Beta-Ketothiolase Deficiency (BKD)

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

Alpha-methylacetoacetic aciduria
BKD
Mitochondrial acetoacetyl-CoA thiolase (MAT) deficiency
3-ketothiolase deficiency
3-oxothiolase deficiency
2-methyl-3-hydroxybutyric acidemia

ICD-10 Coding

E71.19, Other disorders of branched-chain amino-acid metabolism

Disorder Category

Organic acidemia

Screening

Abnormal Finding

Elevated C5-OH (2-methyl-3-hydroxybutyrylcarnitine), elevated C5:1 (tiglycarnitine)

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=NA; specificity=NA

Description

Due to the absence of the enzyme mitochondrial acetoacetyl-CoA thiolase, individuals with beta-ketothiolase deficiency are unable to break down the amino acid isoleucine and utilize ketone bodies. This results in a buildup of organic acids (ketones) and a decreased ability to generate energy. Patients typically present with metabolic acidosis induced by fasting, infection, fever, or vomiting.

Clinical Characteristics

With treatment of beta-ketothiolase deficiency, normal development can be expected with avoidance of severe recurrent metabolic crises.

Without treatment, outcomes can vary widely due to broad clinical heterogeneity with death or severe neurologic impairment possible, particularly in those with severe episodes in infancy. Age of symptom onset ranges from 3 days to 4 years, with the mean age at presentation of 15 months. Symptoms are usually triggered by fasting and illness.
Initial signs/symptoms of beta-ketothiolase deficiency may include:
  • Feeding problems
  • Vomiting
  • Diarrhea
  • Lethargy progressing to coma
  • Hypoglycemia or occasionally hyperglycemia
If not treated promptly, patients may experience:
  • Acute metabolic acidosis
  • Failure to thrive
  • Intellectual disability
  • Death

Incidence

Rare

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family and evaluate the infant for poor feeding, vomiting, and lethargy.
  • Provide emergency treatment/referral for symptoms of hypoglycemia, ketonuria, or acidosis.

Confirming the Diagnosis

  • To confirm the diagnosis of beta-ketothiolase deficiency, work with Newborn Screening Services (see NV providers [2]).
  • Follow-up testing will include quantitative plasma acylcarnitine profile, serum biotinidase assay, urine organic acids. Not all patients will have identifiable biochemical abnormalities at time of follow-up, and DNA testing might be indicated. Patients with milder variants can be missed by newborn screening or have elevation of other acylcarnitine species.

If the Diagnosis is Confirmed

  • For evaluation and ongoing collaborative management, consult Biochemical Genetics (Metabolics) Clinics (see NV providers [2]).
  • Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill.
  • Avoidance of fasting; frequent, low-protein, high-carbohydrate meals. Uncooked cornstarch before bedtime might be indicated in some cases.
  • Some patients tend to spontaneously restrict proteins as they get older.
  • Oral L-carnitine may be indicated for some affected children.
  • Bicarbonate and intravenous glucose need to be utilized during metabolic crisis.
  • Monitor urine ketone levels when the child is sick or unable to eat.
  • For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.

Resources

Information & Support

Related Portal Content
After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

Beta-Ketothiolase Deficiency (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

For Parents and Patients

Beta-Ketothiolase Deficiency - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.

Beta-Ketothiolase Deficiency (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Organic Acidemia Association (OAA)
A nonprofit organization that provides information, support, events, connections with other parents, a discussion board, and nutrition and recipe ideas.

Resources for Beta-Ketothiolase Deficiency (Disease InfoSearch)
Compilation of information, articles, and links to support; from Genetic Alliance.

Tools

NV ACT Sheet for ß-ketothiolase (BKT) deficiency (ACMG) (PDF Document 126 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive, along with resources for consultation and patient education/support; from the American College of Genetics and Genomics

Confirmatory Algorithms for Elevated C5-OH (ACMG) (PDF Document 224 KB)
Basic steps involved in determining the final diagnosis of an infant with a positive newborn screen for this condition; American College of Medical Genetics.

Services for Patients & Families in Nevada (NV)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Helpful Articles

PubMed search for newborn screening and beta-ketothiolase deficiency, last 10 years.

Pasquali M, Monsen G, Richardson L, Alston M, Longo N.
Biochemical findings in common inborn errors of metabolism.
Am J Med Genet C Semin Med Genet. 2006;142C(2):64-76. PubMed abstract

Korman SH.
Inborn errors of isoleucine degradation: a review.
Mol Genet Metab. 2006;89(4):289-99. PubMed abstract

Authors & Reviewers

Initial publication: March 2007; last update/revision: May 2019
Current Authors and Reviewers:
Author: Nicola Longo, MD, Ph.D.
Authoring history
2012: revision: Kimberly Hart, MS, LCGCA
2007: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer