37/1/37_61/_pdf/-char/ja
第17章 ハンチントン病およびクロイツフェルト・ヤコブ病:http://www1.odn.ne.jp/~aag13140/chap17.pdf
ポリグルタミン病(トリプレットリピート病)
3塩基の繰り返し配列(トリプレット・リピート)が異常に伸長することで引き起こされる一群の遺伝性疾患はトリプレットリピート病と総称される。
トリプレットリピート病のうち、ポリグルタミン鎖をコードするCAGリピートが異常伸長するものはポリグルタミン病と呼ばれている。
ポリグルタミン病としてはHuntington病・球脊髄性筋萎縮症・歯状核赤核淡蒼球ルイ体変性症(DRPLA)・Machado-Joseph病(脊髄小脳失調症3型)などが挙げられる。
ポリグルタミン病の機序
原因遺伝子のエキソンにグルタミンをコードするCAGの3塩基単位が異常に繰り返してしまうことで、ポリグルタミン鎖が異常に伸長した変異タンパク質が生じる。
この変異タンパク質は凝集しやすく脳や脊髄に蓄積することで神経細胞死を引き起こす。
ポリグルタミン病の確定診断
遺伝子検査でトリプレットリピートを同定する。
表現促進現象
世代を重ねるごとにリピート数が増加することによって、親世代よりも子世代の方が早期に発症したり重症化してしまう現象を指す。
球脊髄性筋萎縮症(Kennedy-Alter-Sung症候群)
CAGトリプレットリピートの生じた異常アンドロゲンゲン受容体蛋白質が脊髄前角細胞や舌下神経核などの延髄の下位運動ニューロン内に凝集することによって変性・脱落を引き起こす疾患である。
30～60歳頃から球麻痺や筋力低下といった下位運動ニューロン症状が生じる。
他のトリプレットリピート病は全て常染色体優性遺伝形式をとるのに対して、球脊髄性筋萎縮症は唯一伴性劣性遺伝形式をとるのが重要である。
女性化乳房などのアンドロゲン不全症状を呈すことと血清CKが高値となることが特徴的な所見であり、知っておく必要がある。
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