LAUSR

Malonyl-CoA decarboxylase (E.C.4.1.1.9) deficiency (MLYCDD, OMIM 248360) is a rare autosomal recessive inborn error of metabolism MLYCD is encoded by a MLYCD gene located on chromosome 16q23.3 and consists of 5 exons [1,2]. The expression of the protein is highest in the cardiac muscle, followed by the skeletal muscle, brain, small intestine, liver, pancreas and kidney [1–3]. The substrate for MLYCD is malonyl-CoA, which has been recognized as a key player in fatty acid synthesis and oxidation in relation to its dual function: 1) as an intermediate in fatty acid biosynthesis (the formation of malonylCoA by acetyl-CoA carboxylase is the first step in fatty acid biosynthesis); and 2) as a regulatory effector of fatty acid oxidation through inhibition of carnitine palmitoyl transferase 1 (CPT1) [4,5]. CPT1 exists in 3 isoforms – CPT1A, expressed in the liver [6]; CPT1B, expressed predominantly in the muscular/cardiac tissue [6]; and CPT1C, found recently in brain [3]. It has been suggested that malonyl-CoA differentially inhibits these isoforms. CPT1B (expressed predominantly in muscle tissues, where the synthesis of fatty acids is negligible) is 100fold more sensitive to malonyl-CoA concentration [7–10]. These findings argue for predominantly regulatory rather than synthetic role of the malonyl-CoA in the skeletal and heart muscle slight alterations in malonyl-CoA concentration linked to loss of MLYCD activity may have profound effects on substrate consumption and energy supply in heart and muscle and probably can account for the phenotypic similarities of mitochondrial fatty acid oxidation disorders seen in individuals with MLYCDD. Additionally, accumulation of cytoplasmic malonyl-CoA inhibits long-chain acylcarnitine acetyltansferases, resulting in impaired fatty acid uptake and beta oxidation in both mitochondria and peroxisomes [11,12]. The diagnosis of malonic aciduria is based on detection of elevated levels of malonylcarnitine (C3DC) in blood acylcarnitine profiles [13,14]. Urine organic acid analysis shows high levels of malonic acid. In some patients, this is accompanied by mild elevations of methylmalonic acid, especially during the initial presentation, which may resemble combined malonic and methylmalonic aciduria, due to mutations in the ACSF3 gene. In some cases, ketotic dicarboxylic aciduria can be detected by urine organic acid analysis, a finding not typical for most fatty acid oxidation disorders [15]. The diagnosis can be confirmed by molecular testing or detection of reduced enzyme activity in fibroblasts. Individuals with MLYCDD present with a variable phenotype which includes developmental delay, seizures, hypotonia, metabolic acidosis, hypoglycemia, ketosis and cardiomyopathy. Developmental delay is the most prominent feature, and cardiomyopathy is the leading cause of morbidity and mortality. Brain abnormalities characterized by malformation in cortical development and white matter involvement have been reported in some patients [16–18]. If not detected by newborn screening, most cases of MLYCDD present with metabolic decompensation characterized by severe metabolic acidosis and hypoglycemia, associated with poor prognosis. As a result of expanded newborn screening, more patients with MLYCDD have been identified prior to the onset of symptoms, allowing for early initiation of treatment and potential prevention of complications such as hypoglycemia, cognitive impairment and cardiomyopathy. Currently, there are no specific treatment guidelines for MLYCDD. Similar to fatty acid oxidation disorders, a high carbohydrate and lowfat diet has been suggested [2,13,14,19] and medications such as ACE