Accumulation Of Methylmalonic Acid Research Articles

Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis.

Adipose tissue plays important roles in regulating carbohydrate and lipid homeostasis, though less is known about the regulation of amino acid metabolism in adipocytes. Here we applied isotope tracing to pre–adipocytes and differentiated adipocytes to quantify the contributions of different substrates to tricarboxylic acid metabolism and lipogenesis. In contrast to proliferating cells that use glucose and glutamine for acetyl–coenzyme A (AcCoA) generation, differentiated adipocytes increased branched chain amino acid (BCAA) catabolic flux such that leucine and isoleucine from media and/or protein catabolism accounted for as much as 30% of lipogenic AcCoA pools. Medium cobalamin deficiency caused methylmalonic acid accumulation and odd–chain fatty acid synthesis. B12 supplementation reduced these metabolites and altered the balance of substrates entering mitochondria. Finally, inhibition of BCAA catabolism compromised adipogenesis. These results quantitatively highlight the contribution of BCAAs to adipocyte metabolism and suggest that BCAA catabolism plays a functional role in adipocyte differentiation.

Methylmalonic Acidemia.

Methylmalonic Acidemia (MMA) is an inborn error of metabolism that results in accumulation of methylmalonic acid in blood and increased excretion in urine. The effects of MMA vary from mild to life threatening and it usually presents in early infancy. Affected infants can have vomiting, dehydration, hypotonia, developmental delay and failure to thrive. The emergency treatment of the newborn with MMA mainly comprises rehydration and promotion of anabolism, followed by long-term dietary management by both the restriction of precursor amino acids using a low protein diet and avoidance of prolonged fasting. Prognosis depends on the type of MMA and whether the condition is well controlled in general and during episodes of metabolic decompensation. We report here the presentation and management of a 2-year boy with MMA who failed to achieve expected milestones for age. To the best of our knowledge, only one case of MMA has been reported from Pakistan.

"Inverted V sign" in Sub-Acute Combined Degeneration of Cord.

A 54-year-old male patient presented to the outpatient department of neurology with complaints of tingling and numbness of hands since two months. Neurological examination revealed reduced power and decreased proprioception and vibration sense of hands. Laboratory investigations done showed normal Hb-13.7g/dl (normal range, 13.5-17.5 g/dl).Other routine blood, urine parameters were within normal limits. MRI of cervical spine was advised and performed which showed symmetric T2W hyperintense signals in dorsal columns of cervical spinal cord from C2 to C5 [Table/Fig-1a&b,​,2]2] levels (Characteristic Inverted V sign). A provisional diagnosis of Sub-Acute Combined Degeneration of Cord (SACD) was considered. Retrospective investigations of blood showed reduced serum VITAMIN B12 levels of 78.6pg/mL (Normal-200 to 900pg/mL), mild increased mean corpuscular volume 120fl (normal range, 80-100 fl),elevated serum homocysteine levels. Patient was started on vitamin B12 therapy and showed progressive resolution of clinical symptoms. [Table/Fig-1a&b]: Axial T2W MRI at C3 (A) and C4 (B) vertebral level of the spinal cord showing characteristic “inverted v pattern” hyperintene signal (arrow) in the posterior compartment of the spinal cord [Table/Fig-2]: Sagittal T2W MRI showing linear hyperintense signal (arrows) predominantly in the posterior compartment of the cervical spinal cord extending from C2-C5 vertebral levels of the cord Causes of vitamin B12 deficiency include malabsorption syndromes such as pernicious anaemia, crohns disease, celiac disease, bacterial overgrowth in intestinal blind loops, postgastrectomy and ileal resection. Deficiency of vitamin B12 results in failure of conversion of methyl malonyl coenzyme A to succinyl co A resulting in accumulation of methylmalonic acid which causes myelin toxicity of preferential dorsal/posterior columns of the cord [1]. Pathologically multifocal vacuolated and demyelinating lesions involving the dorsal columns, predominately in the lower cervical and upper thoracic region [1] are seen. Demyelination of posterior columns of thoracic spinal cord appears to be the earliest manifestation of vitamin B12 deficiency.It is also considered as the most reversible pathological stage in a case of SACD. MRI findings in SACD of cord are minimal spinal cord enlargement with dorsal spinal cord hypointensity on T1WI, hyperintensity on T2W images. On sagittal images longitudinal signal changes are noted along the dorsal columns of spinal cord.T2WI – axial images show typically characteristic pattern of symmetric bilateral hyperintense signals in the dorsal columns. This specific MRI appearance has been described as the “Inverted V sign” or “Inverted Rabbit Ears appearance”. Some cases may show T2 hyperintense signal in lateral columns of cord and cerebral white matter. Differential diagnsosis for bilateral posterior column involvement [2] include infectious myelitis, infarction of spinal cord, inflammatory demyelination including multiple sclerosis, acute disseminated encephalomyelitis, acute transverse myelitis, and copper deficiency myelopathy. Once the diagnosis of SACD is suspected, treatment with vitamin B12 injection should be started as early as possible to avoid irreversible neurologic damage [3]. Recognition of the specific MRI pattern of cord involvement together with clinical and laboratory analysis helps in early detection and treatment of the Subacute combined degeneration of the spinal cord.

