疾患詳細

疾患詳細





#535000
Leber optic atrophy
(Leber hereditary optic neuropathy; LHON)

Leber 視神経萎縮
(Leber 遺伝性視神経ニューロパチー; LHON)
指定難病302 レーベル遺伝性視神経症
指定難病21 ミトコンドリア病

遺伝形式:ミトコンドリア遺伝
責任遺伝子:
 516000 Complex I, subunit ND1 (MTND1)
 516001 Complex I, subunit ND2 (MTND2)
 516003 Complex I, subunit ND4 (MTND4)
 516004 Complex I, subunit ND4L (MTND4L)
 516005 Complex I, subunit ND5 (MTND5)
 516006 Complex I, subunit ND6 (MTND6)
 516020 Cytochrome b of complex III (MTCYB)
 516030 Complex IV, cytochrome c oxidase subunit I (MTCO1)
 516050 Complex IV, cytochrome c oxidase subunit III (MTCO3)
 516060 ATP synthase 6 (MTATP6)

(症状)
(GARD)
 <80%-99%>
 Mitochondrial respiratory chain defects (ミトコンドリア呼吸鎖障害) [HP:0200125]
 Slow decrease in visual acuity (緩徐な視力低下) [HP:0007924] [06011]
 
 <30%-79%>
 Blurred vision (霧視) [HP:0000622] [06012]
 Central scotoma (中心暗点) [HP:0000603] [06009]
 Centrocecal scotoma (盲点暗点) [HP:0000576] [06009]
 Optic atrophy (視神経萎縮) [HP:0000648] [06522]
 Optic neuropathy (視神経ニューロパチー) [HP:0001138] [06522]
 Retinal telangiectasia (網膜毛細血管拡張) [HP:0007763] [065]
 Retinal vascular tortuosity (網膜血管蛇行) [HP:0012841] [0652]
 
 <5%-29%>
 Ataxia (運動失調) [HP:0001251] [028]
 Myopathy (ミオパチー) [HP:0003198] [0277]
 Peripheral neuropathy (末梢ニューロパチー) [HP:0009830] [0204]
 Postural tremor (姿勢振戦) [HP:0002174] [02604]
 Ventricular preexcitation (心室早期興奮) [HP:0004309] [01700]
 
 
 Arrhythmia (不整脈) [HP:0011675] [01700]
 Central retinal vessel vascular tortuosity (中心網膜血管蛇行) [HP:0007768] [0652]
 Dystonia (ジストニア) [HP:0001332] [0240]
 Incomplete penetrance (不完全浸透) [HP:0003829] [-]
 Leber optic atrophy (Leber 視神経萎縮) [HP:0001112] [06522]
 Mitochondrial inheritance (ミトコンドリア遺伝) [HP:0001427]
 Polyneuropathy (ポリニューロパチー) [HP:0001271] [0204]
 Visual loss (視力喪失) [HP:0000572] [06011]

(UR-DBMS)
【一般】発症時頭痛
 不整脈
【眼】視力のぶれ/混濁 (急性期)
 中心性
 盲点暗点 (急性期)
 中心性網膜血管蛇行 (急性期)
 乳頭周囲毛細血管拡張性微小血管症 (急性期)
 網膜神経線維層腫大 (急性期)
 視神経萎縮 (慢性期)
 視力喪失 (慢性期)
【神経】非特異性ミオパチー
 姿勢性振戦
 運動疾患
 多発性硬化症様疾患 (516003.0001)
 痙性ジストニア
 運動失調
 末梢神経障害
 両側性基底核病変
【その他】1-70歳発症 (95% は50歳代早期までに)
 不完全浸透-病的 mtDNA をもつ約50%の男性と10%の女性が視神経ニューロパチーを発症する
 遺伝的異質性あり
 患者の大多数 (~95%) が, 3つの主要な mtDNA 点変異のうち1つをもつ
(G3460A 516000.0001, G11778A 516003.0001, T14484C 516006.0001)

(要約) Leber 遺伝性視神経ニューロパチー (2016.6.23)
(LHON, Leber'病, Leber 視神経萎縮症, Leber 視神経ニューロパチー)
●Leber 遺伝性視神経ニューロパチー(LHON) は, 若年成人での両側性無痛性亜急性視力不全が特徴である
 男性が女性より4-5倍多い
 患者は通常片眼中心視野のかすみが生じるまでは完全に無症状である
 →類似症状は対眼に平均2-3か月遅れて出現する
 症例の25%では, 視力喪失は発症時両側性である
 視力は大多数で指数以下に重度低下する
 視野は, 拡大する濃い中心または中心または盲点の暗点を示す
 急性期以後, 視神経乳頭は萎縮性となる
 視力の有意な改善はまれで, 大多数は法的盲となる (視力 ≤20/200)
 姿勢振戦, 末梢ニューロパチー.非特異的ミオパチー, 運動障害などの神経学的異常が, 一般集団よりLHONで多い
 一部の患者は (通常女性) は.多発性硬化症様疾患も生じうる
●診断
 若年成人での両側性無痛性亜急性視力不全 +/- 3つの多い mtDNA 病的バリアントの1つ (MT-ND1 の m.3460G>A, MT-ND4 のm.11778G>A, MT-ND6の m.14484T>C in)
●治療;対症療法
 mtDNAのLHONを生じる変異をもつ患者ではECGで pre-excitation syndrome (早期興奮症候群) がみられるかも→心臓科の治療
 眼外神経症状 (失調, 末梢ニューロパチー, 非特異的 mtDNA , 運動障害): 機能障害を最小に
 mtDNAのLHONを生じる変異をもつ患者では緑内障に注意
 アルコールに注意, 禁煙
●遺伝:ミトコンドリア母系遺伝
 性別と年齢依存性に注意してカウンセリング
  mtDNA 変異をもつ母→通常 mtDNA 変異をもつ, 症状は+または-
 母方親戚に視力喪失の親戚をもつことが多いが, 40%は孤発例である
 変異をもつ男性 (患者または患者でない)は子孫に変異を伝達しない
 変異をもつ女性 (患者または患者でない)は全ての子孫に変異を伝達する
 出生前診断は変異がわかっていれば可能であるが, 羊水細胞や胎盤絨毛での変異付加は, 胎児または成人組織より少ないかもしれない
 →変異があることは, 疾患発症, 発症年齢, 重症度, 進行の程度を予測しない
●疑わせる所見
1) 眼科的所見
 若年成人で生じる両側性無痛性亜急性視力不全
 指数以下の重度視力障害
 kinetic または static perimetryでの視野検査での大きな濃い中央または盲点の盲点の暗点
 乳頭充血, 乳頭周囲網膜神経層の浮腫, 網膜毛細血管拡張, 血管蛇行の増加
 (約20%の患者は急性期には眼底異常なし)
 視神経萎縮
 pattern electroretinogram や visual evoked potentialsでの視神経機能障害があり網膜疾患がないことの証明
2) 眼外症状 (神経症状)
 姿勢性振戦
 末梢ニューロパチー
 運動障害
 多発性硬化症様疾患
 非特異的ミオパチー
 不整脈
3) 画像
 MRI は正常のことが多い
 白質病変+/-視神経内の高輝度シグナルがみられうる
4) 生化学
 呼吸鎖障害は他のミトコンドリア病より軽微
 MT-ND1の m.3460G>A 変異が最も重度の生化学的表現型を示す
バリアント  複合体 I 活性      呼吸率   magnetic resonance spectroscopy
m.3460G>A 対照より60%-80% 少ない 30%-35% 0%
m.11778G>A 対照より0%-50% 少ない 30%-50% 75%
m.14484T>C 対照より0%-65% 少ない 10%-20% 50%
5) 家族歴:60%で親戚に患者あり
●確定診断→標的検査, マルチ遺伝子パネル
 m.3460G>A (MT-ND10
 m.11778G>A (MT-ND4): 北欧患者の70%, アジア人患者の80%
 m.14484T>C (MT-ND6): フランス系カナダ人に多い (創始者効果)
○結果の解釈
 LHONでは白血球での Heteroplasmy (変異型と野生型の混合)が10-15%でみられる
 →通常LHONでは白血球での変異 mtDNA は70%以上でみられる
●発症年齢は10〜20歳代がピーク
 視力喪失した患者の95%は50歳以前に喪失
 男性患者が4-5倍女性より多いが, 性別も変異の状態も最初の視力喪失の時期と重症度に有意に影響しない
●遺伝子型-表現型相関
 m.3460G>A →視力障害が最も悪い
 m.11778G>A →中間表現型をもつ
 m.14484T>C →長期的視力予後は最もよい
●視力回復率
 m.11778G>A 4%-25%
 m.14484T>C 37%-64%
 m.3460G>A 15%-25%
●Homoplasmic 患者での視力不全の障害のリスク
       症状リスク     発症中央年齢   男/女比
 m.3460G>A 男32% 女15%  20 歳       4.3:1
 m.3460G>A 男49% 女28% 22 歳       1.7:1
 m.11778G>A 男43% 女11% 24 歳       3.7:1
 m.11778G>A 男51% 女9% 22 歳       5.1:1
 m.14484T>C 男47% 女8% 20 歳       7.7:1
●浸透度: 浸透度の減少が特徴
 変異をもつ男性の50%と女性の90%が盲を生じない
 他の環境因子および遺伝因子が mtDNA 変異と相互作用し視力障害を生じるかを決定している
 →性と年齢が重要なリスク因子
●年齢と関係した浸透度
 発症年齢の95センタイルは50歳である
 →50歳で臨床的に患者でない男性が視力を喪失する確率は1/20となる
●Heteroplasmyと発症
 変異をもつ人の10-15%がHeteroplasmyである
 白血球でのm.11778G>A 変異負荷が75%未満では患者ではなかった
 m.11778G>A 変異負荷が60%以上の男性は視神経ニューロパチーの頻度が以下の男性より多かった
 患者の大多数は homoplasmic である
●表現促進:なし
●命名:以前に使用されたLeber hereditary optic neuroretinopathy は現在使用されない
●頻度
 英国北西部:1:8,500 (1:31,000 が視力障害)
 オランダ:1:39,000
 フィンランド:1:50,000
●アレリック疾患
 少数の家系で mtDNA complex I 変異が視神経萎縮と重度の神経学的症状を示した
 mtDNA complex I バリアント, m.3376G>A と m.3697G>A→ LHON視神経ニューロパチーとMELASの症状
●機序
 ミトコンドリア病であるLHONで何故網膜神経節細胞が選択的に障害されるかは不明である
 健康であった人が若年成人で突然視神経機能障害を生じるのかも不明である

