Journal of Clinical Pediatrics >
Clinical characteristics, genotypes and follow-up analysis of children with isovaleric academia
Received date: 2023-12-20
Online published: 2024-03-06
Objective To explore the clinical features, gene variation and follow-up results of children with isovaleric acidemia (IVA), and to provide evidence for early recognition, diagnosis and treatment of IVA. Methods The clinical data of children diagnosed with IVA in the Department of Pediatric Endocrinology from April 2012 to October 2023 were retrospectively analyzed. Results Of the 34 children with IVA (22 boys and 12 girls), 15 had acute neonatal type, 3 had chronic intermittent type, and 16 had asymptomatic type confirmed by neonatal screening. Compared with asymptomatic group, blood isovalerylcarnitine (C5) level, C5/ acetylcarnitine (C2) ratio, C5/ propionylcarnitine (C3) ratio and urine isovalerylglycine level in the group with clinical symptoms (including acute neonatal type and chronic intermittent type) were significantly increased, with statistical significance (P<0.05). A total of 40 mutations were identified in 34 patients, most of which were missense mutations (30/40, 75.0%) and c.1208A>G (n=8) was the most frequent variant. There was no significant correlation between clinical manifestation and type of gene variation. Four patients, all of whom belonged to the acute neonatal type, died during follow-up. Thirty surviving children had considerably lower urinary isovalerylglycine levels at the most recent follow-up, with a statistically significant difference from before therapy (P<0.05). Conclusions Clinical manifestations of IVA lack specificity. Elevated C5, C5/C2 ratio and C5/C3 ratio in plasm and isovalerylglycine in urine are typical hallmarks of IVA. Newborn screening is pivotal for early diagnosis, treatment, and prognosis.
Key words： isovaleric academia; IVD gene; tandem mass spectrometry; newborn screening
Yuning SUN , Lili LIANG , Si DING , Yuchao LIU , Ting CHEN , Zhuwen GONG , Wenjuan QIU , Huiwen ZHANG , Xuefan GU , Lianshu HAN . Clinical characteristics, genotypes and follow-up analysis of children with isovaleric academia[J]. Journal of Clinical Pediatrics, 2024 , 42(3) : 224 -229 . DOI: 10.12372/jcp.2024.23e1218
| [1] | Tanaka K, Budd MA, Efron ML, et al. Isovaleric acidemia: a new genetic defect of leucine metabolism[J]. Proc Natl Acad Sci U S A, 1966, 56(1): 236-242. |
| [2] | Ensenauer R, Fingerhut R, Maier EM, et al. Newborn screening for isovaleric acidemia using tandem mass spectrometry: data from 1.6 million newborns[J]. Clin Chem, 2011, 57(4): 623-626. |
| [3] | Schulze A, Lindner M, Kohlmüller D, et al. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications[J]. Pediatrics, 2003, 111(6 Pt 1):1399-1406. |
| [4] | Lin WD, Wang CH, Lee CC, et al. Genetic mutation profile of isovaleric acidemia patients in Taiwan[J]. Mol Genet Metab, 2007, 90(2): 134-139. |
| [5] | 胡真真, 杨建滨, 胡凌微, 等. 浙江省新生儿异戊酸血症筛查及临床分析[J]. 浙江大学学报(医学版), 2020, 49(5): 556-564. |
