疾患詳細

疾患詳細





#252011
Mitochondrial complex II deficiency, nuclear type 1 (MC2DN1)
(Mitochondrial complex II deficiency)
(Succinate CoQ reductase deficiency)
(Succinate dehydrogenase deficiency)

ミトコンドリア呼吸鎖, 複合体 II, 欠損症, 核型 1
(ミトコンドリア呼吸鎖, 複合体 II)
(コハク酸 CoQ レダクターゼ欠損症)
(コハク酸デヒドロゲナーゼ欠損症)
指定難病21 ミトコンドリア病
小児慢性特定疾病 代54 ミトコンドリア呼吸鎖複合体欠損症

責任遺伝子:
 600857 Succinate dehydrogenase complex, susbunit A, flavoprotein (SDHA) <5p15.33>
 612848 Succinate dehydrogenase complex assembly factor 1 (SDHAF1) <19q12-q13.2>
遺伝形式:常染色体劣性

(症状)
(GARD)
 <30%-79%>
 Babinski sign (バビンスキー徴候) [HP:0003487] [0213]
 Developmental regression (発達退行) [HP:0002376] [0125]
 Distal amyotrophy (遠位筋萎縮) [HP:0003693] [0270]
 Easy fatigability (易疲労性) [HP:0003388] [01410]
 Generalized muscle weakness (全身性筋力低下) [HP:0003324] [0270]
 Generalized myoclonic seizures (全身性ミオクロニー発作) [HP:0002123] [01405]
 Hyperactive deep tendon reflexes (深部腱反射亢進) [HP:0006801] [0241]
 Hyperactive patellar reflex (膝蓋腱反射亢進) [HP:0007083] [0241]
 Hyperreflexia in upper limbs (上肢反射亢進) [HP:0007350] [0241]
 Hypertrophic cardiomyopathy (肥大型心筋症) [HP:0001639] [0273]
 Left ventricular dysfunction (左心室機能障害) [HP:0005162] [0171]
 Left ventricular hypertrophy (左室肥大) [HP:0001712] [1120]
 Motor delay (運動遅滞) [HP:0001270] [0120]
 Motor deterioration (運動悪化) [HP:0002333] [0125]
 Progressive psychomotor deterioration (進行性精神運動発達悪化) [HP:0007272] [0125]
 Proximal muscle weakness (近位筋筋力低下) [HP:0003701] [0270]
 Severe short stature (重度低身長) [HP:0003510] [0130]
 Skeletal myopathy (骨格筋ミオパチー) [HP:0003756] [0277]
 Weight loss (体重喪失) [HP:0001824] [01411]
 
 <5%-29%>
 Abnormal atrioventricular conduction (房室伝導異常) [HP:0005150] [01700]
 Ataxia (運動失調) [HP:0001251] [028]
 Expressive language delay  0002474
 Feeding difficulties in infancy (哺乳障害, 乳児期) [HP:0008872] [01411]
 Frequent falls (頻回の転倒) [HP:0002359]
 Generalized hypotonia (全身性筋緊張低下) [HP:0001290] [0242]
 Hypoplasia of penis (陰茎低形成) [HP:0008736] [14013]
 Irritability (被刺激性) [HP:0000737] [01418]
 Knee flexion contracture (膝屈曲拘縮) [HP:0006380] [15100]
 Lower limb hypertonia (下肢筋緊張亢進) [HP:0006895] [0241]
 Mild microcephaly (軽度小頭) [HP:0040196] [03013]
 Moderate global developmental delay (中等度全般的発達遅滞) [HP:0011343] [0120]
 Noncompaction cardiomyopathy (緻密化障害性心筋症) [HP:0012817] [0273]
 Segmental myoclonic seizures (分節性ミオクロニー発作) [HP:0025191] [01405]
 Spastic paraparesis (痙性対不全麻痺) [HP:0002313] [02613]
 Spastic tetraparesis (痙性四肢不全麻痺) [HP:0001285] [0241] [02613]
 
 <1%-4%>
 Blindness (盲) [HP:0000618] [06011]
 Dementia (認知症) [HP:0000726] [0123]
 External ophthalmoplegia (外眼筋麻痺) [HP:0000544] [0698]
 Loss of ability to walk (歩行能喪失) [HP:0006957] [0125]
 Nystagmus (眼振) [HP:0000639] [06609]
 Pigmentary retinopathy (網膜色素変性症) [HP:0000580] [06524]
 Poor head control (頭部コントロール不全) [HP:0002421] [0242]
 Vesicoureteral reflux (膀胱尿管逆流) [HP:0000076] [1313]
 
