beta-ketothiolase deficiency

Beta-ketothiolase deficiency is an inherited metabolic disorder that disrupts the normal processing of ketone bodies and the catabolism of the amino acid isoleucine. The condition is caused by pathogenic variants in the ACAT1 gene, which encodes an enzyme integral to these metabolic pathways. Typically, affected individuals present in infancy or early toddlerhood with episodes of metabolic decompensation, and the acute manifestations often lessen by adolescence. Prevalence estimates are not well established, and the condition is recognized as very rare.

The clinical presentation of beta-ketothiolase deficiency is characterized by intermittent episodes of metabolic crisis. Affected children frequently experience vomiting, rapid breathing (tachypnea), and metabolic acidosis during acute episodes. These attacks are often accompanied by signs such as ketonuria and an elevated level of urinary 2-methyl-3-hydroxybutyric acid, which is a hallmark biochemical abnormality. Neurologically, many individuals display hypotonia, lethargy, and episodes of reduced consciousness, with some cases progressing to coma during severe decompensation. Cognitive challenges and abnormalities of mental function have also been reported in a significant proportion of cases. In addition, less consistently observed features can include fever, dehydration, and even signs of hyperammonemia or an increased total leukocyte count. Not all individuals experience every symptom, and severity varies considerably.

Beta-ketothiolase deficiency is caused by mutations in the ACAT1 gene. This gene provides instructions for producing an enzyme that plays a crucial role in breaking down ketone bodies and isoleucine, an essential amino acid. When the enzyme is not functioning properly due to genetic alterations, toxic intermediates can accumulate, leading to episodes of ketoacidosis and metabolic imbalance. The condition follows an autosomal recessive inheritance pattern, which means that an affected individual has inherited one altered copy of the gene from each parent. As a result, parents who share a common ancestor are at an increased likelihood of both carrying the variant, although any couple can be affected. Genetic counseling is recommended for families to discuss recurrence risks and to explore options for family planning.

Currently, management of beta-ketothiolase deficiency focuses on supportive care and symptomatic treatment rather than specific approved therapies. During episodes of metabolic decompensation, treatment is aimed at correcting acidosis, maintaining hydration, and stabilizing metabolic function. In the long term, careful dietary management, including avoidance of fasting and the provision of adequate caloric intake, is central to reducing the frequency of acute crises. Because there are no FDA-approved or foundational therapies explicitly linked to this condition, care is highly individualized and typically involves a multidisciplinary team. Regular surveillance is an essential part of long-term management, as ongoing monitoring helps to identify potential complications at an early stage. Furthermore, families are encouraged to work with metabolic specialists, nutritionists, and genetic counselors to devise a comprehensive care plan that addresses both acute care needs and long-term health considerations.

The long-term outlook for individuals with beta-ketothiolase deficiency is highly variable. Most affected individuals experience episodes of metabolic crisis during infancy and early childhood, with these episodes often becoming less frequent or severe by adolescence. However, the frequency and intensity of metabolic decompensations can differ markedly between individuals, and ongoing health largely depends on prompt recognition and management of acute episodes. With current standards of care and improved supportive strategies, many individuals achieve periods of stability, although vigilance remains important throughout life. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with metabolic specialists and genetic counselors who can provide guidance on managing this condition and accessing appropriate support resources.

There are clinical trials currently underway that are exploring new approaches to manage beta-ketothiolase deficiency. Although the research is in its early stages and involves only a few trials, these studies aim to improve our understanding of the disease mechanisms and to evaluate strategies for reducing the frequency and severity of metabolic crises. Individuals interested in participating in clinical trials are encouraged to consult ClinicalTrials.gov or speak with their healthcare team about potential eligibility for emerging therapies.