P84 – 2801: Two novel, disease-causing mutations in the ACSF3 gene in a patient with combined malonic and methylmalonic aciduria

Abstract

Background Combined malonic and methylmalonic aciduria (CMAMMA) is a rare inborn error of metabolism with elevated excretion of malonic acid (MA) and methylmalonic acid (MMA) in urine commonly caused by mutations in the MLYCD gene leading to malonyl-CoA decarboxylase (MCD) deficiency. Clinical features are metabolic acidosis, seizures, axial hypotonia, developmental delay, failure to thrive, microcephaly, cardiomyopathy, elevated transaminases and gastrointestinal symptoms. Benign clinical courses and asymptomatic patients summarized as non-classical phenotype with mostly normal MCD activity are described. In these patients mutations in the ACSF3 gene encoding a methylmalonyl-CoA and malonyl-CoA synthetase are frequently detected. Case report We describe a 3-year-old boy diagnosed with CMAMMA at the age of 26 months. After an uneventful pregnancy a boy of unrelated Afghan parents was born at term with a birth weight of 2955 g. At three weeks he presented with two generalized seizures and metabolic acidosis. Plasma lactat level was normal. Initially moderately elevated levels of MMA were found in urine. Plasma amino acids, carnitine levels, acylcarnitine profile, homocysteine, folate, vitamin B12, liver and renal function parameters were normal. Initial electroencephalogram (EEG) was pathologic and anticonvulsive therapy with phenobarbital was initiated. No further seizures occurred, EEG normalized at the age of three months and antiepileptic medication was stopped. Besides microcephaly the development is age-appropriate up to now. Asymptomatic cholelithiasis persisted despite therapy with ursodeoxycholic acid. Echocardiography was normal. Genetic analysis revealed two novel, disease-causing mutations in the ACSF3 gene and led to the diagnosis auf CMAMMA. Excretion of MMA in urine decreased spontaneously. A mild protein restricted diet was started. A younger sister also presented generalized seizure and elevated MMA in urine at the age of four weeks. Her genetic analysis is in progress. Conclusion We found two novel mutations in the ACSF3 gene which we assume to cause a non-classic CMAMMA phenotype.