 
 Abnormal mitochondria in muscle tissue (筋組織の異常ミトコンドリア) [HP:0008316]
 Autosomal recessive inheritance (常染色体劣性遺伝) [HP:0000007]
 Cognitive impairment (認知障害) [HP:0100543] [0123]
 Decreased activity of mitochondrial complex II  0008314
 Dilated cardiomyopathy (拡張型心筋症) [HP:0001644 [0273]
 Dystonia (ジストニア) [HP:0001332] [0240]
 Exercise intolerance (運動不耐症) [HP:0003546] [0278]
 Flexion contracture (屈曲拘縮) [HP:0001371] [15100]
 Hyperreflexia (反射亢進) [HP:0001347] [0241]
 Increased intramyocellular lipid droplets (筋細胞内脂質滴増加) [HP:0012240]
 Increased serum lactate (乳酸増加) [HP:0002151] [2044]
 Infantile onset (乳児期発症) [HP:0003593]
 Left ventricular noncompaction (左室緻密化障害) [HP:0030682] [1120]
 Muscle weakness (筋力低下) [HP:0001324] [0270]
 Myoclonus (ミオクローヌス) [HP:0001336] [02612]
 Neonatal hypotonia (新生児筋緊張低下) [HP:0001319] [0242]
 Ophthalmoplegia (眼球運動麻痺) [HP:0000602] [0698]
 Optic atrophy (視神経萎縮) [HP:0000648] [06522]
 Progressive leukoencephalopathy (進行性白質脳症) [HP:0006980] [0201] [160127]
 Ptosis (眼瞼下垂) [HP:0000508] [06807]
 Ragged-red muscle fibers (赤色ぼろ線維) [HP:0003200]
 Seizures (けいれん) [HP:0001250] [01405]
 Short stature (低身長) [HP:0004322] [0130]
 Spasticity (痙縮) [HP:0001257] [0241]
 Stress/infection-induced lactic acidosis (ストレス/感染誘発性乳酸性アシドーシス) [HP:0004897] [2000] [2044]
 Visual impairment (視力障害) [HP:0000505] [06011]

(UR-DBMS)
【一般】精神運動退行 (乳児)
 けいれん
 白質脳症, 進行性
 海綿状脳脊髄症
 Leigh 症候群 (245000)
 患者の一部は Kearns-Sayre 症候群 (530000)をもつ
 低身長
 成長不全
【神経】筋緊張低下, 新生児
 筋力低下
 運動不耐症
 赤色ぼろ線維 (Ragged red fibers) (筋生検)
 準結晶封入体を伴う異常なミトコンドリア (筋生検)
 脂質滴蓄積 (筋生検)
 痙縮
 反射亢進
 開扇反射
 運動失調
 認知障害
 ミオクローヌス
【眼】眼瞼下垂
 眼筋麻痺
 色素性網膜症
 視神経萎縮
 眼振
 視力障害
【心】肥大型心筋症
 拡張型心筋症
 左室緻密化障害
【四肢】Joint 関節拘縮
【検査】乳酸性アシドーシスはストレスまたは感染で生じうる
 ミトコンドリア複合体 II (succinate dehydrogenase) 活性低下
 血清乳酸値軽度増加
【その他】生後1年で発症
 相当な表現型の差異

<指定難病診断基準>
Definite, Probableを対象とする。

1.主要項目
(1)主症状
 ①進行性の筋力低下, 横紋筋融解症又は 外眼筋麻痺を認める。
 ②知的退行, 記銘力障害, 痙攣, 精神症状, 一過性麻痺, 半盲, 皮質盲, ミオクローヌス, ジストニア, 小脳失調などの中枢神経症状のうち, 1つ以上を認める。または, 手足のしびれなどの末梢神経障害を認める。
 ③心伝導障害, 心筋症などの心症状, 肺高血圧症などの呼吸器症状, 糸球体硬化症, 腎尿細管機能異常などの腎症状, 強度の貧血などの血液症状又は中等度以上の肝機能低下, 凝固能低下などの肝症状を認める。
 ④低身長, 甲状腺機能低下症などの内分泌症状や糖尿病を認める。
 ⑤強度視力低下, 網膜色素変性などの眼症状, 感音性難聴などの耳症状を認める。

