Journal of Shandong University (Health Sciences) ›› 2021, Vol. 59 ›› Issue (10): 103-109.doi: 10.6040/j.issn.1671-7554.0.2021.0985

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Pulmonary hypertension in combined methylmalonic acidemia: a report of two cases and literature review

AN Yuanxiaoxue1, ZHAO Yuying2, ZHAO Cuifen3, XU Ruiying3, XUE Yuwen1   

  1. 1. Department of Pulmonary and Critical Care Medicine;
    2. Department of Neurology;
    3. Department of Pediatrics, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
  • Published:2021-10-15

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Abstract: Objective To explore the relationship between methylmalonic acidemia(MMA)and pulmonary hypertension. Methods A retrospective analysis of 2 patients was carried out for clinical and genetic characteristics. Relevant literatures were reviewed and summarized. Results Metabolic screening showed MMA and hyperhomocysteinemia in two patients,which accorded with the diagnosis of combined MMA. Pulmonary hypertension and persistent renal abnormality were presented in both patients. One patient was accompanied with spherocytosis,and the other patient concurrently suffered from nystagmus. Both genetic analysis revealed a heterozygous MMACHC mutation(Cobalamin C type). The gene mutation of Case 1 was identified as c.80A> G(p.Gln27Arg)/ c.609G> A(p.Trp203Ter), and the gene mutation of Case 2 was identified as c80A>G(p.Gln27Arg)/ c.637G>T(p.Glu213Ter). Two patients died of pulmonary hypertension. Conclusion The screening of genetic metabolic diseases, especially MMA, should be performed for children and adolescents with unexplained pulmonary hypertension.

Key words: Pulmonary hypertension, Methylmalonic acidemia, Hyperhomocysteinemia, Vitamin B12

CLC Number: 