<指定難病> レーベル遺伝性視神経症 (Leber hereditary optic neuropathy)
516000 Complex I, subunit ND1 (MTND1)  3460 G to A 
516001 Complex I, subunit ND2 (MTND2)
516003 Complex I, subunit ND4 (MTND4) 11778 G to A
516004 Complex I, subunit ND4L (MTND4L)
516005 Complex I, subunit ND5 (MTND5)
516006 Complex I, subunit ND6 (MTND6) 14484 T to C
516020 Cytochrome b of complex III (MTCYB)
516030 Complex IV, cytochrome c oxidase subunit I (MTCO1)
516050 Complex IV, cytochrome c oxidase subunit III (MTCO3)
516060 ATP synthase 6 (MTATP6)
1.概要
 ミトコンドリア遺伝子変異が母系遺伝形式を規定し, 他の遺伝因子, エピジェネテイック修飾, 環境因子が発症を制御する視神経変性疾患である。若年男性に好発するが, 母系遺伝のため, 罹患男性の子孫には患者は現れず, 無兆候女性保因者の子孫に患者が現れる。一眼の視力低下, 中心暗点で始まり, 不定期間をおいて反対眼も同様の症状を示す。網膜神経節細胞が変性脱落し, 数ヶ月のうちに, 両眼の高度視神経萎縮にいたる(矯正視力0.1以下)。
2.原因
 ミトコンドリア遺伝子変異(3460, 11778, 14484塩基対変異が90%)が母系遺伝を規定している。しかし, 男性好発性, 視神経限局性, 遅発性発症等の原因は不明である。
3.症状
 両眼性である。進行は亜急性(数週から数ヶ月)である。
(1)視力低下
(2)中心暗点
 光視症(photopsia 光が当たっていないのに光を感じる), 羞明を自覚することがある。
4.治療法
 現時点では治療法が確立されていない。
 コエンザイムQ誘導体のイデベノンやEPI-743が一定の患者に有効であったという報告がある。その他, シクロスポリンなどの免疫抑制, 遺伝子治療, 幹細胞治療, 胚細胞治療などについて研究が推進されている。
5.予後
 ほとんど全ての症例で両眼性であり, 10歳代~30歳代と45~50歳代の二峰性の発症ピークをもって, 視力は0.1以下となる。医学的失明(光覚なし)にいたる割合は高くない。青年期・壮年期に中途社会的失明にいたり, 読書・書字・運転・色識別・顔認識障害等のため, 日常生活や就学・就労に多大な支障を来たす。
<診断基準・重症度分類>
Definite, Probable, Possibleを対象とする。
レーベル遺伝性視神経症診断基準
(1)症状
 ①急性~亜急性, 両眼性, 無痛性の視力低下と中心暗点を認める。両眼同時発症の場合もあるが, 通常は片眼に発症し, 数週から数ヶ月を経て, 対側眼も発症する。
 ②急性期に視神経乳頭の発赤・腫脹, 視神経乳頭近傍毛細血管拡張蛇行, 網膜神経線維腫大, 視神経乳頭近傍出血などの検眼鏡的異常所見のうち一つ以上を認める。
 ③慢性期に乳頭黄斑線維束を中心とした, 様々な程度の視神経萎縮を呈する。
(2)検査所見
 ①特定の塩基対におけるミトコンドリア遺伝子ミスセンス変異を認める。塩基対番号3460, 11778, 14484の塩基置換が大半を占め, 中でも我が国では11778番のグアニンからアデニンへの置換を示すものが同定された患者の90%の例に見られる。これら三大変異は委託検査が可能であるが, その他の変異については遺伝子解析を行っている専門施設に検査を依頼する必要がある。
 ②急性期には眼窩部CT/MRIで球後視神経に異常を認めない。
 ③急性期のフルオレセイン蛍光眼底造影検査で, 拡張蛇行した視神経乳頭近傍毛細血管からの蛍光色素漏出がない。視神経乳頭腫脹を呈する他の疾患では同検査で蛍光色素漏出を示すため, 極めて特異度の高い検査所見である。
(3)鑑別診断
 以下の疾患を鑑別する。
 特発性視神経炎, 脱髄性視神経症(多発性硬化症を含む), 視神経脊髄炎(抗アクアポリン4抗体陽性視神経炎を含む), 虚血性視神経症, 圧迫性視神経症, 中毒性・栄養障害性視神経症, 外傷性視神経症, 他の遺伝性視神経症, 黄斑ジストロフィー
<診断のカテゴリー>
Definite LHON(確定例):(1)症状の①と②もしくは①と③を満たし, かつ, (2)検査所見の①~③の全てを満たす。
Probable LHON(確実例):(1)症状の①もしくは③を満たし, かつ, (2)検査所見の①と②を満たす。
Possible LHON(疑い例):(1)症状の①もしくは③と, (2)検査所見の②③を満たし, 詳細な家族歴で母系遺伝が明らかであるが, ミトコンドリア遺伝子変異を検出できないもの。
LHON carrier(保因者):Definite, Probable, 又はPossibleの患者を母系血縁として有し, (2)検査所見の①に該当する視機能無徴候者。または, 視神経炎や圧迫性視神経症など視機能障害を呈する他疾患で発症する患者のうち(2)検査所見の①を満たすもの。この場合, (2)検査所見の②に反してもよい。

(責任遺伝子) *516000 Complex I, subunit ND1 (MTND1)
(1) Leber optic atrophy (535000)
.0001 Leber optic atrophy (Mitochondrial complex I deficiency, mitochondrial type 3, included) [MTND1, LHON3460G-A [dbSNP:rs199476118] RCV000010370...)
Leber Optic Atrophy (Brown et al., 1992; Howell et al., 1991; Howell et al., 1992; Huoponen et al., 1991; Johns, 1992; Johnset al., 1992; Majander et al., 1991; Paulus et al., 1993; Wong et al. 2002; Jaros et al. 2007)
Mitochondrial Complex I Deficiency, Mitochondrial Type 3 (Hinttala et al. 2006)
.0002 Leber optic atrophy [MTND1, LHON4160C [dbSNP:rs199476119] (RCV000010372) (Howell et al., 1991)
.0003 Leber optic atrophy (NADH-dehydrogenase subunit 1, mitochondrial, mutation in) [MTND1, LHON4216C [dbSNP:rs1599988] (RCV000709875...) (Brown et al., 1992; Johns and Berman, 1991)
.0004 Leber optic atrophy [MTND1, LHON3394C [dbSNP:rs41460449] (RCV000507319...) (Brown et al., 1992; Johns et al., 1992; Obayashi et al., 1992)
.0006 Leber optic atrophy [MTND1, LHON4136G [dbSNP:rs199476121] (RCV000010378) (Howell et al., 1991)
.0010 Leber optic atrophy [MTND1, LHON4171A [dbSNP:rs28616230] (RCV000010384) (Kim et al. 2002)
.0015 Leber optic atrophy [MTND1, LHON3733G-A [dbSNP:rs199476125] (RCV000010389) (Valentino et al. 2004)
(2) Alzheimer disease (502500)
.0005 Alzheimer disease (168600 Parkinson disease, included) [MTND1, ADPD3397G [dbSNP:rs199476120] RCV000010376...) (Shoffner et al., 1993)
(3) Sudden infantile death syndrome (272120)
.0007 Cancer of colon (272120 Sudden infant death syndrome, included) [MTND1, 3308T-C, MET1THR [dbSNP:rs28358582] (RCV000010379...) (Polyak et al. 1998; Rocha et al. 1999)
.0008 Sudden infantile death syndrome [MTND1, 3308T-G, MET1TER [dbSNP:rs28358582] (RCV000010381) (Opdal et al. 1999)
(4) Mitochondrial complex I deficiency, mitochondrial type 3 (516000)
.0009 Mitochondrial complex I deficiency, mitochondrial type 3 [MTND1, 7-BP INV] (RCV000010383) (Musumeci et al. 2000)
(5) Dystonia, adult-onset
.0011 Dystonia, adult-onset [MTND1, 3796A-G [dbSNP:rs28357970] (RCV000010382) (Simon et al. 2003)
(6) MELAS syndrome (540000)
.0012 MELAS syndrome (Leber optic atrophy and dystonia, included) [MTND1, 3697G-A [dbSNP:rs199476122] (RCV000010385...) (Kirby et al. 2004)
.0013 MELAS syndrome [MTND1, 3946G-A [dbSNP:rs199476123] (RCV000010387) (Kirby et al. 2004)
.0014 MELAS syndrome [MTND1, 3949T-C [dbSNP:rs199476124] (RCV000010388) (Kirby et al. 2004)
(7) Deafness, nonsyndromic sensorineural, mitochondrial (500008)
.0016 Deafness, nonsyndromic sensorineural, mitochondrial [MTND1, 3388C-A [dbSNP:rs387906730] (RCV000022892) (Leveque et al. 2007)

(責任遺伝子) *516001 Complex I, subunit ND2 (MTND2)
(1) Leber optic atrophy (535000)
.0001 Leber optic atrophy [MTND2, LHON4917G [dbSNP:rs28357980] (Johns and Berman, 1991)
.0002 Leber optic atrophy [MTND2, LHON5244A [dbSNP:rs199476115] (Brown et al., 1992)
.0003 Leber optic atrophy [MTND2, LHON4640A [dbSNP:rs387906426] (Brown et al. 2001)
(2) Mitochondrial complex I deficiency (252010)
.0004 Mitochondrial complex I deficiency [MTND2, 2-BP DEL, 5132AA [dbSNP:rs199476116] (Schwartz and Vissing 2002)
.0005 Mitochondrial complex I deficiency [MTND2, TRP114TER [dbSNP:rs267606888] (Pulkes et al. 2005)
(3) Leigh syndrome due to mitochondrial complex I deficiency (256000)
.0006 Leigh syndrome due to mitochondrial complex I deficiency [MTND2, LEU71PRO [dbSNP:rs267606889] (Hinttala et al. 2006)

(責任遺伝子) *516003 Complex I, subunit ND4 (MTND4)
.0001 Leber optic atrophy (535000) [MTND4, LHON11778A] (rs199476112) (RCV000224219...) (NADH-dehydrogenase subunit 4, mitochondrial, mutation in) (Wallace et al. 1988; Singh et al. 1989; (Bolhuis et al. 1990;Carducci et al. 1991; Cavelier et al. 1993; Cortelli et al. 1991; Cullom et al. 1993; Erickson and Castora 1993; Hiidaet al. 1991 1992; Holt et al. 1989; Hotta et al. 1989; Howell et al. 1992; Huoponen et al. 1990; Isashiki and Nakagawa 1991; Johns 1990; Johns and Berman 1991; Johns et al. 1992 1993; Kormann et al. 1991; Larsson et al.,1991; Lott et al. 1990; Majander et al. 1991; Mashima et al. 1992 1993; Moorman et al. 1993; Nakamura et al.,1993; Newman 1993; Newman et al. 1991; Newman and Wallace 1990; Norby 1993; Poulton et al. 1991; Singh et al.,1989; Smith et al. 1993; Stone et al. 1990 1992; Sudoyo et al. 1992; Vilkki et al. 1989 1990; Wallace et al. 1988;Weiner et al. 1993; Yoneda et al. 1989; Zhu et al. 1992; Torroni et al. 1997; Chinnery et al. 2001; Wong et al. 2002; Guy et al. 2002; Mimaki et al. 2003; Carelli et al. 2006; Phasukkijwatana et al. 2006; Qu et al. 2006; Ellouze et al. 2008; Ji et al. 2008)
.0002 MELAS syndrome (540000) [MTND4, MELAS11084G] (rs199476113) (RCV000854703...) (Danks et al. 1988; Lertrit et al. 1992; Sakuta et al. 1993)
.0003 Leber optic atrophy and dystonia (535000 & 500001) [MTND4, VAL312ILE] (rs200873900) (RCV000854742...) (Bruyn et al. 1992; De Vries et al. 1996)
.0004 Mitochondrial complex I deficiency (252010) [MTND4, 11777C-A] (rs28384199) (RCV000144013...) (Deschauer et al. 2003)