(2)検査・画像所見
 ①安静臥床時の血清又は髄液の乳酸値が繰り返して高い, 又はMRスペクトロスコピーで病変部に明らかな乳酸ピークを認める。
 ②脳CT/MRIにて, 大脳基底核, 脳幹に両側対称性の病変等を認める。
 ③眼底検査にて, 急性期においては蛍光漏出を伴わない視神経乳頭の発赤・腫脹, 視神経乳頭近傍毛細血管蛇行, 網膜神経線維腫大, 視神経乳頭近傍の出血のうち1つ以上の所見を認めるか, 慢性期(視力低下の発症から通常6か月以降)における視神経萎縮所見を両眼に認める。
 ④骨格筋生検や培養細胞又は症状のある臓器の細胞や組織でミトコンドリアの病理異常を認める。
 必要に応じて, 以下の検査を行い,
 ⑤ミトコンドリア関連酵素の活性低下又はコエンザイムQ10などの中間代謝物の欠乏を認める。または, ミトコンドリアDNAの発現異常を認める。
 ⑥ミトコンドリアDNAの質的, 量的異常又はミトコンドリア関連分子をコードする核遺伝子変異を認める。
2.参考事項
(ア)病理検査
 特異度が高い。骨格筋病理における, 酵素活性低下又は赤色ぼろ線維(ゴモリ・トリクローム変法染色におけるragged-red fiber:RRF), 高SDH活性血管(コハク酸脱水素酵素におけるstrongly SDH-reactive blood vessel:SSV), シトクロームc酸化酵素欠損線維, 電子顕微鏡によるミトコンドリア病理学的異常を認める。または, 骨格筋以外でも症状のある臓器野細胞・組織のミトコンドリア病理異常を認める。核の遺伝子変異の場合は, 培養細胞などでミトファジーの変化や融合・分裂の異常を確認する。
(イ)酵素活性・生化学検査
 特異度が高い。罹患組織や培養細胞を用いた酵素活性測定で, 電子伝達系, ピルビン酸代謝関連 及びTCAサイクル関連酵素, 脂質代謝系関連酵素などの活性低下(組織:正常の20%以下, 培養細胞:正常の30%以下)を認める。または, ミトコンドリアDNAの転写, 翻訳の低下を認める。
(ウ)DNA検査
 特異度が高い。病因的と報告されている, 又は証明されたミトコンドリアDNAの質的異常である欠失・重複, 点変異(MITOMAP:http://www.mitomap.org/などを参照)や量的異常である欠乏状態(正常の20%以下)があること, 又は, ミトコンドリア関連分子をコードする核遺伝子の病的変異を認める。
(エ)心症状の参考所見
 心電図で, 房室ブロック, 脚ブロック, WPW症候群, 心房細動, ST-T異常, 心房・心室負荷, 左室側高電位, 異常Q波, 左軸偏位を認める。心エコー図で, 拡張型心筋症様を呈する場合は左心室径拡大と駆出率低下を認める。肥大型心筋症様を呈する場合は左室肥大を認める。拘束型心筋症様を呈する場合は, 心房の拡大と心室拡張障害を認める。心筋シンチグラムで, MIBI早期像での取り込み低下と洗い出しの亢進, BMIPPの取り込み亢進を認める。
(オ)腎症状の参考所見
 蛋白尿(試験紙法で1+(30mg/dL)以上), 血尿(尿沈査で赤血球5/HPF以上), 汎アミノ酸尿(正常基準値以上)を認める。血中尿素窒素の上昇(20mg/dL以上), クレアチニン値の上昇(2mg/dL以上)を認める。
(カ)血液症状の参考所見
 強度の貧血 (Hb 6g/dL以下)もしくは汎血球減少症(Hb 10g/dL, 白血球 4000/µL以下, 血小板 10万/µL以下)を認める。
(キ)肝症状の参考所見
 中等度以上の肝機能障害(AST, ALTが200U/L以上), 血中アンモニア値上昇 (正常基準値以上)を認める。
(ク)糖尿病の参考所見
 血糖値(空腹時≧126mg/dL, OGTT2時間≧200mg/dL, 随時≧200mg/dLのいずれか)とHbA1c (国際標準値)≧6.5% (hA1c(JDS値)≧6.1%)
(ケ)乳酸値
 安静臥床時の血中乳酸値もしくは髄液乳酸値が繰り返して, 2mmol/L(18mg/dL)以上であること, 又はMRスペクトロスコピーで病変部に明らかな乳酸ピークがある。

3.ミトコンドリア病の診断のカテゴリー
  Definite (1)①~⑤のうち1項目あり, かつ(2)①~⑥のうち, 2項目を満たすもの(全体で計3項目必要)
  Probable (1)①~⑤のうち1項目あり, かつ(2)①~⑥のうち, 1項目を満たすもの(計2項目必要)

