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Background: Malonyl-CoA decarboxylase (MLYCD, EC 4.1.1.9) deficiency is a rare autosomal recessive disorder that is widely diagnosed by neonatal screening. Methods: We report long term follow up of a patient with MLYCD deficiency showing signs of neonatal hypoglycemia, mental retardation, developmental delay and rheumatoid arthritis. Brain MRI revealed patchy, symmetrical hyperintensity of the deep white matter with periventricular white matter and subcortical arcuate fibers being spared. MLCYD gene sequence analysis was done to identify possible mutations. Expression analyses at mRNA and protein levels were also performed. Further, immunocytochemical studies were implemented to check for its subcellular localization. Results: MLYCD gene sequencing identified a novel compound heterozygous mutation (c.22 T>A, p.M1K, c.454 C>A; pH152N) in our patient and a heterozygous mutation in the healthy mother c.22 T>A; pM1K. Reduced expression of RNA and protein levels was observed. Immunocytochemical analysis showed diffused staining across the cytoplasm with apparent signs of intracellular mislocalization to the nucleus. Results also indicated subcellular colocalization of MLCYD with mitochondria was scant compared to control. Conclusion: Our patient was identified with a novel compound heterozygous MLYCD mutation at the N-terminal helical domain. This study indicates that protein mislocalization is a characteristic feature of MLYCD deficiency in our patient.

Malonyl-CoA decarboxylase deficiency is an extremely rare autosomal recessive inborn error of fatty acid metabolism. It usually follows a severe disease course and presents poor prognosis without treatment. Here, we report an affected female juvenile with a mild clinical and biochemical phenotype who mainly featured poor schooling without cardiomyopathy and metabolic acidosis. She was suspected of malonyl-CoA decarboxylase deficiency due to a 57-kb deletion in 16q23.3 encompassing the MLCYD gene revealed by chromosome microarray. Malonyl-CoA decarboxylase deficiency was then confirmed by acylcarnitine analysis and organic acid analysis. Real-time PCR analysis of the patient revealed the first three exon deletion of the MLYCD gene, which was maternally inherited. DNA sequencing of the MLYCD gene of the patient identified a novel heterozygous mutation (c.911G>A, p.G304E) in exon 4 that was paternally inherited. The patient urine malonic acid dissolved and had a better school record in 6 month after initiation of fat-limited diet. At 1 year post treatment, the blood malonylcarnitine level decreased remarkably. Our result expands the phenotype of malonyl-CoA decarboxylase deficiency and suggests attentions should be paid to the mild form of disorders, for example, malonyl-CoA decarboxylase deficiency, which usually present a severe disease course.

Malonyl-CoA decarboxylase (MCD) deficiency is an extremely rare inborn error of metabolism that presents with metabolic acidosis, hypoglycemia, and/or cardiomyopathy. Patients also show neurological signs and symptoms that have been infrequently reported. We describe a girl with MCD deficiency, whose brain MRI shows white matter abnormalities and additionally diffuse pachygyria and periventricular heterotopia, consistent with a malformation of cortical development. MLYCD-gene sequence analysis shows normal genomic sequence but no messenger product, suggesting an abnormality of transcription regulation. Our patient has strikingly low appetite, which is interesting in the light of the proposed role of malonyl-CoA in the regulation of feeding control, but this remains to be confirmed in other patients. Considering the incomplete understanding of the role of metabolic pathways in brain development, patients with MCD deficiency should be evaluated with brain MRI and unexplained malformations of cortical development should be reason for metabolic screening.

Malonic aciduria is an extremely rare autosomal recessive inborn error of metabolism. We present clinical, biochemical and genetic information for several years of follow-up of new malonic aciduria patients who were diagnosed by newborn screening. These data are discussed with regard to treatment options and possible diagnostic pitfalls. The cases presented here show that the course of malonic aciduria is unpredictable and can even significantly differ in two siblings harbouring identical mutations. Early treatment can lead to the rapid improvement of cardiomyopathy in the course of malonic aciduria. Biochemical parameters seem to be variable and can intermittently be undetectable in the blood or urine samples of affected patients. Therefore, confirmatory tests following a positive newborn screening should be taken with caution and include both malonyl carnitine detection in dried blood spots and urinary organic acid analysis as initial measures.Patients with a suspected or confirmed diagnosis of malonic aciduria should undergo thorough diagnostic procedures and be regularly screened for complications such as cardiomyopathy even when they are asymptomatic in order to ensure early therapy of treatable complications.

