Ketone metabolism defects in childhood: a spectrum of overlapping presentations and clinical features

Abstract Objectives Ketone body metabolism defects are rare inherited disorders that may present with life-threatening metabolic crises in childhood. This study aimed to describe and compare clinical, biochemical, and genetic findings in patients with three ketone metabolism defects. Methods In this retrospective study, data from eight genetically confirmed patients were analyzed: 3 with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2), 4 with beta-ketothiolase deficiency (BKTD), and 1 with succinyl-CoA:3-oxoacid CoA transferase deficiency (SCOT). Patients were followed at the Pediatric Nutrition and Metabolism Department of Adana City Training and Research Hospital since October 2023. Results Eight patients (5 female, 3 male) were included; consanguinity was present in 7 families. Triggers included vaccination, infections, gastroenteritis, and dietary changes. All presented with severe metabolic acidosis requiring hemodialysis. Ketone levels were absent/very low in HMGCS2 deficiency and markedly elevated in BKTD and SCOT deficiency. Hypoglycemia occurred only in HMGCS2, while hyperglycemia was seen in BKTD and SCOT. Hepatomegaly was present in all HMGCS2, SCOT patients and in half of BKTD cases. Elevated 3-hydroxybutyrylcarnitine/3-hydroxyisobutyrylcarnitine (C4-OH) was found in all BKTD patients. One HMGCS2 patient had thrombocytopenia and coagulopathy. Genetic analysis identified homozygous pathogenic/likely pathogenic variants in HMGCS2, ACAT1 , and OXCT1 , including three novel variants. All patients remained clinically stable on dietary treatment. Conclusions HMGCS2 deficiency, BKTD, and SCOT deficiency show overlapping features but can be distinguished by ketone levels, glucose patterns, and acylcarnitine profiles. Novel variants expand the mutational spectrum. Early diagnosis and management are crucial to prevent irreversible neurological damage.