臺灣博碩士論文加值系統

粒線體疾病是一群相當複雜且異質性的多系統基因疾患，其診斷往往需要多方面的評估，嬰兒及兒童的粒線體疾病，除了已知的特殊症候群外，有很多是屬於無法歸類的非症候群粒線體疾病。本研究目的是描述嬰兒及兒童症候群及非症候群粒線體疾病的臨床表徵、實驗室生化檢驗、神經影像學表現、組織病理學發現及基因分析。
從1983年1月到2009年6月，我們共收集了69位診斷為粒線體疾病的個案，發病年齡分布為1個月到15歲 (中位數15個月)，其中49.3﹪屬於症候群粒線體疾病，50.7﹪為非症候群粒線體疾病。粒線體疾病的臨床表現相當多樣化且各個器官系統均可能受到侵犯，其中以中樞神經系統為臨床表現的比例最高(88.4﹪)。實驗室檢查方面，40.6% 病人的血液乳酸值上升而84.8% 病人的口服葡萄糖刺激試驗為陽性。影像學的表現與臨床表現同樣多變，腦部核磁共振影像顯示26.2%粒線體疾病病人(18.2%症候群粒線體疾病及34.4%非症候群粒線體疾病) 最初的腦部核磁共振檢查是正常的，73.8%粒線體疾病病人於最初的腦部核磁共振檢查出現異常，最常見的異常訊號位於腦部基底核的背殼 (45.5%症候群粒線體疾病及15.6%非症候群粒線體疾病)，腦部氫核磁共振光譜中有31.8%病人出現乳酸值高峰。肌肉切片之光學顯微鏡檢查，51.6%病人可見紅色襤褸肌細胞，粒線體基因突變的陽性率為27.5%。追蹤病人預後可發現，愈早發病則死亡率及致死率愈高。
本篇研究詳述了嬰兒及兒童粒線體疾病多樣化的臨床表現方式以提供兒科醫師如何早期發現粒線體疾病，而口服葡萄糖刺激試驗為篩選粒線體疾病的有效方法。

Mitochondrial diseases (MDs) are a group of clinically and genetically heterogeneous multisystem disorders. Therefore the diagnosis of MDs is based on a multidisciplinary approach. In addition to well known syndromic mitochondrial diseases (SMDs), nonsyndromic mitochondrial diseases (NSMDs) are not uncommon in infants and children.The aim of this study is to compare with the clinical symptoms and signs, laboratory findings, neuroimaging features, histopathological results, and outcome between SMDs and NSMDs.
From January 1983 to June 2009, 69 patients diagnosed with MDs. The age of disease onset was 1 month to 15 years (median 15 months). Among them, 49.3% of petients had SMDs and 50.7% had NSMDs. The commonest clinical manifestation was central nervous system symptoms (88.4%). 40.6% of the patients showed elevation of the initial blood lactate levels and 84.8% revealed abnormal results after oral glucose challenge test. Seventeen patients, 18.2% of SMDs and 34.4% of NSMDs, presented initial normal brain MR imaging features. Forty-eight patients (73.8%) had initial brain MR imaging abnormalities. The most common abnormalities were abnormal signal intensity over the putamen (45.5% of SMDs and 15.6% of NSMDs).Lactate peaks were detected on initial MR spectroscopy in 31.8% of patients. The presence of ragged red fibers was shown in 51.6% of the cases. The positive rate of mitochondrial gene mutation was 27.5%. The younger the age at the initial disease onset, the higher frequency of mortality and morbidity were observed.
This study describes the notorious variability in the presentation of MDs. Greater familiarity those symptoms will facilitate a more accurate diagnosis. Oral glucose lactate stimulation test is an effective screening method for helping the diagnosis of MDs.

