Beyond Newborn Screening: Clinical Outcomes and Genotypic Spectrum Underlying Maple Syrup Urine Disease in Mexico

Maple syrup urine disease (MSUD) is a time-critical inborn error of metabolism in which early detection may prevent irreversible neurological injury, yet the success of newborn screening (NBS) depends on timely post-screening care. We retrospectively characterized the clinical, biochemical, and genotypic spectrum of 88 Mexican patients from 80 unrelated families evaluated between 1995 and 2026 and assessed the relationship between NBS, treatment timing, neurological outcome, and survival. Most patients had severe neonatal disease, and 73/88 (83%) presented with acute metabolic decompensation requiring hospitalization. Nine patients were identified by NBS: six received timely confirmatory diagnosis and treatment and maintained normal age-appropriate neurodevelopment during 10 years of follow-up, whereas three experienced delays in the diagnostic and therapeutic pathway, developed metabolic decompensation, and subsequently had severe neurological disability. None of the successfully screened patients died. Among 33 molecularly characterized unrelated patients, 31 distinct variants were identified in BCKDHA, BCKDHB, and DBT, with marked genotypic heterogeneity. These findings show that National NBS strategies should prioritize the inclusion of this time critical disorder and the shortening of the interval between a positive screening result and treatment initiation. MSUD NBS should serve as the entry point to an optimal continuum of care. Rapid confirmation, immediate referral, treatment initiation, and sustained specialized metabolic follow-up are essential for translating early detection into favorable outcomes.