疾患詳細

疾患詳細





#545000
Myoclonus epilepsy associated with ragged-red fibers (MERRF)
(MERRF syndrome)

ミオクロニー発作-ぼろきれ赤筋
(MERRF 症候群)
指定難病21 ミトコンドリア病

遺伝子座:不明
責任遺伝子:590050 Transfer RNA, mitochondrial, leucine, 1 (MTTL1)
 590060 Transfer RNA, mitochondrial, lysine (MTTK)
 590070 Transfer RNA, mitochondrial, phenylalanine (MTTF)
 590040 Transfer RNA, mitochonrial, histidine (MTTH)
 590075 Transfer RNA, mitochondrial, proline (MTTP)
 590080 Transfer RNA, mitochondrial, serine, 1 (MTTS1)
遺伝形式:ミトコンドリア遺伝

(症状)
(GARD)
 <80%-99%>
 Abnormality of movement (運動異常) [HP:0100022] [026]
 Ataxia (運動失調) [HP:0001251] [028]
 EMG abnormality (筋電図異常) [HP:0003457]
 Generalized myoclonic seizures (全身性ミオクロニー発作) [HP:0002123] [01405]
 Myopathy (ミオパチー) [HP:0003198] [0277]
 Ragged-red muscle fibers (赤色ぼろ線維) [HP:0003200]
 Sensorineural hearing impairment (感音難聴) [HP:0000407] [0910]
 
 <30%-79%>
 Cognitive impairment (認知障害) [HP:0100543] [0123]
 Multiple lipomas (多発性脂肪腫) [HP:0001012] [2313]
 Optic atrophy (視神経萎縮) [HP:0000648] [06522]
 Short stature (低身長) [HP:0004322] [0130]
 
 
 Increased serum lactate (乳酸増加) [HP:0002151] [2044]
 Increased serum pyruvate (血清ピルビン酸増加) [HP:0003542] [2043]
 Mitochondrial inheritance (ミトコンドリア遺伝) [HP:0001427]
 Muscle weakness (筋力低下) [HP:0001324] [0270]
 Myoclonus (ミオクローヌス) [HP:0001336] [02612]
 Seizures (けいれん) [HP:0001250] [01405]
 Spasticity (痙縮) [HP:0001257] [0241]

(UR-DBMS)
【一般】ミオクローヌスで20歳以前に発症
 *全身性またはミオクローヌス性けいれん
 低換気
 脳波 (変化に富む; 全身けいれん的, ないしバックグランド徐波)
【神経】*全身性ミオクローヌス
 痙縮
 *ミオパチー
 *小脳失調歩行
 筋力低下
【耳】(感音難聴
 前庭機能障害)
【X線】脳の海綿状変性
【検査】(乳酸 / ピルビン酸高値)
 ミトコンドリア構造異常 (電顕)

<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)