La vitamine B12 et les maladies génétiques associées

Vitamin B12 (B12, cobalamin (Cbl)) is a water-soluble vitamin that requires complex mechanisms for its assimilation, blood transport and intracellular metabolism. Three proteins, intrinsic factor (IF), haptocorrin (HC), and transcobalamin (TC), and their specific receptors are involved in B12 absorption and transport. Acquired and inherited deficiencies can result in megaloblastic anemia and neurological manifestations. Several genetic diseases are linked to these two steps, namely inherited deficits in FI and TC, and Imerslund-Gräsbeck disease. In mammalian cells, only two enzymes depend on vitamin B12: L-methylmalonyl-CoA mutase (EC 5.4.99.2) in mitochondria, and methionine synthase (EC 2.1.1.13) in cytoplasm. Direct metabolic consequences of impaired B12 absorption and metabolism are the accumulation of methylmalonic acid (MMA) and of homocysteine (HCy), respectively. More than a dozen genes are involved in the intracellular metabolism of B12, and their defects result in several diseases designated cblA through cblJ This article reviews the steps involved in vitamin B12 absorption, transport and intracellular metabolism, and the main related genetic defects.

Methylmalonic acid administration induces DNA damage in rat brain and kidney

Accumulation of methylmalonic acid (MMA) in tissues and biological fluids is the biochemical hallmark of methylmalonic aciduria. Affected patients present renal failure and severe neurological findings. Considering that the underlying pathomechanisms of tissue damage are not yet understood, in the present work we assessed the in vivo e in vitro effects of MMA on DNA damage in brain and kidney, as well as on p53 and caspase 3 levels, in the presence or absence of gentamicin (acute renal failure model). For in vitro studies, tissue prisms were incubated in the presence of different concentrations of MMA and/or gentamicin for one hour. For in vivo studies, animals received a single injection of gentamicin (70 mg/kg) and/or three injections of MMA (1.67 μmol/g; 11 h interval between injections). The animals were killed 1 h after the last MMA injection. Controls received saline in the same volumes. DNA damage was analyzed by the comet assay. We found that MMA and gentamicin alone or combined in vitro increased DNA damage in cerebral cortex and kidney of rats. Furthermore, MMA administration increased DNA damage in both brain and kidney. Gentamicin per se induced DNA damage only in kidney, and the association of MMA plus gentamicin also caused DNA damage in cerebral cortex and kidney. On the other hand, p53 and caspase 3 levels were not altered by the administration of MMA and/or gentamicin. Our findings provide evidence that DNA damage may contribute to the neurological and renal damage found in patients affected by methylmalonic aciduria.

