Identification of a novel ACADSB variant for the presymptomatic diagnosis of 2-Methylbutyryl-CoA dehydrogenase deficiency through newborn screening in Iran

BACKGROUND: 2-Methylbutyryl-CoA dehydrogenase deficiency (2-MBDD), also known as short/branched-chain acyl-CoA dehydrogenase (SBCAD) deficiency, is a rare inborn error of metabolism classified as an organic acidemia. Early detection through neonatal screening is crucial to prevent irreversible complications. This study reports the first documented case of 2-MBDD in Iran, identified through the national neonatal screening program in 2022. MATERIALS AND METHODS: Metabolic screening was performed on dried blood spots (DBS) using electrospray ionization tandem mass spectrometry (ESI-MS/MS). Urine organic acid analysis was conducted via gas chromatography-mass spectrometry (GC/MS). Comprehensive clinical assessments, including ophthalmologic and audiologic evaluations, electroencephalography (EEG), echocardiography, and brain magnetic resonance imaging (MRI), were performed. Whole-exome sequencing (WES) was used to confirm the diagnosis. RESULTS: A male neonate, delivered by cesarean section, was asymptomatic at birth. Initial metabolic screening revealed elevated 2-methylbutyrylcarnitine (C5) levels, confirmed by urine organic acid analysis and genetic testing, which identified a novel likely pathogenic variant in the ACADSB gene (c.907G > C; p.G303R). The infant was managed with a carnitine-supplemented diet and continued breastfeeding. Regular follow-ups demonstrated normal growth, neurodevelopmental milestones, and biochemical parameters, with no abnormalities detected. Post-treatment, C5 levels stabilized at 0.4 µmol/L, within the intermediate range. CONCLUSION: This case underscores the pivotal role of neonatal screening in the early diagnosis and management of rare metabolic disorders. Timely intervention can prevent severe complications and improve clinical outcomes, highlighting the need for expanded newborn screening programs and population-specific genetic studies.