异戊酸血症患儿临床特征、基因型及随访分析

doi:10.12372/jcp.2024.23e1218

摘要/Abstract

摘要：

目的探讨异戊酸血症（IVA）患儿临床特征、基因变异特点及随访结果，为该病的早期识别和诊断治疗提供依据。方法回顾性分析2012年4月至2023年10月在儿内分泌遗传科明确诊断为IVA患儿的临床资料。结果 34例IVA患儿中，男22例、女12例。其中15例为急性新生儿型，3例为慢性间歇型，16例为来自新生儿筛查确诊的无症状型。与无症状型组相比，有临床症状组（包括急性新生儿型和慢性间歇型）血异戊酰肉碱（C5）水平，C5/乙酰肉碱（C2）比值及C5/丙酰肉碱（C3）比值以及尿中异戊酰甘氨酸水平显著升高，差异有统计学意义（P<0.05）。34例患儿IVD基因共检出40种基因变异类型，以错义突变为主（30/40, 75.0%），最常见的突变位点为c.1208A>G（n=8）。临床表现与基因变异类型未见明显相关性。随访死亡4例，均为急性新生儿型起病患儿。30例存活患儿最近1次随访时尿异戊酰甘氨酸水平显著下降，与治疗前相比差异有统计学意义（P<0.05）。结论 IVA患儿临床表现无明显特异性，血C5、C5/C2比值、C5/C3比值及尿异戊酰甘氨酸增高对诊断IVA具有特异性。新生儿筛查有助于该病的早期诊断、治疗及预后。

关键词: 异戊酸血症, IVD基因, 串联质谱, 新生儿筛查

Abstract:

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

孙宇宁, 梁黎黎, 丁思, 刘宇超, 陈婷, 龚珠文, 邱文娟, 张惠文, 顾学范, 韩连书. 异戊酸血症患儿临床特征、基因型及随访分析[J]. 临床儿科杂志, 2024, 42(3): 224-229.

SUN Yuning, LIANG Lili, DING Si, LIU Yuchao, CHEN Ting, GONG Zhuwen, QIU Wenjuan, ZHANG Huiwen, GU Xuefan, HAN Lianshu. Clinical characteristics, genotypes and follow-up analysis of children with isovaleric academia[J]. Journal of Clinical Pediatrics, 2024, 42(3): 224-229.

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组别	例数	血				尿
组别	例数	C5/μmol·L^-1	C0/μmol·L^-1	C5/C2	C5/C3	异戊酰甘氨酸/ mmol·mol肌酐^-1
有临床症状组	18	7.57(4.09~10.07)	29.86(13.36~40.60)	0.45(0.28~0.66)	8.05(4.87~17.14)	366.89(90.43~894.26)
无症状型组	16	1.41(0.75~5.47)	28.62(21.37~37.56)	0.15(0.05~0.43)	1.74(0.58~6.78)	18.14(2.23~152.30)
Z值		3.10	0.13	2.70	2.92	3.30
P		0.002	0.895	0.007	0.003	0.001

时间	血				尿
时间	C5/μmol·L^-1	C0/μmol·L^-1	C5/C2	C5/C3	异戊酰甘氨酸/mmol·mol肌酐^-1
治疗前	4.20(1.25~9.23)	26.31(16.14~40.91)	0.27(0.10~0.57)	6.31 (1.69~13.03)	198.19(8.07~355.22)
最后1次随访时	5.41(1.12~9.21)	33.63(25.44~42.11)	0.30(0.07~0.49)	6.60(1.06~8.49)	16.17(1.57~169.14)
Z值	0.97	0.76	0.26	0.97	3.40
P	0.330	0.446	0.794	0.332	0.001