ACAT1 – Beta-ketothiolase deficiency

Beta-ketothiolase deficiency, also known as mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, is a rare inborn error of metabolism characterized by autosomal recessive inheritance. Patients typically present in infancy or early childhood with intermittent episodes of severe ketoacidosis, often triggered by infections or high protein intake, accompanied by vomiting, lethargy, and metabolic acidosis (PMID:20046049). Early diagnosis enables prompt management with glucose infusion and protein restriction, reducing morbidity and improving outcomes.

Genetic evidence for the ACAT1–beta-ketothiolase deficiency association is strong. Over 100 patients with biallelic pathogenic variants have been reported, including 26 probands across multiple unrelated families, with consistent enzymatic confirmation of T2 deficiency (PMID:11161836). Familial segregation of compound heterozygous and homozygous variants, such as c.578T>C (p.Met193Thr), further supports causality. Segregation analyses have documented at least 6 additional affected relatives carrying disease‐segregating variants across distinct pedigrees.

The variant spectrum is broad, encompassing missense changes (e.g., c.578T>C (p.Met193Thr)), null alleles due to frameshift and nonsense mutations, splice‐site disruptions causing exon skipping (e.g., c.826+1G>T), and large deletions. A common founder splice acceptor mutation, c.1006-1G>C, accounts for a significant proportion of alleles in certain populations, while recurrent missense alleles (e.g., p.Arg208Ter) have been identified in Vietnamese cohorts (PMID:20156697).

Functional studies elucidate pathogenic mechanisms primarily through loss of T2 enzymatic activity. Transient expression of mutant ACAT1 cDNAs in cell models demonstrates absent or severely reduced thiolase function, with temperature-sensitive residual activity observed for certain “mild” mutations (e.g., p.Glu252del exhibited 25% activity at 37 °C) (PMID:17236799). Minigene and cDNA analyses confirm splicing defects caused by exonic and intronic substitutions, underpinning aberrant exon skipping and nonsense‐mediated decay (PMID:27748876).

Although genotype–phenotype correlations are limited—patients with predicted null alleles may have variable clinical severities, and siblings with identical genotypes can exhibit divergent presentations—biochemical phenotypes (organic acid and acylcarnitine profiles) are generally concordant with genotype severity. Disputed cases often involve “mild” variants that retain partial enzyme function and present with subtler metabolic profiles.

In summary, biallelic pathogenic variants in ACAT1 definitively cause beta-ketothiolase deficiency via loss of mitochondrial T2 activity. Genetic testing for ACAT1 variants is essential for confirming diagnosis, guiding family counseling, and initiating early treatment. Functional assays remain valuable for variant classification, while ongoing reporting of novel alleles and longitudinal outcomes will refine management strategies.

References

• The Tohoku journal of experimental medicine • 2010 • Different clinical presentation in siblings with mitochondrial acetoacetyl-CoA thiolase deficiency and identification of two novel mutations. PMID:20046049
• Molecular genetics and metabolism • 2001 • The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients. PMID:11161836
• Molecular genetics and metabolism • 2010 • A common mutation, R208X, identified in Vietnamese patients with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. PMID:20156697
• Molecular genetics and metabolism • 2007 • Kinetic and expression analyses of seven novel mutations in mitochondrial acetoacetyl-CoA thiolase (T2): identification of a Km mutant and an analysis of the mutational sites in the structure. PMID:17236799
• Molecular medicine reports • 2016 • Exon 10 skipping in ACAT1 caused by a novel c.949G>A mutation located at an exonic splice enhancer site. PMID:27748876
• Human mutation • 2019 • Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. PMID:31268215

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