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PubMed1999

4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone)--the odour of maple syrup urine disease.

Maple syrup urine disease is an autosomal recessive inherited disorder of branched-chain amino acid metabolism due to deficiency of the branched-chain alpha-keto acid dehydrogenase complex. The disease was originally named after the characteristic sweet aroma, reminiscent of maple syrup, present in the body fluids of affected patients. Until now, the substance responsible for the odour has not been positively identified. Using enantioselective multidimensional gas chromatography-mass spectrometry (enantio-MDGC-MS), we could demonstrate that 4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone), a well-known flavour impact compound present in fenugreek and lovage, was present in urine from seven patients with maple syrup urine disease. Urine samples from healthy control persons lacked sotolone. We have shown that sotolone is responsible for the characteristic odour of maple syrup urine disease and, since maple syrup also contains sotolone, the naming of this disease appears to be correct.

Furans↗

PubMed2000

Inhibition of glutamate uptake into synaptic vesicles of rat brain by the metabolites accumulating in maple syrup urine disease.

Maple syrup urine disease is an inherited metabolic disorder characterized by tissue accumulation of branched-chain amino acids and their corresponding keto acids in the affected children. Although this disorder is predominantly characterized by neurological symptoms, only few studies were carried out to investigate its neuropathology. In this study we investigated the effect of the metabolites accumulating in maple syrup urine disease on the in vitro uptake of [3H]glutamate by synaptic vesicles of rat brain. Synaptic vesicle preparations from whole brain of male adult Wistar rats (200-250 g) were incubated with the branched-chain amino acids and their corresponding keto acids at final concentrations ranging from 0.25 to 10 mM for the determination of glutamate uptake. Glutamate uptake was significantly inhibited by L-leucine, L-isoleucine, L-2-ketoisocaproic acid and L-2-keto-3-methylvaleric acid by approximately 60%, whereas L-valine and L-2-ketoisovaleric acid showed no effect. We also verified that the metabolites probably act by competitive inhibition. Therefore, it is possible that extracellular glutamate levels may be increased in maple syrup urine disease and that excitotoxicity may be involved in the neuropathology of this disorder.

Animals↗

PubMed1991

Ophthalmic findings in maple syrup urine disease.

Maple Syrup Urine Disease is an autosomal recessive disorder of branched chain amino acid metabolism with an incidence in Ireland of one in 140,154 births. Ocular complications in untreated or late diagnosed patients includes optic atrophy, grey optic papilla, nystagmus, ophthalmoplegia, strabismus and cortical blindness. Seven patients with maple syrup urine disease were studied. All were diagnosed with the aid of newborn screening and commenced on early dietary treatment (mean age at diet introduction = 5 days). All remain physically well, with average intellectual performance, three having minor neurological defects and one strabismus. Early diagnosis, proper therapy and subsequent vigilant management may reduce substantially the risks of ophthalmic complications in this rare disease.

Child↗

PubMed1997

Continuous venovenous haemodiafiltration in the acute phase of neonatal maple syrup urine disease.

Maple syrup urine disease results in accumulation of leucine and its metabolites, which may lead in the long term to neurological dysfunction. In acute neonatal crises, large amounts of leucine may be removed by continuous venovenous haemofiltration. This extracorporeal technique has its risks and hazards, which increase with duration of treatment. We report three neonates in life-threatening conditions due to maple syrup urine disease, treated for not more than 12 h with various continuous venovenous techniques: continuous haemofiltration, haemodiafiltration and haemodialysis. The efficiency of and tolerance to these techniques was evaluated. For all three patients, plasma leucine levels decreased dramatically from 2186, 3818 and 2536 mumol/L to 1131, 1275 and 488 mumol/L, respectively. Leucine clearance obtained was 4.28 ml/min in haemodiafiltration. Their patients' neurological status improved rapidly and they have a normal developmental quotient at 22 months, 13 months, and 11 months of age, respectively. Tolerance was good except for hypothermia and drop in haematocrit in all cases. Haemodiafiltration management was more cumbersome and time consuming because it required continual adjustment of the substitution fluid flow rate to precisely balance inflow and outflow rates. We recommend continuous venovenous haemodialysis as the therapy of choice. It might be anticipated that improvement of this technique, by increasing dialysate flow rate and blood flow rate, will allow leucine concentration to be decreased below 1000 mumol/L within 6-8 h, whatever the initial level.

Acute Disease↗

PubMed1999

Plasma amino acid analyses in two cases of maple syrup urine disease.

