Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening

Kyriakie Sarafoglou, Dietrich Matern, Krista Redlinger-Grosse, Kristi Bentler, Amy Gaviglio, Cary Harding, Piero Rinaldo

Research output: Contribution to journalArticle

26 Citations (Scopus)

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

Original languageEnglish (US)
JournalPediatrics
Volume128
Issue number1
DOIs
StatePublished - Jul 2011

Fingerprint

Ketosis
Siblings
Newborn Infant
Mutation
Acids
Heterozygote
Ketones
Hypoglycemia
Hyperglycemia
Early Diagnosis
Alleles
Incidence
Genes
Beta ketothiolase deficiency
acylcarnitine

Keywords

  • β-ketothiolase deficiency metabolic ketoacidosis
  • Mitochondrial acetoacetyl-CoA thiolase deficiency
  • Newborn screening
  • Tiglylcarnitine
  • Tiglylglycine

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Sarafoglou, K., Matern, D., Redlinger-Grosse, K., Bentler, K., Gaviglio, A., Harding, C., & Rinaldo, P. (2011). Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening. Pediatrics, 128(1). https://doi.org/10.1542/peds.2010-3918

Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening. / Sarafoglou, Kyriakie; Matern, Dietrich; Redlinger-Grosse, Krista; Bentler, Kristi; Gaviglio, Amy; Harding, Cary; Rinaldo, Piero.

In: Pediatrics, Vol. 128, No. 1, 07.2011.

Research output: Contribution to journalArticle

Sarafoglou, K, Matern, D, Redlinger-Grosse, K, Bentler, K, Gaviglio, A, Harding, C & Rinaldo, P 2011, 'Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening', Pediatrics, vol. 128, no. 1. https://doi.org/10.1542/peds.2010-3918
Sarafoglou, Kyriakie ; Matern, Dietrich ; Redlinger-Grosse, Krista ; Bentler, Kristi ; Gaviglio, Amy ; Harding, Cary ; Rinaldo, Piero. / Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening. In: Pediatrics. 2011 ; Vol. 128, No. 1.
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