Malonic aciduria

doi:10.1016/0387-7604(94)90091-4

Brain and Development

Volume 16, Supplement, November 1994, Pages 7-11

https://doi.org/10.1016/0387-7604(94)90091-4 Get rights and content

Three infants with malonic aciduria are reported, one of whom could be studied in detail. All children had severe and progressive encephalopathy with intermittent ketoacidosis and hypoglycemia. One infant died of cardiomyopathy. Biochemical studies revealed that one patient had neither malonyl-CoA decar☐ylase nor glutaryl-CoA dehydrogenase deficiencies. This variant of malonic aciduria is different from that of four patients previously reported, both in its clinical and biochemical presentations. The biochemical pathology of this variant malonic aciduria is unknown.

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Cited by (30)

Malonyl-CoA decarboxylase deficiency: Long-term follow-up of a patient new clinical features and novel mutations
2015, Brain and Development
Citation Excerpt :
Although an enormous amount of work has been done to elucidate the key roles that MLYCD plays in lipid and carbohydrates metabolism, its pathogenesis, metabolic function and subcellular localization still remains obscure [6,8,24]. So far, 34 cases with different MLYCD gene defects comprising point mutations, stop codons and frame-shift mutations have been reported in literature [8–13,16–24] Notably, Wightman et al., have reported that a point mutation in the MLYCD gene lead to protein mislocalization at the subcellular level [8]. Metabolic screening of our patient showed elevated urinary excretion of malonic acid, methylmalonic acids and malonylacylcarntines thus confirming MLYCD deficiency.
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.
A new case of malonic aciduria with a presymptomatic diagnosis and an early treatment
2013, Brain and Development
Citation Excerpt :
Patients with malonic aciduria show a variable phenotype comprising developmental delay, microcephaly, hypotonia, seizure, metabolic acidosis, hypoglycemia, cardiomyopathy and renal dysplasia. Neuroimaging studies revealed brain abnormalities characterized by malformation in cortical development and white matter involvement [4–10]. Since its first description in 1984, 34 cases and 28 disease causing mutations have been reported (see Table 1).
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.
Novel compound heterozygous mutation of MLYCD in a Chinese patient with malonic aciduria
2012, Molecular Genetics and Metabolism
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.
Nonezymatic formation of succinate in mitochondria under oxidative stress
2006, Free Radical Biology and Medicine
The products of the reactions of mitochondrial 2-oxo acids with hydrogen peroxide and tert-butyl hydroperoxide (tert-BuOOH) were studied in a chemical system and in rat liver mitochondria. It was found by HPLC that the decarboxylation of α-ketoglutarate (KGL), pyruvate (PYR), and oxaloacetate (OA) by both oxidants results in the formation of succinate, acetate, and malonate, respectively. The two latter products do not metabolize in rat liver mitochondria, whereas succinate is actively oxidized, and its nonenzymatic formation from KGL may shunt the tricarboxylic acid (TCA) cycle upon inactivation of α-ketoglutarate dehydrogenase (KGDH) under oxidative stress, which is inherent in many diseases and aging. The occurrence of nonenzymatic oxidation of KGL in mitochondria was established by an increase in the CO₂ and succinate levels in the presence of the oxidants and inhibitors of enzymatic oxidation. H₂O₂ and menadione as an inductor of reactive oxygen species (ROS) caused the formation of CO₂ in the presence of sodium azide and the production of succinate, fumarate, and malate in the presence of rotenone. These substrates were also formed from KGL when mitochondria were incubated with tert-BuOOH at concentrations that completely inhibit KGDH. The nonenzymatic oxidation of KGL can support the TCA cycle under oxidative stress, provided that KGL is supplied via transamination. This is supported by the finding that the strong oxidant such as tert-BuOOH did not impair respiration and its sensitivity to the transaminase inhibitor aminooxyacetate when glutamate and malate were used as substrates. The appearance of two products, KGL and fumarate, also favors the involvement of transamination. Thus, upon oxidative stress, nonenzymatic decarboxylation of KGL and transamination switch the TCA cycle to the formation and oxidation of succinate.
Brain abnormalities in a case of malonyl-CoA decarboxylase deficiency
2006, Molecular Genetics and Metabolism
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.
Succinate causes oxidative damage through N-methyl-D-aspartate-mediated mechanisms
2005, Brain Research
Citation Excerpt :
This is an important finding for different areas, particularly those concerned with the study of the succinate-accumulating conditions, such as exposure to exogenous [1,7,17,19,32,40] and endogenous [10,9,12–14,18,24,34,38] SDH inhibitor toxins and inherited deficiencies of SDH [5,6,14,30,31], because it shows that at least some of the deleterious effects of these conditions may arise from secondary succinate accumulation, a possibility that has been overlooked in the literature.
In this study we investigated whether succinate, the accumulating substrate in succinate dehydrogenase (SDH) deficiencies and SDH inhibitor intoxication, causes lipoperoxidation and protein carbonylation, and if NMDA receptors are involved in the succinate-induced oxidative damage. Adult male mice (30–40 g) received an intracerebroventricular injection of succinic acid (0.7, 1.0 and 1.7 μmol/5 μl) or 0.9% NaCl (5 μl) and had their exploratory behavior assessed in an open field for 10 min. Succinate (0.7 and 1.0 μmol/5 μl) decreased locomotor activity behavior and increased thiobarbituric acid reactive substances (TBARS) and protein carbonylation in the forebrain. Conversely, 1.7 μmol of succinate did not alter locomotor activity or oxidative damage parameters. The involvement of NMDA receptors in the succinate-induced increase of total protein carbonylation content and exploratory behavior inhibition was assessed by co-administrating MK-801 (7 nmol/2.5 μl icv), a noncompetitive NMDA receptor antagonist, with succinate (1 μmol/2.5 μl icv). The co-administration of MK-801 protected against succinate-induced increase of total protein carbonylation and decrease of locomotor activity. These results suggest the involvement of NMDA receptors in these effects of succinate, which may of particular relevance for succinate-accumulating conditions, such as SDH inhibitors intoxication and inherited SDH deficiencies.

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^*: Present address: University Teaching Unit, Royal Alexandria Hospital for Children, Sydney, Australia.

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Malonic aciduria

Clin Chim Acta

Anal Biochem

J Biol Chem

Brain Dev

Biochim Biophys Acta

J Biol Chem

J Biol Chem

J Pediatr