  • R544.1
[1] Hansmann G. Pulmonary hypertension in infants, children, and young adults[J]. J Am Coll Cardiol, 2017, 69(20): 2551-2569.
[2] Luciani A, Devuyst O. Methylmalonyl acidemia: from mitochondrial metabolism to defective mitophagy and disease[J]. Autophagy, 2020, 16(6): 1159-1161.
[3] Kovacs G, Dumitrescu D, Barner A, et al. Definition, clinical classification and initial diagnosis of pulmonary hypertension: updated recommendations from the Cologne Consensus Conference 2018[J]. Int J Cardiol, 2018, 272S: 11-19. doi: 10.1016/j.ijcard.2018.08.083.
[4] McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association[J]. J Am Coll Cardiol, 2009, 53(17): 1573-1619.
[5] 中华医学会呼吸病学分会肺栓塞与肺血管病学组, 中国医师协会呼吸医师分会肺栓塞与肺血管病工作委员会, 全国肺栓塞与肺血管病防治协作组, 等. 中国肺动脉高压诊断与治疗指南(2021版)[J]. 中华医学杂志, 2021, 101(1): 11-51.
[6] Wang F, Han L, Yang Y, et al. Clinical, biochemical, and molecular analysis of combined methylmalonic acidemia and hyperhomocysteinemia(cblC type)in China[J]. J Inherit Metab Dis, 2010, 33(Suppl 3): S435-S442.
[7] Zhou W, Li H, Wang C, et al. Newborn screening for methylmalonic acidemia in a Chinese population: molecular genetic confirmation and genotype phenotype correlations[J]. Front Genet, 2018, 9: 726. doi: 10.3389/fgene.2018.00726.
[8] Han B, Cao Z, Tian L, et al. Clinical presentation, gene analysis and outcomes in young patients with early-treated combined methylmalonic acidemia and homocysteinemia(cblC type)in Shandong Province, China[J]. Brain Dev, 2016, 38(5): 491-497.
[9] Baumgartner MR, Hörster F, Dionisi-Vici C, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia[J]. Orphanet J Rare Dis, 2014, 9: 130. doi: 10.1186/s13023-014-0130-8.
[10] Carrillo-Carrasco N, Chandler RJ, Venditti CP. Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management[J]. J Inherit Metab Dis, 2012, 35(1): 91-102.
[11] Watkins D, Rosenblatt DS. Inborn errors of cobalamin absorption and metabolism[J]. Am J Med Genet C Semin Med Genet, 2011, 157C(1): 33-44.
[12] Haberle J, Chakrapani A, Ah Mew N, et al. Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories[J]. Orphanet J Rare Dis, 2018, 13(1): 219.
[13] Fraser JL, Venditti CP. Methylmalonic and propionic acidemias: clinical management update[J]. Curr Opin Pediatr, 2016, 28(6): 682-693.
[14] Martinelli D, Deodato F, Dionisi-Vici C. Cobalamin C defect: natural history, pathophysiology, and treatment[J]. J Inherit Metab Dis, 2011, 34(1): 127-135.
[15] Liu Y, Liu YP, Zhang Y, et al. Heterogeneous phenotypes, genotypes, treatment and prevention of 1 003 patients with methylmalonic acidemia in the mainland of China[J]. Zhonghua Er Ke Za Zhi, 2018, 56(6): 414-420.
[16] Profitlich L, Kirmse B, Wasserstein MP, et al. Resolution of cor pulmonale after medical management in a patient with cblC-type methylmalonic aciduria and homocystinuria: a case report[J]. Cases J, 2009, 2: 8603. doi: 10.4076/1757-1626-2-8603.
[17] Bouts AH, Roofthooft MTR, Salomons GS, et al. CD46-associated atypical hemolytic uremic syndrome with uncommon course caused by cblC deficiency[J]. Pediatr Nephrol, 2010, 25(12): 2547-2548.
[18] Iodice FG, Di Chiara L, Boenzi S, et al. Cobalamin C defect presenting with isolated pulmonary hypertension[J]. Pediatrics, 2013, 132(1): e248-e251.
[19] Kömhoff M, Roofthooft MT, Westra D, et al. Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.[J]. Pediatrics, 2013, 132(2): e540-e544.
[20] Gunduz M, Ekici F, Ozaydin E, et al. Reversible pulmonary arterial hypertension in cobalamin-dependent cobalamin C disease due to a novel mutation in the MMACHC gene[J]. Eur J Pediatr, 2014, 173(12): 1707-1710.
[21] Grangé S, Bekri S, Artaud-Macari E, et al. Adult-onset renal thrombotic microangiopathy and pulmonary arterial hypertension in cobalamin C deficiency[J]. The Lancet, 2015, 386(9997): 1011-1012.
[22] 齐艳华, 齐建光, 刘玉鹏, 等.甲基丙二酸尿症合并同型半胱氨酸血症心血管系统受累10例临床分析及随访[J].中国当代儿科杂志, 2015, 17(9): 965-970. QI Yanhua, QI Jianguang, LIU Yupeng, et al.Clinical analysis and follow-up study of cardiavascular system involvement in 10 children with methylmalonic aciduria combined with hyperhomocysteinemia[J]. Chinese Journal of Contemporary Pediatrics, 2015, 17(9): 965-970.
