malonyl-coenzyme-a and Metabolism--Inborn-Errors

Carnitine palmitoyltransferase (CPT) catalyzes the transfer of long- and medium-chain fatty acids from cytoplasm into mitochondria, where oxidation of fatty acids takes place. Deficiency of CPT enzyme is associated with rare diseases of fatty acid metabolism. CPT is present in two subforms: CPT I at the outer mitochondrial membrane and carnitine palmitoyltransferase II (CPT II) inside the mitochondria. Deficiency of CPT II results in the most common inherited disorder of long-chain fatty acid oxidation affecting skeletal muscle. There is a lethal neonatal form, a severe infantile hepato-cardio-muscular form, and a rather mild myopathic form characterized by exercise-induced myalgia, weakness, and myoglobinuria. Total CPT activity (CPT I + CPT II) in muscles of CPT II-deficient patients is generally normal. Nevertheless, in some patients, not detectable to reduced total activities are also reported. CPT II protein is also shown in normal concentration in patients with normal CPT enzymatic activity. However, residual CPT II shows abnormal inhibition sensitivity towards malonyl-CoA, Triton X-100 and fatty acid metabolites in patients. Genetic studies have identified a common p.Ser113Leu mutation in the muscle form along with around 100 different rare mutations. The biochemical consequences of these mutations have been controversial. Hypotheses include lack of enzymatically active protein, partial enzyme deficiency and abnormally regulated enzyme. The recombinant enzyme experiments that we recently conducted have shown that CPT II enzyme is extremely thermoliable and is abnormally inhibited by different emulsifiers and detergents such as malonyl-CoA, palmitoyl-CoA, palmitoylcarnitine, Tween 20 and Triton X-100. Here, we present a conceptual overview on CPT II deficiency based on our own findings and on results from other studies addressing clinical, biochemical, histological, immunohistological and genetic aspects, as well as recent advancements in diagnosis and therapeutic strategies in this disorder.

Topics: Carnitine; Carnitine O-Palmitoyltransferase; Fatty Acids; Female; Genetic Association Studies; Humans; Male; Malonyl Coenzyme A; Metabolism, Inborn Errors; Mitochondria; Muscle, Skeletal; Oxidation-Reduction

Topics: Animals; Carnitine O-Palmitoyltransferase; Enzyme Stability; Humans; Malonyl Coenzyme A; Metabolism, Inborn Errors; Models, Molecular; Muscles; Muscular Diseases; Mutation; Temperature

Malonic aciduria is an extremely rare inborn error of metabolism due to malonyl-CoA decarboxylase deficiency. This enzyme is encoded by the

Topics: Carboxy-Lyases; Carnitine; Child, Preschool; Consanguinity; Homozygote; Humans; Male; Malonates; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Pedigree; Point Mutation

Expanded carrier screening (ECS) utilizes high-throughput next-generation sequencing to evaluate an individual's carrier status for multiple conditions. Combined malonic and methylmalonic aciduria (CMAMMA) due to ACSF3 deficiency is a rare inherited disease included in such screening panels. Some cases have been reported with metabolic symptoms in childhood yet other cases describe a benign clinical course, suggesting the clinical phenotype is not well defined.. Clinical and laboratory findings during the prenatal period were obtained retrospectively from medical records.. A 37-year-old nulliparous woman and her partner were each identified as carriers of ACSF3 variants and presented at 9 weeks gestation for prenatal genetic consultation. The couple received extensive genetic counseling and proceeded with chorionic villus sampling at 11 weeks gestation. Subsequent analysis confirmed that the fetus inherited both parental ACSF variants. The couple was devastated by the results and after reviewing options of pregnancy continuation and termination, they decided to terminate the pregnancy. Following this decision, the patient was diagnosed with acute stress disorder.. This case highlights how expanded carrier screening adds complexity to reproductive decision-making. Stronger guidelines and additional research are needed to direct and evaluate the timing, composition, and implementation of ECS panels.

