BKT deficiency is inherited in an autosomal recessive pattern. Normally a person has two functional ACAT1 genes. In people with BKT deficiency, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with BKT deficiency typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.
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The severity and age of onset of symptoms in people with BKT deficiency is variable. The symptoms usually begin during the first 2 years of life, but some people with BKT deficiency never develop symptoms. The symptoms of BKT deficiency may be brought on by an illness, fasting or a high protein meal. Symptoms usually begin with vomiting and breathing difficulty and may progress to lethargy, seizures and coma. There are some reports of patients with developmental delay.
- Incidence: BKT deficiency is very rare. It occurs in less than 1 in 1 million newborns.
- New York State Method of Screening (First Tier): Screening for BKT deficiency is accomplished by measuring the acylcarnitines C5:1 and C5OH by tandem mass spectrometry (MS/MS).
- Second Tier Screening: None
- Testing can be affected by: Newborn screening cannot distinguish between BKT deficiency and other disorders with elevated C5OH (3-MCC and HMG-CoA lyase deficiency) or elevated C5:1 (MHBD deficiency).
- Interpretation/reporting of data: Results are reported as screen negative, borderline or as a referral. A repeat specimen must be collected for a borderline result. Prompt consultation with a specialist is required for a referral.
- Referral to Specialty Care Center: Patients with an abnormal newborn screen for BKT deficiency are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of BKT deficiency.
Diagnostic testing may include urine organic acid analysis, plasma acylcarnitine analysis, ACAT1 gene sequencing and enzyme analysis in fibroblasts. The urine organic acid analysis and acylcarnitine profile may be normal in milder cases unless the patient is given an isoleucine challenge.
Treatment is typically dietary management including careful monitoring of protein and carbohydrate intake. Additional medical care, including admission to the hospital for intravenous feedings, may be required during times of illness.
Most patients make a full recovery between episodes, although some patients are left with remaining developmental delay.
Beta-ketothiolase (BKT) deficiency is a disorder of organic acid metabolism (inherited metabolic disorder).
A component of protein (isoleucine) is broken down as part of normal metabolism. The ACAT1 gene provides instructions for an important enzyme in this process. If there is a mutation in the ACAT1 gene, the enzyme does not function and isoleucine is not broken down. The breakdown of ketones, which are needed for the body to make energy, is also impacted. Toxic metabolites accumulate and may cause symptoms. The accumulation of ketones is called ketoacidosis.