標題 頁碼
壹、 中文摘要 ……………………………1
貳、 英文摘要 ……………………………3
參、 縮寫檢索表………………………… 5
肆、 緒論 ……………………………6
伍、 研究動機 ……………………………31
陸、 材料與方法 …………………………32
柒、 結果 ……………………………47
捌、 討論 ……………………………55
玖、 參考文獻 ……………………………63
壹拾、 圖表與說明………………………… 75
附錄 ………………………………………106

[1] Luft R, Ikkos D, Palmieri G, Ernster L, Afzelius B. A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: A correlated clinical, biochemical and morphological study. J Clin Invest 1962;41:1776-1804.
[2] Mak SC, Chi CS, Chen CH, Shian WJ. Clinical manifestation of mitochondrial diseases in children. Acta Paediatr Sin 1993;34:247-256.
[3] Scaglia F, Towbin JA, Craigen WJ, Belmont JW, Smith EO, Neish SR, Ware SM, Hunter JV, Fernbach SD, Vladutiu GD, Wong LJC, Vogel H. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 2004;114:925-931.
[4] García-Cazorla A, De Lonlay P, Nassogne MC, Rustin P, Touati G, Saudubray JM. Long-term follow-up of neonatal mitochondrial cytopathies: a study of 57 patients. Pediatrics 2005;116:1170-1177.
[5] Debray FG, Lambert M, Chevalier I, Robitaille Y, Decarie JC, Shoubridge EA, Robinson BH, Mitchell GA. Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics 2007;119:722-733.
[6] Wang LC, Lee WT, Tsai WY, Tsau YK, Shen YZ. Mitochondrial cytopathy combined with Fanconi’s syndrome. Pediatr Neurol 2000;22:403-406.
[7] Zeviani M, Carelli V. Mitochondrial disorders. Curr Opin Neurol 2003;16:585-594.
[8] Munnich A, Rötig A, Chretien D, Cormier V, Bourgeron T, Bonnefont JP, Saudubray JM, Rustin P. Clinical presentation of mitochondrial disorders in childhood. J Inherit Metab Dis 1996;19:521-527.
[9] Arpa J, Cruz-Martinez A, Campos Y, Gutiérrez-Molina M, García-Rio F, Pérez-Conde C,Martín MA, Rubio JC, Del Hoyo P, Apra-Fernández A, Arenas J. Prevalence and progression of mitochondrial diseases: a study of 50 patients. Muscle Nerve 2003;28:690-695.
[10] 麥淑珍、遲景上：從粒線體DNA看粒線體疾病.中兒醫誌1998；第39卷增刊B:24-28.
[11] Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics 2000;105:e10.
[12] Skladal D, Halliday J, Thorburn DR. Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 2003;136:1905-1912.
[13] Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol 2001;49:377-383.
[14] DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. NEJM 2003;348:2656-2668.
[15] Schapira AHV. Mitochondrial disease. Lancet 2006;368:70-82
[16] Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 2002;59:1406-1411.
[17] Farina L, Chiapparini L, Uziel G, Bugiani M, Zeviani M, Savoiardo M. MR findings in Leigh syndrome with COX deficiency and SURF-1 mutations. Am J Neuroradiol 2002;23:1095-1100.
[18] Finsterer J. Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol 2008;39:223-235.
[19] Iizuka T, Sakai F, Kan S, Suzuki N. Slowly progressive spread of the stroke-like lesions in MELAS. Neurology 2003;61:1238-1244.
[20] Ito H, Mori K, Harada M, Minoto M, Naito E, Takeuchi M, Kuroda Y, Kagami S. Serial brain imaging analysis of stroke-like episodes in MELAS. Brain Dev 2008;30:483-488.
[21] Millar WS, Lignelli A, Hirano M. MRI of five patients with mitochondrial neurogastrointestinal encephalomyopathy. Am J Radiol 2004;182:1537-1541.
[22] Chu BC, Terae S, Takahashi C, Kikuchi Y, Miyasaka K, Abe S, Minowa K, Sawamura T. MRI of the brain in the Kearns-Sayre syndrome: report of four cases and a review. Neuroradiology 1999;41:759-764.
[23] Finsterer J, Kopsa W. Basal ganglia calcification in mitochondrial disorders. Metab Brain Dis 2005;20:219-226.
