Clinical and molecular basis of hepatocerebral mitochondrial DNA depletion syndrome in Japan: evaluation of outcomes after liver transplantation

被引：36

作者：

Shimura, Masaru ^{[1
]}

Kuranobu, Naomi ^{[2
]}

Ogawa-Tominaga, Minako ^{[1
]}

Akiyama, Nana ^{[1
]}

Sugiyama, Yohei ^{[1
]}

Ebihara, Tomohiro ^{[1
]}

Fushimi, Takuya ^{[1
]}

Ichimoto, Keiko ^{[1
]}

Matsunaga, Ayako ^{[1
]}

Tsuruoka, Tomoko ^{[1
]}

Kishita, Yoshihito ^{[3
]}

Umetsu, Shuichiro ^{[4
]}

Inui, Ayano ^{[4
]}

Fujisawa, Tomoo ^{[4
]}

Tanikawa, Ken ^{[5
]}

Ito, Reiko ^{[6
]}

Fukuda, Akinari ^{[7
]}

Murakami, Jun ^{[2
]}

Kaji, Shunsaku ^{[8
]}

Kasahara, Mureo ^{[7
]}

Shiraki, Kazuo ^{[2
]}

Ohtake, Akira ^{[9
,10
]}

Okazaki, Yasushi ^{[3
]}

Murayama, Kei ^{[1
]}

机构：

[1] Chiba Childrens Hosp, Ctr Med Genet, Dept Metab, Midori Ku, 579-1 Heta Cho, Chiba 2660007, Japan

[2] Tottori Univ, Div Pediat & Perinatol, Fac Med, 36-1 Nishi Cho, Yonago, Tottori 6838504, Japan

[3] Juntendo Univ, Intractable Dis Res Ctr, Grad Sch Med, Diagnost & Therapeut Intractable Dis,Bunkyo Ku, Hongo 2-1-1, Tokyo 1138421, Japan

[4] Saiseikai Yokohama City Tobu Hosp, Dept Pediat Hepatol & Gastroenterol, Tsurumi Ku, 3-6-1 Shimosueyoshi, Yokohama, Kanagawa 2300012, Japan

[5] Yame Gen Hosp, Dept Diagnost Pathol, 540-2 Takatsuka, Yame, Fukuoka 8340034, Japan

[6] Natl Ctr Child Hlth & Dev, Dept Gen Pediat & Interdisciplinary Med, Setagaya Ku, 2-10-1 Okura, Tokyo 1578535, Japan

[7] Natl Ctr Child Hlth & Dev, Organ Transplantat Ctr, Setagaya Ku, 2-10-1 Okura, Tokyo 1578535, Japan

[8] Tsuyama Chuo Hosp, Dept Pediat, Kawasaki 1756, Tsuyama, Okayama 7080841, Japan

[9] Saitama Med Univ, Fac Med, Dept Pediat & Clin Genom, 38 Morohongo, Moroyama, Saitama 3500495, Japan

[10] Saitama Med Univ Hosp, Ctr Intractable Dis, 38 Morohongo, Moroyama, Saitama 3500495, Japan

来源：

ORPHANET JOURNAL OF RARE DISEASES | 2020年 / 15卷 / 01期

关键词：

MPV17; DGUOK; POLG; MICOS13; Liver transplantation; Mitochondrial disease; Mitochondrial DNA maintenance defects; RESPIRATORY-CHAIN DISORDERS; SINGLE-CENTER EXPERIENCE; MPV17; GENE; MUTATIONS; MAINTENANCE; FAILURE; MANIFESTATIONS; DIAGNOSIS;

D O I：

10.1186/s13023-020-01441-5

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Background Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and neurological complications during infancy. Liver transplantation (LT) remains controversial due to poor outcomes associated with extrahepatic symptoms. The purposes of this study were to clarify the current clinical and molecular features of hepatocerebral MTDPS and to evaluate the outcomes of LT in MTDPS patients in Japan. Results We retrospectively assessed the clinical and genetic findings, as well as the clinical courses, of 23 hepatocerebral MTDPS patients from a pool of 999 patients who were diagnosed with mitochondrial diseases between 2007 and 2019. Causative genes were identified in 18 of 23 patients:MPV17(n = 13),DGUOK(n = 3),POLG(n = 1), andMICOS13(n = 1). Eight MPV17-deficient patients harbored c.451dupC and all three DGUOK-deficient patients harbored c.143-307_170del335. The most common initial manifestation was failure to thrive (n = 13, 56.5%). The most frequent liver symptom was cholestasis (n = 21, 91.3%). LT was performed on 12 patients, including nine MPV17-deficient and two DGUOK-deficient patients. Among the 12 transplanted patients, five, including one with mild intellectual disability, survived; while seven who had remarkable neurological symptoms before LT died. Five of the MPV17-deficient survivors had either c.149G > A or c.293C > T. Conclusions MPV17was the most common genetic cause of hepatocerebral MTDPS. The outcome of LT for MTDPS was not favorable, as previously reported, however, patients harboringMPV17 mutations associated with mild phenotypes such as c.149G > A or c.293C > T, and exhibiting no marked neurologic manifestations before LT, had a better prognosis after LT.

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页数：9