Asymptomatic methylmalonic acidemia in a homozygous MUT mutation (p.P86L)

Deficiency in methylmalonyl-coenzyme A mutase (MCM) is associated with accumulation of methylmalonic acid (MMA) and clinical outcomes that include early death and neurological impairment. Reported here are two unrelated patients with a homozygous p.P86L mutation in the MUT gene, which encodes MCM, diagnosed following newborn screening. This is the first description of a homozygous mutation in the N-terminal extended segment of the MCM apoenzyme. Both in vitro and in vivo testing did not find a response to supplemental hydroxocobalamin. After discontinuation of hydroxocobalamin in one patient, serum MMA level remained elevated but stable, while urine MMA increased. Both patients have remained asymptomatic with normal development. The observed homozygous p.P86L mutation in the N-terminal extended segment may yield reduced MCM activity and is refractory to hydroxocobalamin supplementation, while not inducing a metabolically unstable phenotype. These genotype-phenotype associations further enhance the understanding of methylmalonic acidemia, which will continue to improve patient care.

An X-Linked Cobalamin Disorder Caused by Mutations in Transcriptional Coregulator HCFC1

Derivatives of vitamin B12 (cobalamin) are essential cofactors for enzymes required in intermediary metabolism. Defects in cobalamin metabolism lead to disorders characterized by the accumulation of methylmalonic acid and/or homocysteine in blood and urine. The most common inborn error of cobalamin metabolism, combined methylmalonic acidemia and hyperhomocysteinemia, cblC type, is caused by mutations in MMACHC. However, several individuals with presumed cblC based on cellular and biochemical analysis do not have mutations in MMACHC. We used exome sequencing to identify the genetic basis of an X-linked form of combined methylmalonic acidemia and hyperhomocysteinemia, designated cblX. A missense mutation in a global transcriptional coregulator, HCFC1, was identified in the index case. Additional male subjects were ascertained through two international diagnostic laboratories, and 13/17 had one of five distinct missense mutations affecting three highly conserved amino acids within the HCFC1 kelch domain. A common phenotype of severe neurological symptoms including intractable epilepsy and profound neurocognitive impairment, along with variable biochemical manifestations, was observed in all affected subjects compared to individuals with early-onset cblC. The severe reduction in MMACHC mRNA and protein within subject fibroblast lines suggested a role for HCFC1 in transcriptional regulation of MMACHC, which was further supported by the identification of consensus HCFC1 binding sites in MMACHC. Furthermore, siRNA-mediated knockdown of HCFC1 expression resulted in the coordinate downregulation of MMACHC mRNA. This X-linked disorder demonstrates a distinct disease mechanism by which transcriptional dysregulation leads to an inborn error of metabolism with a complex clinical phenotype.

Bilateral subthalamic nucleus deep brain stimulation for refractory total body dystonia secondary to metabolic autopallidotomy in a 4-year-old boy with infantile methylmalonic acidemia

The methylmalonic acidemias (MMAs) are a group of inborn errors of metabolism resulting in the accumulation of methylmalonic acid in body tissues and fluids. A recognized complication of MMA is bilateral liquefaction of the globus pallidi, resulting in a fulminant total body dystonia of childhood often refractory to medical treatment. This case of total body dystonia due to MMA in a 4-year-old boy had been medically refractory for 15 months. Complete metabolic destructive liquefaction of the pallidi, that is, autopallidotomy, necessitated an alternative, bilateral subthalamic nucleus (STN) target for deep brain stimulation (DBS) with a marked improvement in dystonia and reduction in pain. The case illustrates the efficacy of STN DBS in this condition and the technical challenges in targeting the STN in a small child.

Methylmalonic Acid Accumulation and the Development of Peripheral Neuropathy (IN1-1.010)