Maple syrup urine disease is a rare inborn error of metabolism, characterized by elevated plasma levels of branched chain amino acids and urinary excretion of branched chain keto acids. Plasma amino acid levels in two subjects were followed by deproteinizing plasma, derivatizing the free amino acids with phenylisothiocyanate, and analysis by HPLC. The results indicate that valine, leucine and isoleucine are elevated in Maple syrup urine disease, and that leucine remains high even after dietary treatment.

Amino Acids↗

PubMed2000

Chloride-dependent inhibition of vesicular glutamate uptake by alpha-keto acids accumulated in maple syrup urine disease.

Maple syrup urine disease is a metabolic disorder caused by mutations of the branched chain keto acid dehydrogenase complex, leading to accumulation of alpha-keto acids and their amino acid precursors in the brain. We now report that alpha-ketoisovaleric, alpha-keto-beta-methyl-n-valeric and alpha-ketoisocaproic acids accumulated in the disease inhibit glutamate uptake into rat brain synaptic vesicles. The alpha-keto acids did not affect the electrochemical proton gradient across the membrane, suggesting that they interact directly with the vesicular glutamate carrier. Chloride anions have a biphasic effect on glutamate uptake. Low concentrations activate the uptake (0.2 to 8 mM), while higher concentrations are inhibitory. The alpha-keto acids inhibited glutamate uptake by a new mechanism, involving a change in the chloride dependence for the activation of glutamate uptake. The activation of glutamate uptake by low chloride concentrations was shifted toward higher concentrations of the anion in the presence of alpha-keto acids. Inhibition by alpha-keto acids was abolished at high chloride concentrations (20 to 80 mM), indicating that alpha-keto acids specifically change the stimulatory effect of low chloride concentrations. High glutamate concentrations also reduced the inhibition by alpha-keto acids, an effect observed both in the absence and in the presence of low chloride concentrations. The results suggest that in addition to their possible pathophysiological role in maple syrup urine disease, alpha-keto acids are valuable tools to study the mechanism of vesicular transport of glutamate.

ATP-Binding Cassette Transporters↗

PubMed2001

Natural osmolyte trimethylamine N-oxide corrects assembly defects of mutant branched-chain alpha-ketoacid decarboxylase in maple syrup urine disease.

Maple syrup urine disease is caused by deficiency in the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. The clinical phenotype includes often fatal ketoacidosis, neurological derangement, and mental retardation. The type IA mutations Y393N-alpha, Y368C-alpha, and F364C-alpha, which occur in the E1alpha subunit of the decarboxylase (E1) component of the BCKD complex, impede the conversion of an alphabeta heterodimeric intermediate to a native alpha(2)beta(2) heterotetramer in the E1 assembly pathway. In the present study, we show that a natural osmolyte trimethylamine N-oxide (TMAO) at the optimal 1 m concentration restores E1 activity, up to 50% of the wild type, in the mutant E1 carrying the above missense mutations. TMAO promotes the conversion of otherwise trapped mutant heterodimers to active heterotetramers. This slow step does not involve dissociation/reassociation of the mutant heterodimers, which are preformed in the presence of chaperonins GroEL/GroES and Mg-ATP. The TMAO-stimulated mutant E1 activity is remarkably stable upon removal of the osmolyte, when cofactor thiamine pyrophosphate and the transacylase component of the BCKD complex are present. The above in vitro results offer the use of chemical chaperones such as TMAO as an approach to mitigate assembly defects caused by maple syrup urine disease mutations.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

PubMed1991

Molecular defects in the E1 alpha subunit of the branched-chain alpha-ketoacid dehydrogenase complex that cause maple syrup urine disease.

Maple syrup urine disease (MSUD) results from an inborn metabolic error caused by a deficiency of the branched-chain alpha-ketoacid dehydrogenase complex (BCKDC). cDNA clones encoding the E1 alpha subunit of BCKDC from rat and human liver have been isolated and characterized. The chromosomal location of E1 alpha on chromosome 19q13.1-13.2 has been determined using complementary methods. The etiology of MSUD has been studied by determining the enzyme activity, protein mass and mRNA level of BCKDC in fibroblasts from a human family and Polled Hereford calves, both with classic MSUD. A TACTyr to AACAsn substitution at residue 394 of the E1 alpha subunit was identified in the human patient by using enzymatic amplification of mRNA followed by DNA sequencing. Amplification of both mRNA and genomic DNA, in combination with allele-specific oligonucleotide hybridization, demonstrated that the patient was a compound heterozygote, inheriting an allele with a structural mutation from the father, and an allele from the mother containing a presumably cis-acting defect in regulation that abolished the expression of one of the E1 alpha alleles. The results revealed for the first time that a case of MSUD was caused by structural and regulatory mutations involving the E1 alpha subunit. Recent studies by others have demonstrated that the same structural mutation as is found in this patient is responsible for the high incidence of MSUD in the Philadelphia Mennonite population.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

PubMedDate not supplied

Computed tomography in maple syrup urine disease.

