The first case of mitochondrial acetoacetyl-CoA thiolase deficiency identified by expanded newborn metabolic screening in Italy: the importance of an integrated diagnostic approach.
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.
Catanzano
Francesca
F
CEINGE-Biotecnologie Avanzate, Napoli, Dipartimento di Scienze Biologiche ed Ambientali, Università del Sannio, Benevento, Naples, Italy.
Ombrone
Daniela
D
Di Stefano
Cristina
C
Rossi
Anna
A
Nosari
Norberto
N
Scolamiero
Emanuela
E
Tandurella
Igor
I
Frisso
Giulia
G
Parenti
Giancarlo
G
Ruoppolo
Margherita
M
Andria
Generoso
G
Salvatore
Francesco
F
D000101:Acetyl-CoA C-Acetyltransferase / Q000172:deficiency / Q000235:genetics; D000102:Acetyl-CoA C-Acyltransferase / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000652:urine; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000652:urine; D015415:Biomarkers / Q000097:blood / Q000652:urine; D002331:Carnitine / Q000031:analogs & derivatives* / Q000097:blood; D002853:Chromatography, Liquid; D004252:DNA Mutational Analysis; D059788:Dried Blood Spot Testing; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D040941:Heredity; D006801:Humans; D007231:Infant, Newborn; D007558:Italy; D009154:Mutation; D015997:Neonatal Screening / Q000379:methods*; D010375:Pedigree; D010641:Phenotype; D011237:Predictive Value of Tests; D053719:Tandem Mass Spectrometry
D015415:Biomarkers; C116917:acylcarnitine; D000102:Acetyl-CoA C-Acyltransferase; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase; D002331:Carnitine