Topics: Adult; Amino Acid Metabolism, Inborn Errors; Amniocentesis; Carboxy-Lyases; Coenzyme A Ligases; Female; Genetic Carrier Screening; Genetic Counseling; Heterozygote; Humans; Male; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation; Pregnancy; Truth Disclosure

Malonyl-CoA, a product of acetyl-CoA carboxylase is a metabolic intermediate in lipogenic tissues that include liver and adipose tissue, where it is involved in the de novo fatty acid synthesis and elongation. Malonyl-CoA decarboxylase (MLYCD, E.C.4.1.1.9), a 55-kDa enzyme catalyses the conversion of malonyl-CoA to acetyl-CoA and carbon dioxide, thus providing a route for disposal of malonyl-CoA from mitochondria and peroxisomes, whereas in the cytosol, the malonyl-CoA pool is regulated by the balance of MLYCD and acetyl-CoA carboxylase activities. So far, 34 cases with different MLYCD gene defects comprising point mutations, stop codons, and frameshift mutations have been reported in the literature. Here, we describe the follow-up of a patient affected by malonic aciduria upon neonatal onset. Molecular analysis showed novel homozygous mutations in the MLYCD gene. Our findings expand the number of reported cases and add a novel variant to the repertoire of MLYCD mutations.

Topics: Carboxy-Lyases; Humans; Infant, Newborn; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation

Malonic aciduria (MA, OMIM#248360) is an extremely rare inherited metabolic disorder caused by the deficiency of malonyl-CoA decarboxylase. The phenotype exhibited by patients with MA is variable, but may include symptoms, such as developmental delay in early childhood, seizures, vomiting, metabolic acidosis, hypoglycemia, ketosis, and cardiomyopathy. We describe the first case of a Korean child with MA who presented with dilated cardiomyopathy (DCMP) at the age of 3 months.. A 3-month-old Korean boy visited our hospital for diagnosis and management of cardiomegaly. Newborn screening for inherited metabolic diseases showed a normal result; therefore, DCMP management was initiated. Biochemical and the MLYCD gene analyses subsequently confirmed diagnosis of MA. Elevated plasma C3DC level and excessive excretion of urinary malonate were observed, and two pathogenic variants, including a novel start codon mutation (c.1A>G), were identified in MLYCD. A low long-chain fat diet with middle-chain triglyceride formula and L-carnitine supplementation was initiated. The patient is now 5 years old and exhibits considerably improved cardiac function.. MA can be diagnosed using newborn screening; however, negative results do not exclude the possibility of disease. Metabolic screening for differential diagnosis of infantile DCMP is recommended to rule out rare, but manageable, metabolic cardiomyopathies.

Topics: Carboxy-Lyases; Cardiomyopathy, Dilated; Codon, Initiator; Humans; Infant; Male; Malonates; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation; Phenotype

Fibroblast growth factor 21 (FGF-21) is known to be a biomarker for mitochondrial disorders. An upregulation of FGF-21 in serum and muscle of carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II) knock-out mice has been reported. In human CPT II deficiency, enzyme activity and protein content are normal, but the enzyme is abnormally regulated by malonyl-CoA and is abnormally thermolabile. Citrate synthase (CS) activity is increased in patients with CPT II deficiency. This may indicate a compensatory response to an impaired function of CPT II. In this study, FGF-21 serum levels in patients with CPT II deficiency during attack free intervals and in healthy controls were measured by enzyme linked immunosorbent assay (ELISA). The data showed no significant difference between FGF-21 concentration in the serum of patients with CPT II deficiency and that in the healthy controls. The results of the present work support the hypothesis that in muscle CPT II deficiency, in contrast to the mouse knockout model, mitochondrial fatty acid utilization is not persistently reduced. Thus, FGF-21 does not seem to be a useful biomarker in the diagnosis of CPT II deficiency.

