Abstract
Introduction: Combined malonic and methylmalonic aciduria (CMAMMA) is a rare metabolic disease caused by biallelic variants in ACSF3 gene. The clinical phenotype is highly heterogeneous in this disorder, ranging from asymptomatic to severe symptoms. No cases with CMAMMA were reported in China.Materials and Methods: In this study, three Chinese pediatric patients were diagnosed with CMAMMA unexpectedly while being treated for other ailments. To better characterize CMAMMA in a Chinese population, we made a multidimensional analysis with detailed clinical phenotype, semi-quantitative detection of urine organic acid, and analysis of ACSF3 gene variants.Results: The clinical presentation of these patients is quite different; their main complaints were anemia, jaundice, or abnormal urine test, respectively. They showed no symptoms of the classic methylmalonic academia, but urine organic acid analysis showed elevated malonic acid and methylmalonic acid in all the patients repeatedly. Variants were found at four sites in ACSF3 gene. Patient 1 carried the compound heterogeneous variant c.689G> A (p.Trp230*)/c.1456G> A (p.Ala486Thr). A compound heterozygous variant c.473C> T (p.Pro158Leu)/c.1456G> A (p.Ala486Thr) was identified in patient 2. Patient 3 harbored a novel homozygous variant c.1447A> G (p.Lys483Glu).Conclusions: Three Chinese patients were diagnosed with CMAMMA caused by ACSF3 variants. Their clinical course revealed that CMAMMA can be a benign condition that does not affect individual growth and development, but severe clinical phenotype may appear when other triggers exist. This study systematically elaborates CMAMMA in a Chinese population for the first time, broadens the spectrum of gene variant, and provides a strong basis for the etiological study of this disorder.
Highlights
Combined malonic and methylmalonic aciduria (CMAMMA) is a rare metabolic disease caused by biallelic variants in ACSF3 gene
Methylmalonic academia (MMAemia) is a common inborn error of metabolism characterized by abnormal accumulation of methylmalonic acid in body fluids, resulting in many serious clinical manifestations
MMAemia is mainly caused by the defect of methylmalonyl-CoA mutase (MUT) or its coenzyme cobalamin (Cbl) (1)
Summary
Combined malonic and methylmalonic aciduria (CMAMMA) is a rare metabolic disease caused by biallelic variants in ACSF3 gene. No cases with CMAMMA were reported in China. Methylmalonic academia (MMAemia) is a common inborn error of metabolism characterized by abnormal accumulation of methylmalonic acid in body fluids, resulting in many serious clinical manifestations. MMAemia is mainly caused by the defect of methylmalonyl-CoA mutase (MUT) or its coenzyme cobalamin (Cbl) (1). Combined malonic and methylmalonic aciduria (CMAMMA) is a rare atypical form of MMAemia featured with increased concentrations of malonic acid (MA) and methylmalonic acid (MMA) in urine (2). CMAMMA is caused by biallelic variants in the AcylCoA synthetase family member 3 (ACSF3, OMIM:614265) gene. Patients who carried ACSF3 gene variants excrete more MMA than MA in reported cases, which make them distinct from the patients with classical MMAemia (4)
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