イソ吉草酸血症

BACKGROUND AND OBJECTIVE: Congenital and developmental disorders should be detected early to avoid complications such as disability and death. The Philippine clinical practice guidelines (CPG) were developed to guide healthcare professionals on screening for congenital and developmental disorders among apparently healthy neonates and children. METHODS: Following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to CPG development recommended by the Department of Health (DOH), the steering committee, composed of clinical geneticists, developmental pediatricians, family and community medicine physicians, and ambulatory and community pediatricians, set the objectives of the CPG and formulated clinical questions in consultation with stakeholders. There were 15 priority guideline questions that covered various disorders including inborn errors of metabolism, critical congenital heart disease, developmental delay, learning disabilities, and autism. Evidence review experts systematically reviewed existing clinical practice guidelines, appraised, and summarized the evidence. A multisectoral panel formulated recommendations through a formal consensus based on the evidence summaries. The CPG was externally reviewed prior to publication. RESULTS: The CPG provides twenty (20) recommendations on fifteen (15) prioritized questions in the screening for certain congenital and developmental disorders. This CPG contains recommendations for the screening for critical congenital heart disease, thalassemia, Glucose-6-phosphate dehydrogenase (G6PD) deficiency, developmental delay, and autism spectrum disorder. Recommendations against routine screening of cystic fibrosis, sickle cell disease, methionine adenosyltransferase deficiency, tyrosinemia, long chain 3-hydroxy acyl CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MTPD), carnitine palmitoyl transferase types 1 and 2 (CPT1, CPT2) and glutaric aciduria type 2 (GA2), biotidinase deficiency, beta-ketothiolase deficiency, holocarboxylase synthetase deficiency, and isovaleric acidemia were made. CONCLUSION: The consensus panel recommended the screening of certain conditions, based on the available evidence, the burden of disease, the cost of the confirmatory testing, and its applicability to the population. Although this CPG intends to influence the direction of health policies for the general population, it should not be the sole basis for recreating or abolishing practices that aim to improve the health conditions of many Filipinos, particularly those part of the workforce.

Organic acidemias (OAs) are a group of inherited disorders, most commonly caused by defects in mitochondrial enzymes involved in amino acid and fatty acid metabolism. While they characteristically present with metabolic and neurological crises, growing evidence reveals a significant burden of chronic immune dysregulation in some disorders and patients. This review provides a synthesis of clinical and mechanistic evidence discussing immune dysregulation in OAs. Cytopenia can occur in OAs and predispose patients to recurrent and severe infections. Adaptive immune deficits, such as hypogammaglobulinemia, reduced B and T cell populations, and impaired vaccine-specific antibody responses, including to diphtheria and tetanus in MSUD and to the inactivated COVID-19 vaccine in propionic acidemia, have also been reported. Additionally, some case series note hyperinflammatory conditions, such as hemophagocytic lymphohistiocytosis. Mechanistic studies indicate that accumulated metabolites disrupt innate and adaptive hematopoietic progenitor function, mitochondrial homeostasis, and inflammatory signaling. Emerging therapeutic avenues, such as gene and mRNA-based therapies, hold the potential to improve or normalize the biochemical phenotype in OAs. While their impact on immune abnormalities remains largely unexplored, future clinical trials offer an opportunity to systematically assess potential effects on immune parameters. OAs are increasingly recognized as disorders with intrinsic immune dysregulation, extending beyond their well-characterized metabolic and neurological manifestations. Future clinical trials will benefit from including immunological endpoints to evaluate immunological recovery for novel therapies.

Hemophagocytic lymphohistiocytosis (HLH) continues to pose a diagnostic challenge in pediatric critical care, not only because of its severity but also due to the wide range of conditions that can underlie its presentation. Among these, metabolic disorders are often overlooked. We describe an 18-month-old boy who initially presented with persistent fever and respiratory symptoms, later evolving to pancytopenia, hepatosplenomegaly, and neurological deterioration, the patient fulfilled seven of the eight HLH-2004 criteria. Along the way, adenovirus and parainfluenza virus type III were identified, and anti-NMDA receptor encephalitis was confirmed, adding further complexity to the clinical picture. What proved decisive was the identification of a homozygous pathogenic variant in the IVD gene (c.1174C > T; p.Arg392Cys), establishing the diagnosis of isovaleric acidemia. This finding reframed the case. Rather than an isolated hyperinflammatory syndrome, the clinical course can be better understood as the result of a metabolic disorder capable of amplifying immune dysregulation, particularly in the setting of intercurrent infection. In this context, the features of HLH appear not as a separate entity but as part of a broader process, where metabolic decompensation, accumulation of toxic intermediates, and systemic inflammation converge. This overlap is likely underrecognized in clinical practice. Recognizing this possibility has practical implications. It shifts the diagnostic focus, but also opens the door to more tailored management strategies. In similar cases, HLH may be less an endpoint diagnosis and more a signal pointing toward an underlying metabolic or genetic condition that requires specific attention.

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.