(責任遺伝子1) *590050 Transfer RNA, mitochondrial, leucine, 1 (MTTL1)
(1) MELAS syndrome (540000)
.0001 MELAS syndrome (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) (MERRF/MELAS overlap syndrome, included) [MTTL1, 3243A-G [dbSNP:rs199474657] (dbSNP:rs199474657) (RCV000010206...)
Phenotypes (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; Matthews et al. 1994; Vilarinho et al. 1997; de Vries et al. 1994; Reardon et al. 1992; Schulz et al. 1993; Manouvrier et al. 1995; Odawara et al. 1995; Yang et al. 1995; Chuang et al. 1995; Yorifuji et al. 1996; Morten et al. 1995; Damian et al. 1996; Stone and Biesecker 1997; Feigenbaum et al. 1996; Velho et al. 1996; Tamagawa et al. 1997; Lam et al. 1997; Wilichowski et al. 1998; Dashe and Boyer 1998); Chinnery et al. 1998; Sue et al. 1999; Deschauer et al. 1999; Smith et al. 1999; Latkany et al. 1999; Aggarwal et al. 2001; De Kremer et al. 2001; Uimonen et al. 2001; Deschauer et al. 2001; Chinnery et al. 2001; Petruzzella et al. 2004; Jones et al. 2004; Salpietro et al. 2003; Bohm et al. 2006; Donovan and Severin 2006; Jeppesen et al. 2006; Janssen et al. 2008; Kaufmann et al. 2009; Costello and Sims 2009; Nakamura et al. 2010
Studies of the 3243A-G mutation (Yoneda et al. 1992; Matthews et al. 1995; Janssen et al. 1999; Borner et al. 2000; Chomyn et al. 2000; Olsson et al. 2001; Rahman et al. 2001; Pyle et al. 2007; Durham et al. 2007; Janssen et al. 2007; Rajasimha et al. 2008; Sasarman et al. 2008; Dvorakova et al. 2016)
Population genetics (Majamaa et al. 1998; Moilanen and Majamaa 2001; Nagata et al. 2001; Torroni et al. 2003; Uusimaa et al. 2007; Elliott et al. 2008)
.0002 MELAS syndrome [MTTL1, 3271T-C [dbSNP:rs199474658] (RCV000010212) (Goto et al. 1991; Stenqvist et al. 2005)
(2) MERRF syndrome
.0003 MERRF syndrome (Diabetes mellitus, noninsulin-dependent, maternally transmitted) [MTTL1, 3256C-T [dbSNP:rs199474659] (RCV000010214...) (Moraes et al. 1993; Hirai et al. 1998)
(3) Cardiomyopathy with or without skeletal myopathy
.0004 Cardiomyopathy with or without skeletal myopathy [MTTL1, 3303C-T [dbSNP:rs199474660] (RCV000010215) (Silvestri et al. 1994; Bruno et al. 1999)
(4) Encephalomyopathy, mitochondrial
.0005 Encephalomyopathy, mitochondrial [MTTL1, 3252T-C [dbSNP:rs199474661] (RCV000010217) (Morten et al. 1993)
.0007 Cardiomyopathy with or without skeletal myopathy [MTTL1, 3260A-G [dbSNP:rs199474663] (RCV000010219) (Mariotti et al. 1994)
(5) Progressive external ophthalmoplegia, proximal myopathy, and sudden death
.0006 Progressive external ophthalmoplegia, proximal myopathy, and sudden death [MTTL1, 3251A-G [dbSNP:rs199474662] (RCV000010218) (Sweeney et al. 1993; Houshmand et al. 1996)
(6) Skeletal myopathy, responsive to riboflavin
.0008 Skeletal myopathy, responsive to riboflavin [MTTL1, 3250T-C [dbSNP:rs199474664] (RCV000010216) (Ogle et al. 1997)
(7) Sudden infantile death syndrome (272120)
.0009 Sudden infantile death syndrome [MTTL1, 3290T-C [dbSNP:rs199474665] (RCV000010220) (Opdal et al. 1999)
(8) Nenuropsychiatic disorder and early-onset cataract
.0010 Nenuropsychiatic disorder and early-onset cataract [MTTL1, 3274A-G [dbSNP:rs199474666] (RCV000010221) (Jaksch et al. 2001)
(9) Kearns-Sayre syndrome (530000)
.0011 Kearns-Sayre syndrome [MTTL1, 3249G-A [dbSNP:rs199474667] (RCV000010222) (Seneca et al. 2001)
(10) Myelodysplastic syndrome
.0012 Myelodysplastic syndrome [MTTL1, 3242G-A [dbSNP:rs193303018] (RCV000010223) (Gattermann et al. 2004)

(Responsible gene 2) *590060 Transfer RNA, mitochondrial, lysine (MTTK)
(1) MERRF syndrome (545000)
.0001 MERRF syndrome (Leigh syndrome, included) (Parkinson disease, mitochondrial, included) [MTTK, 8344A-G [dbSNP:rs118192098] (RCV000010194...)
MERRF syndrome (Shoffner et al. 1990; Yoneda et al. 1990; Berkovic et al. 1991; Seibel et al. 1991, Shih et al. 1991, Tanno et al. 1991; Zeviani et al. 1991; Noer et al. 1991; Boulet et al. 1992; Suomalainen et al. 1993; Lertrit et al. 1992; Shoffner and Wallace 1992 [80-90% of MERRF]; Penisson-Besnier et al. 1992; Silvestri et al. 1993; Hammans et al. 1993; Fang et al. 1994; Enriquez et al. 1995; Shoffner et al. 1990; Chomyn 1998
multiple symmetric lipomas (MSL; 151800) (Holme et al. 1993; Gamez et al. 1998)
parkinsonism (556500) (Horvath et al. 2007)
severe cavitating leukoencephalopathy (Biancheri et al. 2010)
.0002 MERRF syndrome (MERRF/MELAS overlap syndrome) [MTTK, 8356T-C [dbSNP:rs118192099] (RCV000010195...) (Silvestri et al. 1992; Zeviani et al. 1993; Nakamura et al. 2010)
.0007 MERRF syndrome [MTTK, 8361G-A [dbSNP:rs118192104] (RCV000010202) (Rossmanith et al. 2003)
(2) Cardiomyopathy and deafness
.0003 Cardiomyopathy and deafness [MTTK, 8363G-A [dbSNP:rs118192100] (RCV000144004...) (Santorelli et al. 1996)
(3) Mitochondrial neurogastrointestinal encephalopathy syndrome; MNGIE syndrome
.0004 Mitochondrial neurogastrointestinal encephalopathy syndrom [MTTK, 8313G-A [dbSNP:rs118192101] (RCV000010200) (Verma et al. 1997)
(4) Diabetes mellitus-deafness syndrome, maternally inherited
.0005 Diabetes mellitus-deafness syndrome, maternally inherited [MTTK, 8296A-G [dbSNP:rs118192102] (v) (Kameoka et al. 1998)
(5) Progressive external ophthalmoplegia with myoclonus
.0006 Progressive external ophthalmoplegia with myoclonus [MTTK, 8342G-A [dbSNP:rs118192103] (RCV000010198...) (Tiranti et al. 1999)

