Lethal Neonatal Progression of Fetal Cardiomegaly Associated to ACAD9 Deficiency

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• ACAD9 (acyl-CoA dehydrogenase 9) is vital for mitochondrial respiratory chain complex I assembly.
• ACAD9 deficiency presents a spectrum of clinical severity, from lethal forms to exercise intolerance.
• ACAD9 shares homology with VLCAD and possesses a homodimer structure.

Purpose of the Study:

• To investigate the genetic basis and molecular consequences of ACAD9 deficiency in a prenatal case.
• To analyze the impact of identified mutations on ACAD9 protein structure and function.

Main Methods:

• Genetic sequencing to identify mutations in the ACAD9 gene.
• Protein modeling to predict the functional effects of identified mutations.
• Analysis of protein structure and expression levels.

Main Results:

• A prenatal case of ACAD9 deficiency presented with intrauterine growth retardation and cardiomegaly, resulting in a fatal outcome.
• Compound heterozygous mutations, c.1030-1G>T (splice-site) and c.1249C>T (p.Arg417Cys missense), were identified in the ACAD9 gene.
• Protein modeling indicated that c.1030-1G>T leads to a truncated protein, while p.Arg417Cys results in an aberrant dimer.

Conclusions:

• ACAD9 is essential for normal cardiac function, as evidenced by the severe prenatal phenotype.
• Specific ACAD9 mutations can disrupt protein integrity and dimerization, leading to severe clinical manifestations.
• Understanding ACAD9's role is critical for diagnosing and potentially managing related mitochondrial disorders.