[23] Kido J, Mitsubuchi H, Sakanashi M, et al. Pulmonary artery hypertension in methylmalonic acidemia[J]. Hemodial Int, 2017, 21(2): E25-E29.
[24] 刘雪芹, 闫辉, 邱建星, 等.甲基丙二酸尿症相关肺高血压临床特点与基因突变[J].北京大学学报(医学版), 2017, 49(5): 768-777 LIU Xueqin, YAN Hui, QIU Jianxing, et al. Pulmonary arterial hypertension as leading manifestation of methylmalonic aciduria: clinical characteristics and gene testing in 15 cases[J]. Journal of Peking University(Health Sciences), 2017, 49(5): 768-777.
[25] De Simone L, Capirchio L, Roperto RM, et al. Favorable course of previously undiagnosed Methylmalonic Aciduria with Homocystinuria(cblC type)presenting with pulmonary hypertension and aHUS in a young child: a case report[J]. Ital J Pediatr, 2018, 44(1): 90.
[26] Petropoulos TE, Ramirez ME, Granton J, et al. Renal thrombotic microangiopathy and pulmonary arterial hypertension in a patient with late-onset cobalamin C deficiency[J]. Clin Kidney J, 2018, 11(3): 310-314.
[27] Yoshizawa H, Nogami K, Yaoi H, et al. Pulmonary hypertension with diffuse lung lesions in cobalamin C defect[J]. Pediatr Int, 2019, 61(10): 1062-1063.
[28] 林毅, 张冲, 张秋业.以肺动脉高压及慢性肾功能不全为主要表现的合并型甲基丙二酸血症1例[J].中华实用儿科临床杂志, 2019, 34(10): 788-789 LIN Yi, ZHANG Chong, ZHANG Qiuye. Case report of combined methylmalonic acidemia mainly manifested by pulmonary hypertension and chronic kidney failure[J]. Chinese Journal of Applied Clinical Pediatrics, 2019, 34(10): 788-789.
[29] 唐晓蕾, 杨海明, 刘辉, 等.以弥漫性肺疾病为突出或首发表现的甲基丙二酸血症合并高同型半胱氨酸血症临床分析[J].中华儿科杂志, 2019, 57(8): 620-624 TANG Xiaolei, YANG Haiming, LIU Hui, et al. Clinical analysis of methylmalonic acidemia and hyperhomocysteinemia with diffuse lung disease as an initial or main presentation[J]. Chinese Journal of Pediatrics, 2019, 57(8): 620-624.
[30] Liao HY, Shi XQ, Li YF. Metabolic and genetic assessments interpret unexplained aggressive pulmonary hypertension induced by methylmalonic acidemia: a case report[J]. World J Clin Cases, 2020, 8(6): 1137-1141.
[31] Liu J, Tang X, Zhou C, et al. Cobalamin C deficiency presenting with diffuse alveolar hemorrhage and pulmonary microangiopathy[J]. Pediatr Pulmonol, 2020, 55(6): 1481-1486.
[32] Wen LY, Guo YK, Shi XQ. Pulmonary hypertension in late-onset Methylmalonic Aciduria and Homocystinemia: a case report[J]. BMC Pediatr, 2020, 20(1): 243.
[33] Zhang YN, Pi YL, Yan X, et al. Methylmalonic acidemia complicated by homocystinuria diseases: a report of three cases[J]. Adv Ther, 2020, 37(1): 630-636.
[34] 白薇, 齐建光, 齐艳华, 等.甲基丙二酸尿症并同型半胱氨酸血症患儿心血管系统受累情况、血浆硫化氢水平及基因分析[J].中华实用儿科临床杂志, 2020, 35(9): 681-685 BAI Wei, QI Jianguang, QI Yanhua, et al. Clinical characteristics, plasma levels of hydrogen sulfide and gene analysis of cardiovascular involvement in children with methylmalonic acidemia and homocystinemia[J]. Chinese Journal of Applied Clinical Pediatrics, 2020, 35(9): 681-685.
[35] Steed MM, Tyagi SC. Mechanisms of cardiovascular remodeling in hyperhomocysteinemia[J]. Antioxid Redox Signal, 2011, 15(7): 1927-1943.
[36] Esse R, Barroso M, Tavares de Almeida I, et al. The contribution of homocysteine metabolism disruption to endothelial dysfunction: state-of-the-art[J]. Int J Mol Sci, 2019, 20(4): 867.
[37] Küpeli E, Cengiz C, Cila A, et al. Hyperhomocysteinemia due to pernicious anemia leading to pulmonary thromboembolism in a heterozygous mutation carrier[J]. Clin Appl Thromb Hemost, 2008, 14(3): 365-368.
[38] Sun W, Liao JP, Hu Y, et al. Pulmonary embolism and deep vein thrombosis caused by nitrous oxide abuse: a case report[J]. World J Clin Cases, 2019, 7(23): 4057-4062.
[39] Low LYH, Sia CH, Tay EL, et al. Chronic thromboembolic pulmonary hypertension and homocysteinaemia[J]. QJM, 2018, 111(2): 121-122.
[40] Kim J, Kim H, Roh H, et al. Causes of hyperhomocysteinemia and its pathological significance[J]. Arch Pharm Res, 2018, 41(4): 372-383.
[41] Montani D, Lau EM, Dorfmüller P, et al. Pulmonary veno-occlusive disease[J]. Eur Respir J, 2016, 47(5): 1518-1534.
[42] Haijes HA, van Hasselt PM, Jans JJM, et al. Pathophysiology of propionic and methylmalonic acidemias. Part 2: Treatment strategies[J]. J Inherit Metab Dis, 2019, 42(5): 745-761.
[43] Montani D, Price LC, Dorfmuller P, et al. Pulmonary veno-occlusive disease[J]. Eur Respir J, 2009, 33(1): 189-200.
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