3-methylglutaric Acid Research Articles

Reply: Early-onset Behr syndrome due to compound heterozygous mutations in OPA1

Reply: Early-onset Behr syndrome due to compound heterozygous mutations in OPA1

Dietary therapy for a patient affected with 3-hydroxy-3-methylglutaric aciduria

3-Hydroxy-3-methylglutaric aciduria (OMIM 246450) is an extremely rare genetic metabolic disorder of leucine caused by deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase). Affected patients present with life-threatening metabolic acidosis, hyperammonemia, and nonketotic hypoglycemia. Optimal outcome for patients depends on early diagnosis and treatment, prompt management of acute metabolic decompensation during the chronic stage, and long-term interprofessional health care programs. Nutritionists play a pivotal role in the care of metabolic disorders throughout the rest of a patient’s life. A 4-year-old intubated Bunun tribe female patient was admitted to the pediatric intensive care unit of the Buddhist Tzu Chi General Hospital (Hualien, Taiwan) due to status epilepticus, hypoglycemia, and severe metabolic acidosis. Results of urine gas chromatography with mass spectrometry revealed markedly elevated 3-methylglutaric acid, 3-hydroxy-3-methylglutaryl-CoA, and 3-hydroxyisovaleric acid, a finding consistent with a diagnosis of HMG-CoA lyase deficiency. She received an interdisciplinary health care program after acute management. Dietary therapy was the major part of the transdisciplinary health delivery process. Total daily calories were increased from 1400 kcal/day (targeted 60e80%) to 2100e2200 kcal/day (targeted 100%). The ratio of protein lipid and carbohydrate was 13%:24%:63% as recommended for healthy children. Lifelong protein restriction was essential. Total daily protein was given at a dose of 1.5e2 g/kg/day (target: above 50 g/day after the age of 4 years) and was administered at different growth and developmental stages. The daily leucine dose was 1000 mg (suggested dose ¼ 700e900 mg/day), 1.5% of the total protein amount was designed for her. Because leucine is an essential amino acid, close monitoring of optimal serum levels through blood sampling should be reached for better growth and development. Food avoidance was a major focus on restriction of protein from milk, meat, cheese, fish, poultry (including egg), beans, and nutlets, and even any foods containing milk and egg. Partial limited foods included sprouts (alfalfa, clover), radish, red bean, and murgbean. Unlimited fruits included vegetables and low protein starch such as green bean noodles, rice flour, pearl sago, lotus root powder, cornstarch, and corn flour, and low leucine foods such as potato powder were advised. The patient’s major protein source was from a special formula (I-Valex I and II; Abbott, Chicago, USA). Other nutrients such as multivitamins and minerals were prescribed. Daily oral L-carnitine was also prescribed to increase excretion of organic acid. The ability to recognize food labeling was taught to the parents, the patient, and school nurses. Servings for daily dietary content (Table 1) and sample meal plans were designed (Table 2).

Two novel compound heterozygous mutations in OPA3 in two siblings with OPA3-related 3-methylglutaconic aciduria

OPA3-related 3-methylglutaconic aciduria, or Costeff Optic Atrophy syndrome, is a neuro-ophthalmologic syndrome of early-onset bilateral optic atrophy and later-onset spasticity, and extrapyramidal dysfunction. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is markedly increased. OPA3-related 3-methylglutaconic aciduria is due to mutations in the OPA3 gene located at 19q13.2–13.3. Here we describe two siblings with novel compound heterozygous variants in OPA3: c.1A>G (p.1M>V) in the translation initiation codon in exon 1 and a second variant, c.142+5G>C in intron 1. On cDNA sequencing the c.1A>G appeared homozygous, indicating that the allele without the c.1A>G variant is degraded. This is likely due to an intronic variant; possibly the IVS1+5 splice site variant. The older female sibling initially presented with motor developmental delay and vertical nystagmus during her first year of life and was diagnosed subsequently with optic atrophy. Her brother presented with mildly increased hip muscle tone followed by vertical nystagmus within the first 6months of life, and was found to have elevated urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid, and optic atrophy by 1.5years of age. Currently, ages 16 and 7, both children exhibit ataxic gaits and dysarthric speech. Immunofluorescence studies on patient's cells showed fragmented mitochondrial morphology. Thus, though the exact function of OPA3 remains unknown, our experimental results and clinical summary provide evidence for the pathogenicity of the identified OPA3 variants and provide further evidence for a mitochondrial pathology in this disease.