Objective: This study evaluated the pathophysiology of peripheral neuropathy seen with MMA accumulation both in vivo and in vitro. Background A potential cause of peripheral neuropathy is cobalamin (vitamin B12) deficiency, which leads to accumulation of methylmalonic acid (MMA). The mechanism by which cobalamin deficiency is uncertain, but recent evidence in Parkinson9s Disease and Diabetic Neuropathy clinical studies has implicated MMA. Design/Methods: We performed mouse dorsal root ganglia neuronal and Schwann cell cultures exposed to a dose range of methylmalonic acid or placebo. We examined cellular viability, reactive oxygen species and mitochondrial function in vitro. Complementary in vivo studies with either daily systemic (intraperitoneal), intrathecal or near-nerve MMA or placebo delivery were performed in mice. Electrophysiological, structural and molecular studies were performed for dorsal root ganglia and sciatic nerves after 3 months of exposure to MMA or placebo. Results: There was no impact upon in vitro Schwann cells with exposure to amiodarone. However, MMA was associated with a dose-related somal atrophy of neurons and neuronal loss in vitro. In vivo, MMA had little impact when delivered with localized near-nerve delivery, but led to diffuse development when delivered systemically and dramatic neuropathy when delivered intrathecally. Peripheral neuropathy was associated with gradual loss of motor and sensory nerve potential amplitudes, loss of large and small nerve fibers, and loss of intraepidermal nerve fiber density. Increased reactive oxygen species and mitochondrial dysfunction were detected in the dorsal root ganglia with MMA when delivered intrathecally or systemically. Conclusions: MMA has a direct impact upon the dorsal root ganglia neurons without any observed effect upon Schwann cells. Accumulation of MMA is associated with induction of experimental peripheral axonal neuropathy due to direct effects upon dorsal root ganglia neuronal well being. Supported by: Alberta Heritage Foundation for Medical Research. Disclosure: Dr. Francis has nothing to disclose. Dr. Hohol has nothing to disclose. Dr. Jawad has nothing to disclose. Dr. Ayer has nothing to disclose. Dr. Toth has received personal compensation for activities with Pfizer and Eli Lilly & Company as a speaker. Dr. Toth has received research support from Pfizer Inc, Valeant Pharmaceuticals International and Eli Lilly & Company.

Methylmalonic Acid Accumulation and the Development of Peripheral Neuropathy (P03.190)

Methylmalonic Acid Accumulation and the Development of Peripheral Neuropathy (P03.190)

Methylmalonic acidemia and hyperglycemia: An unusual association

Introduction: Hyperglycemia is an exceptional manifestation of methylmalonic acidemia (MMA). We describe a patient with MMA in whom we observed a hyperglycemia which improved under treatment of the metabolic crisis. Case report: A 14 month-old boy presented with an acute generalized dystonia and lethargy preceded by fever, vomiting and lethargy at the age of 13 months. Biological investigations showed a hyperglycemia, a lactic acidosis and a hyperammonemia. Urinary organic acid analysis showed accumulation of methylmalonic acid, tiglylglycine and methylcitrate leading to the diagnosis of MMA. The patient underwent symptomatic treatment with rapid improvement of general condition, consciousness and gradual normalization of biological parameters especially glycemia after 6 days without using insulinotherapy. Discussion: MMA is an autosomal recessive disorder caused by a deficiency of methylmalonyl-CoA mutase resulting in methylmalonic acid accumulation. Biochemically, the disorder is typically characterized by: metabolic acidosis, ketonemia or ketonuria, hyperammonemia, leukopenia, thrombocytopenia and anemia. Hypoglycemia is a frequent manifestation of MMA. Our patient presented a hyperglycemia, which is unusual in MMA, since we found only three patients reported with this association. Pathophysiology remains unknown. In reported cases, hyperglycemia was treated by insulin therapy and reducing glucose intravenous infusion, with fatal outcome. In our patient glycemia spontaneously normalized after treatment of the metabolic crisis. Conclusion: Hyperglycemia is an exceptional manifestation of MMA and could be a seriousness marker.

Experimental evidence that methylmalonic acid provokes oxidative damage and compromises antioxidant defenses in nerve terminal and striatum of young rats.