<小児慢性特定疾病 代54 ミトコンドリア呼吸鎖複合体欠損症>
概要・定義
ミトコンドリアの役割は多数あるが、最も大切なのはエネルギー(ATP)の生合成であり、その役割を担うのが呼吸鎖複合体である。したがって、「ミトコンドリア病はミトコンドリア呼吸鎖複合体異常症(MRCD)」と読み替えることができる。いかなる症状、いかなる臓器・組織、いかなる年齢、そしていかなる遺伝形式でも発病しうるのがミトコンドリア病である。従来神経・筋肉の病気と考えられていたが、ミトコンドリア心筋症、肝症など単独の臓器障害を呈するミトコンドリア病も多い1)。
疫学
全てを加えれば最も多いエネルギー代謝系の先天代謝異常症であり、出生5,000人に1人とされる2,3)。
病因
呼吸鎖はミトコンドリア遺伝子と核遺伝子の共同作業で形成される。したがってミトコンドリア病は、ミトコンドリア遺伝(母系遺伝)形式以外に常染色体優性・劣性、X連鎖のすべての遺伝形式で発病しうる4)。特に幼少時期発症例は症状が多彩で重篤な症例が多く、その9割以上は核遺伝子異常によるものである5)。
症状
小児科医の出会うミトコンドリア病の3大症状は、①脳筋症状、②消化器・肝症状、③心筋症状とされる6)。従来ミトコンドリア病の主体とされてきた、いわゆる“ミトコンドリア脳筋症”は比較的軽症のミトコンドリア病に属し、年長発症例に多い。
診断
診断方法
<表>に特定疾患としてのミトコンドリア病認定基準を示す。
確実例は(1)の主症候の1項目以上を満たし、かつ(2)の検査・画像所見の2 項目以上を満たすもの(計3 項目必要)とされ、疑い例は主症候の1項目以上を満たし、かつ検査・画像所見の1 項目以上を満たすもの(乳酸値は非特異的であるので①は除く)(計2 項目必要)とされる。
表.ミトコンドリア病 認定基準
(http://www.nanbyou.or.jp/upload_files/112_s.pdf)
1.主要項目
(1)主症候

①進行性の筋力低下、又は外眼筋麻痺を認める。
②知的退行、記銘力障害、痙攣、精神症状、失語・失認・失行、痙攣、強度視力低下、一過性麻痺、半盲、皮質盲、ミオクローヌス、ジストニア、小脳失調などの中枢神経症状のうち、1つ以上を認める。
③心伝導障害、心筋症などの心症状、糸球体硬化症、腎尿細管機能異常などの腎症状、強度の貧血などの血液症状、中等度以上の肝機能低下などの肝症状のうち、1つ以上を認める。
(2)検査・画像所見
①安静臥床時の血清又は髄液の乳酸値が繰り返して高い、又 はMRスペクトロスコピーで病変部に明らかな乳酸ピークを認める。
②脳CT/MRIにて、梗塞様病変、大脳・小脳萎縮像、大脳基底核、脳幹に両側対称性の病変等を認める。
③筋生検又は症状のある臓器でミトコンドリアの形態異常を認める。
なお、必要に応じて、以下の検査を行った場合
④ミトコンドリア関連酵素の欠損又はコエンザイムQ10などの中間代謝物の欠乏を認める。
⑤ミトコンドリアDNAの質的、量的異常、またはミトコンドリア関連核遺伝子変異を認める。
当該事業における対象基準
全A  疾患名に該当する場合
治療
対症療法が中心である。発作時はエネルギー消費を抑えるため安静・睡眠が奨励される。糖質制限と脂質優先摂取、バルプロ酸などのミトコンドリア毒を避けること、発作時にはL-カルニチン、コエンザイムQ、ビタミンB1・Cを中心とするビタミンカクテル療法を行う。いくつかの原因療法も考案中であり、中でもMELASに対するL-アルギニン療法はまもなく保険認可される見通しである。他に治験が進行ないし計画中の薬剤として、ピルビン酸ナトリウム、PBI-743、5-アミノレブリン酸などがあげられる。
成人期以降
病型により千差万別であり一概には言えないが、多くのミトコンドリア病の患者は大小のハンディキャップを背負いつつ成人期に移行する。年少の内から、小児科医は成人各科医師との移行期医療を模索しつつ診療に当たる必要がある。そのための重症度分類も、9つのセクション(日常生活動作(ADL)、高次脳機能、運動、視覚、聴覚、心合併症、腎機能、血液機能、肝機能)から成るミトコンドリア病の症状の多様性に配慮したものが、診断基準に続いて難病ホームページに公開されている。

