title: Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening.
abstract: Screened for by all state newborn screening (NBS) programs in the United States, mitochondrial acetoacetyl-coenzyme A thiolase (T2), or β-ketothiolase, deficiency is a rare autosomal recessive disorder that causes ketoacidosis and hypoglycemia/hyperglycemia. Outcomes vary from normal development to severe cognitive impairment or even death after an acute episode of ketoacidosis. The classical biochemical profile of T2 deficiency is a result of null mutations in both alleles of the ACAT1 gene and consists of persistently increased urinary excretion of ketones, characteristic organic acids, and tiglylglycine as well as abnormal blood or plasma acylcarnitine profiles in acute and stable conditions. Early diagnosis and aggressive management can prevent further episodes of ketoacidosis and lead to normal development. We report the cases of 3 children, all subsequently found to have mutations predicted to be associated with no residual T2 enzymatic activity, but only 1 was identified by NBS in Minnesota since 2001. To our knowledge, this is the first description of compound heterozygotes for null mutations associated with no enzymatic activity exhibiting normal urinary organic acid, blood, and plasma acylcarnitine profiles when clinically well, thereby explaining the false-negative NBS results. We suggest that T2 deficiency may be underrecognized, because the incidence of T2 deficiency in Minnesota, on the basis of these 3 cases, is 1 in 232 000, higher than the reported <1 in 1 million incidence. Our cases emphasize that T2 deficiency must be considered in patients who present with ketoacidosis disproportionately severe to the triggering illness despite normal NBS results or nonspecific biochemical findings in blood and urine during asymptomatic periods.
authors.affiliation: Department of Pediatrics, University of Minnesota Medical School, MMC 8404 13-124 PWB, 516 Delaware St SE, Minneapolis, MN 55455, USA. saraf010@umn.edu
authors.forename: Kyriakie
authors.initials: K
authors.lastname: Sarafoglou
authors.forename: Dietrich
authors.initials: D
authors.lastname: Matern
authors.forename: Krista
authors.initials: K
authors.lastname: Redlinger-Grosse
authors.forename: Kristi
authors.initials: K
authors.lastname: Bentler
authors.forename: Amy
authors.initials: A
authors.lastname: Gaviglio
authors.forename: Cary O
authors.initials: CO
authors.lastname: Harding
authors.forename: Piero
authors.initials: P
authors.lastname: Rinaldo
mesh_terms: D000102:Acetyl-CoA C-Acyltransferase / Q000172:deficiency; D000592:Amino Acid Metabolism, Inborn Errors; D002675:Child, Preschool; D005188:False Negative Reactions; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008661:Metabolism, Inborn Errors / Q000175:diagnosis; D015997:Neonatal Screening
chemical_list: D000102:Acetyl-CoA C-Acyltransferase