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

Abstract

Background Beta-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. Results We 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. Conclusion This 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.

Characteristics of Transcriptome and Metabolome Concerning Intramuscular Fat Content in Beijing Black Pigs

“…Several carnitines, such as tiglylcarnitine, propionylcarnitine, and 3-hydroxyoctanoyl carnitine, were down-regulated in the low IMF pigs. Tiglylcarnitine is a potential biomarker for many diseases, such as irritable bowel syndrome, chronic kidney disease, and metabolic syndrome. − It is also proposed as a biomarker for beta-ketothiolase deficiency and is related to insulin sensitivity and melanoma lipolysis. − Propionylcarnitine and 3-hydroxyoctanoyl carnitine are involved in fatty acid oxidation. , Propionylcarnitine is also correlated with body mass index . The glucose oxidation of diabetic hearts is increased after treatment with propionylcarnitine, leading to an increase in tricarboxylic acid (TCA) cycle activity and ATP production .…”

Portuguese Neonatal Screening Program: A Cohort Study of 18 Years Using MS/MS

“… * Not calculated due to changes in the screening protocol. ** Not calculated due to not being included in the PNSP panel; a [ 11 ], b data obtained from Orphanet, c [ 12 ], d [ 13 ], e [ 14 ], f [ 15 ]. …”

Hypoglycaemia Metabolic Gene Panel Testing

“…Neurological outcome, such as particularly extrapyramidal signs can occur, even in patients without any apparent decompensation ( 67 ). A characteristic increase in urinary 2-methyl-3-hydroxybutyrate and tiglylglycine, and a raise of C4OH levels at acylcarnitine profile are typical metabolic biomarkers ( 68 ).…”