(Comment) Complex II has 4 or 5 polypeptides, all coded by the nuclear genome.
(c.f.)
complex I (NADH-coenzyme Q reductase: 7 of 25 polypeptide subunits encoded in mitochondria),
complex II (succinate coenzyme Q reductase: 4 or 5 polypeptides encoded in nuclear genome),
complex III (coenzyme Q H2-cytochrome c reductase: 1 of 9 or 10 polypeptides encoded in mitochondira),
complex IV (cytochrome c reductase: 3 of 13 in mitochondria),
complex V (ATP synthetase: 2/ 12 to 14 in mitochondria)
(Responsible gene) *600857 Succinate dehydrogenase complex, susbunit A, flavoprotein (SDHA) <5p15.33>
(1) Mitochondrial complex II deficiency, nuclear type 1 (252011)
.0001 Mitochondrial complex II deficiency, nuclear type 1 [SDAH, ARG554TRP] (rs9809219) (gnomAD:rs9809219) (RCV000009281...) (Bourgeron et al. 1995)
.0002 Mitochondrial complex II deficiency, nuclear type 1 [SDHA, ALA524VAL] (rs137852767) (RCV000009282...) (Parfait et al. 2000)
.0003 Mitochondrial complex II deficiency, nuclear type 1 [SDHA, MET1LEU] (rs1061517) (gnomAD:rs1061517) (RCV000009283) (Parfait et al. 2000)
.0004 Mitochondrial complex II deficiency, nuclear type 1 (613642 Cardiomyopathy, dilated, 1GG, included) [SDHA, GLY555GLU] (rs137852768) (gnomAD:rs137852768) (RCV000009284...)
Mitochondrial Complex II Deficiency (Van Coster et al. 2003; Pagnamenta et al. 2006)
Dilated Cardiomyopathy 1GG (Levitas et al. 2010)
(2) Paraganglioma 5 (614165)
.0005 Paragangliomas 5 [SDHA, ARG589TRP] (rs387906780) (gnomAD:rs387906780) (RCV000554026...) Burnichon et al. 2010)
.0006 Mitochondrial complex II deficiency, nuclear type 1 [SDHA, THR508ILE] (rs151266052) (gnomAD:rs151266052) (RCV000032785...) (Alston et al. 2012)
.0007 Mitochondrial complex II deficiency, nuclear type 1 [SDHA, SER509LEU] (rs397514541) (gnomAD:rs397514541) (RCV000032786...) (Alston et al. 2012)
.0008 Paraganglioma 5 [SDHA, ARG31TER] (rs142441643) (gnomAD:rs142441643) (RCV000148026...) (Korpershoek et al. 2011)
.0009 Paraganglioma 5 [SDHA, ARG585TRP] (rs200397144) (gnomAD:rs200397144) (RCV000148027...) (Korpershoek et al. 2011)
.0010 Paraganglioma 5 [SDHA, ARG75TER] (rs781764920) (gnomAD:rs781764920) (RCV000191050...) (Welander et al. 2013)
(3) Neurodegeneration with ataxia and late-onset optic atrophy (619259)
.0011 Neurodegeneration with ataxia and late-onset optic atrophy [SDHA, ARG451CYS] (Birch-Machin et al. 2000; Courage et al. 2017)