Methylmalonic acidemia and propionic acidemia are organic acidemias biochemically characterized by predominant tissue accumulation of methylmalonic acid (MMA) and propionic acid (PA), respectively. Affected patients present predominantly neurological symptoms, whose pathogenesis is not yet fully established. In the present study we investigated the invitro effects of MMA and PA on important parameters of lipid and protein oxidative damage and on the production of reactive species in synaptosomes from cerebrum of developing rats. Synaptosomes correspond to nerve terminals that have been used to investigate toxic properties of compounds on neuronal cells. The invivo effects of intrastriatal injection of MMA and PA on the same parameters and on enzymatic antioxidant defenses, were also studied. MMA-induced invitro and invivo lipid peroxidation and protein oxidative damage. Furthermore, the lipid oxidative damage was attenuated or prevented, pending on the doses utilized, by the free radical scavengers α-tocopherol, melatonin and by the NMDA glutamate receptor antagonist MK-801, implying the involvement of reactive species and glutamate receptor activation in these effects. In addition, 2',7'-dichlorofluorescein diacetate oxidation was significantly increased in synaptosomes by MMA, reinforcing that reactive species generation is elicited by this organic acid. We also verified that glutathione peroxidase activity was inhibited by intrastriatal MMA injection. In contrast, PA did not induce any significant effect on all parameters examined invitro and invivo, implying a selective action for MMA. The present data demonstrate that oxidative stress is induced by MMA invitro in nerve terminals and invivo in striatum, suggesting the participation of neuronal cells in MMA-elicited oxidative damage.

Inborn errors of cobalamin absorption and metabolism

Derivatives of cobalamin (vitamin B(12)) are required for activity of two enzymes in humans. Adenosylcobalamin is required for activity of mitochondrial methylmalonylCoA mutase and methylcobalamin is required for activity of cytoplasmic methionine synthase. Deficiency in cobalamin, or inability to absorb cobalamin normally, can result in accumulation of methylmalonic acid and homocysteine in blood and urine. Methylmalonic acidemia can result in metabolic acidosis which in severe cases may be fatal. Hyperhomocysteinemia along with hypomethioninemia can result in hematologic (megaloblastic anemia, neutropenia, thrombocytopenia) and neurologic (subacute combined degeneration of the cord, dementia, psychosis) defects. Inborn errors affecting cobalamin absorption (inherited intrinsic factor deficiency, Imerslund–Gra¨ sbeck syndrome) and transport (transcobalamin deficiency) have been described. A series of inborn errors of intracellular cobalamin metabolism, designated cblA-cblG, have been differentiated by complementation analysis. These can give rise to isolated methylmalonic acidemia (cblA, cblB, cblD variant 2), isolated hyperhomocysteinemia (cblD variant 1, cblE, cblG) or combined methylmalonic acidemia and hyperhomocysteinemia (cblC, classic cblD, cblF). All these disorders are inherited as autosomal recessive traits. The genes underlying each of these disorders have been identified. Two other disorders, haptocorrin deficiency and transcobalamin receptor deficiency, have been described, but it is not clear that they have any consistent clinical phenotype.

Cobalamin C defect presenting as severe neonatal hyperammonemia

Cobalamin C (Cbl-C) defect is the most common inborn error of cobalamin metabolism which causes a block in the pathway responsible for the synthesis of its two metabolically active forms methyl- and adenosylcobalamin. Cbl-C defect causes the accumulation of methylmalonic acid and homocysteine and decreased methionine synthesis. The clinical presentation of patients with early-onset Cbl-C defect, characterized by a multisystem disease with severe neurological, ocular, hematological, renal, gastrointestinal, cardiac, and pulmonary manifestations, differs considerably from what observed in the "classical" form of methylmalonic aciduria caused by defect of methylmalonyl-CoA mutase. This last condition is in most cases dominated in the neonatal period by a metabolic encephalopathy "intoxication type" with severe hyperammonemia and ketoacidosis. We report a Cbl-C defect patient presenting a neonatal encephalopathy with severe hyperammonemia and ketoacidosis who was successfully treated with peritoneal dialysis. To the best of our knowledge, there are no reported cases of Cbl-C defect showing an acute presentation resembling a classical methylmalonic aciduria. This observation enlarges the spectrum of inherited diseases to be considered in the differential diagnosis of neonatal hyperammonemia.