(Responsible gene 3) *590070 Transfer RNA, mitochondrial, phenylalanine (MTTF)
(1) MELAS syndrome (540000)
.0001 MELAS syndrome [MTTF, 583G-A] (dbSNP:rs118203885) (RCV000010186) (Hanna et al. 1998)
(2) MERRF syndrome (545000)
.0002 MERRF syndrome[MTTF, 611G-A] (dbSNP:rs118203886) (RCV000010187) (Mancuso et al. 2004; Ling et al. 2007)
(3) Myopathy, mitochondrial, late-onset
.0003 Myopathy, mitochondrial, late-onset [MTTF, 622G-A] (dbSNP:rs118203887) (RCV000010188) (Deschauer et al. 2006)
(4) Epilepsy, mitochondrial
.0004 Epilepsy, mitochondrial [MTTF, 616T-C] (dbSNP:rs387906420) (RCV000010189) (Zsurka et al. 2010)
.0005 Epilepsy, mitochondrial [MTTF, 616T-G] (dbSNP:rs387906420) (RCV000010190) (Zsurka et al. 2010)
(5) Encephalopathy, mitochondrial
.0006 Encephalopathy, mitochondrial [MTTF, 586G-A] (dbSNP:rs387906734) (RCV000022903) (Young et al. 2010)
(6) Nephropathy, tubulointestinal
.0007  Nephropathy, tubulointestinal [MTTF, 608A-G] (dbSNP:rs387906735) (RCV000022904) (Tzen et al. 2001)

(Responsible gene 4) *590040 Transfer RNA, mitochonrial, histidine (MTTH)
.0001 Cardiomyoppathy, idiopathic dilated, mitochondrial [MTTH, 12192G-A] (Cardiomyopathy, hypertrophic, mitochondrial, included) (Shin et al. 2000; Mimaki et al. 2003)
.0002 Pigmentary retinopathy and sensorineural deafness [MTTH, 12183G-A] (Crimi et al. 2003)
.0003 MERRF/MELAS overlap syndrome (540000, 545000) [MTTH, 12147G-A] (Melone et al. 2004; Taylor et al. 2004)
.0004 Deafnes, nonsyndromic sensorineural, mitochondrial (500008) [MTTH, 12201T-C] (Yan et al. 2011)

(責任遺伝子) *590075 Transfer RNA, mitochondrial, proline (MTTP)
.0001 Myopathy [MTTP, UGG-TO-UGA ANTICODON MUTATION] (Moraes et al. 1993)
.0002 Parkinson disease, susceptibility to (556500) [MTTP, 15965T-C] (Grasbon-Frodl et al. 1999)
.0003 MERFF syndrome (545000) [MTTP, 15967G-A] (Blakely et al. 2009)