[24] Cheon FE, Kim IO, Hwang YS, Kim KF, Wang KC, Cho BK, Chi FG, Kim CF, Kim WS, Yeon KM. Leukodystrophy in children: A pictorial review of MR imaging features. Radiographics 2002;22:461-476.
[25] de Koning TJ, de Vries LS, Groenendaal F, Ruitenbeek W, Jansen GH, Poll-The BT, Barth PG. Pontocerebellar hypoplasia associated with respiratory-chain defects. Neuropediatrics 1999;30:93-95.
[26] Janson CG, McPhee SW, Francis J, Shera D, Assadi M, Freese A, Hurh P, Haselqrove J, Wang DJ, Bilaniuk L, Leone P. Natural history of Canavan disease revealed by proton magnetic resonance spectroscopy (1H-MRS) and diffusion-weighted MRI. Neuropediatrics 2006;37:209-221.
[27] Leuzzi V, Bianchi MC, Tosetti M, Carducci C, Cerquiglini CA, Cioni G, Antonozzi I. Brain creatine depletion: guanidinoacetate methyltransferase deficiency (improving with creatine supplementation). Neurology 2000;55:1407-1409.
[28] Eichler FS, Barker PB, Cox C, Edwin D, Ulug AM, Moser HW, Raymond GV. Proton MR spectroscopic imaging predicts lesion progression on MRI in X-linked adrenoleukodystrophy. Neurology 2002;58:901-907.
[29] Bianchi MC, Tosetti M, Battini R, Manca ML, Mancuso M, Cioni G, Canapicchi R, Siciliano G. Proton MR spectroscopy of mitochondrial diseases: analysis of brain metabolic abnormalities and their possible diagnostic relevance. Am J Neuroradiol 2003;24:1958-1966.
[30] Dinopoulos A, Cecil KM, Schapiro MB, Papadimitriou A, Hadjigeorgiou GM, Wong B, deGrauw T, Egelhoff JC. Brain MRI and proton MRS findings in infants and children with respiratory chain defects. Neuropediatrics 2005;36:290-301.
[31] Vedolin L, de Souza CFM, Silveira RS, Lopes BC, Laybauer LS, Saraiva Pereira ML, Giugliani R. Conventional MRI and MR spectroscopy in nonclassical mitochondrial disease: report of three patients with mitochondrial DNA deletion. Childs Nerv Syst 2006;22:1355-1359.
[32] Lin Doris DM, Crawford TO, Barker PB. Proton MR spectroscopy in the diagnostic evaluation of suspected mitochondrial disease. Am J Neuroradiol 2003;24:33-41.
[33] Möller HE, Kurlemann G, Pützler M, Wiedermann D, Hilbich T, Fiedler B. Magnetic resonance spectroscopy in patients with MELAS. J Neurol Sci 2005;229-230:131-139.
[34] Chi CS, Kao KP, Hsu NY, Lin E, Chen YC, Fu MC. Kearns-Sayre syndrome with proteinuria, glucosuria, copperuria and prolapse of the mitral valve: report of a case. J Formos Med Assoc 1988;87:95-100.
[35] Tsai ML, Hung KL, Chen TY. Subacute necrotizing encephalomyelopathy (Leigh’s disease): report a case. J Formos Med Assoc 1990;89:799-802.
[36] Lii YP, Chi CS, Mak SC, Chen CH. Myoclonic epilepsy with raggered-red fibers: report of one case. Acta Paediatr Sin 1991;32:251-256.
[37] Mak SC, Chi CS, Chen CH. Mitochondrial encephalomyopathy presenting with clinical Leigh’s disease: report of a case. Chin Med J (Taipei) 1991;47:54-58.
[38] Wu TS, Lee CC, Lin JT, Hsu HH, Lin ST, Jong YJ, Shen EY. Leigh disease (subacute necrotizing encephalomyelopathy): report of one case. Acta Paediatr Sin 1993;34:301-307.
[39] Fang W, Huang CC, Lee CC, Cheng SY, Pang CY, Wei YH. Ophthalmologic manifestations in MELAS syndrome. Arch Neurol 1993;50:977-980.