Cobalamin C defect: natural history, pathophysiology, and treatment

Cobalamin C (Cbl-C) defect is the most common inborn cobalamin metabolism error; it causes impaired conversion of dietary vitamin B12 into its two metabolically active forms, methylcobalamin and adenosylcobalamin. Cbl-C defect causes the accumulation of methylmalonic acid and homocysteine and decreased methionine synthesis. The gene responsible for the Cbl-C defect has been recently identified, and more than 40 mutations have been reported. MMACHC gene is located on chromosome 1p and catalyzes the reductive decyanation of CNCbl. Cbl-C patients present with a heterogeneous clinical picture and, based on their age at onset, can be categorized into two distinct clinical forms. Early-onset patients, presenting symptoms within the first year, show a multisystem disease with severe neurological, ocular, haematological, renal, gastrointestinal, cardiac, and pulmonary manifestations. Late-onset patients present a milder clinical phenotype with acute or slowly progressive neurological symptoms and behavioral disturbances. To improve clinical course and metabolic abnormalities, treatment of Cbl-C defect usually consists of a combined approach that utilizes vitamin B12 to increase intracellular cobalamin and to maximize deficient enzyme activities, betaine to provide a substrate for the conversion of homocysteine into methionine through betaine-homocysteine methyltransferase, and folic acid to enhance remethylation pathway. No proven efficacy has been demonstrated for carnitine and dietary protein restriction. Despite these measures, the long-term follow-up is unsatisfactory especially in patients with early onset, with frequent progression of neurological and ocular impairment. The unfavorable outcome suggests that better understanding of the pathophysiology of the disease is needed to improve treatment protocols and to develop new therapeutic approaches.

Coma Caused by Methylmalonic Acidemia in a Taiwanese Girl

Methylmalonic acidemia (MMA) is an inborn error of metabolism caused by an accumulation of methylmalonic acid in blood and body tissue due to severe defi ciency or a lack activity of the mitochondrial methylmelonyl-CoA mutase (MCM) enzyme. Affected individuals are typically presented during the newborn period with vomiting, failure to thrive, hyperammoninemia and ketoacidosis. Several mutations on MCM gene (MUT gene) were reported worldwide, but Taiwan. Here, we described a previously healthy 2-year-old Taiwanese girl, who had normal growth and developmental milestones, presented with abdominal pain, vomiting and was in coma. Physical examination revealed tachycardia, tachypnea and poor skin tugor. Laboratory investigations showed high anion gap (anion gap 35 mmol/L) metabolic acidosis (HCO3 - 2.7 mmol/ L), normal plasma osmolar gap (10 mosm/kgH2O), β-hydroxybutyrate (4 mmol/l), ketonuria, hypoglycemia (2.6 mmol/l), hyperammoneemia (152.9 μmol/l), normal lactic acid level, normal renal function, suggesting a clinical diagnosis of organic acidemia. Urinary analysis for organic acid showed increased excretion of methylmalonic acid and in vitro MCM enzyme activity analysis by detecting the lymphoblast revealed trivial residual activity. Molecular analysis of MCM gene revealed that she was compound heterozygous for two mutation of MUT gene, a recurrent G427D and a novel mutation F307L; these two mutations are not identified of 100 alleles for 50 unrelated normal Taiwanese. MMA should be considered as a cause of high anion gap metabolic acidosis in children, even without previous episode and normal development milestone. Molecular study is needed to make a diagnosis of MMA under the trivial residual activity of MCM enzyme.

Long‐term exposure of human proximal tubule cells to hydroxycobalamin[c‐lactam] as a possible model to study renal disease in methylmalonic acidurias

Dysfunction of proximal tubules resulting in tubulointerstitial nephritis and chronic renal failure is a frequent long-term complication of methylmalonic acidurias. However, the underlying pathomechanisms have not yet been extensively studied owing to the lack of suitable in vitro and in vivo models. Application of hydroxycobalamin[c-lactam] has been shown to inhibit the metabolism of hydroxycobalamin and, thereby, to induce methylmalonic aciduria in rats, oligodendrocytes, and rat hepatocytes. Our study characterizes the biochemical and bioenergetic effects of long-term exposure of human proximal tubule cells to hydroxycobalamin[c-lactam], aiming to establish a novel in vitro model for the renal pathogenesis of methylmalonic acidurias. Incubation of human proximal tubule cells with hydroxycobalamin[c-lactam] and propionic acid resulted in a strong, time-dependent intra- and extracellular accumulation of methylmalonic acid. Bioenergetic studies of respiratory chain enzyme complexes revealed an increase of complex II-IV activity after 2 weeks and an increase of complex I and IV activity as well as a decrease of complex II and III activity after 3 weeks of incubation. In addition, human proximal tubule cells displayed reduced glutathione content after the exposure to hydroxycobalamin[c-lactam] and propionic acid.

