丙酮酸脱氢酶 E1α 亚基基因突变所致 Leigh 综合征的临床进展_Journal of Epilepsy

Authors：

张会婷 ¹ ,  廖建湘 ²

1. ;
2. ;

Corresponding author：

廖建湘, Email: liaojianxiang@vip.sina.com

Keywords：

Leigh 综合征; 丙酮酸脱氢酶; 丙酮酸; PDHA1 基因; 生酮饮食

DOI：

10.7507/2096-0247.20200069

Video：

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Leigh 综合征（Leigh syndrome，LS）是一种罕见的致死性亚急性脑病，是儿童线粒体病的常见表型，核基因及线粒体基因上多种基因位点突变均可导致这一罕见病，其中丙酮酸脱氢酶 E1α 亚基（PDHA1）基因所致的 LS（PDH-LS）约占比 10%，主要临床表现为肌无力、共济失调、神经退行性障碍等，但却缺乏特异性。该疾病预后较差，目前尚无特异性治疗方案，早期诊断及干预有助于改善 PDH-LS 预后，除了传统的药物治疗及改善营养状态外，生酮饮食亦是一种有益的治疗选择，因此早期明确诊断及相关基因型改变具有重大意义。LS 临床表现多变且缺乏一致的特异性，为早期诊断治疗带来了挑战。文章讨论了 PDH-LS 的临床表现，并总结了文献报道的 PDH-LS 患者的表现及有预警意义的表现，以期提高其早期诊断率和相关的治疗建议，希望能够对此类患者的诊治有所帮助。

Citation： 张会婷, 廖建湘. 丙酮酸脱氢酶 E1α 亚基基因突变所致 Leigh 综合征的临床进展. Journal of Epilepsy, 2020, 6(5): 423-427. doi: 10.7507/2096-0247.20200069 Copy