(Responsible gene) *602690 Succinate dehydrogenase complex, subunit D, integral membrane protein (SDHD) <11q23>
(1) Paragangliomas 1 (168000)
.0001 Paragangliomas 1 [SDHD, GLN36TER] (rs104894303) (RCV000492417...) (Baysal et al. 2000)
.0002 Paragangliomas 1 (Pheochromocytoma, included) [SDHD, ARG38TER] (rs80338843) (gnomAD:rs80338843) (RCV000492087...) (Baysal et al. 2000; Gimm et al. 2000; Neumann et al. 2002)
.0003 Paragangliomas 1 [(Pheochromocytoma, somatic, included) (Paragangliomas, familial, with sensorineural hearing loss, included) SDHD, PRO81LEU] (rs80338844) (gnomAD:rs80338844) (RCV000162448...)
Paragangliomas 1 with or without Sensorneural Hearing Loss (Baysal et al. 2000; Milunsky et al. 2001; Badenhop et al. 2001; Astrom et al. 2003)
Pheochromocytoma, Somatic (Gimm et al. 2000)
.0004 Paragangliomas 1 (Pheochromocytoma, included) [SDHD, ASP92TYR] (rs80338845) (RCV000007305...) (Baysal et al. 2000; Neumann et al. 2002)
.0005 Paragangliomas 1 [SDHD, HIS102LEU] (rs104894302) (gnomAD:rs104894302) (RCV000566289...) (Baysal et al. 2000)
.0006 Paragangliomas 1 [SDHD, 1-BP INS, 13732T] (rs587776645) (RCV000007308) (Milunsky et al. 2001)
.0007 Paragangliomas 1 [SDHD, TYR114CYS] (rs104894304) (RCV000155750...) (Milunsky et al. 2001)
.0008 Paragangliomas 1 [SDHD, SER32TER] (rs104894305) (RCV000821648...) (Milunsky et al. 2001)
.0009 Paragangliomas 1 [SDHD, 1-BP DEL, 13838G] (rs587776646) (RCV000007311) (Milunsky et al. 2001)
.0010 Paragangliomas 1 [SDHD, IVS1DS, T-G, +2] (rs587776644) (RCV000007298) (Gimm et al. 2000)
.0012 Paragangliomas 1 [SDHD, ARG22TER] (rs104894306) (RCV000492341...) (Gimenez-Roqueplo et al. 2001)
.0013 Paragangliomas with sensorineural hearing loss LOSS [SDHD, 2-BP DEL] (rs387906358) (RCV000007313...) (Badenhop et al. 2001)
.0014 Paragangliomas 1 [SDHD, TYR93DEL] (rs121908983) (RCV000007314) (Badenhop et al. 2001)
.0015 Paragangliomas 1 [SDHD, MET1ILE] (rs80338842) (RCV000007315...) (Badenhop et al. 2001)
.0016 Paragangliomas 1 [SDHD, LEU139PRO] (rs80338847) (RCV000007316...) (Taschner et al. 2001)
.0017 Paragangliomas 1 [SDHD, 2-BP DEL] (rs397514034) (RCV000492163...) (Astuti et al. 2001)
.0020 Paragangliomas 1 [SDHD, 1-BP DEL, 463A] (rs587776647) (RCV000007319) (Leube et al. 2004)
.0021 Paraganglioma, carotid body, somatic [SDHD, MET1VAL] (rs104894307) (gnomAD:rs104894307) (RCV000471388...) (Riemann et al. 2004)
.0022 Paragangliomas 1 [SDHD, 4-BP DEL] (rs587776648) (RCV000485947...) (Cascon et al. 2002)
.0023 Paragangliomas 1 [SDHD, TRP43TER] (rs104894308) (RCV000627761...) (Cascon et al. 2002)
.0024 Paragangliomas 1 [SDHD, 96-KB DEL] (RCV000007323) (McWhinney et al. 2004)
.0027 Paraganglioma and gastric stromal sarcoma [SDHD, 1-BP DEL, 57G] (rs587776649) (RCV000505302...) (McWhinney et al. 2007)
(2) Cowden disease 3 (615106)
.0011 Reclassified - variant of unknown significance [SDHD, GLY12SER (rs34677591) [rs34677591] (RCV000007302...)
Cowden Syndrome (Ni et al. 2008; Bayley 2011)
Pheochromocytoma (Gimm et al. 2000; Cascon et al. 2002)
Carcinoid Tumors and Merkel Cell Carcinoma (Kytola et al. 2002)
Paragangliomas (Masuoka et al. 2001; Perren et al. 2002)
.0028 Reclassified - variant of unknown significance [SDHD, HIS145ASN] (rs121908984) (gnomAD:rs121908984) (RCV000007327...) (Cowden-like syndrome) (Ni et al. 2008; Bayley 2011)
(3) Carcinoid tumors, intestinal (114900)
.0019 Reclassified - variant of unknown significance [SDHD, HIS50ARG] (rs11214077) (gnomAD:rs11214077) (RCV000988743...) (Cascon et al. 2002)
Carcinoid Tumors and Merkel Cell Carinoma (Kytola et al. 2002)
Pheochromocytoma (Perren et al. 2002)
Cowden Syndrome (Ni et al. 2008; Bayley 2011)
(4) Pheochromocytoma (171300)
.0025 Pheochromocytoma [SDHD, CYS11TER] (rs104894309) (gnomAD:rs104894309) (RCV000221327...) (Neumann et al. 2002)
.0026 Pheochromocytoma [SDHD, TRP5TER] (rs104894310) (RCV000007325) (Neumann et al. 2002)
(5) Mitochondrial complex II deficiency (252011)
.0029 Mitochondrial complex II deficiency [SDHD, GLU69LYS] (rs202198133) (gnomAD:rs202198133) (RCV000484125...) (Jackson et al. 2014)
.0030 Mitochondrial complex II deficiency [SDHD, TER164LEU] (rs201372601) (gnomAD:rs201372601) (RCV000505355...) (Jackson et al. 2014)
.0031 Mitochondrial complex II deficiency [SDHD, ASP92GLY] (rs786205436) (RCV000171136...) (Alston et al. 2015)

.0018 REMOVED FROM DATABASE

(Note)
A number sign (#) is used with this entry because of evidence that mitochondrial complex II deficiency nuclear type 1 (MC2DN1) is caused by homozygous or compound heterozygous mutation in the SDHA gene (600857) on chromosome 5p15.

Mitochondrial complex II deficiency is an autosomal recessive disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others have only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. Measurement of complex II activity in muscle is the most reliable means of diagnosis; however, there is no clear correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin may have clinical benefit (summary by Jain-Ghai et al., 2013).

Complex II, also known as succinate dehydrogenase, is part of the mitochondrial respiratory chain.

Genetic Heterogeneity of Mitochondrial Complex II Deficiency
See MC2DN2 (619166), caused by mutation in the SDHAF1 gene (612848) on chromosome 19q13; MC2DN3 (619167), caused by mutation in the SDHD gene (602690) on chromosome 11q23; and MC2DN4 (619224), caused by mutation in the SDHB gene (185470) on chromosome 1p36.

▼ Clinical Features
Riggs et al. (1984) described 2 sibs with deficiency of complex II. A 7-year-old boy and his 9-year-old sister had progressive encephalomyopathy with dementia, myoclonic seizures, and short stature. A muscle biopsy showed mitochondrial aggregates and excessive lipid droplets in muscle fibers. In muscle mitochondria, the activity of succinate cytochrome c reductase was deficient. The activities of NADH-cytochrome c reductase and cytochrome oxidase were normal. The defect was thought to lie somewhere between succinate dehydrogenase and coenzyme Q10 in complex II.

