Retrospective analysis on clinical data and genetic variations of patients with beta-ketothiolase deficiency.
10.3760/cma.j.issn.1003-9406.2019.03.002
- Author:
Feng XU
1
;
Lianshu HAN
;
Wenjuan QIU
;
Huiwen ZHANG
;
Wenjun JI
;
Ting CHEN
;
Xia ZHAN
;
Jun YE
;
Xuefan GU
Author Information
1. Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China. yejun@xinhuamed.com.cn.
- Publication Type:Journal Article
- MeSH:
Acetyl-CoA C-Acyltransferase;
deficiency;
Amino Acid Metabolism, Inborn Errors;
Carnitine;
Humans;
Infant, Newborn;
Retrospective Studies;
Tandem Mass Spectrometry
- From:
Chinese Journal of Medical Genetics
2019;36(3):199-202
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To summarize the clinical, biochemical and molecular characteristics of 8 patients with beta-ketothiolase deficiency (BKD).
METHODS:Clinical characteristics, biochemical markers detected by tandem mass spectrometry (MS-MS) and gas chromatography-mass spectrometry (GC-MS), and variations of ACAT1 gene of the 8 patients were reviewed.
RESULTS:Three patients were diagnosed by newborn screening and were asymptomatic. Five patients showed dyspnea and metabolic acidosis through high risk screening. Blood methylcrotonyl carnitine (C5:1) were 0.43 (0.20-0.89) μmol/L and 3-hydroxyisovaleryl carnitine(C5-OH) were 1.37 (0.98-3.40) μmol/L. Both were significantly higher than those of healthy controls (P<0.01). Urinary 2-methyl-3-hydroxybutyric acid was 56.04 (7.69-182.20) and methylcrotonyl glycine was 42.83 (9.20-127.01), both were higher than normal levels. In 5 patients urinary 2-methyl-3-hydroxybutyric acid level was remarkably decreased (P<0.05) after treatment. Analysis of ACAT1 gene mutation was performed in six families. Missense variations were detected in 78.6% of the cases. 42.8% of the 7 BKD patients have carried c.1124A>G (p.N375S) variant, which accounted for 28.6% of all 14 mutant alleles. Four novel variants, namely c.229delG (p.E77KfsTer10), c.373G>T (p.V125F), c.419T>G (p.L140R) and c.72+1G>A, were discovered. Pathogenicity assessment of two highly conservative missense variants (p.V125F) and (p.L140R) were 0.994 and 1.0 (Scores obtained from PolyPhen2), and PROVEAN scores were -4.652 and -5.399, respectively. c.72+1g>a was suspected (by Human Splicing Finder) to alter the wild type donor motif and most probably affect the splicing.
CONCLUSION:Clinicians should consider MS/MS and GC/MS testing for those with unexplained neurological symptoms and metabolic acidosis in order to attain early diagnosis of BKD. Genetic testing should be used to confirm the diagnosis.
