C4OH is a potential newborn screening marker\u2014a multicenter retrospective study of patients with beta-ketothiolase deficiency in China

Yiming Lin,Mingfang Liu,Yun Sun,Yuanyuan Kong,Xiaole Li,Dongjuan Wang,Chiju Yang,Yuyan Shen,Haili Hu,Tingting Niu,Xinwen Huang,Haiyan He,Zhantao Yang,Huiming Yan

doi:10.1186/s13023-021-01859-5

Abstract

BackgroundBeta-ketothiolase deficiency (BKTD) is an autosomal recessive disorder caused by biallelic mutation of ACAT1 that affects both isoleucine catabolism and ketolysis. There is little information available regarding the incidence, newborn screening (NBS), and mutational spectrum of BKTD in China.ResultsWe collected NBS, biochemical, clinical, and ACAT1 mutation data from 18 provinces or municipalities in China between January 2009 and May 2020, and systematically assessed all available published data from Chinese BKTD patients. A total of 16,088,190 newborns were screened and 14 patients were identified through NBS, with an estimated incidence of 1 per 1 million newborns in China. In total, twenty-nine patients were genetically diagnosed with BKTD, 12 of which were newly identified. Most patients exhibited typical blood acylcarnitine and urinary organic acid profiles. Interestingly, almost all patients (15/16, 94%) showed elevated 3-hydroxybutyrylcarnitine (C4OH) levels. Eighteen patients presented with acute metabolic decompensations and displayed variable clinical symptoms. The acute episodes of nine patients were triggered by infections, diarrhea, or an inflammatory response to vaccination. Approximately two-thirds of patients had favorable outcomes, one showed a developmental delay and three died. Twenty-seven distinct variants were identified in ACAT1, among which five were found to be novel.ConclusionThis study presented the largest series of BKTD cohorts in China. Our results indicated that C4OH is a useful marker for the detection of BKTD. The performance of BKTD NBS could be improved by the addition of C4OH to the current panel of 3-hydroxyisovalerylcarnitine and tiglylcarnitine markers in NBS. The mutational spectrum and molecular profiles of ACAT1 in the Chinese population were expanded with five newly identified variants.

Highlights

Beta-ketothiolase deficiency (BKTD) is an autosomal recessive disorder caused by biallelic mutation of ACAT1 that affects both isoleucine catabolism and ketolysis
Beta-ketothiolase deficiency (BKTD, OMIM #203750) is an autosomal recessive disorder caused by a defect in mitochondrial acetoacetyl-CoA thiolase (T2, EC 2.3.1.9) that affects both isoleucine catabolism and ketolysis [1,2,3]
BKTD newborn screening (NBS) and acylcarnitine analysis In this cohort, 29 Chinese patients were genetically diagnosed with BKTD, 14 of which were diagnosed through NBS while 17 were previously reported [12,13,14,15,16]

Summary

Introduction

Beta-ketothiolase deficiency (BKTD) is an autosomal recessive disorder caused by biallelic mutation of ACAT1 that affects both isoleucine catabolism and ketolysis. Beta-ketothiolase deficiency (BKTD, OMIM #203750) is an autosomal recessive disorder caused by a defect in mitochondrial acetoacetyl-CoA thiolase (T2, EC 2.3.1.9) that affects both isoleucine catabolism and ketolysis [1,2,3]. This disease is clinically characterized by intermittent episodes of ketoacidosis. NBS for BKTD can be challenging as some patients fail to be identified, indicating that the use of only two markers, C5OH and C5:1, is insufficient for BKTD NBS. It remains challenging to detect BKTD even using post-analytic interpretative tools, further indicating the complexity of early diagnosis of BKTD [6, 7]

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