(責任遺伝子) *516005 Complex I, subunit ND5 (MTND5)
(1) Leber optic atrophy
.0001 Leber optic atrophy [MTND5, LHON13708A [dbSNP:rs28359178] (RCV000010336) (Brown et al. 1992; Johns and Berman 1991; Johns et al. 1992; Johns and Neufield 1991)
.0002 Leber optic atrophy [MTND5, LHON13730A [dbSNP:rs387906425] (RCV000010337) (Howell et al. 1993)
.0009 Leber optic atrophy [MTND5, 12848C-T, ALA171VAL [dbSNP:rs267606899] (RCV000010350) (Mayorov et al. 2005)
.0011 Leber optic atrophy [MTND5, 12338T-C, MET1THR [dbSNP:rs201863060] (RCV000022893) (Liu et al. 2011)
(2) Leigh syndrome due to mitochondrial complex I deficiency (256000, 252010)
.0003 Leigh syndrome due to mitochondrial complex I deficiency [MTND5, 12706T-C, PHE124LEU [dbSNP:rs267606893] (RCV000144015...) (Taylor et al. 2002)
.0006 Leigh syndrome due to mitochondrial complex I deficiency (MELAS syndrome, included) [MTND5, 13084A-T, SER250CYS [dbSNP:rs267606896] (RCV000010343...) (Crimi et al. 2003)
(3) MELAS syndrome (540000)
.0004 MELAS syndrome [MTND5, 12770A-G, GLU145GLY [dbSNP:rs267606894] (RCV000010339) (Liolitsa et al. 2003)
.0005 MELAS syndrome (Leber optic atrophy, included) (Leigh syndrome due to mitochondrial complex I deficiency, included) [MTND5, 13045A-C, MET237LEU [dbSNP:rs267606895] (RCV000010341...) (Liolitsa et al. 2003)
.0007 MELAS syndrome (Leigh syndrome due to mitochondrial complex I deficiency, included) [MTND5, 13513G-A, ASP393ASN [dbSNP:rs267606897] (RCV000144016...) (Santorelli et al. 1997; Kirby et al. 2003; Chol et al. 2003; Sudo et al. 2004; Dickerson et al. 2005; Blok et al. 2007; Shanske et al. 2008)
.0008 MELAS syndrome (545000 MERRF syndrome, included) [MTND5, 13042G-A, ALA236THR [dbSNP:rs267606898] (RCV000010349...) (Naini et al. 2005)
(4) Parkinson disease 6, modifier of (605909)
.0010 Parkinson disease 6, modifier of [MTND5, 12397A-G [dbSNP:rs200890363] (RCV000010351) (Piccoli et al. 2008)

(責任遺伝子) *516006 Complex I, subunit ND6 (MTND6)
(1) Leber optic atrophy
.0001 Leber optic atrophy [MTND6, LHON14484C [dbSNP:rs199476104] (Brown et al. 1992; Johns et al. 1992 1993; Mackey and Howell 1992; Brown et al. 1997; Carelli et al. 1998; Macmillan et al. 2000; Nishioka et al. 2003; Carelli et al. 1999; Howell et al. 2003)
.0002 Leber optic atrophy and dystonia [MTND6, LDYT14459A [dbSNP:rs199476105] (Leigh syndrome due to mitochondrial complex I deficiency) (Kirby et al. 2000; Gropman et al. 2004)
.0003 Leber optic atrophy and dystonia [MTND6, LDYT14596A [dbSNP:rs387906424] (De Vries et al. 1996)
.0004 Leber optic atrophy [MTND6, LHON14495G [dbSNP:rs199476106] (Chinnery et al. 2001)
.0006 Leber optic atrophy [MTND6, LHON14482A [dbSNP:rs199476108] (Valentino et al. 2002)
(2) MELAS syndrome
.0005 MELAS syndrome [MTND6, MELAS14453A [dbSNP:rs199476107] (Ravn et al. 2001)
(3) Leigh syndrome due to mitochondrial complex I deficiency
.0007 Leigh syndrome due to mitochondrial complex I deficiency [MTND6, 14487T-C [dbSNP:rs199476109] (Striatal necrosis, bilateral, with dystonia) (Ugalde et al. 2003; Solano et al. 2003)
(4) Parkinson disease 6, modifier of (605909)
.0008 Parkinson disease 6, modifier of [MTND6, 14319T-C [dbSNP:rs199476110] (Piccoli et al. 2008)
(5) Oncocytoma (553000)
.0009 Oncocytoma [MTND6, 1-BP INS, 14249C] (Bartoletti-Stella et al. 2011)

(責任遺伝子) *516020 Cytochorome b of complex III (MTCYB)
(1) Leber optic atrophy
.0001 Leber optic atrophy [MTCYB, LHON15257A [dbSNP:rs41518645] (Brown et al. 1992; Brown et al. 1991; Brown et al. 1992; Heher and Johns 1993; Huoponen et al. 1993; Johns and Neufeld 1991; Johns et al. 1993; Mackey et al. 1996)
.0002 Leber optic atrophy [MTCYB, LHON15812A [dbSNP:rs200336777] (Brown et al. 1991; Brown et al. 1992; Johns and Neufeld 1991)
(2) Colorectal cancer
.0003 Colorectal cancer [MTCYB, 14985G-A, ARG80HIS [dbSNP:rs207459995] (Polyak et al. 1998)
.0004 Colorectal cancer [MTCYB, 15572T-C, PHE276LEU [dbSNP:rs207459996] (Polyak et al. 1998)
(3) Exercise intolerance
.0005 Exercise intolerance [MTCYB, 15615G-A, GLY290ASP [dbSNP:rs207459997] (Andreu et al. 1999)
.0006 Exercise intolerance [MTCYB, 14846G-A, GLY34SER [dbSNP:rs207459998] (Andreu et al. 1999)
.0008 Exercise intolerance [MTCYB, 15150G-A, TRP135TER [dbSNP:rs207460000] (Legros et al. 2001)
.0009 Exercise intolerance [MTCYB, 15197T-C, SER151PRO [dbSNP:rs207460001] (Legros et al. 2001)
.0012 Exercise intolerance, cardiomyopathy, and septooptic dysplasia [MTCYB, 14849T-C, SER35PRO [dbSNP:rs207460004] (Schuelke et al. 2002)
(4) Encephalopathy, mitochondrial
.0007 Encephalopathy, mitochondrial [MTCYB, 15242G-A, GLY166TER [dbSNP:rs207459999] (Keightley et al. 2000)
(5) Multisystem disorder
.0010 Multisystem disorder [MTCYB, 15579A-G, TYR278CYS [dbSNP:rs207460002] (Wibrand et al. 2001)
(6) Cardiomyopathy, infantile histiocytoid
.0011 Cardiomyopathy, infantile histiocytoid [MTCYB, 15498G-A, GLY251ASP [dbSNP:rs207460003] (Andreu et al. 2000)
(7) Parkinsonism/MELAS overlap syndrome
.0013 Parkinsonism/MELAS overlap syndrome [MTCYB, 4-BP DEL, 14787TTAA [dbSNP:rs207460005] (De Coo et al. 1999)
(8) Obesity, susceptibility to (601665)
.0014 Obesity, susceptibility to [MTCYB, 15497G-A, GLY251SER [dbSNP:rs199951903] (Okura et al. 2003)

(Responsible gene) *516030 Complex IV, cytochrome c oxidase subunit I (MTCO1)
(1) Leber optic atrophy
.0001 Leber optic atrophy (Deafness, aminoglycoside-induced, included) (Deafness, nonsyndromic sensorineural, included) [MTCO1, LHON7444A] (rs199474822) (RCV000010301...) (Brown et al., 1992; Johns and Neufield, 1993; Brown and Wallace, 1994; Yuan et al. 2005)
(2) Sideroblastic anemia, acquired idiopathic
.0002 Sideroblastic anemia, acquired idiopathic [MTCO1, AISA6742C] (rs199476126) (RCV000010302) (Gattermann et al. 1997)
.0003 Sideroblastic anemia, acquired idiopathic [MTCO1, AISA6721C] (rs199476127) (RCV000010303) (Gattermann et al. 1997)
(3) Cytochrome c oxidase deficiency (220110)
.0004 Cytochrome c oxidase deficiency [MTCO1, COX6480A] (rs199476128) (RCV000010304) (Jaksch et al. 1998)
.0006 Cytochrome c oxidase I deficiencyt [MTCO1, 6930G-A] (rs28679680) (RCV000010306) (Bruno et al. 1999)
.0008 Cytochrome c oxidase I deficiencyt [MTCO1, LEU196ILE] (rs28461189) (RCV000010308) (Varlamov et al. 2002)
.0009 Cytochrome c oxidase I deficiencyt [MTCO1, SER142PHE] (rs267606883) (RCV000010309) (Lucioli et al. 2006)
(4) Colorectal cancer (114500)
.0005 Colorectal cancer [MTCO1, GLY121TER] (rs267606882) (RCV000010305) (Polyak et al. 1998)
.0010 Colorectal cancer [MTCO1, GLY125ASP] (rs281865417) (RCV000010310) (Greaves et al. 2006; Namslauer and Brzezinski 2009)
.0011 Colorectal cancer [MTCO1, SER458PRO] (rs267606884) (RCV000010311) (Greaves et al. 2006; Namslauer and Brzezinski 2009)
(5) Myoglobinuria, recurrent
.0007 Myoglobinuria, recurrent [MTCO1, 5920G-A] (rs199476129) (RCV000010307) (Karadimas et al. 2000)

Responsible gene) *516050 Complex IV, cytochrome c oxidase subunit III (MTCO3)
.0001 Leber optic atrophy [MTCO3, LHON9438A] (rs267606611) (RCV000854514...) (Johns and Neufeld 1993, Howell 1994, Oostra et al. 1995)
.0002 Leber optic atrophy [MTCO2, 8009G-A, VAL142MET] (rs200613617) (RCV000756352...) (Johns and Neufeld 1993)
.0003 Mitochondrial complex IV deficiency (220110) [MTCO2, 7671T-A ] (rs267606612) (RCV000010290...) (Keightley et al. 1996)
.0004 Mitochondrial complex IV deficiency [MTCO3, 9952G-A, TRP-TER] (rs267606613) (RCV000010291) (Hanna et al. 1998)
.0005 Mitochondrial complex IV deficiency [MTCO3, 1-BP INS, 9537C] (rs267606614) (RCV000010292...) (Tiranti et al. 2000)
.0006 Mitochondrial complex IV deficiency [MTCO3, 9379G-A, TRP58TER] (rs267606615) (RCV000854509...) (Horvath et al. 2002)
.0007 Seizurtes and lactic acidosis [MTCO3, 2-BP DEL, 9205TA] (rs199476137) (RCV000010281) (Temperley et al. 2003)

