Beta-Ketothiolase Deficiency · BKT

Description

Beta-ketothiolase deficiency, also called T2 deficiency or mitochondrial acetoacetyl-CoA thiolase deficiency, is an autosomal recessive disorder of isoleucine catabolism and ketone body utilization. The enzyme mitochondrial acetoacetyl-CoA thiolase, encoded by ACAT1 on chromosome 11, catalyzes a reversible step in both pathways. Pathogenic variants in ACAT1 reduce or abolish enzyme activity. 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine accumulate in urine, and acylcarnitine analysis shows elevated tiglylcarnitine and 2-methyl-3-hydroxybutyrylcarnitine in plasma.

The classical presentation is episodic ketoacidosis between months six and twenty-four of life, triggered by infection, fasting, or a high-protein meal. Episodes include vomiting, dehydration, lethargy, tachypnea, and progression to coma without intervention. Children appear well between episodes, and growth and development are usually normal. Late-onset and atypical presentations occur, and a subset of children identified by newborn screening remain asymptomatic.

Detection is by newborn screening on the dried blood spot, using tandem mass spectrometry to flag elevated tiglylcarnitine, C5:1, and 2-methyl-3-hydroxybutyrylcarnitine, C5-OH. C5-OH is a shared marker that also flags 3-MCC, isovaleric acidemia, holocarboxylase synthetase deficiency, biotinidase deficiency, and HMG-CoA lyase deficiency, and second-tier testing distinguishes them. Confirmation uses urine organic acids, plasma acylcarnitines, and ACAT1 sequencing. Beta-ketothiolase deficiency is rare. Reported incidence in expanded newborn screening programs is on the order of 1 in 100,000 to 1 in 250,000 live births, with regional variation.

Treatments to date

There is no FDA-approved disease-specific therapy for beta-ketothiolase deficiency. Standard of care is preventive and supportive. Families avoid prolonged fasting and follow age-appropriate feeding intervals. During febrile illness, vomiting, or reduced intake, a sick-day protocol provides oral carbohydrate at home and intravenous dextrose at the emergency department when oral intake fails. Mild protein restriction is used in some centers, particularly for isoleucine, and a metabolic dietitian supervises adequacy.

Acute decompensations are managed with intravenous dextrose, correction of acidosis with bicarbonate when severe, fluid resuscitation, and L-carnitine supplementation. Hyperammonemia is uncommon in beta-ketothiolase deficiency relative to other organic acidemias. Most children identified through newborn screening and managed with fasting avoidance and sick-day rules reach adulthood without significant cognitive or motor sequelae. Outcomes worsen when episodes are severe or recurrent before diagnosis.