Neurological Outcomes of Newborn Screening-Identified Isovaleric Acidemia: A Case Series Exploring Initial C5 Acylcarnitine Levels.

Abstract

Isovaleric acidemia (IVA) is a rare autosomal recessive disorder caused by isovaleryl-CoA dehydrogenase deficiency, leading to toxic metabolite accumulation and potentially life-threatening metabolic crises. Newborn screening (NBS) has enabled early detection through elevated C5 acylcarnitine levels, yet the prognostic value of initial C5 concentrations remains unclear. This single-center retrospective study examined 10 Australian patients diagnosed with IVA via NBS between 2004 and 2025. Patients were stratified as "mild" or "classic" based on initial C5 levels and clinical severity. Developmental outcomes were assessed using standardized tools and clinical evaluations. Despite biochemical evidence of metabolic instability, including hyperammonemia, acidosis, and hospitalizations, no patients demonstrated neurological impairment on follow-up. Notably, individuals with markedly elevated C5 levels (up to 63.6 μmol/L) remained neurologically intact, suggesting that early diagnosis and timely metabolic management (protein restriction, carnitine/glycine supplementation, emergency protocols) may mitigate long-term CNS involvement. Dietary practices varied, with some patients maintaining protein restriction due to self-limited intake. Our findings reveal substantial heterogeneity in biochemical profiles and clinical trajectories, with minimal correlation between initial C5 levels and neurodevelopmental outcomes. These results align with prior studies questioning the predictive value of isolated NBS markers and support a more nuanced, individualized approach to IVA management. Limitations include small sample size, retrospective design, and incomplete standardized neurocognitive testing. Further prospective studies incorporating genotype data and formal assessments are needed to refine risk stratification and optimize long-term care strategies.