Biallelic ACSF3 variants with combined malonic and methylmalonic acidemia and associated developmental epileptic encephalopathy phenotype: A novel genotype-phenotype correlation

Purpose

Combined malonic and methylmalonic acidemia (CMAMMA) is a rare genetic disorder caused by biallelic variants in the acyl-CoA synthetase family member 3 (ACSF3) gene (Witkowski et al., 2011) and is associated with elevated levels of malonic acid (MA) and methylmalonic acid (MMA) in urine (Sloan et al., 2011). CMAMMA is generally considered a benign disorder, with recent descriptions of potential neuropsychiatric symptoms in children (Levtova et al., 2019). We expand the phenotype by describing a case of severe developmental and epileptic encephalopathy with a CMAMMA-associated Lennox-Gastaut Syndrome (LGS) phenotype and comorbid neuropsychiatric abnormalities.

Methods and Results

An 8-year-old boy with CMAMMA, referred to our clinic’s neurogenetic center, presented with refractory epilepsy and severe neurobehavioral symptoms. His epilepsy consisted of tonic, atonic, and generalized tonic-clonic seizures with electroclinical features consistent with LGS. The patient had comorbid autism, aggression, and intellectual disability with a history of developmental regression. Genetic testing confirmed pathogenic biallelic ACSF3 variants, and urine organic acid testing showed elevated levels of MA and MMA in urine.

Conclusion

This case suggests that CMAMMA can lead to severe epilepsy and a neuropsychiatric phenotype, expanding the clinical spectrum of the disorder.