Diabetic ketoacidosis in an adult with beta-ketothiolase deficiency (BKD) involving a novel ACAT1 variant : first report of established diabetes in BKD and a review of the literature

Abstract

Background: Diabetes presenting in young adults is often challenging to classify. Diabetic ketoacidosis is typically seen in autoimmune type 1 diabetes mellitus and more rarely in young onset type 2 diabetes mellitus. Beta-ketothiolase deficiency (BKD) is a rare autosomal recessive condition affecting isoleucine catabolism and ketone body metabolism. BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age. There is a paucity of data with respect to the co-existence of persistent dysglycemia with BKD.

Case presentation and literature review: We present a novel case of diabetes presenting as diabetic ketoacidosis in a 34-year-old man with BKD, with genetically confirmed compound heterozygosity for variants in ACAT1, including a novel ACAT1 c.481T>C, p.(Tyr161His) variant. Diabetes in people with BKD presents unique diagnostic and management challenges. To further contextualize our findings, we conducted a comprehensive narrative review of the existing literature with respect to dysglycemia in those with BKD, especially in adulthood. There are no existing reports describing diabetes in adults with BKD. Stress hyperglycemia is not uncommon when children with BKD are acutely unwell, with several pediatric case reports describing short-lived hyperglycemia but normal HbA1c measurements during metabolic crises (indicating the absence of persistent hyperglycemia).

Conclusions: This is the first report of diabetic ketoacidosis in an adult with BKD, with an elevated HbA1c consistent with persistent hyperglycemia. This case highlights the importance of checking HbA1c in people with BKD and hyperglycemia in order to uncover potential coexisting diabetes, facilitating timely management and preventing complications. Increased reporting on the longitudinal outcomes of those with rare metabolic disorders is essential for identifying potential associations with conditions like diabetes.

Keywords: Beta-ketothiolase deficiency; Diabetes; Ketoacidosis; T2 deficiency.

Fig. 1

Summary of isoleucine catabolism and ketone metabolism. The short red bar denotes the site of action of beta-ketothiolase. 2M3HB = 2-methyl-3-hydroxybutyrate; 2M3HB- = 2-methyl-3-hydroxylbutyryl-; 2MAA = 2-methylacetoacetate; 2MAA- = 2‐methylacetoacetyl-; AA = acetoacetyl; AcAc = acetoacetate; CoA = Coenzyme A; FFA = free fatty acids; HMG = 3-hydroxy-3-methylglutaryl; TCA = tricarboxylic acid; TIG = tiglylglycine. Tiglylcarnitine and 2M3HB-carnitine (pink boxes) are characteristically elevated on blood acylcarnitine analysis in those with BKD. TIG, 2M3HB, and 2MAA (yellow boxes) are characteristically elevated on urinary organic acid analysis in those with BKD

Fig. 2

Two detected ACAT1 variants (next-generation sequencing data visualisation with Integrative Genomics Viewer). Left (brown): Chr11(GrCh37):108009661 NM_000019.3 c.472A>G, p.(Asn158Asp). Right (blue): Chr11(GrCh37)11:108009670 NM_000019.3 c.481T>C, p.(Tyr161His)