(責任遺伝子) *516060 ATP synthase 6 (MTATP6)
(1) Mitochondrial complex V (ATP synthase) deficiency, mitochondrial type 1 (500015)
.0001 Mitochondrial complex V (ATP synthase) deficiency, mitochondrial type 1 (500015) (551500 NARP syndrome, included) [MTATP6, 8993T-G, LEU156ARG [dbSNP:rs199476133] (RCV000191106...) (Holt et al. 1990, Tatuch et al. 1992, Pastores et al. 1994; Degoul et al. 1995; Blok et al. 1997; Kempken et al. 1998; White et al. 1999; Baracca et al. 2000; Kerrison et al. 2000; Hayashi et al. 2000; Nijtmans et al. 2001; Geromel et al. 2001; Porto et al. 2001; Manfredi et al. 2002; Srivastava and Moraes 2001; Carelli et al. 2002; Mattiazzi et al. 2004; Jung et al. 2007; Sgarbi et al. 2009)
.0002 Mitochondrial complex V (ATP synthase) deficiency, mitochondrial type 1 (Ataxia and polyneuropathy, adult-onset, included) [MTATP6, 8993T-C, LEU156PRO [dbSNP:rs199476133] (RCV000495030...) (de Vries et al. 1993; Chakrapani et al. 1998; Fujii et al. 1998; Vilarinho et al. 2001; Rantamaki et al. 2005; Debray et al. 2007; Craig et al. 2007)
.0008 Mitochondrial complex V (ATP synthase) deficiency, mitochondrial type 1 [MTATP6, 9185T-C, LEU220PRO [dbSNP:rs199476138] (RCV000240612...) (Castagna et al. 2007)
.0011 Mitochondrial complex V (ATP synthase) deficiency, mitochondrial type 1 [MTATP6, 9176T-G, LEU217ARG [dbSNP:rs199476135] (RCV000010285) (Carrozzo et al. 2001; Kucharczyk et al. 2009)
(2) Leber optic atrophy (535000)
.0003 Leber optic atrophy [MTATP6, 9101T-C, ILE192THR [dbSNP:rs199476134] (RCV000010277) (Lamminen et al. 1995)
(3) Bilateral striatal necrosis, infantile, mitochondrial (500003)
.0005 Bilateral striatal necrosis, infantile, mitochondrial (Leigh syndrome, included) [MTATP6, 9176T-C [dbSNP:rs199476135] (RCV000010279...) (Thyagarajan et al. 1995; Dionisi-Vici et al. 1998, Makino et al. 1998)
.0006 Bilateral striatal necrosis, infantile, mitochondrial [MTATP6, 8851T-C [dbSNP:rs199476136] (RCV000144005...) (De Meirleir et al. 1995)
(4) Seizues and lactic acidosis
.0007 Seizues and lactic acidosis [MTATP6, 2-BP DEL, 9205TA] (RCV000010281) (Temperley et al. 2003)
(5) NARP syndrome (551500)
.0009 NARP syndrome [MTATP6, 1-BP INS, 8618T [dbSNP:rs387906423] (RCV000010283) (Lopez-Gallardo et al. 2009)
(6) Cardiomyopathy, infantile hypertrophic
.0010 Cardiomyopathy, infantile hypertrophic [MTATP6, MET1THR [dbSNP:rs387906422] (RCV000010272) (Ware et al. 2009)
(7) Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia 3 (500011)
.0012 Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia 3 [MTATP6, SER148ASN [dbSNP:rs794726857] (RCV000171545) (Burrage et al. 2014)

.0004 Removed from database

(責任遺伝子) *590050 Transfer RNA, mitochondrial, leucine, 1 (MTTL1)
(1) MELAS syndrome (540000)
.0001 MELAS syndrome [MTTL1, A-G, NT3243; A3243G; G3243] (520000 Diabetes mellitus-deafness syndrome, maternally transmitted, included) (Muscle stiffness, painful, included) (3-@Methylglutaconicaciduria) (Maculopathy, age-related, included) (Cyclic vomiting syndrome, included) (Mitochondrial complex IV deficiency, included) (Goto et al. 1990; Kobayashi et al. 1990; Kobayashi et al. 1991; Enter et al. 1991; Moraes et al. 1992; Ciafaloni et al. 1992; Lertrit et al. 1992; Mosewich et al. 1993; Matthews et al. 1994; Yoneda et al. 1992; Vries et al. 1994; Manouvrier et al. 1995; Odawara et al. 1995; Yang et al. 1995; Chuang et al. 1995; Matthews et al. 1995; Morten et al. 1995; Damian et al. 1996; Feigenbaum et al. 1996; Yorifuji et al. 1996; Velho et al. 1996; Tamagawa et al. 1997; Lam et al. 1997; Wilichowski et al. 1998; Majamaa et al. 1998; Dashe and Boyer 1998; Chinnery et al. 1998; Sue et al. 1999; Deschauer et al. 1999; Smith et al. 1999; Janssen et al. 1999; Borner et al. 2000; Chomyn et al. 2000; Rahman et al. 2001; Aggarwal et al. 2001; De Kremer et al. 2001; Moilanen and Majamaa 2001; Uimonen et al. 2001; Nagata et al. 2001; Chinnery et al. 2001; Olsson et al. 2001; Torroni et al. 2003; Petruzzella et al. 2004, Jones et al. 2004; Salpietro et al. 2003; Bohm et al. 2006; Pyle et al. 2007; Durham et al. 2007; Donovan and Severin 2006; Uusimaa et al. 2007; Rajasimha et al. 2008)
.0002 MELAS syndrome [MTTL1, T-C, NT3271; T3271C] (Goto et al. 1991; Hayashi et al. 1993)
(2) MERRF syndrome
.0003 MERRF syndrome [MTTL1, C3256T] (Diabetes mellitus, noninsulin-dependent, maternally transmitted) (Moraes et al. 1993; Hirai et al. 1998)
(3) Cardiomyopathy with or without skeletal myopathy
.0004 Cardiomyopathy with or without skeletal myopathy [MTTL1, C-T, NT3303; C3303T] (Silvestri et al. 1994; Bruno et al. 1999)
(4) Encephalomyopathy, mitochondrial
.0005 Encephalomyopathy, mitochondrial [MTTL1, T-C, NT3252; T3252C] (Morten et al. 1993)
.0007 Cardiomyopathy with or without skeletal myopathy [MTTL1, A-G, NT3260; A3260G] (Mariotti et al. 1994)
(5) Progressive external ophthalmoplegia, proximal myopathy, and sudden death
.0006 Progressive external ophthalmoplegia, proximal myopathy, and sudden death [MTTL1, A-G, NT3251; A3251G] (Sweeney et al. 1993; Houshmand et al. 1996)
(6) Skeletal myopathy, responsive to riboflavin
.0008 Skeletal myopathy, responsive to riboflavin [MTTL1, T-C, NT3250; T3250C] (Ogle et al. 1997)
(7) Sudden infantile death syndrome (272120)
.0009 Sudden infantile death syndrome [MTTL1, 3290T-C] (Opdal et al. 1999)
(8) Nenuropsychiatic disorder and early-onset cataract
.0010 Nenuropsychiatic disorder and early-onset cataract [MTTL1, 3274G-A] (Jaksch et al. 2001)
(9) Kearns-Sayre syndrome (530000)
.0011 Kearns-Sayre syndrome [MTTL1, 3249G-A] (Seneca et al. 2001)
(10) Myelodysplastic syndrome
.0012 Myelodysplastic syndrome [MTTL1, 3242G-A] (Gattermann et al. 2004)

(責任遺伝子) *516004 Complex I, subunit ND4L (MTND4L)
(1) Colorectal cancer
.0001 Colorectal cancer [MTND4L, CYS32ARG [dbSNP:rs267606892] (Polyak et al. 1998)
(2) Leber optic atrophy (535000)
.0002 Leber optic atrophy [MTND4L, 10663T-C [dbSNP:rs193302933] (Brown et al. 2002)

(責任遺伝子) +516060 ATP synthase 6 (MTATP6)
(1) Leigh syndrome (256000)
.0001 Leigh syndrome [MTATP6, 8993T-G, LEU156ARG [dbSNP:rs199476133] (551500 NARP syndrome, included) (Holt et al. 1990, Tatuch et al. 1992, Pastores et al. 1994; Degoul et al. 1995; Blok et al. 1997; Kempken et al. 1998; White et al. 1999; Baracca et al. 2000; Kerrison et al. 2000; Hayashi et al. 2000; Nijtmans et al. 2001; Geromel et al. 2001; Porto et al. 2001; Manfredi et al. 2002; Srivastava and Moraes 2001; Carelli et al. 2002; Mattiazzi et al. 2004; Jung et al. 2007; Sgarbi et al. 2009)
.0002 Leigh syndrome [MTATP6, 8993T-C, LEU156PRO [dbSNP:rs199476133] (Ataxia and polyneuropathy, adult-onset, included) (de Vries et al. 1993; Chakrapani et al. 1998; Fujii et al. 1998; Vilarinho et al. 2001; Rantamaki et al. 2005; Debray et al. 2007; Craig et al. 2007)
.0008 Leigh syndrome [MTATP6, 9185T-C, LEU220PRO] (Castagna et al. 2007)
.0011 Leigh syndrome [MTATP6, 9176T-G, LEU217ARG [dbSNP:rs199476135] (Carrozzo et al. 2001; Kucharczyk et al. 2009)
(2) Leber optic atrophy (535000)
.0003 Leber optic atrophy [MTATP6, 9101T-C, ILE192THR [dbSNP:rs199476134] (Lamminen et al. 1995)
(3) Bilateral striatal necrosis, infantile, mitochondrial (500003)
.0005 Bilateral striatal necrosis, infantile, mitochondrial [MTATP6, 9176T-C [dbSNP:rs199476135] (Leigh syndrome, included) (Thyagarajan et al. 1995; Dionisi-Vici et al. 1998, Makino et al. 1998)
.0006 Bilateral striatal necrosis, infantile, mitochondrial [MTATP6, 8851T-C [dbSNP:rs199476136] (De Meirleir et al. 1995)
(4) Seizues and lactic acidosis
.0007 Seizues and lactic acidosis [MTATP6, 2-BP DEL, 9205TA] (Temperley et al. 2003)
(5) NARP syndrome (551500)
.0009 NARP syndrome [MTATP6, 1-BP INS, 8618T [dbSNP:rs387906423] (Lopez-Gallardo et al. 2009)
(6) Cardiomyopathy, infantile hypertrophic
.0010 Cardiomyopathy, infantile hypertrophic [MTATP6, MET1THR [dbSNP:rs387906422] (Ware et al. 2009)
(7) Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia 3 (500011)
.0012 Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia 3 [TATP6, SER148ASN] (Burrage et al. 2014)

.0004 Removed from database

(責任遺伝子) *516030 Complex IV, cytochrome c oxidase subunit I (MTCO1)
(1) Leber optic atrophy
.0001 Leber optic atrophy (Deafness, aminoglycoside-induced, included) (Deafness, nonsyndromic sensorineural, included) [MTCO1*LHON7444A] (rs199474822) (RCV000010301...) (Brown et al., 1992; Johns and Neufield, 1993; Brown and Wallace, 1994; Yuan et al. 2005)
(2) Sideroblastic anemia, acquired idiopathic
.0002 Sideroblastic anemia, acquired idiopathic [MTCO1, AISA6742C] (rs199476126) (RCV000010302) (Gattermann et al. 1997)
.0003 Sideroblastic anemia, acquired idiopathic [MTCO1, AISA6721C] (rs199476127) (RCV000010303) (Gattermann et al. 1997)
(3) Mitochondrial syndromic encephalopathy with cytochrome c oxidase deficiency
.0004 Mitochondrial syndromic encephalopathy with cytochrome c oxidase deficiency [MTCO1, COX6480A] (rs199476128) (RCV000010304) (Jaksch et al. 1998)
(4) Colorectal cancer (114500)
.0005 Colorectal cancer [MTCO1, GLY121TER] (rs267606882) (RCV000010305) (Polyak et al. 1998)
.0010 Colorectal cancer [MTCO1, GLY125ASP] (rs281865417) (RCV000010310) (Greaves et al. 2006; Namslauer and Brzezinski 2009)
.0011 Colorectal cancer [MTCO1, SER458PRO] (rs267606884) (RCV000010311) (Greaves et al. 2006; Namslauer and Brzezinski 2009)
(5) Cytochrome c oxidase I deficiencyt (220110)
.0006 Cytochrome c oxidase I deficiencyt [MTCO1, 6930G-A] (rs28679680) (RCV000010306) (Bruno et al. 1999)
.0008 Cytochrome c oxidase I deficiencyt [MTCO1, LEU196ILE] (rs28461189) (RCV000010308) (Varlamov et al. 2002)
.0009 Cytochrome c oxidase I deficiencyt [MTCO1, SER142PHE] (rs267606883) (RCV000010309) (Lucioli et al. 2006)
(6) Myoglobinuria, recurrent
.0007 Myoglobinuria, recurrent [MTCO1, 5920G-A] (rs199476129) (RCV000010307) (Karadimas et al. 2000)

