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

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.

Appendices

Synopsis

Beta-ketothiolase deficiency, causing episodic, severe ketoacidosis, can present with metabolic stroke and may be difficult to diagnose biochemically.

Monica H. Wojcik conceptualized this case report, contributed to the writing of the manuscript, and provided clinical care for one of the patients reported.

Klaas J. Wierenga provided clinical care for one of the patients reported and contributed to the writing of the manuscript.

Lance H. Rodan provided clinical care for one of the patients reported and contributed to the writing of the manuscript.

Inderneel Sahai performed the newborn screen analysis for one of the patients reported and critically reviewed the manuscript.

Sacha Ferdinandusse performed the fibroblast enzyme assay for one of the patients reported and critically reviewed the manuscript.

Casie A. Genetti contributed to the whole exome sequencing for one of the patients reported.

Meghan C. Towne contributed to the whole exome sequencing for one of the patients reported.

Roy W.A. Peake aided in the biochemical laboratory interpretation for one of the patients reported and critically reviewed the manuscript.

Philip James provided clinical care for one of the patients reported and critically reviewed the manuscript.

Alan H. Beggs contributed to the whole exome sequencing for one of the patients reported and critically reviewed the manuscript.

Catherine A. Brownstein contributed to the whole exome sequencing for one of the patients reported.

Gerard T. Berry provided clinical care for one of the patients reported and critically reviewed the manuscript.

Pankaj B. Agrawal conceptualized this case report, contributed to the whole exome sequencing for one of the patients reported, and contributed to the writing of the manuscript.

Corresponding Author

Pankaj B. Agrawal, who serves as guarantor for the chapter, accepts full responsibility for the work, had access to the data, and controlled the decision to publish.

Competing Interests

No competing interests are reported by the authors.

Funding

MHW is supported by training grant T32 HD07466 through the National Institutes of Health (NIH). PBA was supported by R01 AR068429 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH and U19 HD077671 from the National Institute of Child Health and Human Development/National Human Genome Research Institute/NIH. The Gene Discovery Core of The Manton Center for Orphan Disease Research, Boston Children’s Hospital also supported the work. Whole exome sequencing was performed by the Yale Center for Mendelian Genomics, supported by NIH grant 2UM1HG006504. Sanger sequencing was performed by the Molecular Genetics Core Facility of the Intellectual and Developmental Disabilities Research Center (IDDRC) at Boston Children’s Hospital, supported by NIH grant U54 HD090255.

Ethics Approval

As these are retrospective case reports, approval by an Institutional Review Board was not required. Patient one and the patient’s parents had whole exome sequencing performed on a research basis through an IRB-approved protocol with the Manton Center for Orphan Disease Research at Boston Children’s Hospital.

Patient Consent Statement

As these are retrospective case reports without identifiable information, patient consent was not obtained.