1.	Gerards M, Sallevelt SC, Smeets HJ. Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options. Mol Genet Metab, 2016, 117(3): 300-312.
2.	Rahman J, Noronha A, Thiele I, <italic>et al</italic>. Leigh map: A novel computational diagnostic resource for mitochondrial disease. Ann Neurol, 2017, 81(1): 9-16.
3.	Chang X, Wu Y, Zhou J, <italic>et al</italic>. A meta-analysis and systematic review of Leigh syndrome: clinical manifestations, respiratory chain enzyme complex deficiency, and gene mutations. Medicine (Baltimore), 2020, 99(5): e18634.
4.	Bonfante E, Koenig MK, Adejumo RB, <italic>et al</italic>. The neuroimaging of Leigh syndrome: case series and review of the literature. Pediatr Radiol, 2016, 46(4): 443-451.
5.	陆相朋, 张婧韬, 梁瑞星, 等. 丙酮酸脱氢酶复合物缺陷 Leigh 综合征 2 例临床及 PDHA1 基因分析. 临床儿科杂志, 2019, 37(3): 218-222.
6.	Pirot N, Crahes M, Adle-Biassette H, <italic>et al</italic>. Phenotypic and neuropathological characterization of fetal pyruvate dehydrogenase deficiency. J Neuropathol Exp Neurol, 2016, 75(3): 227-238.
7.	Berendzen K, Theriaque DW, Shuster J, <italic>et al</italic>. Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency. Mitochondrion, 2006, 6(3): 126-135.
8.	Pliss L, Jatania U, Patel M S. Beneficial effect of feeding a ketogenic diet to mothers on brain development in their progeny with a murine model of pyruvate dehydrogenase complex deficiency. Mol Genet Metab Rep, 2016, 7: 78-86.
9.	van Dongen S, Brown RM, Brown GK, <italic>et al</italic>. Thiamine-responsive and non-responsive patients with PDHC-E1 deficiency: A retrospective assessment. JIMD Rep, 2015, 15: 13-27.
10.	吴莫龄. 丙酮酸脱氢酶复合物缺乏症 PDHA1 基因突变研究. 广州医科大学, 硕士学位论文, 2015: 1-61.
11.	Ebertowska A, Ludkiewicz B, Klejbor I, et al. Pyruvate dehydrogenase deficiency - morphological and metabolic effects, creation of animal model to study and research for treatment therapy. Folia Morphol (Warsz), 2020, 2 [Epub ahead of print].
12.	廖建湘. 生酮饮食疗法在难治性癫痫中的应用. 中国实用儿科杂志, 2016, 31(1): 41-45.
13.	Gorman GS, Chinnery PF, DiMauro S, <italic>et al</italic>. Mitochondrial diseases. Nature Reviews Disease Primers, 2016, 2(1): 16080.
14.	Baertling F, Rodenburg RJ, Schaper J, <italic>et al</italic>. A guide to diagnosis and treatment of Leigh syndrome. Neurosurgery & Psychiatry, 2013, 85(3): 257-265.
15.	Debray FG, Lambert M, Gagne R, <italic>et al</italic>. Pyruvate dehydrogenase deficiency presenting as intermittent isolated acute ataxia. Neuropediatrics, 2008, 39(1): 20-23.
16.	Sofou K, De Coo IF, Isohanni P, <italic>et al</italic>. A multicenter study on Leigh syndrome: disease course and predictors of survival. Orphanet J Rare Dis, 2014, 9: 52.
17.	张开慧, 李洪英, 李晓莺, 等. 一例罕见的丙酮酸脱氢酶复合物缺乏症女性患儿的分析. 中华医学遗传学杂志, 2018, 35(4): 548-552.