(ノート)
●LHON は, 中年で, 中心暗点と盲を生じる, 急性または亜急性中心視力喪失としてみられる
 疾患は, mtDNA の多くのミスセンス変異を伴っている
  変異は自律的または互いに連関して疾患を生じる
●18のアレルバリアントがある
 MTND6*LDYT14459A (516006.0002)
 MTND4*LHON11778A (516003.0001)
 MTND1*LHON3460A (516000.0001)
 MTND6*LHON14484A (516006.0001)
 MTCYB*LHON15257A (516020.0001)
 MTCO3*LHON9438A (516050.0001)
 MTCO3*LHON9804A (516050.0002)
 MTND5*LHON13730A (516005.0002)
 MTND1*LHON4160C (516000.0002)
 MTND2*LHON5244A (516001.0002)
 MTCOI*LHON7444A (516030.0001)
 MTND1*LHON3394C (516000.0004)
 MTND5*LHON13708A (516005.0001)
 MTCYB*LHON15812A (516020.0002)
 MTND2*LHON4917G (516001.0001)
 MTND1*LHON4216C (516000.0003)
 MTND1*LHON4136G (516000.0002)
 MTATP6*LHON9101C (516060.0003)
 MTND4L*LHON10663C (516004.0002)
 これらのバリアントの最初の17は MIM12 の表にまとめられている

●Riordan-Eva and Harding (1995)が指摘したように、LHON 家系で証明された多数の mtDNA 変異が、各々の変異の病態機序で混乱を生じているが、少なくとも90%の家系で、主要な3つの変異が 11778, 3460, 14484 bp 位で確定されている
 14484 変異と良好な視力予後との相関は、患者での希望ばかりでなく、LHON 機序へのさらなる研究へのアプローチを提供する

●Yu-Wai-Man et al. (2009) は,LHON と常染色体優性視神経萎縮症 (OPA1; 165500) をレビューした
 →両疾患でミトコンドリア機能障害への網膜神経節細胞の選択的脆弱性を強調した

臨床症状
●LHON 患者は, 中年の, 急性または亜急性, 無痛性, 盲点暗点となる中心視力喪失をもつ
 神経眼科的検査は, 乳頭周囲毛細血管拡張, 微小血管症, 視神経乳頭偽浮腫, および血管蛇行を明らかにすることが多い
  これらの特徴はヌクレオチドペア 11778 変異をもつ患者の58%と, まれに彼らの無症状の母方親戚に観察される
 平均発症年齢は, 27-34歳と報告され, 1歳から70歳までの範囲である
 眼は, 同時または連続性に侵されうる
  両眼間の平均時間は約2か月である
 各々の眼の進行は, 突然で完全視力喪失から, 2年以上かけての進行性低下である
  平均進行歯間は約3.7か月である
 最終視力は 20/50 から光覚なしまでである
  より軽度の変異 (MIM12の表M1参照) は, より軽度の予後をもつ
 したがって, 最も重症の np 11778 患者は, 光覚なしがないかもしれず, 最も重度のnp 15257 患者は, 手動を保存する
 最も重度の np 14484 患者は, 指を数えられる
 視力回復の可能性も, 変異によって変化する
 np 11778 患者の4%のみが, 平均発症後36か月で回復を示す
 np 3460 患者の22%が, 68か月後で回復を示す
 np 15257 患者の28%が, 16か月後回復を示す
 np 14484 患者の37%が, 16か月後回復を示す (Newman, 1993; Newman et al., 1991; Johns et al., 1993)

●Cullom et al. (1993) は,以前に古典的症状に基づき,タバコ-アルコール弱視と診断され,知られている LHON変異を受けた12例中2例が陽性であることを発見した
 →1例は 11778 変異,1例は3460 変異
 タバコやアルコールを乱用する極少数の患者が視神経ニューロパチーを生じるという事実は,個人の感受性の要素を示唆していた (Carroll, 1944)
 Cullom et al. (1993) は,感受性は LHON 連関性ミトコンドリア変異の結果かもしれないと提唱した

●Sadun et al. (2004)は,LHON と11778/haplogroup J 変異をもつ7世代のブラジル人家系からの96例の母方がつながった患者の192眼での眼科所見を報告した
 所見は,LHON発症と臨床症状の重症度への有意な環境リスク因子 (特に喫煙)を証明した
 しかし,喫煙は保因者で検出されたサブクリニカル異常とは相関しなかった
 さらに,サブクリニカル異常は男女間に同等に分布していた

●Mann et al. (2000) は,LHON と 11778 変異をもつ患者1例で末梢網膜静脈炎を報告した
 頭痛に伴う両側性中心性視力喪失に加え,患者は硝子体炎,血管炎および視神経炎をもっていた
 彼女は最初は多発性硬化症をもつと考えられたが,検査はこの診断または他の血管炎の原因をを確証できなかった
 著者らは,かれらの報告は LHON は遺伝子型特異的表現型の幅広いスペクトラムをもつ神経網膜症であるという理論を支持した

●Sadun et al. (2000)は,LHON 2例の視神経で神経線維スペクトラムを調べた
 神経線維の総枯渇は95-99%であった
 光顕および電顕はより小さな神経節細胞である P細胞に一致する最も小さな軸索の主な喪失を明らかにした
 著者らは LHON 患者での P細胞の喪失は色覚異常,中心暗点および瞳孔の対光反射の保持を説明するかもしれないと結論した

● Huoponen (2001)は,LHONの臨床および分子遺伝学的側面のレビューで,乳頭周囲の微小血管症は最初から存在し,末期へ疾患が進行するにつれ消失することを指摘した

●Newman-Toker et al. (2003)は,発症数年後,視力悪化または視野狭窄を生じた LHONの2例を報告した
 片眼の視力20/400で17歳で受診した女性1例は,さらに,8年後に無痛性視野喪失をもった
 →最終視力は右眼が光覚,左眼が4フィートで指数であった
 血液検査は,彼女が 11778 mtDNA 変異をもつことを示した
 もう1例の患者は35歳時片眼の視力を失った
 最初の眼での視力 20/200 は6か月以上かかって 20/40に改善した
 1年後,2番目の眼の視力は手動まで悪化した
 1か月後,最初の眼は 20/400まで悪化した
 患者は10年以上かかって各々右眼o 20/30, 左眼20/100 まで改善した
 78歳時,視力は各眼とも 20/800 に低下した
 血液検査は 14484 mtDNA 変異を明らかにした.

● Phillips et al. (2003)は,脳と眼窩のMRIはLHON患者では典型的には正常であるが,MRI が視神経の異常な強調または交叉拡大を明らかにしたLHONの2例を記載した

●Barboni et al. (2005) は,LHON 患者で網膜神経線維層 (RNFL) を調べるため optical coherence tomography (OCT) を使用した
 OCTデータに基づき,RNFL は早期 LHON (ELHON, 疾患期間が6か月未満)で肥厚しており,萎縮性 LHON (ALHON, 疾患期間が9か月より長い)で重度に薄かった
 RNFL は視力回復をもつALHONでは部分的に保持されているようであった
 側頭側線維 (乳頭黄斑束) は最初に最も重度に障害された
 尾側線維は疾患後期で部分的に障害から逃れているようであった

●Savini et al. (2005) はLHON 変異をもつ罹患していない保因者で OCTでRNFLの厚さを調べた
 彼らは罹患していない保因者のサブグループで側頭側RNFL肥厚を発見した
 これらの違いは11778変異をもつ患者で統計学的に有意であったが,3460 変異をもつ患者では傾向のみが検出された
 Savini et al. (2005) は,彼らの所見はサブクリニカルLHONでの乳頭黄斑束が好発されること,男性は女性よりびまん性病変をもつことを示す最初の証拠を提供すると結論した

● Kerrison (2005) は,Barboni et al. (2005) と Savini et al. (2005)の所見をレビューして,LHONは単相疾患である必要はないと結論した
 軸索肥厚と正常視覚機能を伴う臨床的に有意な視力喪失に先行する潜伏期がみられる
 →臨床的に有意な視力障害を伴う軸索外傷の急性期が続く
  一部の患者では視力の自然回復がみられ,尤度の減少または再発する慢性期が続く

●Ventura et al. (2007) は,LHON 11778G-A 変異の無症候性保因者で色彩喪失を調べた
 保因者の65%は,異常な protan (303900) +/- deutan (303800) 閾値をもっていた
 高い閾値をもつ保因者の一部は tritan (190900) 閾値の上昇 (13%)ももっていた
 男性保因者は LHON 患者に典型的な赤緑パターンの色覚喪失をもっていた
 → tritan 閾値の上昇ももっていた
 この主な小細胞性(赤緑)障害は ほとんどが乳頭黄斑束を障害するというLHON の組織病理学に一致した
 男性の喪失とは対照的に,女性の喪失は頻度が少なく軽度である
 →最も重度の喪失では,女性はびまん性障害の例をもっていた
 Ventura et al. (2007) は,ホルモン因子が LHON の病態生理学では非常に重要かもしれないと示唆した

その他の症状
●LHON 患者とその母方親戚は,いろんな付随症状をもつことも報告されている
 心伝導障害が一部の家系で報告されている
Among the Finnish patients, preexcitation syndromes including Wolff-Parkinson-White and Lown-Ganong-Levine are common (Nikoskelainen et al., 1985). Prolongation of the corrected QT interval was also observed in an African American family with the np 11778 mutation (Ortiz et al., 1993). Various minor neurologic problems including altered reflexes, ataxia, and sensory neuropathy have been described as well as skeletal abnormalities. Interestingly, the np 11778 mutation has also been associated with multiple sclerosis in some families (Harding et al., 1992; Newman et al., 1991). In studies of 35 Japanese LHON families, Mashima et al. (1996) found that, as in Finnish families, the preexcitation syndromes, Wolff-Parkinson-White syndrome and Lown-Ganong-Levine syndrome, were found relatively commonly, being seen in 5 of 63 individuals (8%) with mtDNA mutations. Nikoskelainen et al. (1985) had found the preexcitation syndrome in 14 of 163 Finns (9%) with mitochondrial DNA mutations.

While visual loss is the primary and generally the only clinical manifestation in most LHON pedigrees with the np 11778, np 3460, np 14484, or np 15257 mutations, occasional individuals present with much more severe clinical disease with neurologic manifestations. The proband in 1 Swedish np 11778 pedigree experienced optic atrophy at age 37 and more severe neurologic disease at age 38 including bilateral lesions of the putamen on MRI, tremor, ataxia, posterior column dysfunction, dystonia, corticospinal tract dysfunction and extrapyramidal rigidity. Muscle biopsy of this individual revealed a subsarcolemmal increase in mitochondria as well as a few fibers exhibiting mitochondria with paracrystalline inclusions. These findings anticipate the wide range of clinical presentations observed in 2 LHON families with more deleterious mtDNA genotypes: an Australian pedigree harboring the MTND1*LHON4160C + MTND6*LHON14484C mtDNA haplotype and an American Hispanic family with the MTND6*LDYT14459A mutation (see Table M1, MIM12). The Australian pedigree is homoplasmic for both mutations yet includes individuals ranging from asymptomatic, through optic atrophy, to severe neurodegenerative disease. The most severe symptoms were observed in 9 of 56 maternal relatives and included headache, vomiting, focal or generalized seizures with a hemiparesis that generally resolves, and a cerebral edema (Wallace, 1970). Specific neuropathologic abnormalities were not found in 3 individuals who died, and 1 female who recovered is clinically normal as an adult but had 4 affected children (Howell et al., 1991). Other neurologic symptoms in this family included dysarthria, deafness, ataxia, tremor, posterior column dysfunction, corticospinal trait dysfunction, and skeletal deformities (Howell et al., 1991; Wallace, 1970). One branch of the pedigree harbored an additional homoplasmic mtDNA mutation, MTND1*LHON4136G, and showed milder clinical presentations. It was speculated that this second mutation may reduce the severity of the np 4160 and np 14484 mutations (Howell et al., 1991).