(Responsible gene) *590080 Transfer RNA, mitochondrial, serine, 1 (MTTS1)
(1) MERRF (545000)/MELAS (540000) overlap syndrome
.0001 MERRF (545000)/MELAS (540000) overlap syndrome [MTTS1, T-C, NT7512, T7512C, C7512] (Nakamura et al. 1995; Jaksch et al. 1998)
(2) Keratoderma, palmoplantar, with deafness (148350)
.0002 Keratoderma, palmoplantar, with deafness [MTTS1, T7445C] (500008 Deafness, nonsyndromic sensorineural, mitochondrial) (Reid et al. 1994; Reid et al. 1994; Sevior et al. 1998; Guan et al. 1998; Martin et al. 2000; Hutchin et al. 2001)
(3) Mitochondrial cytochrome c oxidase deficiency (220110) (500008 Deafness, sensorineural, with neurologic features, included) (500008 Deafness, nonsyndromic sensorineural, mitochondrial, included)
.0003 Mitochondrial syndromic encephalopathy with cytochrome c oxidase deficiency [MTTS1, 1-BP INS, 7472C] (Jaksch et al. 1998; Verhoeven et al. 1999); Friedman et al. 1999; Toompuu et al. 1999; Hutchin et al. 2001)
(4) Deafness, nonsyndromic sensorineural, mitochondrial (500008)
.0004 Deafness, nonsyndromic sensorineural, mitochondrial [MTTS1, 7510T-C] (Hutchin et al. 2000)
.0005 Deafness, nonsyndromic sensorineural, mitochondrial [MTTS1, 7511T-C] (Chapiro et al. 2002)
.0007 Deafness, nonsyndromic sensorineural, mitochondrial [MTTS1, 7445A-C] (Jin et al. 2007)
.0009 Deafness, nonsyndromic sensorineural, mitochondrial [MTTS1, 7505T-C] (Tang et al. 2010)
(5) Deafness, aminoglycoside-induced (580000)
.0006 Deafness, aminoglycoside-induced [MTTS1, 7444G-A] (Jin et al. 2007)
(6) Exercise ntolerance, muscle pain, and lctic acidemia
.0008 Exercise ntolerance, muscle pain, and lctic acidemia [MTTS1, 7497G-A] (Grafakou et al. 2003)

●MT-TS1 (Mitochondrially Encoded TRNA-Ser (UCN) 1)
 Genome size 74 bp, Minus strand
●RNA 遺伝子で,tRNA クラスに入る

(ノート)
●A number sign (#) is used with this entry because this syndrome represents a phenotype that can be produced by mutation in more than 1 mitochondrial gene, e.g., MTTK (590060), MTTL1 (590050), MTTH (590040), MTTS1 (590080), MTTS2 (590085), MTTF (590070). Features of the MERRF syndrome have also been associated with mutation in the MTND5 gene (516005).

臨床症状
●Fukuhara ら(1980) は, ragged-red fibers を伴うミオクロニー発作の早期の報告をした
For detailed clinical features, see MOLECULAR GENETICS

遺伝
●Rosing ら(1985) は, この異常の組合わせをもつ大家系を記載し, MERRF 症候群という頭字語を使用した
 常染色体優性, 常染色体劣性およびX連鎖遺伝が除外できた
 表現型の差異と遺伝の特徴の差異がミトコンドリアDNAの変異に一致した
 臨床的スペクトラムは変異および野生型 mtDNA の比率モデルに一致した
 血清のピルビン酸と乳酸値が上昇していた

●母系細胞により遺伝子障害は伝達されるが, 臨床表現型は家系内で大きな差異がある
 mtDNA のヘテロ接合体プラスミック集団, あるものは野生型をもち, 他は変異をもつ, に一致する
 骨格筋では, 生化学的障害はしばしば分節的である (Matsuoka ら, 1991)
  筋細胞内での変異および野生型 mtDNA のランダムでない分布を示唆する

分子遺伝学
●Shoffner ら(1990)は, mtDNA の特異的変異を最初に記載した
 リジンに対する transfer RNAのミスセンス変異であった (MTTK, TRMK; 590060.0001)
●ヌクレオチド8344 のA-to-G 変異が MERRF 症例の80-90%を説明する (Shoffner and Wallace, 1992)
 生化学的には, 変異は呼吸鎖の酵素複合体の多数の欠損を生じ , チトクロム c 酸化酵素 (COX) (複合体 IV)のNADH-CoQ reductase (複合体 I) が最も多い, 全ての mtDNA をコードする遺伝子の翻訳障害に一致する (Wallace ら, 1988; Bindoff ら, 1991)
●Chomyn ら(1991)は, 自身の mtDNA を欠損するヒト細胞系への変異をもつ mtDNA の transfer は, 核遺伝子背景とは独立して, 受け取った細胞のミトコンドリア翻訳の重度の障害をなることを示した
 tRNA 変異自体が疾患を生じるのに十分であることを示す

