Longitudinal biochemical profiles in beta-ketothiolase deficiency: Phase-dependent diagnostic challenges and...

Beta-ketothiolase deficiency (BKTD) is a rare autosomal recessive metabolic disorder affecting isoleucine catabolism and ketone body utilization, demonstrating marked clinical and biochemical heterogeneity. This study aims to characterize the longitudinal clinical, biochemical, and genetic features of a single-center BKTD cohort and evaluate phase-dependent dynamics in metabolic biomarkers during acute crises and stable follow-up periods.

Twenty patients from 11 families diagnosed with BKTD were included in this retrospective study. Longitudinal clinical findings, plasma acylcarnitines via LC-MS/MS, and urinary organic acids via GC-MS were comprehensively evaluated during both acute catabolic crises and stable follow-up intervals. ACAT1 variants and genotype-phenotype correlations were statistically analyzed.

The median age at diagnosis was 9.5 months, and parental consanguinity was present in 81.8% of families. Clinical manifestations ranged from asymptomatic disease to severe metabolic crises, with neurological involvement in 10% of patients and mortality in 5%. The most frequent ACAT1 variant was c.158G > A, accounting for 42.1% of cases. Plasma C5OH was the most consistent biomarker, remaining elevated in 100% of acute and 97.1% of stable samples. Plasma C5:1 was elevated in 85.7% and 73.5% of acute and stable samples, respectively. In contrast, C4OH elevation was observed only during acute crises (28.6%) and was absent during stable follow-up. Urinary 2M3HB and TIG were elevated in all acute samples but showed reduced positivity rates during remission.

BKTD exhibits significant phase-dependent metabolic variability driven by catabolic stress. Longitudinal multi-marker evaluation is essential, as single-time-point biochemical assessments during stable remission carry a distinct risk of false-negative results.