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

CHnical and mutational study of a Chinese infant with isovaleric acidemia

目的了解异戊酸血症患儿的临床、实验室特点以及异戊酰辅酶A脱氢酶（IVD）基因突变情况。方法对1例异戊酸血症患儿的病史、实验室检查以及血串联质谱和尿气相色谱质谱结果进行了分析，对IVD基因12个外显子及两端内含子行PCR扩增和DNA测序，限制性内切酶片段长度多态性分析c．466G〉C（G127A）新突变。结果患儿男，2岁7个月，生后3d起出现呕吐和酸中毒，行幽门切开术后仍反复呕吐，伴有酸中毒发作，智力发育明显落后。血串联质谱分析显示C5酰基肉碱水平增高至12．89μmol／L，尿气相色谱质谱分析显示异戊酰甘氨酸明显升高，临床诊断为异戊酸血症。IVD基因DNA测序显示，患儿存在复合杂合突变：c．149G〉A（R21H）和c．466G〉C（G127A），c．466G〉C（G127A）突变在／VD基因第5外显子上，是以往未报道的新突变。结论报道1例异戊酸血症，新生儿期发病，反复呕吐，酸中毒和智力落后，血C5酰基肉碱明显升高，尿中有异戊酰、甘氨酸大量排出，基因诊断发现1个IVD基因新突变。

Objectives Isovaleric acidemia （IVA） is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase （IVD） resulting in the accumulation of derivatives of isovaleryl-CoA. IVA is considered to be a severe, potentially life-threatening disorder that manifests with acute neonatal encephalopathy in approximately half of affected individuals, and recurrent episodes of vomiting, lethargy, coma and varying degrees of developmental delay in the other half of patients. This study was conducted to investigate the clinical features and IVD gene mutations of a Chinese patient with IVA. Methods The clinical features, routine laboratory data, blood amino acid and acylcarnitine profiles and urinary organic acid profiles of a patient with IVA were reviewed. Whole coding exons of/VD gene were PCR-amplified for DNA sequencing. The novel mutation c. 466G 〉 C （G127A） was confirmed by RFLP with restriction endonuclease Hph I. Results The patient was a 2 year and 7 month-old boy. At 3 days of age, he began to show severe vomiting and acidosis. He was treated with pyloromyotomy at 10 days of age. His recurrent vomiting was not ameliorated until beginning transition to a diet that included more carbohydrate from 4 months. He had 3 recurrent severe vomiting and acidosis later and showed obvious psychomotor retardation. Blood spot acylcarnitine profiles by MS-MS demonstrated an elevation of CS-carnitine with a peak concentration of 12. 89 μmol/L （ 〈 0. 5 μmol/L）. Organic acid analysis of urine by GC-MS revealed a relatively high level of isovaleric glycine. Mutational analysis of the patient＇s/VD gene revealed heteroallelic mutations of c. 149G 〉 A （R21H） and c. 466G 〉 C （G127A） which is a novel missense mutatiorL G127A mutation was not detected in any of 50 normal controls. Conclusions From the clinical course, obvious elevation of blood CS-carnitine and urine isovaleric glycine, this patient＇s disorder should be classified as ＂metabolically severe＂ type of IVA which suggest that c. 466G 〉 C （G127A） mutation could severely damage the function of the IVD protein. To our knowledge, this is the first characterization of IVD gene mutations in the mainland of China.