Holme et al. (1993) reported a woman with multiple symmetric lipomas (MSL; see 151800) in the neck and shoulder area associated with a heteroplasmic c.8344A-G mutation in the MTTK gene (590060.0001). Her son, who also carried the mutation, had MERRF syndrome; the mother had no signs of MERRF syndrome. The fraction of mutant mtDNA in the woman varied between 62% and 80% in cultured skin fibroblasts, lymphocytes, normal adipose tissue, and muscle, whereas the fraction of mutant mtDNA in the lipomas ranged from 90 to 94%. Ultrastructural examination of the lipomas revealed numerous mitochondria and electron-dense inclusions in some adipocytes. Holme et al. (1993) concluded that the mutation may either directly or indirectly perturb the maturation process of the adipocytes, increasing the risk of lipoma formation.

In several affected members of 3-generation Sardinian kindred with a maternally inherited syndrome characterized by features of both MERRF and MELAS (540000), Zeviani et al. (1993) identified a mutation in the MTTK gene (590060.0002). The relative amount of mutant mtDNA in muscle correlated with the severity of the clinical presentation. Clinical features included myoclonic epilepsy, neural deafness, ataxia, and stroke-like episodes.

In a mother and daughter with MERFF/MELAS overlap syndrome, Nakamura et al. (1995) identified a heteroplasmic mutation in the MTTS1 gene (590080.0001). The proband in their study was a mentally retarded 26-year-old woman who had had epileptic attacks since the age of 15 years. At the age of 20 years, clear symptoms of MERRF syndrome developed, including myoclonic seizures, generalized tonic-clonic seizures, and paroxysmal hearing disturbance. She also showed mental deterioration, muscle atrophy weakness, and truncal ataxia. Lactate levels in both blood and cerebrospinal fluid were elevated. The brain CT scan showed cerebral atrophy and bilateral calcification of the basal ganglia. Muscle biopsies showed many ragged-red fibers and abnormal mitochondria with concentric cristae. The mother was a 55-year-old woman who had myoclonic jerks of the arms and generalized seizures since the age of 37 years. At age 47 years, she was moderately demented. Muscle weakness and ataxia were not apparent. The brain CT scan revealed calcification of the basal ganglia and bilateral occipital lobe atrophy. At age 55 years, she developed blindness after an episode of generalized seizure, and thereafter was bedridden and severely demented; the phenotype suggested stroke-like episodes consistent with MELAS syndrome.

Melone et al. (2004) reported a 20-year-old man who experienced sudden migrainous headache and vomiting, followed by left hemiparesis and lateral homonymous hemianopia. Seizures also occurred. The clinical picture was consistent with MELAS syndrome. At age 25 years, he developed myoclonus and ataxia, suggesting progression to MERRF syndrome. His mother had shown similar stroke-like episodes and had died at age 36 years. Muscle biopsy of the proband showed abnormal mitochondrial proliferation and COX-negative fibers. Genetic analysis identified a heteroplasmic mutation in the MTTH gene (590040.0003).

Mancuso et al. (2004) reported an Italian woman who experienced panic attacks at age 11 years. In her twenties, she developed migraine and progressive limb myoclonus. In her thirties, she had exercise intolerance, loss of balance, and memory problems, and later developed bilateral sensorineural hearing loss and mild cognitive deficits. Other features included short stature, pes cavus, ataxia, and mild ophthalmoparesis. Skeletal muscle biopsy showed multiple COX-negative fibers and ragged red fibers. Genetic analysis identified a heteroplasmic mutation in the MTTF gene (590070.0002).

Blakely et al. (2009) reported a woman who developed myoclonic jerks and generalized seizures at age 27 years, acute bilateral sensorineural hearing loss at age 37, underwent bilateral cataract surgery at age 39, and showed progressive loss of balance and arm weakness at age 47. Physical examination at age 49 showed some retinal pigmentary changes, dysarthria, proximal muscle weakness, and cerebellar ataxia. Skeletal muscle biopsy showed COX deficiency and ragged red fibers, consistent with mitochondrial accumulation. Genetic analysis identified a heteroplasmic mutation in the MTTP gene (590075.0003). The mutation segregated with cytochrome c oxidase activity in single muscle fibers.

(文献)
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