[40] Chi CS, Mak SC, Shian WJ. Leigh syndrome with progressive ventriculomegaly. Pediatr Neurol 1994;10:244-246.
[41] Lee ML, Chaou WT, Yang AD, Jong YJ, Tsai JL, Pang CY, Wei YH.
Mitochondrial myopathy, encephalopathy, lactic acidosis and
strokelike episodes (MELAS): report of a sporadic case and review
of the literature. Acta Paediatr Sin 1994;35:148-156.
[42] Huang WY, Chi CS, Mak SC, Wu HM, Yang MT. Leigh syndrome presenting with dystonia: report of one case. Acta Paediatr Sin 1995;36:378-381.
[43] Chiang LM, Jong YJ, Huang SC, Tsai JL, Pang CY, Lee HC, Wei YH. Heteroplasmic mitochondrial DNA mutation in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. J Formos Med Assoc 1995;94:42-47.
[44] Huang MY, Jong YJ, Tsai JL, Liu GC, Chiang CH, Pang CY, Wei YH. Mitochondrial NADH-coenzyme Q reductase deficiency in Leigh’s disease. J Formos Med Assoc 1996;95:325-328.
[45] Lee WT, Wang PJ, Young C, Wang TR, Shen YZ. Cytochrome c oxidase
deficiency in fibroblasts of a patient with mitochondrial
encephalomyopathy. J Formos Med Assoc 1996;95:709-711.
[46] Mak SC, Chi CS, Liu CY, Pang CY, Wei YH. Leigh syndrome associated with mitochondrial DNA 8993 T-->G mutation and ragged-red fibers. Pediatr Neurol 1996;15:72-75.
[47] Liu AM, Mak SC, Tsai CR, Chi CS. Childhood MELAS syndrome presenting with seizure and cortical blindness: a case report. Chin Med J (Taipei) 1998;61:730-735.
[48] Mak SC, Chi CS, Tsai CR. Mitochondrial DNA 8993 T > C mutation presenting as juvenile Leigh syndrome with respiratory failure. J Child Neurol 1998;13:349-351.
[49] Lin YC, Lee WT, Wang PJ, Shen YZ. Vocal cord paralysis and hypoventilation in a patient with suspected Leigh disease. Pediatr Neurol 1999;20:223-225.
[50] Chi CS, Mak SC, Shian WJ, Chen CH. Oral glucose lactate stimulation test in mitochondrial disease. Pedriatr Neurol 1992;8:445-449.
[51] Finsterer J. Central nervous system manifestations of mitochondrial disorders. Acta Neurol Scand 2006;114:217-238.
[52] Rose LVT, Rose NT, Elder JE, Thorburn DR, Boneh A. Ophthalmologic presentation of oxidative phosphorylation diseases of childhood. Pediatr Neurol 2008;38:395-397.
[53] Murayama K, Nagasaka H, Tsuruoka T, Omata Y, Horie H, Tregoning S, Thouburn DR, Takayanagi M, Ohtake A. Intractable secretory diarrhea in a Japanese boy with mitochondrial respiratory chain complex I deficiency. Eur J Pediatr 2009;168:297-302.
[54] Holmgren D, Wahlander H, Eriksson BO, Oldfors A, Holme E, Tulinius M. Cardiomyopathy in children with mitochondrial disease: clinical course and cardiological findings. Eur Heart J 2003;24:280-288.
[55] Yaplito-Lee J, Weintraub R, Jamsen K, Chow CW, Thorburn DR, Boneh A. Cardiac manifestations in oxidative phosphorylation disorders of childhood. J Pediatr 2007;150:407-411.
[56] Fischel-Ghodsian N. Mitochondrial deafness. Ear Hearing 2003;24:303-313.
[57] Sokol RJ, Treem WR. Mitochondria and childhood liver diseases. J Pediatr Gastroenterol Nutr 1999;28:4-16.