| [6] | 郑泉志, 傅清流, 彭维林, 等. 新生儿异戊酸血症串联质谱法与相关基因突变检测的价值研究[J]. 现代检验医学杂志, 2022, 37(5): 61-64. |
| [7] | 顾学范, 韩连书, 余永国. 中国新生儿遗传代谢病筛查现状及展望[J]. 罕见病研究, 2022, 1(1): 13-19. |
| [8] | Dercksen M, Duran M, Ijlst L, et al. Clinical variability of isovaleric acidemia in a genetically homogeneous population[J]. J Inherit Metab Dis, 2012, 35(6): 1021-1029. |
| [9] | 邱文娟, 顾学范, 叶军, 等. 异戊酸血症一例临床及异戊酰辅酶A脱氢酶基因突变研究[J]. 中华儿科杂志, 2008, 46(7): 526-530. |
| [10] | 顾学范. 临床遗传代谢病[M]. 北京: 人民卫生出版社, 2015. |
| [11] | 赵云飞, 祝莎莎, 黄新文. 异戊酸血症的研究进展[J]. 中华医学遗传学杂志, 2022, 39(1): 88-91. |
| [12] | 韩连书, 高晓岚, 叶军, 等. 串联质谱分析干血滤纸片酰基肉碱方法的建立[J]. 中华检验医学杂志, 2005, 28(1): 245-248. |
| [13] | 罗小平, 王慕逖, 魏虹, 等. 尿滤纸片法气相色谱-质谱分析技术在遗传性代谢病高危筛查诊断中的应用[J]. 中华儿科杂志, 2003, 41(4): 245-248. |
| [14] | 唐雅楠, 叶贤涛, 顾学范, 等. Menke-Hennekam综合征表型及基因型分析[J]. 临床儿科杂志, 2023, 41(8): 613-617. |
| [15] | Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. |
| [16] | Ribeiro CA, Balestro F, Grando V, et al. Isovaleric acid reduces Na+, K+-ATPase activity in synaptic membranes from cerebral cortex of young rats[J]. Cell Mol Neurobiol, 2007, 27(4): 529-540. |
| [17] | Grünert SC, Wendel U, Lindner M, et al. Clinical and neurocognitive outcome in symptomatic isovaleric acidemia[J]. Orphanet J Rare Dis, 2012, 7: 9. |
| [18] | Shibata N, Hasegawa Y, Yamada K, et al. Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: selective screening vs. expanded newborn screening[J]. Mol Genet Metab Rep, 2018, 16: 5-10. |
| [19] | 宋燕红, 张琪, 容翠环, 等. 串联质谱技术测定C5酰基肉碱水平在新生儿短链酰基辅酶A脱氢酶缺乏症筛查中的应用[J]. 广东医学院学报, 2021, 39(6): 729-731. |
| [20] | Couce ML, Aldamiz-Echevarría L, Bueno MA, et al. Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia[J]. J Hum Genet, 2017, 62(3): 355-360. |
| [21] | Chinen Y, Nakamura S, Tamashiro K, et al. Isovaleric acidemia: therapeutic response to supplementation with glycine, l-carnitine, or both in combination and a 10-year follow-up case study[J]. Mol Genet Metab Rep, 2017, 11: 2-5. |
| [22] | Li Y, Shen M, Jin Y, et al. Eight novel mutations detected from eight Chinese patients with isovaleric acidemia[J]. Clin Chim Acta, 2019, 498: 116-121. |
| [23] | Lee YW, Lee DH, Vockley J, et al. Different spectrum of mutations of isovaleryl-CoA dehydrogenase (IVD) gene in Korean patients with isovaleric acidemia[J]. Mol Genet Metab, 2007, 92(1-2): 71-77. |
| [24] | Vatanavicharn N, Liammongkolkul S, Sakamoto O, et al. Phenotypic and mutation spectrums of Thai patients with isovaleric acidemia[J]. Pediatr Int, 2011, 53(6): 990-994. |
| [25] | 李溪远, 华瑛, 丁圆, 等. 3例非典型异戊酸尿症患儿临床及基因型研究[J]. 临床儿科杂志, 2014, 32(12): 1107-1111. |
| [26] | Tan J, Chen D, Chang R, et al. Tandem mass spectrometry screening for inborn errors of metabolism in newborns and high-risk infants in Southern China: disease spectrum and genetic characteristics in a Chinese population[J]. Front Genet, 2021, 12: 631-688. |
| [27] | Wiley V, Webster D, Loeber G. Screening pathways through China, the Asia Pacific region, the world[J]. Int J Neonatal Screen, 2019, 5(3): 26. |
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