Topics: Adult; Animals; Biomarkers; Carnitine O-Palmitoyltransferase; Citrate (si)-Synthase; Enzyme-Linked Immunosorbent Assay; Female; Fibroblast Growth Factors; Humans; Male; Malonyl Coenzyme A; Metabolism, Inborn Errors; Mice; Mice, Knockout; Middle Aged; Mitochondrial Diseases

Malonic acid (MA), methylmalonic acid (MMA), and ethylmalonic acid (EMA) metabolites are implicated in various non-cancer disorders that are associated with inborn-error metabolism. In this study, we have slightly modified the published 3-nitrophenylhydrazine (3NPH) derivatization method and applied it to derivatize MA, MMA, and EMA to their hydrazone derivatives, which were amenable for liquid chromatography- mass spectrometry (LC-MS) quantitation. 3NPH was used to derivatize MA, MMA, and EMA, and multiple reaction monitoring (MRM) transitions of the corresponding derivatives were determined by product-ion experiments. Data normalization and absolute quantitation were achieved by using 3NPH derivatized isotopic labeled compounds

Topics: Animals; Biomarkers; Carboxy-Lyases; Female; Humans; Limit of Detection; Male; Malonates; Malonyl Coenzyme A; Mass Spectrometry; Metabolism, Inborn Errors; Metabolomics; Methylmalonic Acid; Mice, Inbred C57BL; Phenylhydrazines

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.

Topics: Acidosis; Adolescent; Base Sequence; Carboxy-Lyases; Cardiomyopathies; Child; Chromosomes; Exons; Female; Humans; Malonates; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Microarray Analysis; Sequence Deletion

Malonyl-CoA decarboxylase (MLYCD, EC 4.1.1.9) deficiency is a rare autosomal recessive disorder that is widely diagnosed by neonatal screening.. 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.. 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.. 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.

Topics: Adolescent; Age of Onset; Base Sequence; Blotting, Western; Carboxy-Lyases; Child; Child, Preschool; DNA Mutational Analysis; Female; Humans; Immunohistochemistry; Infant; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Molecular Sequence Data; Mutation; Polymerase Chain Reaction

Methyl malonic academia (MMA) is characterized by abnormal accumulation of methyl malonic acid in body fluids. Patients usually have a variety of clinical symptoms including recurrent vomiting, metabolic acidosis, developmental delay, seizure, or death. However, a few cases where the patients have no symptom are also reported. Here, we conducted clinical, biochemical, and molecular analysis of eight Chinese patients identified through newborn screening between 2003 and 2013. All the patients had significantly higher blood propionylcarnitine (C3) concentrations, ratio of propionylcarnitine/acetylcarnitine (C3/C2); and their urine methyl malonic acid and methylcitric acid (MCA) excretions were remarkably higher than normal at diagnosis and during follow-ups. In addition, five different known mutations were identified in seven of the eight patients in either MUT or MMACHC. All these mutations were expected to produce defective proteins that would result in decreased or even total loss of methyl malonyl-CoA mutase activity. However, normal outcomes were found in all patients in physical growth, intellectual performance and cerebral MRI analysis at diagnosis (range, 14-53 days) and during follow-ups (range, 1.8-10 years). Our study is the first report of Chinese MMA patients with increased secretion of methyl malonic acid and molecular defects in MUT or MMACHC yet remain asymptomatic.

Topics: Acetylcarnitine; Acidosis; Asian People; Asymptomatic Diseases; Carboxy-Lyases; Carnitine; Carrier Proteins; Child; Citrates; Female; Gene Expression; Humans; Infant; Infant, Newborn; Male; Malonates; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Mutation; Neonatal Screening; Oxidoreductases