A patient with complex II deficiency reported by Rustin et al. (1993) had isolated hypertrophic cardiomyopathy. Reichmann and Angelini (1994) reported 2 brothers with hypertrophic cardiopathy and skeletal muscle myopathy associated with complex II deficiency.

Bourgeois et al. (1992) reported 2 sisters with a degenerative neurologic disorder presenting clinically as a leukodystrophy. Brain imaging showed symmetric foci of necrosis in the substantia nigra and basal ganglia typical of Leigh syndrome (see 256000). Mitochondria isolated from skeletal muscle, fibroblasts, and lymphocytes showed complex II deficiency. The heart was not involved in these sisters.

Arpa et al. (1994) reviewed 10 previously published cases of succinate dehydrogenase deficiency and reported another case. Their patient was a 22-year-old woman, the daughter of consanguineous parents, with generalized muscle weakness and easy fatigability. She had mild proximal muscle weakness with distal wasting and an elevation of creatine kinase. Histopathologically, there were no ragged-red fibers, but there was a mild excess of neutral lipids and subsarcolemmal granular accumulations. Enzymatic analysis of isolated muscle mitochondria showed mild diminution of all respiratory complexes, most markedly of succinate-cytochrome c reductase. Free carnitine was also reduced.

Parfait et al. (2000) reported a girl with complex II deficiency presenting as Leigh syndrome. The patient was the first child of unrelated healthy parents and was born at term after a normal pregnancy and delivery. She developed normally until 9 months of age, when psychomotor delay was noted. She could not sit unaided before 16 months of age, when truncal ataxia and cerebellar syndrome were noticed. There was mild hyperlactatemia, and cerebrospinal fluid lactate was mildly elevated. Magnetic resonance imaging showed necrotic lesions in the basal ganglia compatible with the diagnosis of Leigh syndrome.

Alston et al. (2012) reported a boy who presented at 3 months of age with symptoms of dilated cardiomyopathy after a normal neonatal period. He later showed delayed motor development with hypertonia, hyperreflexia, and joint contractures. Speech was delayed. Brain MRI at age 2.5 years showed cystic changes and abnormal symmetric signals in the central cerebral white matter, as well as abnormal signals in the corpus callosum, ventral pons, medulla, and throughout the majority of the gray matter of the spinal cord. Laboratory studies showed normal plasma lactate, but evidence of ketosis and increased urinary lactate and urinary tricarboxylic acid cycle metabolites. Skeletal muscle biopsy showed severe deficiency of mitochondrial complex II activity. Western blot analysis of patient fibroblasts showed decreased amounts of fully assembled complex II with almost complete absence of SDHA.

Van Coster et al. (2003) reported a female infant, born of first-cousin parents, with mitochondrial complex II deficiency who died at 5.5 months of age following a respiratory infection. Although her clinical course differed from that in the patients reported by Bourgeron et al. (1995) and Parfait et al. (2000), Van Coster et al. (2003) noted that she died before any sign of Leigh syndrome could develop.

Jain-Ghai et al. (2013) reported a female infant, born of unrelated parents of Middle Eastern descent, with complex II deficiency. She was born at 28 weeks' gestation due to preeclampsia. Echocardiogram showed dilated cardiomyopathy and left ventricular noncompaction, and laboratory studies showed increased serum lactate. The patient later showed developmental delay, failure to thrive, and hypotonia. She died at age 13 months. Electron microscopic analysis of muscle biopsy showed mitochondria with a dense array of parallel cristae and matrix granules, isolated complex II deficiency, and low levels of SDHA protein (24%) compared to controls. However, genetic analysis did not reveal mutations in the SDHA, SDHAF1, or ISCU (611911) genes. Jain-Ghai et al. (2013) postulated that this patient had a novel genetic defect.

Jain-Ghai et al. (2013) reviewed 36 published cases of complex II deficiency. The phenotype was highly variable: some patients had multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others had only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. Neurologic findings, although variable, included developmental delay or regression following infection, hypotonia, hypertonia, and spasticity. Ophthalmologic features included ophthalmoplegia, retinopathy, nystagmus, optic atrophy, and blindness. Measurement of complex II activity in muscle was the most reliable means of diagnosis; however, there was no correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin had some clinical benefit.

▼ Molecular Genetics
In 2 sibs with complex II deficiency presenting as Leigh syndrome reported by Bourgeois et al. (1992), Bourgeron et al. (1995) identified a homozygous mutation in the SDHA gene (R554W; 600857.0001). Bourgeron et al. (1995) claimed that this was the first report of a nuclear gene mutation causing a mitochondrial respiratory chain deficiency in humans.

In a girl with mitochondrial complex II deficiency manifesting as Leigh syndrome, Parfait et al. (2000) identified compound heterozygous mutations in the SDHA gene (A524V, 600857.0002; M1L, 600857.0003).

