Case Report: Homozygous mutation in the ACAD9 gene revealed in a pediatric patient initially diagnosed with familial cardiac hypertrophy.

BACKGROUND: Severe hypertrophic cardiomyopathy presenting in infancy occurs at an estimated frequency of 1:47,000 neonates and is characterized by rapid progression and poor prognosis. Differential diagnosis and timely identification of potentially treatable conditions amenable to genotype-specific therapeutic approaches are of critical importance; however, this is not always achievable in a timely manner. ACAD9 deficiency is a rare autosomal recessive disorder of mitochondrial complex I assembly and fatty acid ß-oxidation, typically presenting in early infancy with progressive cardiac hypertrophy and lactic acidosis. Differential diagnosis might be challenging due to phenotypic overlap with sarcomeric and other metabolic cardiomyopathies and limited availability of rapid diagnostic approaches.

METHODS: We performed comprehensive clinical, instrumental, and laboratory assessment of a 4-month-old girl with progressive biventricular hypertrophy, metabolic acidosis, persistent hyperlactatemia, and elevated NT-proBNP. Whole-exome sequencing (Illumina NovaSeq 6000; SureSelect All Exon V7) was followed by ACMG-based variant interpretation, database review (ClinVar), and segregation analysis with Sanger sequencing in the proband and parents.

RESULTS: A homozygous missense variant NM_014049.5:c.659C > T (p.Ala220Val) in the ACAD9 gene identified and classified as likely pathogenic (LP, Class IV). Carrier status was confirmed in both consanguine parents by Sanger sequencing. The variant is located near the catalytic core of ACAD9 and has been previously associated with severe complex I impairment and riboflavin-nonresponsive disease. Despite supportive metabolic and cardioprotective therapy, the proband died from an acute metabolic crisis and progressive heart failure before the genetic testing was complete. Parents were informed about genetic results and importance of genetic counseling and testing for further family planning.

CONCLUSION: This case highlights the clinical significance and importance of precise diagnostics in families burdened with early sibling death. Neonatal cardiomyopathy is a critical «red flag» constellation warranting urgent molecular workup and appropriate therapy adjustment. Establishing a precise molecular diagnosis-even when it cannot alter the proband's outcome-carries essential value for family counseling, recurrence risk assessment (25% per pregnancy), and access to reproductive options including prenatal diagnosis and preimplantation genetic testing.