A Deep Clinical and Biochemical Characterization of a Patient With Combined Malonic and Methylmalonic Aciduria...

Combined malonic and methylmalonic aciduria (CMAMMA) is an inborn error of metabolism caused by a deficiency in mitochondrial malonyl-CoA synthetase, the enzyme responsible for activating malonic acid (MA) to malonyl-CoA, a precursor of lipoic acid. The clinical phenotype is highly heterogeneous, ranging from asymptomatic cases to severe neurological impairment. We describe a patient affected by CMAMMA. The patient presented in the neonatal period with hyperinsulinemic hypoglycemia. Urinary organic acid analysis revealed elevated levels of both malonic and methylmalonic acids. The diagnosis of CMAMMA was confirmed through molecular testing of the ACSF3 gene. Levels of both lipoylated pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (αKGDH) were decreased. Given the role of lipoic acid in regulating insulin secretion, the involvement of impaired mitochondrial lipoic acid biosynthesis in the clinical presentation of hyperinsulinemic hypoglycemia cannot be excluded. We describe a case of CMAMMA associated with hyperinsulinemic hypoglycemia. While a definitive association between CMAMMA and hyperinsulinism cannot be established based on a single case, the observed reduction in lipoic acid levels may suggest a mechanistic connection between the two disorders. We suggest considering urinary organic acid testing in patients with hyperinsulinism, especially when the cause is unknown.