We investigated the compartmentation of the catabolism of dodecanedioate (DODA), azelate, and glutarate in perfused rat livers, using a combination of metabolomics and mass isotopomer analyses. Livers were perfused with recirculating or nonrecirculating buffer containing one fully (13)C-labeled dicarboxylate. Information on the peroxisomal versus mitochondrial catabolism was gathered from the labeling patterns of acetyl-CoA proxies, i.e. total acetyl-CoA, the acetyl moiety of citrate, C-1 + 2 of β-hydroxybutyrate, malonyl-CoA, and acetylcarnitine. Additional information was obtained from the labeling patterns of citric acid cycle intermediates and related compounds. The data characterize the partial oxidation of DODA and azelate in peroxisomes, with terminal oxidation in mitochondria. We did not find evidence of peroxisomal oxidation of glutarate. Unexpectedly, DODA contributes a substantial fraction to anaplerosis of the citric acid cycle. This opens the possibility to use water-soluble DODA in nutritional or pharmacological anaplerotic therapy when other anaplerotic substrates are impractical or contraindicated, e.g. in propionic acidemia and methylmalonic acidemia.

Topics: Amino Acid Metabolism, Inborn Errors; Animals; Citric Acid Cycle; Coenzyme A; Dicarboxylic Acids; Fatty Acids; Glutarates; Humans; Liver; Malonyl Coenzyme A; Metabolism, Inborn Errors; Mitochondria; Myocardium; Oxidation-Reduction; Peroxisomes; Propionic Acidemia; Rats

The protein substrates of sirtuin 5-regulated lysine malonylation (Kmal) remain unknown, hindering its functional analysis. In this study, we carried out proteomic screening, which identified 4042 Kmal sites on 1426 proteins in mouse liver and 4943 Kmal sites on 1822 proteins in human fibroblasts. Increased malonyl-CoA levels in malonyl-CoA decarboxylase (MCD)-deficient cells induces Kmal levels in substrate proteins. We identified 461 Kmal sites showing more than a 2-fold increase in response to MCD deficiency as well as 1452 Kmal sites detected only in MCD-/- fibroblast but not MCD+/+ cells, suggesting a pathogenic role of Kmal in MCD deficiency. Cells with increased lysine malonylation displayed impaired mitochondrial function and fatty acid oxidation, suggesting that lysine malonylation plays a role in pathophysiology of malonic aciduria. Our study establishes an association between Kmal and a genetic disease and offers a rich resource for elucidating the contribution of the Kmal pathway and malonyl-CoA to cellular physiology and human diseases.

Topics: Animals; Carboxy-Lyases; Cell Line; Fatty Acids; Fibroblasts; Humans; Liver; Lysine; Male; Malonates; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Mice; Mice, Knockout; Mitochondria; Models, Molecular; Oxidation-Reduction; Sirtuins

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.

Topics: Carboxy-Lyases; Child; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Male; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Neonatal Screening; Siblings; Time Factors

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 (8days 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 2years 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.

Topics: Carboxy-Lyases; Child, Preschool; Early Diagnosis; Humans; Infant, Newborn; Male; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation; Neonatal Screening

A 3-year-old Chinese boy presented with prominent clinical features of malonic aciduria, including developmental delay, short stature, brain abnormalities and massive excretion of malonic acid and methylmalonic acid. Molecular characterization by DNA sequencing analysis and multiplex ligation-dependent probe amplification of the MLYCD gene revealed a heterozygous mutation (c.920T>G, p.Leu307Arg) in the patient and his father and a heterozygous deletion comprising exon 1 in the patient and his mother. The missense mutation (c.920T>G) was not found in 100 healthy controls and has not been reported previously. Our findings expand the number of reported cases and add a novel entry to the repertoire of MLYCD mutations.