Maple Syrup Urine Disease (MSUD) is an inherited metabolic disorder characterized by a severe, usually lethal, neonatal course in the early stages with pseudotumor cerebri and pathologically documented increased cerebral water content. CT and MRI studies in MSUD are few and the data are overlapping. This study reports CT features before and after dietary treatment in three patients; two with classical MSUD and one with an intermediate variant of MSUD. At diagnosis, CT consistently showed evidence of abnormally high lucidity involving not only white matter, but also areas of grey matter, particularly the pallidum. Furthermore, these CT changes are present both in the acute phase of classical MSUD and in an intermediate variant of the disease. The observed abnormalities evolve favorably under dietary treatment, simultaneously with clinical and neurological improvement. It is concluded that the observed CT changes indicate a diagnosis of MSUD and are relevant findings in the neuroradiologic differential diagnosis in acutely ill newborns, in which a metabolic disease may be not immediately suspected.

Humans↗

PubMed2004

Changes in the auditory nerve brainstem evoked responses in a case of maple syrup urine disease.

Maple syrup urine disease (MSUD) is a rare metabolic disease due to deficiency in the enzyme that breaks down branched chain amino acids. Lack of the enzyme causes accumulation of these amino acids and, if untreated, causes severe neurological damage. A case study of a 10-day old female infant, born after 40 weeks' gestation with a birthweight of 2740 g with MSUD hospitalized in the acute stage with respiratory failure and severe brain oedema is described. As part of the neurological evaluation, auditory nerve brainstem evoked response testing was conducted and revealed bilateral presence of the first wave from the auditory nerve, with no later brainstem waves. Over the course of days when her condition improved following dialysis treatment and a diet to reach balanced levels of branched chain amino acids, the later brainstem waves appeared on one side, and several weeks later they were also observed on the other side. The possible mechanisms of the reversibility of the appearance of brainstem waves in this case are discussed.

Acute Disease↗

PubMed2003

Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease.

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder of panethnic distribution caused by a deficiency of the activity of branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. Mutations in the human BCKD genes E1alpha (BCKDHA), E1beta (BCKDHB) and E2 (DBT) are known to result in MSUD, referred to as type Ia, Ib and II mutations respectively. In this study 16 patients with the classic severe form of MSUD and three patients with milder variant forms of the disease were investigated for mutations in the E1alpha-, E1beta- and E2-gene by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. The patients' clinical and biochemical phenotypes were well characterized. One novel type Ia missense mutation, eight novel type Ib (three missense, two nonsense, two small deletions, one small duplication) and three novel type II (two missense, one splice site) mutations were identified in patients. Moreover, eleven previously described mutations were detected: five type Ia (four missense, one nonsense), three type Ib mutations (two missense, one nonsense) and three type II mutations (two missense, one small deletion). Fourteen patients are homozygous for one single mutation, five patients are compound-heterozygous for two different mutations affecting one of the three genes. Thus, in all 19 patients the identified mutations can most probably be considered the molecular basis of the disease.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

PubMed1993

[Methodology of care for children with phenylketonuria and maple-syrup urine disease].

Maple Syrup Urine Disease (MUSD) and Phenylketonuria (PKU), are two metabolic disease in which the nutritional management are essential. Nevertheless, in Costa Rica and the rest of Central America, the dietetical attention of the children with this illness aren't normalized. These work was developed to fill this necessity. The nutritional management was separate in three steps: 1-Initial diet: is the feeding that the children must receive while the blood amino acid level falls, 2-Stabilization diet: is the one where the requirement of limits amino acid are defined, 3-Follow up diet: this is the diet that is prescribed for the rest of his life. This attention methodology, was very important to an adequate physical and neurological development of the children with PKU and MSUD.

Amino Acids↗

PubMed1989

Oral clinicopathologic manifestations in maple syrup urine disease.

Maple syrup urine disease is a rare inborn error of metabolism that manifests mainly by neurologic deterioration, coma, and death in early childhood. Oral manifestations described in this article were mostly gingival enlargement and rampant caries, while histopathologic findings revealed a picture compatible osteomyelitis.

Adolescent↗

PubMed1997

Metabolism of branched-chain amino acids in maple syrup urine disease.