Malonyl-CoA decarboxylase deficiency is a rare inborn error of metabolism. It has been suggested but never demonstrated that many of the clinical features arise due to inhibition of mitochondrial fatty acid oxidation by accumulated malonyl-CoA. We studied the oxidation of fatty acids in cultured skin fibroblasts from a recently described patient with malonyl-CoA decarboxylase deficiency. There was a marked reduction in the oxidation of palmitic and myristic acids both under baseline conditions and when the cells were cultured in the presence of high concentrations of acetate, a malonyl-CoA precursor. These results suggest that there is inhibition of fatty acid oxidation in malonyl-CoA decarboxylase deficiency and that this inhibition may be related to some of the clinical phenotypes.

Malonyl coenzyme A (CoA) decarboxylase (E.C.4. 1.1.9) catalyzes the conversion of malonyl CoA to acetyl CoA. The metabolic role of malonyl CoA decarboxylase has not been fully defined, but deficiency of the enzyme has been associated with mild mental retardation, seizures, hy- potonia, cardiomyopathy, vomiting, hypoglycemia, meta- bolic acidosis, and malonic aciduria. Here we report the iso- lation and sequencing of the human gene encoding malonyl CoA decarboxylase, and the identification of a mutation causing malonyl CoA decarboxylase deficiency. Human mal- onyl CoA decarboxylase cDNA sequences were identified by homology to the goose gene, and the intron/exon bound- aries were determined by direct sequencing of a PAC clone containing the entire human gene. The 1479 basepair hu- man cDNA is 70 percent identical to the goose sequence, and the intron/exon boundaries are completely conserved between the two species. The genetic mutation underlying malonyl CoA decarboxylase deficiency was determined in a patient with clinical features of this defect, malonic aci- duria, and markedly reduced malonyl CoA decarboxylase activity.— Gao, J., L. Waber, M. J. Bennett, K. M. Gibson, and J. C. Cohen. Cloning and mutational analysis of human malonyl-coenzyme A decarboxylase. J. Lipid Res. 1999. 40: 178-182.

Malonyl-CoA decarboxylase deficiency is an inborn error of metabolism that may cause hypotonia and a fatal cardiomyopathy in infancy. Newborn metabolic screening programs do not include this disorder, although there is a possibility that presymptomatic treatment may attenuate the development of cardiomyopathy. We report a case of malonyl-CoA decarboxylase deficiency in a 5-month-old boy who presented with cardiomyopathy and hypotonia. Retrospective analysis of the newborn screening test showed an elevation in the concentration of malonylcarnitine at age 3 days. Unfortunately, this perturbation was missed because the screening test did not routinely measure malonylcarnitine in the newborn blood. Our experience confirms the possibility of screening for malonyl-CoA decarboxylase deficiency with tandem mass spectrometry. This finding should enable studies to determine if presymptomatic treatment could change the outcome in this often fatal disorder.

Malonyl-CoA decarboxylase deficiency (MLYCD) is a rare autosomal recessive inborn error of metabolism presenting a variable clinical phenotype. We report an affected Italian male receiving an early diagnosis (8 days after birth) and a timely dietary therapy (high carbohydrate, low long chain fatty acid and medium chain triglyceride supplemented diet with l -carnitine supplementation). The boy was born at term and presented normal function of the heart (except for a tricuspid Ebstein-like dysplasia) and neurodevelopmental status. Genomic sequencing of MLYCD gene revealed two point mutations (c.672G>A, c.869C>T) not listed in the Human MLYCD Allelic Variant Database nor in Human Gene Mutation Database, responsible for a deleterious effect on protein structure and function according to a computational analysis (MuPro, SIFT, ConSEQ v1.1). At the age of 2 years he only showed a mild language and psychomotor delay, while heart functioning became normal. Brain MRI examination was normal. Thirty-five cases, including our patient, have been described to date. This is the first report concerning a malonic aciduria patient diagnosed on newborn screening and treated in a presymptomatic stage of the disease.