High prevalence of structural heart disease in children with cblC-type methylmalonic aciduria and homocystinuria

Objective To characterize the frequency and nature of cardiovascular defects in patients with CblC-type methylmalonic aciduria and homocystinuria (cblC), an inborn error of cobalamin (vitamin B12) metabolism resulting in accumulation of methylmalonic acid and homocysteine. Study design A retrospective observational study was conducted investigating 10 patients with cblC ranging in age from 2 weeks to 24 years (mean 4.4 years +/− 7.5 years, median 0.6 years). All patients underwent a complete 2-D echocardiogram including quantitative assessment of left ventricular systolic function. Results Structural heart defects were detected in 50% of patients with cblC. Heart defects included left ventricular (LV) non-compaction (3), secundum atrial septal defect (2), muscular ventricular septal defect (1), dysplastic pulmonary valve without pulmonary stenosis (1) and mitral valve prolapse with mild mitral regurgitation (1). One patient had resolved cor pulmonale and right heart failure secondary to pulmonary embolism. All patients had quantitatively normal LV systolic function. Conclusions Diverse and clinically significant structural heart defects appear to be highly prevalent in cblC, perhaps due to abnormal DNA and histone methylation during embryogenesis. The specific cardiac defects detected in our cohort were variable, and studies with a larger number of patients are needed to establish which forms are most common. Routine and periodic cardiovascular evaluation may be indicated in patients with cblC.

Infantile spasms, cerebral venous thrombosis and acute extrapyramidal symptoms in a child with methylmalonic acidemia

Methylmalonic acidemia is a genetically heterogeneous disorder characterized by accumulation of methylmalonic acid and its by-products in biological fluids that leads to numerous neurologic sequelae such as hypotonia, stroke, encephalopathy and mental retardation. Infantile spasms with hypsarrhythmias and acute extrapyramidal symptoms are rarely reported. We report a three and a half year old child with methylmalonic acidemia who presented at 1 year of age with infantile spasms, which were controlled with adrenocorticotrophin hormone therapy. Later, he presented with altered sensorium, cerebral venous thrombosis and acute extrapyramidal symptoms during decompensation phase. The child showed significant response to dietary protein restriction and hydroxycobalamin and carnitine supplementation.

Diazoxide protects against methylmalonate-induced neuronal toxicity

Methylmalonic acidemia is an inherited metabolic disorder that leads to brain damage associated to the accumulation of methylmalonic acid (MMA) and impairment of energy metabolism. We demonstrate here that treatment with diazoxide, an agonist of mitochondrial ATP-sensitive K + channels (mitoK ATP), can prevent death promoted by treatment with MMA in PC12 cells and freshly prepared rat brain slices. This diazoxide effect was reversed by 5-hydroxydecanoate, a mitoK ATP antagonist, confirming it occurs due to the activity of this channel. Diazoxide was not capable of preventing inner membrane potential loss promoted by MMA and Ca 2+ in isolated mitochondria, indicating it does not directly prevent mitochondrial damage. Furthermore, diazoxide did not prevent respiratory inhibition in cells treated with MMA. Interestingly, we found that the mitochondrial inner membrane potential within intact cells treated with MMA was maintained in part by the reverse activity of ATP synthase (ATP hydrolysis) and that diazoxide prevented the formation of the membrane potential in the presence of MMA, in a manner sensitive to 5-hydroxydecanoate. Furthermore, the effects of diazoxide on cell survival after treatment with MMA were similar to those of ATP synthase inhibitor oligomycin and adenine nucleotide translocator inhibitor atractyloside. These results indicate that diazoxide prevents PC12 cell death promoted by MMA by decreasing mitochondrial ATP hydrolysis. These results uncover new potential neuroprotective effects of mitoK ATP agonists under situations in which oxidative phosphorylation is inhibited.