The American Hispanic family reported by Novotny et al. (1986) harbored a Native American mtDNA and was heteroplasmic for the MTND6*LDYT14459A mutation (Jun et al., 1994). Maternal relatives in the pedigree ranged from normal, through adult-onset optic atrophy, to pediatric dystonia associated with bilateral striatal necrosis. One interesting feature of this pedigree is that LHON predominated in the earlier generations while dystonia predominated in the more recent generations. The phenotype associated with dystonia and striatal lucencies may be considered part of a spectrum of LHON (see 500001).

Funalot et al. (2002) reported 3 unrelated patients with LHON harboring mtDNA mutations at position 3460 of the MTND1 gene and positions 14459 and 14484 of the MTND6 gene. In addition to visual loss, each patient developed a complicated neurologic syndrome resembling Leigh syndrome (256000). Features included gaze palsy, hearing loss, spastic ataxia, cerebellar ataxia, rigidity, hyperreflexia, and multiple hyperintensities in the brainstem.

Gropman et al. (2004) reported a family with a homoplasmic 14459G-A mtDNA mutation of the ND6 gene (516006.0002) and a broad spectrum of clinical manifestations. The proband was a 3-year-old girl with anarthria, dystonia, spasticity, and mild encephalopathy, whose MRI revealed bilateral, symmetric basal ganglia lucencies associated with cerebral and systemic lactic acidosis. Her maternal first cousin presented with a limp and mild hemiparesis along with similar MRI findings with a much milder phenotype. Gropman et al. (2004) investigated additional family members with the mutation and found both asymptomatic and symptomatic individuals with variable clinical and laboratory features, confirming the heterogeneous phenotype of homoplasmic 14459G-A mtDNA mutations, even within the same family.

Jaros et al. (2007) reported a 39-year-old woman with severe complicated LHON who developed progressive gait and sensory disturbances 5 years after onset of subacute bilateral visual failure. Visual symptoms included loss of acuity, central scotomata, optic atrophy, and nystagmus. She also had symmetric pyramidal-pattern lower limb weakness, hyperreflexia, and distal loss of vibratory sensation. Brain MRI showed symmetric high T2 signals in the substantia nigra, pons, and dorsal columns of the spinal cord. After an unexpected death, postmortem examination showed myelin loss and macrophage activation in the posterior columns of the upper spinal cord and neurodegeneration at multiple levels. Molecular analysis detected a homoplasmic 3460G-A mutation in blood and spinal cord. Her mtDNA haplotype H and HLA-DR8 status did not explain the severe phenotype.

La Morgia et al. (2008) reported 6 individuals from 2 unrelated Italian families with LHON confirmed by the findings of mutations in the ND1 and ND4 genes, respectively. All 6 individuals had recurrence of myoclonus as an extraocular feature, and EEG/EMG studies showed myoclonus to be of cortical origin. One family had cosegregation of LHON with psychiatric problems. Four of 6 patients had evidence of increased CSF lactate, which was not found in 6 mutation-matched LHON patients without myoclonus or in controls, suggesting greater bioenergetic impairment in those with myoclonus. Mitochondrial sequence analysis identified other nonsynonymous variants, which La Morgia et al. (2008) postulated may play a role in the LHON-plus phenotype.

Biochemical Features
Larsson et al. (1991) observed that all mutations associated with LHON have been missense mutations in Complex I, III, and IV polypeptides, suggesting that the disease results from a defect in the respiratory chain. Analysis of respiratory Complex I from patients harboring the MTND4*LHON11778A mutation suggests that this defect may occur during the interaction of the NADH generating enzymes with Complex I. Polarographic studies using NADH-linked substrates revealed a 55% reduction in the respiration rate of muscle mitochondria (Larsson et al., 1991) and a 77% reduction in lymphoblast mitochondrial respiration (Majander et al., 1991). Direct assays of NADH:ubiquinone oxidoreductase in skeletal muscle (Larsson et al., 1991) and lymphoblast mitochondria failed to detect a deficiency.

Studies on Complex I in MTND1*LHON3460A patients has revealed a marked deficiency in Complex I activity. Rotenone sensitive NADH:ubiquinone oxidoreductase activity was reduced about 80% in both lymphoblast mitochondria (Majander et al., 1991) and platelet mitochondria (Howell et al., 1991).

A Complex I deficiency was also observed in the Australian pedigree harboring the MTND1*LHON4160C + MTND6*LHON14484C mtDNA haplotype. Analyzing platelet mitochondrial, the NADH: Coenzyme Q oxidoreductase in 4 family members was reduced an average of 79%, while Complexes III and IV showed no significant reduction (Parker et al., 1989).

Danielson et al. (2002) investigated the possibility that the LHON mutation confers a pro-apoptotic stimulus and tested the sensitivity of osteosarcoma-derived cybrid cells carrying the most common and severe mutations (11778 and 3460) to cell death induced by FAS (134637). They observed that LHON cybrids were sensitized to FAS-dependent death. Control cells that carried the same mitochondrial genetic background (the J haplogroup) without the pathogenic 11778 mutation were no more sensitive than other controls, which indicated that increased FAS-dependent death in LHON cybrids was induced by the LHON pathogenic mutations. The type of death was apoptotic by several criteria.

Wong et al. (2002) created cybrids using a neuronal precursor cell line, NT2, containing mitochondria from patient lymphoblasts bearing the LHON mutations 11778 and 3460. The undifferentiated LHON-NT2 mutant cells were not significantly different from the parental cell control in terms of mtDNA/nDNA ratio, mitochondrial membrane potential, reactive oxygen species (ROS) production, or the ability to reduce the reagent Alamar blue. Differentiation of NT2s resulted in a neuronal morphology, a neuron-specific pattern of gene expression, and a 3-fold reduction in mtDNA/nDNA ratio in both mutant and control cells; however, the differentiation protocol yielded 30% less LHON cells than controls, indicating either a decreased proliferative potential or increased cell death of the LHON-NT2 cells. Differentiation of the cells to the neuronal form also resulted in significant increases in ROS production in the LHON-NT2 neurons versus controls, which was abolished by rotenone (a specific inhibitor of complex I). Wong et al. (2002) inferred that the LHON genotype may require a differentiated neuronal environment in order to induce increased mitochondrial ROS, which may be the cause of the reduced NT2 yield. They hypothesized that the LHON degenerative phenotype may be the result of an increase in mitochondrial superoxide which is caused by the LHON mutations, possibly mediated through neuron-specific alterations in complex I structure.

In fibroblasts derived from 16 patients with hereditary optic neuropathy, including either LHON, OPA1 (165500), or OPA3 (165300), Chevrollier et al. (2008) found a common coupling defect of oxidative phosphorylation resulting in reduced efficiency of ATP synthesis. LHON fibroblasts showed a mean decrease of 39% in complex I activity compared to controls. OPA1 and OPA3 fibroblasts showed normal complex I activities, but a mean decrease of 25% in complex IV activity and a mean 60% increase in complex V activity. Resting respiration was about twice as high in all LHON, OPA1, and OPA3 fibroblasts compared to controls, reflecting a proton leak or electron slip. However, all mutant cell lines used a greater proportion of routine respiratory capacity compared to controls, suggesting a compensatory mechanism. The energy defect was most pronounced in fibroblasts from patients with additional neurologic symptoms.

A modifier of LHON penetrance and expressivity (LOAM; 308905) in families with the LHON11778A variant in MTND4 (516003.0001) has been reported in the PRICKLE3 gene (300111.0001).

Molecular Genetics
While LHON is traditionally considered to be familial, many individuals represent isolated cases. The proportion of cases with family histories have been reported to be 43% for np 11778, to be 78% for np 3460, to be 57% for np 15257, and to be 65% for np 14484 (Newman et al., 1991; Johns et al., 1993). Families homoplasmic for these common mutations generally exhibit reduced penetrance, with the percentage of affected relatives in np 11778 families ranging from 33 to 60%, for np 3460 from 14 to 40%, for np 14484 from 27 to 80%, and for np 15257 from 27 to 80%. The common mutations also show a strong male bias in Europeans, ranging from 80% for np 11778 to 33-67% for np 3460, 68% for np 14484, and 75-100% for np 15257 (see Table M1, MIM12) (Newman et al., 1991; Johns et al., 1993). Interestingly, in Asia, greater than 90% of LHON patients harbor the np 11778 mutation, yet only 58% of the patients are males (Mashima et al., 1993).

Estimates of recurrence risks differ between sexes and vary among published reports. Studies based on multiple families have suggested recurrence risks for males to be between 50 and 60%, with one study that followed males to age 50 suggesting a risk of 83%. The comparable risk for women ranges from 8 to 32%. However, the prevalence of singleton families confirmed by molecular testing indicates that these values are over-estimated. Using genetic analysis as the starting point, one Australian study proposed that the risk of visual loss for males with the np 11778 mutation is 20% and for females is 4% (Mackey and Buttery, 1992; Newman, 1993).

In familial cases of LHON, all affected individuals are related through the maternal lineage, consistent with the inheritance of human mtDNA (Giles et al., 1980; Case and Wallace, 1981). However, the incomplete penetrance of the clinical phenotype obscures the strict maternal transmission of the mtDNA, and the strong male basis of expression in Europeans (Newman et al., 1991) has frequently led to the erroneous conclusion that the disease results from an X-linked recessive mutation. In fact, most if not all LHON cases are associated with specific mtDNA mutations that occur in isolation or together.

Seventeen mtDNA missense mutations have been proposed to contribute to LHON (see Table M1, MIM12), though to varying degrees. Five of these are generally felt to be 'primary' mutations, the presence of which greatly increases the probability of blindness. Each disease mutation is designated by the gene followed by an asterisk (*), a phenotypic descriptor (LDYT means LHON plus dystonia), the nucleotide number, and the disease-associated base. Listed in order from highest to lowest disease-causing potential, these are MTND5*LDYT14459A (Jun et al., 1994), MTND4*LHON11778A (Wallace et al., 1988), MTND1*LHON3460A (Huoponen et al., 1991; Howell et al., 1991), MTND6*LHON14484C (Johns et al., (1992, 1993);Mackey and Howell, 1992; Howell et al., 1991), and MTCYB*LHON15257A (Brown et al., 1991; Johns and Neufeld, 1991). Three additional mutations may also be primary, but require confirmation; these are MTND5*LHON13730A (Howell et al., 1993); MTCO3*LHON9438A and MTCO3*LHON9804A (Johns and Neufeld, 1993). Nine other mutations have been found at increased frequencies in LHON patients, but generally in conjunction with one of these primary mutations. Hence, these are felt to be 'secondary' mutations which may interact with the primary mutation to increase the probability of clinical expression. Among the more important of these mutations are MTND5*LHON13708A (Brown et al., 1992; Johns and Berman, 1991); MTND1*LHON3394C (Brown et al., 1992); MTCO1*LHON7444A (Brown et al., 1992); MTND1*LHON4160C (Howell et al., 1991); and MTND2*LHON5244A (Brown et al., 1992).

The criteria for ranking the severity of the primary mutations include (a) range of clinical manifestations with mild being LHON alone and the more severe involving LHON plus other neurologic disease; (b) specificity for the disease meaning the proportion of the 'normal' population that harbors the mutation; (c) association with specific mtDNA lineages with the more severe mutations being rapidly eliminated by selection and hence appearing on multiple different haplotypes; (d) co-occurrence with secondary LHON mutations with the more severe mutations able to cause LHON alone while the milder mutations require interaction with secondary mutations to cause disease; (e) heteroplasmy, with the severe mutations appearing repeatedly and hence more likely to be recent and heteroplasmic; (f) amino acid conservation with the more severe variants altering more conserved amino acids; (g) penetrance with the more severe mutations affecting a greater proportion of the maternal relatives; and (f) spontaneous recovery with the milder mutations being more prone to visual recovery (Wallace and Lott, 1993; Newman et al., 1991; Brown et al., 1992; Huoponen et al., 1993; Johns et al., 1993).

