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The first case of mitochondrial acetoacetyl-CoA thiolase deficiency identified by expanded newborn metabolic screening in Italy: the importance of an integrated diagnostic approach.
- Source :
-
Journal of inherited metabolic disease [J Inherit Metab Dis] 2010 Dec; Vol. 33 Suppl 3, pp. S91-4. Date of Electronic Publication: 2010 Feb 16. - Publication Year :
- 2010
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Abstract
- A pilot expanded newborn screening programme to detect inherited metabolic disorders by means of liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) began in the Campania region, southern Italy, in 2007. By October 2009, >8,800 dried blood samples on filter paper from 11 hospitals had been screened. Within this screening programme, we identified a case of mitochondrial acetoacetyl-coenzyme A (CoA) thiolase deficiency [β-ketothiolase (β-KT) deficiency] by analysing the acylcarnitine profile from a dried blood spot with LC-MS/MS. Gas chromatography coupled with mass spectrometry analysis of urinary organic acids and LC-MS/MS analysis of urinary acylcarnitines were in line with this disorder. In fact, concentrations were well beyond the cut-off values of tiglyl carnitine, 3-hydroxybutyrylcarnitine and 2-methyl-3-hydroxybutyrylcarnitine, 2-methyl-3-hydroxybutyric acid and tiglyl glycine. The absence of 2-methylacetoacetic acid in urine may be attributed to: (i) the instability of this β-ketoacid because it undergoes spontaneous decarboxylation to 2-butanone, which is highly volatile and thus difficult to detect, and (ii) the good health of the patient in the first days of life. β-KT deficiency was subsequently diagnosed in the patient's older sister, who showed increased levels of the same metabolites but also small amounts of 2-methylacetoacetic acid, which is considered a key marker for β-KT diagnosis. Genomic analysis revealed mutation c.1189C >G in exon 12 of the ACAT1 gene, which results in a severe defect because of the p.H397D amino acid change in both alleles of both patients.
- Subjects :
- Acetyl-CoA C-Acetyltransferase deficiency
Acetyl-CoA C-Acetyltransferase genetics
Acetyl-CoA C-Acyltransferase blood
Acetyl-CoA C-Acyltransferase genetics
Acetyl-CoA C-Acyltransferase urine
Amino Acid Metabolism, Inborn Errors blood
Amino Acid Metabolism, Inborn Errors enzymology
Amino Acid Metabolism, Inborn Errors genetics
Amino Acid Metabolism, Inborn Errors urine
Biomarkers blood
Biomarkers urine
Carnitine blood
DNA Mutational Analysis
Genetic Predisposition to Disease
Genetic Testing
Heredity
Humans
Infant, Newborn
Italy
Mutation
Pedigree
Phenotype
Predictive Value of Tests
Acetyl-CoA C-Acyltransferase deficiency
Amino Acid Metabolism, Inborn Errors diagnosis
Carnitine analogs & derivatives
Chromatography, Liquid
Dried Blood Spot Testing
Neonatal Screening methods
Tandem Mass Spectrometry
Subjects
Details
- Language :
- English
- ISSN :
- 1573-2665
- Volume :
- 33 Suppl 3
- Database :
- MEDLINE
- Journal :
- Journal of inherited metabolic disease
- Publication Type :
- Academic Journal
- Accession number :
- 20157782
- Full Text :
- https://doi.org/10.1007/s10545-009-9028-3