Topics: Asian People; Base Sequence; Carboxy-Lyases; Child, Preschool; China; DNA Mutational Analysis; Heterozygote; Humans; Infant; Infant, Newborn; Male; Malonyl Coenzyme A; Metabolic Networks and Pathways; Metabolism, Inborn Errors; Methylmalonic Acid; Molecular Sequence Data; Mutation

Malonyl coenzyme A (CoA) decarboxylase (MCD) deficiency is a rare autosomal recessive organic acidemia characterized by varying degrees of organ involvement and severity. MCD regulates fatty acid biosynthesis and converts malonyl-CoA to acetyl-CoA. Cardiomyopathy is 1 of the leading causes of morbidity and mortality in this disorder. It is unknown if diet alone prevents cardiomyopathy development based in published literature. We report a 10-month-old infant girl identified by newborn screening and confirmed MCD deficiency with a novel homozygous MLYCD mutation. She had normal echocardiogram measurements before transition to high medium-chain triglycerides and low long-chain triglycerides diet. Left ventricular noncompaction development was not prevented by dietary interventions. Further restriction of long-chain triglycerides and medium-chain triglycerides supplementation in combination with angiotensin-converting enzyme inhibitors helped to improve echocardiogram findings. Patient remained asymptomatic, with normal development and growth. Our case emphasizes the need for ongoing cardiac disease screening in patients with MCD deficiency and the benefits and limitations of current dietary interventions.

Topics: Alleles; Carboxy-Lyases; Cardiomyopathies; Carnitine; Chromosome Aberrations; Chromosome Deletion; Codon, Terminator; Dietary Fats; DNA Mutational Analysis; Echocardiography, Doppler, Color; Female; Frameshift Mutation; Genes, Recessive; Homozygote; Humans; Infant; Infant Formula; Infant, Newborn; Isolated Noncompaction of the Ventricular Myocardium; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Neonatal Screening; Phenotype; Rare Diseases; Triglycerides

Within a 7-month period at our institution, newborn screening by tandem mass spectrometry revealed 10 cases with elevated levels of malonylcarnitine, which suggested malonic aciduria. Malonic aciduria is a rare autosomal recessive inborn error of metabolism. Confirmatory testing yielded normal results in all the newborns involved. The application of quality improvement practices dictated investigating the dried blood spot collection process, which revealed the use of multiple blood-collection techniques by newborn nursery staff, improper handling of the dried blood spot specimens, and sanitary wipe contamination as the causes of the aberrant false-positive results at our institution. This systematic evaluation identified the cause of the aberrant false-positive results and a strategy was implemented to avoid aberrant results in the future. Thus far, no false-positive results have occurred since the investigative process. False-positive results on a newborn screen can cause unnecessary emotional and economic stress on families, a finding that was identified at our institution. Historically, false-positive newborn screening results have been identified in infants born by cesarean delivery in which iodine antiseptic was used and in newborns who receive total parenteral nutrition, such as premature infants in the NICU. Therefore, if an unusually high number of false-positive results are found during the newborn screening process, contamination should be considered as a contributing factor.

Topics: Blood Chemical Analysis; Carboxy-Lyases; Drug Contamination; Equipment and Supplies, Hospital; False Positive Reactions; Humans; Infant, Newborn; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Neonatal Screening

Combined Malonic and Methylmalonic Aciduria (CMAMMA) is a rare recessive inborn error of metabolism characterised by elevations of urine malonic acid (MA) and methylmalonic acid (MMA). Nearly all reported cases are caused by malonyl-CoA decarboxylase (MCD) deficiency. Most patients have metabolic acidosis, developmental delay, seizures and cardiomyopathy. CMAMMA was also described in symptomatic patients with normal MCD activity, suggesting heterogeneity in this disorder.. We identified two probands with a non-classical CMAMMA variant through the Quebec newborn urine screening program. While they share the biochemical phenotype of elevated MA and MMA, the MMA excretion was higher than MA, the clinical courses were benign, MYLCD gene sequencing was normal and MCD activity, measured in one proband, was normal. Using exome sequencing in the single consanguineous proband, we identified a homozygous missense allele in the ACSF3 gene, encoding an Acyl-CoA Synthetase (ACS) with unknown substrate and function. The second proband was homozygous for a different ACSF3 missense allele. Both substitutions were in conserved residues and were identified in less than 0.5% of their respective ethnic control populations.. These results suggest that ACSF3 is a candidate gene for non-classical CMAMMA observed in our patients and document the value of exome sequencing of a limited number of patients for the identification of novel disease genes.