Maple syrup urine disease (MSUD) is an autosomal recessive disorder. Impaired activity of the branched-chain 2-oxo acid dehydrogenase complex (BCOA-DH) causes accumulation of branched-chain L-amino (BCAA) and 2-oxo acids (BCOA) that can exert neurotoxic effects. MSUD presents as a heterogeneous clinical and molecular phenotype. Severity of the disease, ranging from classical to mild variant types, is commonly classified on the basis of indirect parameters, e.g. onset, leucine tolerance and/or residual enzyme activity in cells. Available information on BCAA turnover in vivo suggests that renal clearance is low and that the main route of BCAA disposal in MSUD is via protein synthesis, similar to healthy subjects. Information on BCAA oxidation is poor. In vivo oxidation rates have been assessed in a few studies in patients with claimed classical form of MSUD, using (stable) isotopically labelled L-leucine and both the (primed) continuous infusion and the oral bolus test approach. However, highly variable results have been obtained with both methods not only with respect to the number of patients exhibiting measurable leucine oxidation (range: 0%-100%; two to seven patients investigated) but also considering the extent of residual whole body leucine oxidation (range: < or = 2%-43% of control). Whether the different findings on whole body leucine oxidation actually reflect the variability of in vivo severity in classical MSUD as opposed to the measurements in cultured cells (generally < or = 2% of control), alternative pathways of leucine oxidation in some patients or were rather attributable to inadequate classification of patients or/and to inherent methodological problems remains to be clarified.

Amino Acids, Branched-Chain↗

PubMed2006

Evidence that oxidative stress is increased in plasma from patients with maple syrup urine disease.

Maple syrup urine disease (MSUD) or branched-chain alpha-keto aciduria (BCKA) is an inherited disorder caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKAD) activity. The blockage of this pathway leads to tissue accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine and their respective keto-acids. The clinical features presented by MSUD patients include ketoacidosis, convulsions, coma, psychomotor delay and mental retardation. The mechanism of brain damage in this disease is still poorly understood. However, an increase in lipid peroxidation in vitro in cerebral cortex of young rats as well as a decrease in the antioxidant defenses has been previously observed. In the present work we evaluated different oxidative stress parameters, named reactive species of thiobarbituric acid (TBARS), total antioxidant reactivity (TAR) and total antioxidant status (TAS) in plasma of MSUD patients in order to evaluate whether oxidative stress is involved in this disorder. We verified a marked increase of plasma TBARS measurements, which is indicative of increased lipid peroxidation, as well as a decrease on plasma TAR reflecting a deficient capacity to efficiently modulate the damage associated with an increased production of reactive species. In contrast, TAS was not changed indicating that the total content of antioxidants in plasma of patients affected by MSUD was not altered. These results suggest that free radical generation is elicited in MSUD and is possibly involved in the pathophysiology of the tissue damage found in this disorder.

Antioxidants↗

PubMed1984

Cerebral computed tomography in maple syrup urine disease.

Maple syrup urine disease (MSUD) is an inherited metabolic disorder due to decreased decarboxylation of branched chain keto acids triggering an accumulation of leucine, isoleucine, and valine. We describe two infants with biochemically confirmed MSUD in whom computed tomography (CT) revealed cerebral edema. In one of these cases repeat CT 40 days after institution of appropriate therapy revealed that the edema had disappeared and the ventricles had enlarged.

Brain Edema↗

PubMed1998

Computed tomography findings in maple syrup urine disease.

Maple syrup urine disease (MSUD) is an inherited metabolic disorder characterised by a severe, usually lethal, neonatal course unless dietary intake of branched chain amino acids is restricted. We describe a patient with MSUD who had computed tomography (CT) changes of diffuse white matter hypodensity, particularly in the deep white cerebellar matter, brain stem, cerebral peduncles, thalamus and posterior limb of the internal capsule. With dietary treatment, there was neurological improvement with simultaneous disappearance of the oedema. These CT changes are typical of MSUD, hence are relevant findings in the neuroradiologic differential diagnosis of a possible metabolic disorder.

Amino Acids, Branched-Chain↗

PubMed2005

Markers associated with inborn errors of metabolism of branched-chain amino acids and their relevance to upper levels of intake in healthy people: an implication from clinical and molecular investigations on maple syrup urine disease.

Maple syrup urine disease (MSUD) is caused by a deficiency in the branched-chain alpha-ketoacid dehydrogenase complex. Accumulations of branched-chain amino acids (BCAAs) and branched-chain alpha-ketoacids (BCKAs) in patients with MSUD induce ketoacidosis, neurological disorders, and developmental disturbance. BCAAs and BCKAs influence on the nervous system can be estimated by analyzing these patients. According to clinical investigations on MSUD patients, leucine levels over 400 micromol/L apparently can cause any clinical problem derived from impaired function of the central nervous system. Damage to neuronal cells found in MSUD patients are presumably because of higher concentrations of both blood BCAAs or BCKAs, especially alpha-ketoisocapronic acids. These clinical data from MSUD patients provide a valuable basis on understanding leucine toxicity in the normal subject.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