Objective: To investigate the incidence,clinical,biochemical and genetic characteristics of isovaleric acidemia (IVA) in Zhejiang province.
Methods: Between January 2009 and December 2019, a total of 3 510 004 newborns were screened for IVA using tandem mass spectrometry. Patients of IVA were confirmed by urine organic acid and IVD gene detection. IVA patients were given diet and life management, supplemented with L-carnitine and glycine treatment, long-term followed up to observe and evaluate the growth and intellectual development.
Results: A total of 15 patients with IVA were diagnosed, with an incidence of 1/234 000. Three patients had acute neonatal IVA, and the rest were asymptomatic. The isovalerylcarnitine (C5) levels were increased in all patients. Twelve children underwent urinary organic acid analysis, of which 11 cases had elevated isovalerylglycine levels, 4 cases with 3-hydroxyisovalerate increased simultaneously. Eleven IVA patients underwent genetic testing, 9 patients were compound heterozygous variants in IVD gene, one with homozygous variants in IVD gene, and one harbored one IVD variant. Nineteen IVD variants (14 missense mutations, 3 intron mutations, 1 code shift mutation, and 1 synonymous mutation) were identified, 11 of which were not reported. Among the 15 IVA patients, one patient died and two patients were followed up locally. The remaining patients had no obvious clinical symptoms during the follow-up (2-79 months). Three patients presented with growth and development delay, the remaining had normal physical and mental development.
Conclusions: The clinical manifestations of IVA are non-specific, and the gene spectrum is scattered. Newborn patients screened by tandem mass spectrometry can receive early diagnosis and treatment, so as to correct metabolic defects and pathophysiological changes.
目的: 了解浙江省新生儿异戊酸血症（IVA）的患病率、临床特征及基因突变特点。
方法: 采用串联质谱技术对2009年1月至2019年12月浙江省新生儿疾病筛查中心的3 510 004名新生儿进行遗传代谢病筛查，结合尿有机酸分析及 IVD基因检测进行IVA诊断。IVA确诊患儿进行饮食和生活管理，补充左卡尼汀和甘氨酸治疗，长期随访观察并评估患儿的生长和智能发育情况。
结果: 共确诊IVA患儿15例，3例为急性新生儿型，其余无临床症状，患病率为1/234 000。所有患儿的血异戊酰基肉碱浓度均不同程度增加。12例患儿进行尿有机酸分析，其中11例异戊酰甘氨酸升高，4例伴3-羟基异戊酸升高。11例患儿进行基因检测，9例为 IVD基因复合杂合突变，1例为 IVD基因纯合突变，1例只检测出一个 IVD基因位点。发现 IVD基因突变19种（错义突变14种、内含子突变3种、移码突变1种、同义突变1种），其中11种突变未见报道。15例患儿中1例死亡，2例在当地随访，其余暂未发现明显临床症状（随访时间2~79个月），其中3例生长发育落后，其他患儿体格和智力发育均正常。
结论: IVA临床表现无特异性，基因谱分散。使用串联质谱开展IVA新生儿筛查，实现早期诊断和治疗能纠正代谢缺陷及其引发的病理生理改变。
Keywords: Genotype; IVD gene; Isovaleric acidemia; Neonatal screening; Phenotype; Prevalence rate; Tandem mass spectrometry.