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

Abstract

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.

Keywords: Lennox-Gastaut Syndrome (LGS); anti-seizure medications (ASMs); attention-deficit/hyperactivity disorder (ADHD); autism spectrum disorder (ASD); developmental delay.