The MTND6*LDYT14459A mutation (516006.0002) results in the most severe phenotype (see Table M1, MIM12). It was identified by Jun et al. (1994) in the large Hispanic family reported by Novotny et al. (1986) that showed variable clinical manifestations ranging from normal, through late-onset optic atrophy, to early-onset dystonia accompanied by bilateral basal ganglial degeneration (500001). This G-to-A transition is a new mutation that arose on the Native American haplogroup D mtDNA background. It was not found on any of 38 related mtDNA haplotypes nor in 310 control mtDNAs representing the major ethnic groups. The mutation is heteroplasmic in some maternally related family members and converts the moderately conserved alanine at position 72 in MTND6 to a valine. An alanine is found in this position in all mammals, Xenopus, and sea urchin, whereas a serine is present in all other species that have been examined. When the mutation approaches homoplasmy, the penetrance is high, with 48% of maternal relatives manifesting pediatric dystonia, 10% LHON, and 3% LHON plus dystonia (Novotny et al., 1986: Wallace et al., 1985) (see Table M1, MIM12).

The next most severe mutation and the most common cause of LHON is MTND4*LHON11778A (516003.0001). It accounts for more than 50% of European cases and 95% of Asian cases, but has not been found in controls (Wallace et al., 1988;Newman et al., 1991). Whereas most individuals with this mutation present with LHON (Newman et al., 1991), 1 patient experienced central vision loss at 37 years of age and cerebellar-extrapyramidal tremor and left-side rigidity associated with bilateral basal ganglial lesions at 38 years of age(Larsson et al., 1991). The mutation has arisen repeatedly on different mtDNA lineages (Singh et al., 1989), and is occasionally found with other LHON mutations (Huoponen et al., 1993). It is frequently heteroplasmic (Lott et al., 1990), converts a highly conserved arginine to a histidine, is about 82% penetrant in males and shows only a 4% spontaneous recovery rate (see Table M1, MIM11) (Newman et al., 1991; Wallace and Lott, 1993;Johns et al., 1993).

The MTND1*LHON3460A (516000.0001) mutations account for about 35% of European LHON, and has not been identified in controls (Huoponen et al., 1991; Howell et al., 1991). It has been observed on several mtDNA lineages, occasionally co-occurs with other LHON mutations, is generally homoplasmic, changes a moderately conserved alanine to a threonine, is expressed in 69% of males, and exhibits a 22% spontaneous recovery rate (see Table M1, MIM12) (Howell et al., 1991; Howell et al., 1992; Huoponen et al., 1991; Huoponen et al., 1993; Johns et al., 1993).

The fourth primary mutation is MTND6*LHON14484C (516006.0001). This mutation accounts for about 20% of European LHON patients, has not been observed in 250 controls (Johns et al., 1992), and is commonly associated with specific mtDNA lineages, often in association with MTND5*LHON13708A, MTCYB*LHON15257A, or MTND1*LHON3394C. It has been homoplasmic in every case but one (Mackey and Howell, 1992), changes a weakly conserved methionine to a valine, has a penetrance in males of 82%, and a visual recovery rate of 37% (see Table M1, MIM12) (Johns et al., 1993).

The mildest primary mutation is MTCYB*LHON15257A (516020.0001). This is found in about 15% of LHON patients, and in 0.3% of the general population (Brown et al., 1992). The mutation has been observed on the same mtDNA lineage, usually together with the MTND5*LHON13708A and MTND6*LHON14484C mutations in all but 1 case (Howell et al., 1993). This mutation is consistently homoplasmic, changes a highly conserved aspartate to an asparagine, has a penetrance in males of 72%, and a probability of visual recovery of 28% (see Table M1, MIM12) (Johns et al., 1993).

Five secondary mutations of particular note are MTND5*LHON13708A, MTND1*LHON3394C, MTCO1*LHON7444A, MTND2*LHON5244A and MTND1*LHON4160C. The first 3 mutations are consistently homoplasmic and occur on specific mtDNA lineages prone to LHON. The MTND5*LHON13708A mutation changes a moderately conserved alanine to a threonine, is frequently associated with MTND6*LHON14484C, MTCYB*LHON15257A, and MTND1*LHON3394C mutations, and is found in about 15% of patients and in 4% of controls (Brown et al., 1992; Johns and Berman, 1991). The MTND1*LHON3394C mutation changes a highly conserved tyrosine to a histidine, is commonly associated with MTND6*LHON14484C in French Canadians, and has also been found in 1% of the general population (Brown et al., 1992;Johns et al., 1992). The MTCOI*LHON7444A mutation converts the termination codon of MTCOI to lysine. This extends the polypeptide by 3 charged amino acids, changes the protein electrophoretic mobility, and diminishes the cytochrome c oxidase specific activity 35%. The mutation is found in about 9% of patients, and also in 1% of the general population (see Table M1, MIM12)(Brown et al., 1992).

The MTND1*LHON4160C and MTND2*LHON5244A mutations have been observed in individual families and appear to be relatively recent mutations. MTND1*LHON4160C converts a highly conserved leucine to a proline and is associated with the MTND6*LHON14484C mutation (Howell et al., 1991). This combination is associated with amblyopia in more than 80% of family members and with neurodegenerative disease in many individuals. One branch of the family also harbors the MTND1*LHON4136G mutation, which as has been proposed to ameliorate some of the symptoms (Wallace, 1970; Howell et al., 1991). The MTND2*LHON5244A mutation occurred on a MTND6*LHON14484C + MTCYB*LHON15257A haplotype. It changed a highly conserved glycine to a serine (Brown et al., 1992) and probably was an important contributor to the disease in this patient.

The remaining LHON mutations are of ambiguous significance. MTCYB*LHON15812A mutation converts a moderately conserved valine to a methionine and is consistently found with MTND6*LHON14484C and MTCYB*LHON15257A mutations on a specific mtDNA lineage (Brown et al., 1992). The MTND1*LHON4216C and MTND2*LHON4917G mutations alter poorly and highly conserved amino acids, respectively, and are in somewhat higher frequencies in LHON patients (Johns and Berman, 1991).

Chinnery et al. (2001) described 2 LHON pedigrees that harbored the same novel point mutation within the MTND6 gene at position 14495. The mutation was heteroplasmic in both families, and sequencing of the mitochondrial genome confirmed that the mutation arose on 2 independent occasions. Protein modeling studies indicated that the 7 known mutations in the MTND6 gene that cause LHON lie in close proximity in a hydrophobic cleft or pocket. The authors concluded that this was the first evidence for a relationship between a specific structural domain within a mitochondrial respiratory chain subunit and a specific disease phenotype. They suggested that the MTND6 gene be sequenced in all patients with clinical LHON who do not harbor one of the 3 primary LHON mutations at basepair 11778 (MTND4), 3460 (MTND1), or 14484 (MTND6).

Fauser et al. (2002) sequenced the complete mitochondrial DNA in 14 LHON patients with typical clinical features but without a primary mtDNA mutation. The results suggested that the mutation at np 15257 should be included in a routine screening, as well as the ND6 gene (516006), a hotspot for LHON mutations. Fauser et al. (2002) suggested that screening for the secondary LHON mutations at np 4216 and np 13708 might also help in making the diagnosis of LHON, as these changes seem to modify the expression of LHON mutations.

The male bias and incomplete penetrance of LHON in Europeans has led to the hypothesis that blindness results when two factors coincide, a maternally inherited mtDNA mutation and an X-linked recessive mutation (308905). In a model based on this hypothesis, the penetrance for females was estimated at 0.11 +/- 0.02, and the frequency of the X-linked gene was estimated at 0.08 (Bu and Rotter, 1991). Support for this model was obtained from X-chromosome linkage studies which revealed a linkage between LHON susceptibility and the DXS7 chromosomal marker, with a LOD score of 2.32 (Vilkki et al., 1991). However, this linkage has not been confirmed by other groups (Chen et al., 1989; Chen and Denton, 1991; Carvalho et al., 1992; Sweeney et al., 1992).

Oostra et al. (1994) described the distribution of 7 different mtDNA mutations and the associated clinical findings in 334 LHON patients belonging to 29 families. Mutations described only in LHON at nucleotide positions 11778, 3460, and 14484 were found in 15, 2, and 9 families, respectively. In 3 families, none of these mutations was found. Mutations described in LHON but also in controls at nucleotide positions 15257, 13708, 4917, and 4216 were found in 1, 10, 3, and 12 families, respectively. Combinations of mtDNA mutations were found in most families. In 11 families in which only the 11778 mutation was found, affected males had a mean age of onset of 29.2 years and a mean visual outcome of 0.113. Observations in groups of patients with other mutations indicated that the clinical severity is dependent on the mitochondrial genotype.

Mackey et al. (1996) screened 159 LHON families of northern European origin living in Australia, New Zealand, the United Kingdom (including Ireland), the Netherlands, Denmark, and Finland. These pedigrees comprised more than 12,000 maternally related individuals and more than 1,500 affected individuals. In the 159 families, 153 (97%) carried 1 of the 3 previously identified primary LHON mutations at nucleotides 3460 (13% of the 159 LHON families), 11778 (69%), or 14484 (14%). The primary mutation was not identified in the other families. The 15257 mutation occurred in 6 of the 159 LHON families. However, in every one of these instances, it was associated with 1 of the 3 established LHON mutations: 11778 (4 of 78 families), 3460 (1 of 14 families), and 14484 (1 of 23 families). Because it did not occur in isolation of an established primary LHON mutation, the results did not support a primary pathogenic role for the 15257 mutation.

Liu et al. (2011) investigated the molecular pathogenesis of LHON in 6 Han Chinese families in which 9 (6 males/3 females) of 86 matrilineal relatives exhibited variable severity and age of onset of optic neuropathy. The average age of onset was 20 years. Molecular analysis of mtDNA in these families identified the homoplasmic ND5 12338T-C mutation (516005.0011) and a distinct set of variants belonging to the Asian haplogroup F2. The 12338T-C mutation was present in the maternal lineage of the 6 pedigrees and not in 178 Chinese controls.

A modifier of LHON penetrance and expressivity (LOAM; 308905) in families with the LHON11778A variant in MTND4 (516003.0001) has been reported in the PRICKLE3 gene (300111.0001).

A modifier of LHON penetrance and expressivity (LOAM; 308905) in families with the LHON11778A variant in MTND4 (516003.0001) has been reported in the PRICKLE3 gene (300111.0001).

Population Genetics
Carelli et al. (2006) evaluated the mtDNA of 87 index cases with LHON sequentially diagnosed in Italy, including an exceedingly large Brazilian family of Italian maternal ancestry. The results revealed that the large majority of the LHON mutations in affected Italian families are due to independent mutational events; only 7 pairs of families and 3 triplets of families showed identical haplotypes. Thus, the study confirmed that the preferential association of the LHON mutations 11778/ND4 (516003.0001) with haplogroups J1 and J2 and 14484/ND6 (516006.0001) with haplotype J1 is attributable not to founder events but to a true mtDNA background effect. In the case of the 11778/ND4 mutation, such a role of the mtDNA background was narrowed to the subclades J1c and J2b, which both, intriguingly, harbor unique combinations of amino acid changes in cytochrome b (516020). Carelli et al. (2006) reinvestigated the genealogies of the families with identical haplotypes and were able to reconnect 3 pairs of families, including the Brazilian family and its Italian counterpart, into extended pedigrees. The survey of the 2 control region sites that were heteroplasmic in the Brazilian family showed triplasmy in most cases, but there was no evidence of the tetraplasmy that would be expected in the case of mtDNA recombination.