18.	Willemsen M, Rodenburg RJ, Teszas A, <italic>et al</italic>. Females with PDHA1 gene mutations: a diagnostic challenge. Mitochondrion, 2006, 6(3): 155-159.
19.	Pronicka E, Piekutowska-Abramczuk D, Ciara E, <italic>et al</italic>. New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre. J Transl Med, 2016, 14(1): 174.
20.	Barnerias C, Saudubray JM, Touati G, <italic>et al</italic>. Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Dev Med Child Neurol, 2010, 52(2): e1-9.
21.	Debray FG, Mitchell GA, Allard P, <italic>et al</italic>. Diagnostic accuracy of blood lactate-to-pyruvate molar ratio in the differential diagnosis of congenital lactic acidosis. Clin Chem, 2007, 53(5): 916-921.
22.	Koene S, Rodenburg RJ, van der Knaap MS, <italic>et al</italic>. Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases. Journal of Inherited Metabolic Disease, 2012, 35(5): 737-747.
23.	惠丽红, 肖江喜, 谢晟, 等. SURF1基因突变与 PDHA1 基因缺陷导致的 Leigh 病的 MRS 特点. 实用放射学杂志, 2010, 26(5): 624-628.
24.	方方, 沈颖, 沈丹敏, 等. 儿童 Leigh 综合征临床及遗传特征分析. 中华儿科杂志, 2017, 55(3): 205-209.
25.	Neubauer D, Frelih J, Zupancic N, <italic>et al</italic>. 'Pyruvate dehydrogenase deficiency presenting as dystonia and responding to levodopa'. Dev Med Child Neurol, 2005, 47(7): 504.
26.	Head RA, de Goede CG, Newton RW, <italic>et al</italic>. Pyruvate dehydrogenase deficiency presenting as dystonia in childhood. Dev Med Child Neurol, 2004, 46(10): 710-712.
27.	Rahman S, Thorburn D. Nuclear Gene-Encoded Leigh Syndrome Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993.
28.	Chen L, Cui Y, Jiang D, <italic>et al</italic>. Management of Leigh syndrome: Current status and new insights. Clin Genet, 2018, 93(6): 1131-1140.
29.	Zhang L, Zhang Z, Khan A, <italic>et al</italic>. Advances in drug therapy for mitochondrial diseases. Annals of Translational Medicine, 2020, 8(1): 17-17.
30.	Enns GM, Kinsman SL, Perlman SL, <italic>et al</italic>. Initial experience in the treatment of inherited mitochondrial disease with EPI-743. Mol Genet Metab, 2012, 105(1): 91-102.
31.	Longo R, Peri C, Cricrì D, <italic>et al</italic>. Ketogenic Diet: A new light shining on old but gold biochemistry. Nutrients, 2019, 11(10): 2497.
32.	Sofou K, Dahlin M, Hallbook T, <italic>et al</italic>. Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes. J Inherit Metab Dis, 2017, 40(2): 237-245.
33.	Wexler ID, Hemalatha SG, McConnell J, <italic>et al</italic>. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology, 1997, 49(6): 1655-1661.
34.	Patel KP, O'Brien TW, Subramony SH, <italic>et al</italic>. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab, 2012, 105(1): 34-43.
35.	高恒妙. 先天性代谢病代谢危象的急诊识别与处理. 中国小儿急救医学, 2014, 21(6): 346-350.