Malonic aciduria (OMIM 248360) is a rarely diagnosed autosomal-recessive inborn error of metabolism caused by congenital deficiency of malonyl-CoA decarboxylase (MCD; EC 4.1.1.9). Hypoglycemia, seizures, developmental delay, and cardiomyopathy are among the most common symptoms, but both clinical signs and the time of presentation of patients with MCD deficiency can be variable. To date, only eight cases have been reported in the literature (1)(2)(3)(4)(5)(6)(7)(8), and recently molecular defects within the MCD gene (MLYCD) have been elucidated for the first time in some of these cases (8)(9)(10)(11). At least in part, clinical heterogeneity might be caused by the fact that MCD is expressed in different compartments of the cell and that MLYCD mutations with different effects on the subcellular localization of the MCD protein may thus affect different metabolic pathways (Wightman et al., submitted for publication). To date, only symptomatic patients with MCD deficiency have been detected, and many of them were already severely handicapped at the time of diagnosis because of residues of acute metabolic crises or from episodes of cardiac decompensation, which may develop as a consequence of secondary carnitine deficiency. Typically, the key to diagnosis is the excessive amount of malonic acid in the patient’s urine, which can be detected by gas chromatography–mass spectrometry. This then leads to a confirmatory test, such as the measurement of MCD activity in cell extracts, or to molecular genetic testing. Detection of the carnitine ester of malonic acid has been mentioned previously in single cases of malonic aciduria (4)(6)(7). In the study reported here, we systematically investigated the concentration of malonylcarnitine in the …

A new case of mitochondrial malonyl coenzyme A decarboxylase deficiency is described. The patient presented with an initial episode of metabolic acidosis, seizures, hypoglycemia, and cardiac failure at 2 months of age which slowly resolved. Subsequent evaluations at 4 years of age for developmental delay revealed a prominent elevation of malonic acid in urine. Malonyl carnitine was also elevated. The activity of Malonyl CoA decarboxylase in cultured fibroblasts was 7% of normal.Malonyl CoA decarboxylase deficiency may result in inhibition of fatty acid oxidation, which may account for the cardiomyopathy.

Two new cases of malonyl coenzyme A (CoA) decarboxylase deficiency are described. Hitherto, the worldwide experience of the disorder has been confined to reports on two affected Australian children. The new cases are Scots born and are the offspring of consanguinous parents of Scots/Irish origin. They were investigated during episodes of vomiting and febrile convulsions associated with concomitant developmental delay. Malonic aciduria and grossly reduced malonyl CoA decarboxylase activity were demonstrated and the total ion current chromatograms of urinary organic acid profiles obtained by gas chromatography-mass spectrometry are presented. The clinical and biochemical features of the Scots and Australian patients are compared.

A second child with a more severe deficiency of malonyl CoA decarboxylase is described. He is mildly mentally retarded and presented with vomiting, a seizure, hypoglycaemia and mild metabolic acidosis during a urinary tract infection. The urine contained increased, amounts of malonic, methylmalonic, succinic, adipic, glutaric and suberic acids. Mitochondrial malonyl CoA decarboxylase activity in cultured fibrobast extracts was 4% of the mean control value. A high fat, low carbohydrate diet led to symptomatic hypyglycaemia, a moderate metabolic acidosis and excretion in the urine of large amounts of the same organic acids and 3-hydroxybutyrate. Only relatively small quantities of malonic, methylmalonic and succinic acid were excreted in the urine when the boy was fed an isocaloric low fat, high carbohydrate diet. Acute fat and lysine loads led to increased excretion of malonic acid in the urine without affecting the excretion of the other organic acids. Experience with this patient, suggests that malonyl CoA decarboxylase serves an important function in the mitochondrion by preventing accumulation of malonyl CoA. The importance of the enzyme is best seen when fat is the main metabolic fuel. The mechanisms by which malonyl CoA produces its complex metabolic effects remain to be elucidated.

A patient is described with a deficiency of the mitochondrial enzyme, malonyl CoA decarboxylase — an inborn error of metabolism not recognized previously. The enzyme defect was first suspected because of persistent excretion of malonic and methylmalonic acids in urine in a child with repeated episodes of vomiting, some requiring hospitalization. Disturbances of lipid metabolism were demonstrated.