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Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals

  • Monica H. Wojcik
  • Klaas J. Wierenga
  • Lance H. Rodan
  • Inderneel Sahai
  • Sacha Ferdinandusse
  • Casie A. Genetti
  • Meghan C. Towne
  • Roy W. A. Peake
  • Philip M. James
  • Alan H. Beggs
  • Catherine A. Brownstein
  • Gerard T. Berry
  • Pankaj B. Agrawal
Research Report
Part of the JIMD Reports book series (JIMD, volume 39)

Abstract

Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase) deficiency is a genetic disorder characterized by impaired isoleucine catabolism and ketone body utilization that predisposes to episodic ketoacidosis. It results from biallelic pathogenic variants in the ACAT1 gene, encoding mitochondrial beta-ketothiolase. We report two cases of beta-ketothiolase deficiency presenting with acute ketoacidosis and “metabolic stroke.” The first patient presented at 28 months of age with metabolic acidosis and pallidal stroke in the setting of a febrile gastrointestinal illness. Although 2-methyl-3-hydroxybutyric acid and trace quantities of tiglylglycine were present in urine, a diagnosis of glutaric acidemia type I was initially suspected due to the presence of glutaric and 3-hydroxyglutaric acids. A diagnosis of beta-ketothiolase deficiency was ultimately made through whole exome sequencing which revealed compound heterozygous variants in ACAT1. Fibroblast studies for beta-ketothiolase enzyme activity were confirmatory. The second patient presented at 6 months of age with ketoacidosis, and was found to have elevations of urinary 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine. Sequencing of ACAT1 demonstrated compound heterozygous presumed causative variants. The patient exhibited choreoathethosis 2 months after the acute metabolic decompensation. These cases highlight that, similar to a number of other organic acidemias and mitochondrial disorders, beta-ketothiolase deficiency can present with metabolic stroke. They also illustrate the variability in clinical presentation, imaging, and biochemical evaluation that make screening for and diagnosis of this rare disorder challenging, and further demonstrate the value of whole exome sequencing in the diagnosis of metabolic disorders.

Keywords

3-Ketothiolase 3-Oxothiolase Beta-ketothiolase Ketoacidosis Metabolic stroke Mitochondrial acetoacetyl-coenzyme A thiolase Organic acidemia T2 

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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Monica H. Wojcik
    • 1
    • 2
    • 3
  • Klaas J. Wierenga
    • 4
  • Lance H. Rodan
    • 2
    • 3
  • Inderneel Sahai
    • 5
  • Sacha Ferdinandusse
    • 6
  • Casie A. Genetti
    • 2
    • 3
  • Meghan C. Towne
    • 2
    • 3
  • Roy W. A. Peake
    • 2
  • Philip M. James
    • 2
    • 7
  • Alan H. Beggs
    • 2
    • 3
  • Catherine A. Brownstein
    • 2
    • 3
  • Gerard T. Berry
    • 2
    • 3
  • Pankaj B. Agrawal
    • 1
    • 2
    • 3
  1. 1.Division of Newborn MedicineBoston Children’s Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Division of Genetics and GenomicsBoston Children’s Hospital and Harvard Medical SchoolBostonUSA
  3. 3.The Manton Center for Orphan Disease ResearchBoston Children’s Hospital and Harvard Medical SchoolBostonUSA
  4. 4.Department of Pediatrics, Section of GeneticsOklahoma University Health Sciences CenterOklahoma CityUSA
  5. 5.New England Newborn Screening ProgramUniversity of Massachusetts Medical SchoolWorcesterUSA
  6. 6.Laboratory Genetic Metabolic Diseases, Department of Clinical ChemistryAcademic Medical CenterAmsterdamThe Netherlands
  7. 7.Division of Genetics and MetabolismPhoenix Children’s HospitalPhoenixUSA

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