1. Gerards M, Sallevelt SC, Smeets HJ. Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options. Mol Genet Metab, 2016, 117(3): 300-312.
2. Rahman J, Noronha A, Thiele I, <italic>et al</italic>. Leigh map: A novel computational diagnostic resource for mitochondrial disease. Ann Neurol, 2017, 81(1): 9-16.
3. Chang X, Wu Y, Zhou J, <italic>et al</italic>. A meta-analysis and systematic review of Leigh syndrome: clinical manifestations, respiratory chain enzyme complex deficiency, and gene mutations. Medicine (Baltimore), 2020, 99(5): e18634.
4. Bonfante E, Koenig MK, Adejumo RB, <italic>et al</italic>. The neuroimaging of Leigh syndrome: case series and review of the literature. Pediatr Radiol, 2016, 46(4): 443-451.
5. 陆相朋, 张婧韬, 梁瑞星, 等. 丙酮酸脱氢酶复合物缺陷 Leigh 综合征 2 例临床及 PDHA1 基因分析. 临床儿科杂志, 2019, 37(3): 218-222.
6. Pirot N, Crahes M, Adle-Biassette H, <italic>et al</italic>. Phenotypic and neuropathological characterization of fetal pyruvate dehydrogenase deficiency. J Neuropathol Exp Neurol, 2016, 75(3): 227-238.
7. Berendzen K, Theriaque DW, Shuster J, <italic>et al</italic>. Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency. Mitochondrion, 2006, 6(3): 126-135.
8. Pliss L, Jatania U, Patel M S. Beneficial effect of feeding a ketogenic diet to mothers on brain development in their progeny with a murine model of pyruvate dehydrogenase complex deficiency. Mol Genet Metab Rep, 2016, 7: 78-86.
9. van Dongen S, Brown RM, Brown GK, <italic>et al</italic>. Thiamine-responsive and non-responsive patients with PDHC-E1 deficiency: A retrospective assessment. JIMD Rep, 2015, 15: 13-27.
10. 吴莫龄. 丙酮酸脱氢酶复合物缺乏症 PDHA1 基因突变研究. 广州医科大学, 硕士学位论文, 2015: 1-61.
11. Ebertowska A, Ludkiewicz B, Klejbor I, et al. Pyruvate dehydrogenase deficiency - morphological and metabolic effects, creation of animal model to study and research for treatment therapy. Folia Morphol (Warsz), 2020, 2 [Epub ahead of print].
12. 廖建湘. 生酮饮食疗法在难治性癫痫中的应用. 中国实用儿科杂志, 2016, 31(1): 41-45.
13. Gorman GS, Chinnery PF, DiMauro S, <italic>et al</italic>. Mitochondrial diseases. Nature Reviews Disease Primers, 2016, 2(1): 16080.
14. Baertling F, Rodenburg RJ, Schaper J, <italic>et al</italic>. A guide to diagnosis and treatment of Leigh syndrome. Neurosurgery & Psychiatry, 2013, 85(3): 257-265.
15. Debray FG, Lambert M, Gagne R, <italic>et al</italic>. Pyruvate dehydrogenase deficiency presenting as intermittent isolated acute ataxia. Neuropediatrics, 2008, 39(1): 20-23.
16. Sofou K, De Coo IF, Isohanni P, <italic>et al</italic>. A multicenter study on Leigh syndrome: disease course and predictors of survival. Orphanet J Rare Dis, 2014, 9: 52.
17. 张开慧, 李洪英, 李晓莺, 等. 一例罕见的丙酮酸脱氢酶复合物缺乏症女性患儿的分析. 中华医学遗传学杂志, 2018, 35(4): 548-552.
18. Willemsen M, Rodenburg RJ, Teszas A, <italic>et al</italic>. Females with PDHA1 gene mutations: a diagnostic challenge. Mitochondrion, 2006, 6(3): 155-159.
19. Pronicka E, Piekutowska-Abramczuk D, Ciara E, <italic>et al</italic>. New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre. J Transl Med, 2016, 14(1): 174.
20. Barnerias C, Saudubray JM, Touati G, <italic>et al</italic>. Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Dev Med Child Neurol, 2010, 52(2): e1-9.
21. Debray FG, Mitchell GA, Allard P, <italic>et al</italic>. Diagnostic accuracy of blood lactate-to-pyruvate molar ratio in the differential diagnosis of congenital lactic acidosis. Clin Chem, 2007, 53(5): 916-921.
22. Koene S, Rodenburg RJ, van der Knaap MS, <italic>et al</italic>. Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases. Journal of Inherited Metabolic Disease, 2012, 35(5): 737-747.
23. 惠丽红, 肖江喜, 谢晟, 等. SURF1基因突变与 PDHA1 基因缺陷导致的 Leigh 病的 MRS 特点. 实用放射学杂志, 2010, 26(5): 624-628.
24. 方方, 沈颖, 沈丹敏, 等. 儿童 Leigh 综合征临床及遗传特征分析. 中华儿科杂志, 2017, 55(3): 205-209.
25. Neubauer D, Frelih J, Zupancic N, <italic>et al</italic>. 'Pyruvate dehydrogenase deficiency presenting as dystonia and responding to levodopa'. Dev Med Child Neurol, 2005, 47(7): 504.
26. Head RA, de Goede CG, Newton RW, <italic>et al</italic>. Pyruvate dehydrogenase deficiency presenting as dystonia in childhood. Dev Med Child Neurol, 2004, 46(10): 710-712.
27. Rahman S, Thorburn D. Nuclear Gene-Encoded Leigh Syndrome Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993.
28. Chen L, Cui Y, Jiang D, <italic>et al</italic>. Management of Leigh syndrome: Current status and new insights. Clin Genet, 2018, 93(6): 1131-1140.
29. Zhang L, Zhang Z, Khan A, <italic>et al</italic>. Advances in drug therapy for mitochondrial diseases. Annals of Translational Medicine, 2020, 8(1): 17-17.
30. Enns GM, Kinsman SL, Perlman SL, <italic>et al</italic>. Initial experience in the treatment of inherited mitochondrial disease with EPI-743. Mol Genet Metab, 2012, 105(1): 91-102.
31. Longo R, Peri C, Cricrì D, <italic>et al</italic>. Ketogenic Diet: A new light shining on old but gold biochemistry. Nutrients, 2019, 11(10): 2497.
32. Sofou K, Dahlin M, Hallbook T, <italic>et al</italic>. Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes. J Inherit Metab Dis, 2017, 40(2): 237-245.
33. Wexler ID, Hemalatha SG, McConnell J, <italic>et al</italic>. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology, 1997, 49(6): 1655-1661.
34. Patel KP, O'Brien TW, Subramony SH, <italic>et al</italic>. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab, 2012, 105(1): 34-43.
35. 高恒妙. 先天性代谢病代谢危象的急诊识别与处理. 中国小儿急救医学, 2014, 21(6): 346-350.

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