ACACA – Acetyl-CoA Carboxylase Deficiency

Acetyl-CoA carboxylase deficiency is a rare autosomal recessive metabolic disorder resulting from biallelic loss-of-function variants in ACACA, the gene encoding acetyl-CoA carboxylase 1 (ACACA; acetyl-CoA carboxylase deficiency). To date, three unrelated probands have been reported, all presenting in infancy with hypotonia, motor delay, growth retardation, muscle weakness, language impairment, dysmorphic facial features and, in the most recent case, seizures (PMID:36709796). The index patient harbored a homozygous ACACA c.6641C>A (p.Pro2214His) variant confirmed by Sanger sequencing, consistent with autosomal recessive inheritance and loss of enzymatic function.

Functional characterization in patient-derived lymphoblasts and fibroblasts demonstrated reduced ACC1 mRNA and protein levels, a marked decrease in enzyme activity, and disrupted lipidomic profiles. In vitro assays revealed impaired cellular motility in ACC1-deficient cells that was substantially rescued by palmitate supplementation, implicating defective malonyl-CoA synthesis as the disease mechanism (PMID:34552920). Although these data provide mechanistic insight, the small number of documented cases and limited segregation data necessitate additional cohorts to reach a definitive ClinGen classification. Key Take-home: ACACA sequencing should be considered in infants with hypotonia, developmental delay and dysmorphism, as early molecular diagnosis may guide nutritional and metabolic support.

References

• European journal of medical genetics • 2023 • The third patient of ACACA-related acetyl-CoA carboxylase deficiency with seizure and literature review. PMID:36709796
• Frontiers in cell and developmental biology • 2021 • Biallelic Mutations in ACACA Cause a Disruption in Lipid Homeostasis That Is Associated With Global Developmental Delay, Microcephaly, and Dysmorphic Facial Features. PMID:34552920

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