[58] Garcia-Cazorla A, De Lonlay P, Rustin P, Chretien D, Touati G, Rabier D, Slama A, Saudubray JM. Mitochondrial respiratory chain deficiencies expressing the enzymatic deficiency in the hepatic tissue: A study of 31 patients. J Pediatr 2006;149:401-405.
[59] Morris AA. Mitochondrial respiratory chain disorders and the liver. Liver 1999;19:357-368.
[60] Niaudet P, Rötig A. Renal involvement in mitochondrial cytopathies. Pediatr Nephrol 1996;10:368-373.
[61] Hall AM, Unwin RJ, Hanna MG, Duchen MR. Renal function and mitochondrial cytopathy (MC): more questions than answers? Q J Med 2008;101:755-766.
[62] Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N, Cohen BH. Mitochondrial disease: a practical approach for primary care physicians. Pediatrics 2007;120:1326-1333.
[63] Kim J, Lee SK, Kim EY, Kim DI, Lee YM, Lee JS, Kim HD. Neuroradiologic findings in children with mitochondrial disorder: correlation with mitochondrial respiratory chain defects. Eur Radiol 2008;18:1741-1748.
[64] Scaglia F, Wong LJC, Vladutiu GD, Hunter JV. Predominant cerebellar volume loss as a neuroradiologic feature of pediatric respiratory chain defects. Am J Neuroradiol 2005;26:1675-1680.
[65] Haas R, Dietrich R. Neuroimaging of mitochondrial disorders. Mitochondrion 2004;4:471-490.
[66] Moslemi AR, Darin N, Tulinius M, Wiklund LM, Holme E, Oldfors A. Progressive encephalopathy and complex I deficiency associated with mutations in MTND1. Neuropediatrics 2008;39:24-28.
[67] Leshinsky-Silver E, Lebre AS, Minai L, Saada A, Steffann J, Cohen S, Rötig A, Munnich A, Lev D, Lerman-Sagie T. NDUFS4 mutations cause Leigh syndrome with predominant brainstem involvement. Mol Genet Metab 2009;97:185-189.
[68] Lerman-Sagie T, Leshinsky-Silver E, Watemberg N, Luckman Y, Lev D. White matter involvement in mitochondrial diseases. Mol Genet Metab 2005;84:127-136.
[69] Moroni I, Bugiani M, Bizzi A, Castelli G, Lamantea E, Uziel G. Cerebral white matter involvement in children with mitochondrial encephalopathies. Neuropediatrics 2002;33:79-85.
[70] Tzoulis C, Engelsen BA, Telstad W, Aasly J, Zeviani M, Winterthun S, Ferrari G, Aarseth JH, Bindoff LA. The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. Brain 2006;129:1685-1692.
[71] Rahman S, Brown RM, Chong WK, Wilson CJ, Brown GK. A SURF1 gene mutation presenting as isolated leukodystrophy. Ann Neurol 2001;49:797-800.
[72] Bizzi A, Castelli G, Bugiani M, Barker PB, Herskovits EH, Danesi U, Erbetta A, Moroni I, Farina L, Uziel G. Classification of childhood white matter disorders using proton MR spectroscopic imaging. Am J Neuroradiol 2008;29:1270-1275.
[73] Bianchi MC, Sgandurra G, Tosetti M, et al. Brain magnetic resonance in diagnostic evaluation of mitochondrial encephalopathies. Biosci Rep 2007;27:69-85.
[74] Saneto RP, Friedman SD, Shaw DWW. Neuroimaging of mitochondrial disease. Mitochondrion 2008;8:396-413.
[75] Inao S, Marmarou A, Clarke GD, et al. Production and clearance of lactate from brain tissue, cerebrospinal fluid, and serum following experimental brain injury. J Neurosurg 1988;69:736-744.
[76] Mancuso M, Filosto M, Choub A, Tentorio M, Broglio L, Padovani A, Siciliano G. Mitochondrial DNA-related disorders. Biosci Rep 2007;27:31-37.
[77] Debray FG, Lambert M, Mitchell GA. Disorders of mitochondrial function. Curr Opin Pediatr 2008;20:471-482.