In a female infant who died at 5.5 months of age following a respiratory infection and was found to have MC2DN1, Van Coster et al. (2003) identified homozygosity for a missense mutation in the SDHA gene (G555E; 600857.0004). The authors noted that the patient died in infancy before signs of Leigh syndrome could develop.

Pagnamenta et al. (2006) reported a 10-year-old Palestinian boy with MC2DN1 manifest as Leigh syndrome in whom they identified homozygosity for the G555E mutation in the SDHA gene. Pagnamenta et al. (2006) noted that the patient previously reported by Van Coster et al. (2003) with the G555E mutation was also of Middle Eastern origin, suggesting the possibility of an ancestral mutation.

In a boy with complex II deficiency who presented with cardiomyopathy and leukodystrophy, Alston et al. (2012) identified compound heterozygous mutations in the SDHA gene (T508I, 600857.0006 and S509L, 600857.0007). Each parent was heterozygous for one of the mutations.

Associations Pending Confirmation
For discussion of a possible association between mitochondrial complex II deficiency and variation in the SDHB gene, see 185470.0020.

(文献)
(1) Riggs JE et al. Mitochondrial encephalomyopathy with decreased succinate-cytochrome-c-reductase activity. Neurology 34: 48-53, 1984
(2) Rivner, M. D.; Shamsnia, M.; Swift, T. R.; Trefz, J.; Roesel, R. A.; Carter, A. L.; Yanamura, W.; Hommes, F. A. : Kearns-Sayre syndrome and complex II deficiency. Neurology 39: 693-696, 1989
(3) Burgeois, M.; Goutieres, F.; Chretien, D.; Rustin, P.; Munnich, A.; Aicardi, J. : Deficiency in complex II of the respiratory chain, presenting as a leukodystrophy in two sisters with Leigh syndrome. Brain Dev. 14: 404-408, 1992
(4) Rustin, P.; Lebidois, J.; Chretien, D.; Bourgeron, T.; Piechaud, J.-F.; Rotig, A.; Sidi, D.; Munnich, A. : The investigation of respiratory chain disorders in heart using endomyocardial biopsies. J. Inherit. Metab. Dis. 16: 541-544, 1993
(5) Arpa J et al. Benign mitochondrial myopathy with decreased succinate cytochrome C reductase activity. Acta Neurol. Scand. 90: 281-284, 1994
(6) Reichmann, H.; Angelini, C. : Single muscle fibre analyses in 2 brothers with succinate dehydrogenase deficiency. Europ. Neurol. 34: 95-98, 1994
(7) Bourgeron, T.; Rustin, P.; Chretien, D.; Birch-Machin, M.; Bourgeois, M.; Viegas-Pequignot, E.; Munnich, A.; Rotig, A. : Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nature Genet. 11: 144-149, 1995
(8) Brockmann K et al. Succinate in dystrophic white matter: a proton magnetic resonance spectroscopy finding characteristic for complex II deficiency. Ann. Neurol. 52: 38-46, 2002
(9) Bugiani, M.; Lamantea, E.; Invernizzi, F.; Moroni, I.; Bizzi, A.; Zeviani, M.; Uziel, G. : Effects of riboflavin in children with complex II deficiency. Brain Dev. 28: 576-581, 2006
(10) Ghezzi, D.; Goffrini, P.; Uziel, G.; Horvath, R.; Klopstock, T.; Lochmuller, H.; D'Adamo, P.; Gasparini, P.; Strom, T. M.; Prokisch, H.; Invernizzi, F.; Ferrero, I.; Zeviani, M. : SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nature Genet. 41: 654-656, 2009
(11) Alston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L., Hornig-Do, H.-T., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I., Wassmer, E., McFarland, R., Taylor, R. W. Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency. J. Med. Genet. 49: 569-577, 2012
(12) Jain-Ghai, S., Cameron, J. M., Al Maawali, A., Blaser, S., MacKay, N., Robinson, B., Raiman, J. Complex II deficiency--a case report and review of the literature. Am. J. Med. Genet. 161A: 285-294, 2013
(13) Jackson, C. B., Nuoffer, J.-M., Hahn, D., Prokisch, H., Haberberger, B., Gautschi, M., Haberli, A., Gallati, S., Schaller, A. Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency. J. Med. Genet. 51: 170-175, 2014
(14) Alston, C. L., Ceccatelli Berti, C., Blakely, E. L., Olahova, M., He, L., McMahon, C. J., Olpin, S. E., Hargreaves, I. P., Nolli, C., McFarland, R., Goffrini, P., O'Sullivan, M. J., Taylor, R. W. A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency. Hum. Genet. 134: 869-879, 2015

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2014/09/25 ノート追記
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2015/10/30 症状改訂
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2018/07/12 変異改訂
2019/07/25 RCV改訂
2021/01/29 病名改訂
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2021/03/09 異質性追加
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