Topics: Alleles; Amino Acid Metabolism, Inborn Errors; Base Sequence; Carboxy-Lyases; Coenzyme A Ligases; Exome; Genetic Association Studies; Humans; Infant; Malonates; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Molecular Sequence Data; Mutation; Pedigree; Phenotype; Sequence Analysis, DNA

We used exome sequencing to identify the genetic basis of combined malonic and methylmalonic aciduria (CMAMMA). We sequenced the exome of an individual with CMAMMA and followed up with sequencing of eight additional affected individuals (cases). This included one individual who was identified and diagnosed by searching an exome database. We identify mutations in ACSF3, encoding a putative methylmalonyl-CoA and malonyl-CoA synthetase as a cause of CMAMMA. We also examined a canine model of CMAMMA, which showed pathogenic mutations in a predicted ACSF3 ortholog. ACSF3 mutant alleles occur with a minor allele frequency of 0.0058 in ∼1,000 control individuals, predicting a CMAMMA population incidence of ∼1:30,000. ACSF3 deficiency is the first human disorder identified as caused by mutations in a gene encoding a member of the acyl-CoA synthetase family, a diverse group of evolutionarily conserved proteins, and may emerge as one of the more common human metabolic disorders.

Topics: Adolescent; Aged; Amino Acid Sequence; Carboxy-Lyases; Child, Preschool; Coenzyme A Ligases; Exons; Female; Humans; Male; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Middle Aged; Molecular Sequence Data; Mutation, Missense

Malonyl coenzyme A (CoA) decarboxylase (EC 4.1.1.9, MCD) deficiency, or malonic aciduria, is a rare inborn error of metabolism characterised by a variable phenotype of developmental delay, seizures, cardiomyopathy and acidosis. There is no consensus for dietary treatment in this condition. This case describes the effect of a long-chain triglyceride (LCT)-restricted/medium-chain triglyceride (MCT)-supplemented diet upon the progress of an affected child. A full-term Asian girl of birth weight 3590 g was screened for malonic aciduria after birth due to a positive family history. She had elevated urine malonic and methylmalonic acids and was presumably homozygous for a deleterious mutation in the MLYCD gene. Her echocardiography showed mild cardiomyopathy at 0.5 months of age, but heart function was good. She was treated with carnitine 100 mg/kg per day and continued a high-energy formula feed, as her growth was slow. At 3 months of age, echocardiography showed deteriorating cardiac function with a fractional shortening of 18%. She started an angiotensin-converting enzyme (ACE) inhibitor (Captopril). Over the next few months, her diet was altered to comprise 1.9% energy from LCT, 25% from MCT and the remainder carbohydrate. Cardiac function improved and was optimal at 23 months of age, with a fractional shortening of 28% and good systolic function. During a period of low MCT intake, her cardiac function was noted to deteriorate. This reversed and stabilised following reinstatement of the diet. This case of malonic aciduria with cardiomyopathy demonstrates improvement in cardiac function attributable to LCT-restricted/MCT-supplemented diet.

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Carboxy-Lyases; Cardiomyopathies; Carnitine; Child, Preschool; Combined Modality Therapy; Dietary Supplements; Female; Genetic Predisposition to Disease; Humans; Infant; Infant Formula; Infant Nutritional Physiological Phenomena; Infant, Newborn; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Mutation; Nutritional Status; Phenotype; Treatment Outcome; Triglycerides

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.

Topics: Acyl Coenzyme A; Carboxy-Lyases; Child, Preschool; Fatty Acid Synthases; Fibroblasts; Humans; Male; Malonates; Malonyl Coenzyme A; Metabolism, Inborn Errors; Methylmalonic Acid; Methylmalonyl-CoA Mutase; Mitochondria

Topics: Acyl Coenzyme A; Gas Chromatography-Mass Spectrometry; Humans; Infant; Male; Malonates; Malonyl Coenzyme A; Metabolism, Inborn Errors