In affected members of a 3-generation Chinese family exhibiting high penetrance and expressivity of visual impairment due to LHON, Qu et al. (2006) identified the homoplasmic 11778G-A mutation as well as a novel secondary homoplasmic mutation, 4435A-G, belonging to the Asian haplogroup D5.

In a European multicenter study of 3,613 individuals with LHON from 159 different families, Hudson et al. (2007) found evidence that clinical penetrance of the 3 most common mtDNA mutations is influenced by mtDNA haplotype group. The risk of visual failure was greater when the 11778G-A or 14484T-C mutations were present in haplotype subgroups J2 and J1, respectively, and when the 3460G-A mutation occurred in haplotype K. In contrast, the risk of visual failure was slightly decreased (OR = 0.79) when 11778G-A was present on haplotype H.

By examining data from a population-based study (1970-2004), Puomila et al. (2007) estimated that the prevalence of LHON in Finland is 1 in 50,000, and that 1 in 9,000 Finns is a carrier of 1 of the 3 LHON primary mutations (MTND4, 11778G-A; MTND1, 3460G-A; and MTND6, 14484T-C).

Spruijt et al. (2006) investigated the genotype/phenotype correlation of the 3 major LHON mutations in the Dutch population. They found that the specific mtDNA mutation did not influence disease penetrance (50% in male subjects; 10-20% in female subjects). Regardless of the acuteness of disease onset, more than 50% of patients with the MTND6 14484C mutation exhibited partial recovery of vision, whereas only 22% of the MTND4 11778A carriers and 15.4% of the MTND1 3460A carriers recovered. The recovery did not take place within the first year after onset and was uncommon after 4 years. In general, onset of LHON is very acute but might be more gradual in 11778A carriers and in children. Spruijt et al. (2006)concluded that the LHON genotype influences the recovery of vision and disease onset but is unrelated to age, acuteness of onset, or gender.

By studying the penetrance of LHON in 1,859 individuals from 182 Chinese families (including 1 from Cambodia) with the MTND4 11778G-A mutation (516003.0001), Ji et al. (2008) found that mitochondrial haplogroup M7b1-prime-2 was associated with increased risk of visual loss, whereas the M8a haplogroup was associated with decreased risk of visual loss. Further sequence analysis suggested that the M7b1-prime-2 effect was due to variation in the MTND5 gene, and that the M8a effect was due to variation in the MTATP6 gene.

Inheritance
Mitochondrial DNA point mutations are exclusively maternally inherited (nonmendelian).

Imai and Moriwaki (1936) suggested that LHON might be cytoplasmically transmitted, a hypothesis again enunciated by Ronne (1944, 1945). Wallace (1970) described a large Australian pedigree in which amaurosis and neurologic disease were maternally transmitted, leading him to suggest that the disease was transmitted by a cytoplasmic slow virus (Wallace, 1970). These and related historical studies were summarized by Erickson (1972), who concluded that LHON was maternally transmitted.

Wallace and co-workers demonstrated that human mtDNA was maternally inherited and suggested that maternally transmitted diseases might be due to mtDNA mutations (Giles et al., 1980; Case and Wallace, 1981). This hypothesis was elaborated by Egger and Wilson (1983). The maternal transmission of LHON was further documented by Nikoskelainen et al. (1984, 1987), who emphasized a possible mtDNA etiology. This hypothesis was confirmed by Wallace et al. (1988) who demonstrated that the majority of LHON families harbored the same mtDNA mutation at MTND4*LHON11778A, regardless of mtDNA sequence background (Singh et al., 1989).

Oostra et al. (1997) described 2 LHON pedigrees atypical with respect to sex, age of onset, interval between the eyes becoming affected, course of the disease, concomitant disorders, additional test results, final visual acuity, and/or results of mtDNA analysis. Furthermore, the pedigrees did not suggest maternal inheritance. One pedigree had an affected grandmother and granddaughter through an unaffected carrier; the females in all 3 generations had the 11778 mutation. In the second pedigree, a grandfather and grandson through 1 of his daughters were affected and carried the 11778 mutation; the affected grandmother and the unaffected daughter likewise carried the 11778 mutation, suggesting that the grandson inherited the mutation from his mother.

Incomplete Penetrance
While mtDNA mutations now explain the maternal transmission of LHON, the incomplete penetrance and male bias in Caucasian expression remain enigmatic. One hypothesis is that the expression of LHON is the product of both an mtDNA mutation plus an X-linked recessive allele (Bu and Rotter, 1991). This hypothesis was supported by the report of the cosegregation of the DXS7 X-chromosome marker with LHON (Vilkki et al., 1991, see 308905), though this has not been corroborated by other studies (Chen et al., 1989; Chen and Denton, 1991; Carvalho et al., 1992; Sweeney et al., 1992).

Environmental effects have also been hypothesized to play a role in LHON expression. Heavy tobacco smoking was proposed to be a possible factor by Wilson (1963, 1965), and this idea generalized to cyanide intoxication which for genetic reasons was not adequately detoxified to thiocyanate (Adams et al., 1966; Wilson, 1965). This hypothesis was extended to propose that rhodanase (180370) deficiency might contribute to LHON (Cagianut et al., 1981), but rhodanase deficiency has not been consistently documented in LHON patients (Whitehouse et al., 1989). Recently, heavy tobacco smoking has again been noted in some LHON patients (Cullom et al., 1993).

In a large, multicenter epidemiologic study of 196 affected and 206 unaffected mutation carriers from 125 LHON pedigrees confirmed by genetic analysis, Kirkman et al. (2009) found a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93% in men who smoked. There was a trend towards increased visual failure with alcohol, but only with heavy intake. Based on these findings, Kirkman et al. (2009) concluded that asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate alcohol intake.

A final hypothesis to explain the male bias could be that LHON is hormonally influenced by androgens. In an anecdotal case, a heteroplasmic carrier of the MTND4*LHON11778A mutations experienced precipitous vision loss after androgen therapy (Wallace and Lott, unpublished data; Newman et al., 1991).

Mapping
Allelic variants map to specific nucleotides in the mitochondrial DNA.

Diagnosis
Optic Atrophy; See description of phenotype (above).

Clinical Management
See description of phenotype (above). No proven therapeutic agents have been found.

Gene Therapy
Guy et al. (2002) found that cybrid cells containing the G11778A mutation (516003.0001), found in 50% of LHON cases, showed a 60% reduction in the rate of complex I-dependent ATP synthesis compared to wildtype cells. Using 'allotopic expression,' a technique in which a mitochondrial gene is expressed in the nucleus and the protein product is then imported back to the mitochondria, Guy et al. (2002) transfected a fusion ND4 subunit gene into cybrids containing the G11778A mutation. Cybrid cell survival after 3 days was 3-fold greater for the allotopically transfected cells, and these cells showed a 3-fold increase in the rate of complex I-dependent ATP synthesis, to a level indistinguishable from that in normal cybrids.Guy et al. (2002) suggested that this rescue of a severe oxidative phosphorylation deficiency held promise for development of gene therapy for mitochondrial disorders.

Qi et al. (2007) explored a treatment paradigm for LHON. They augmented mitochondrial antioxidant defenses to rescue cells with the G11778A mutation in mtDNA. An adeno-associated viral (AAV) vector containing the human mitochondrial superoxide dismutase (SOD2; 147460) gene increased LHON cell survival relative to controls. Qi et al. (2007) concluded that protection against mitochondrial oxidative stress might be useful for the treatment of LHON, and that gene therapy with antioxidant genes might protect patients with LHON against visual loss.

History
LHON was named for German ophthalmologist Theodor Leber (1840-1917) (pronounced LAY-ber) and was recognized as a familial neuro-ophthalmologic disease in the late 1800's (Leber, 1871; von Graefe, 1858). Subsequently, many affected pedigrees were reported from Europe, North America, Asia, and Australia (Carroll and Mastaglia, 1979; de Weerdt and Went, 1971; Hiida et al., 1991; Livingstone et al., 1980; Lundsgaard, 1944; Mackey and Buttery, 1992; Morlet, 1921; Muller-Jensen et al., 1978; Nakamura et al., 1992; Newman et al., 1991; Newman et al., 1991; Nikoskelainen et al., 1987; Plauchu et al., 1976; Seedorff, 1968; Seedorff, 1985; van Senus, 1963; Waardenburg, 1924; Wallace, 1970; Went, 1972). A major focus of the earlier studies was the elucidation of the mode of inheritance of LHON. Perplexing features of the disease transmission included the exclusive matrilineal transmission and predilection for males to be affected. Most forms of genetic and epigenetic transmission together with environmental factors have been considered (Adams et al., 1966; Cagianut et al., 1981;Erickson, 1972; Nikoskelainen, 1984; van Senus, 1963; Wallace, 1970; Whitehouse et al., 1989; Wilson, (1963, 1965)).

Animal Model
To develop an animal model system for study of oxidative injury to the optic nerve, Qi et al. (2003) designed hammerhead ribozymes to degrade superoxide dismutase-2 (SOD2; 147460) mRNA, thereby decreasing mitochondrial defenses against reactive oxygen species (ROS). Several potential ribozymes were analyzed in vitro. The one with the best kinetic characteristics was cloned into a recombinant adeno-associated virus (rAAV) vector for delivery and testing in cells and animals. The rAAV ribozyme was then injected into the eyes of DBA/1J mice, and the effect on the optic nerve was evaluated by ocular histopathologic examination. The AAV-expressing ribozyme decreased SOD2 mRNA and protein levels by as much as 85%, increased cellular superoxide, reduced mitochondrial membrane potential, and culminated in the death of infected cell lines by apoptosis without significantly altering complex I and III activity, somewhat spared in the most common LHON mutation (G11778A; 516003.0001) although ATP synthesis is markedly reduced. When inoculated into the eyes of mice, the AAV-expressing ribozyme led to loss of axons and myelin in the optic nerve and ganglion cells in the retina, the hallmarks of optic nerves examined at autopsy of patients with LHON. The striking similarity of the mouse model's optic neuropathy to the histopathology of LHON patients is evidence supporting ROS as a key factor in the pathogenesis of LHON.

Qi et al. (2007) described expression of the wildtype ND4 gene in the mouse visual system and produced a mouse model of Leber hereditary optic neuropathy by delivery of a nuclear-encoded version (R340H) of the mutant human ND4 gene. The mutant ND4 disrupted mitochondrial cytoarchitecture, elevated ROS, induced swelling of the optic nerve head, and induced apoptosis, with a progressive demise of ganglion cells in the retina and their axons comprising the optic nerve. In contrast, ocular expression of the wildtype ND4 subunit in mice appeared safe, suggesting that it might be useful for treatment of patients with LHON.

To create an animal model of LHON, Ellouze et al. (2008) introduced the human ND4 gene harboring the 11778G-A mutation (516003.0001), responsible for 60% of LHON cases, into rat eyes by in vivo electroporation. The treatment induced the degeneration of retinal ganglion cells, which were 40% less abundant in treated eyes than in control eyes. This deleterious effect was also confirmed in primary cell culture, in which both RGC survival and neurite outgrowth were compromised. Importantly, RGC loss was clearly associated with a decline in visual performance. A subsequent electroporation with wildtype ND4 prevented both RGC loss and the impairment of visual function. Ellouze et al. (2008)concluded that their data provided the proof of principle that optimized allotopic expression can be an effective treatment for LHON, and that they opened the way to clinical studies of other devastating mitochondrial disorders.

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