Vapor pressures of substituted polycarboxylic acids are much lower than previously reported

Abstract. The partitioning of compounds between the aerosol and gas phase is a primary focus in the study of the formation and fate of secondary organic aerosol. We present measurements of the vapor pressure of 2-methylmalonic (isosuccinic) acid, 2-hydroxymalonic (tartronic) acid, 2-methylglutaric acid, 3-hydroxy-3-carboxy-glutaric (citric) acid and DL-2,3-dihydroxysuccinic (DL-tartaric) acid, which were obtained from the evaporation rate of supersaturated liquid particles levitated in an electrodynamic balance. Our measurements indicate that the pure component liquid vapor pressures at 298.15 K for tartronic, citric and tartaric acids are much lower than the same quantity that was derived from solid state measurements in the only other room temperature measurement of these materials (made by Booth et al., 2010). This strongly suggests that empirical correction terms in a recent vapor pressure estimation model to account for the inexplicably high vapor pressures of these and similar compounds should be revisited, and that due caution should be used when the estimated vapor pressures of these and similar compounds are used as inputs for other studies.

Morphologies of mixed organic/inorganic/aqueous aerosol droplets

Despite major progress in the understanding of properties of tropospheric aerosol particles, it remains challenging to understand their physical state and morphology. To obtain more detailed knowledge of the phases, phase transitions and morphologies of internally mixed organic/inorganic aerosol particles, we evaluated liquid-liquid phase separation (LLPS), deliquescence relative humidity (DRH) and efflorescence relative humidity (ERH) of 33 organic/ammonium sulfate (AS)/H2O systems from our own and literature data. The organic fraction consists of single compounds or mixtures with up to ten aliphatic and/or aromatic components with carboxylic acid, hydroxyl, carbonyl, ether, and ester functionalities, covering O : C ratios between 0.29 and 1.33. Thirteen out of these 33 systems did not show LLPS for any of the studied organic-to-inorganic mixing ratios, sixteen underwent LLPS showing core-shell morphology, and four showed both core-shell and partially engulfed configurations depending on the organic-to-inorganic ratio and RH. In all cases the organic fractions of the systems with partially engulfed configurations consisted of dicarboxylic acids. AS in mixed organic/AS/H2O particles deliquesced between 70 and 84% RH. AS effloresced below 58% RH or remained in a one-liquid-phase state. AS in droplets with LLPS always showed efflorescence with ERH between 30 and 50% RH, providing clear evidence that the presence of LLPS facilitates AS efflorescence. Spreading coefficients of the organic-rich phase on the AS-rich phase for systems containing polyethylene glycol 400 (PEG-400) and a mixture of dicarboxylic acids are in agreement with the optically observed morphologies of droplets deposited on the hydrophobic substrate. Analysis of high resolution elastic Mie resonance spectra allowed the detection of LLPS for single levitated droplets consisting of PEG-400/AS/ H2O, whereas LLPS was difficult to detect in (2-methylglutaric acid + 3-methylglutaric acid + 2,2-dimethylsuccinic acid)/AS/H2O. Measured Mie spectra of PEG-400/AS/H2O at 93.5% and at 80.9% RH agreed with computed Mie spectra for a homogeneous and a core-shell configuration, respectively, confirming the results obtained from droplets deposited on a hydrophobic substrate. Based on the presented evidence, we therefore consider the core-shell morphology to be the prevalent configuration of liquid-liquid-phase-separated tropospheric organic/AS/H2O particles.

Properties of a Model Aryl Boronic Acid and Its Boroxine

Many boronic acid-containing molecules are currently under investigation as possible therapeutics. An increase in the knowledge of the physical and chemical properties of these compounds will lead to their improved formulation into usable dosage forms. The current study describes the formation and characterization of a boronic acid anhydride, called a boroxine. The model boronic acid, 4-methoxybenzeneboronic acid is used. The current study demonstrates the utility of thermal (differential scanning calorimetry and thermogravimetric analysis) and spectral (solid-state nuclear magnetic resonance and ultraviolet spectroscopy) methods to quantitate and characterize the boronic acid and its boroxine, validated against definitive structures solved by single-crystal X-ray diffraction. The present work also demonstrates that the hydrolysis of the boroxine in the presence of water is very rapid in a time scale relative to drug substance manufacture and product formulation.

Chiral self-assembly of triorganotin complexes: Syntheses, characterization, crystal structures and antitumor activity of organotin(IV) complexes containing ( R)-(+)-methylsuccinic acid, ( S)-(+)-methylglutaric acid and l-(−)-malic acid ligands

Six new chiral triorganotin(IV) complexes, {(R 3Sn) 2[C 3H 6(COO) 2]} n (R = Me: 1; Bu: 2), {(R 3Sn) 2[C 4H 8(COO) 2]} n (R = Me: 3; Bu: 4), and {(R 3Sn) 2[C 2H 4O(COO) 2]} n (R = Me: 5; Bu: 6) have been prepared by treatment of ( R)-(+)-methylsuccinic acid, ( S)-(+)-methylglutaric acid and l-(−)-malic acid, with the corresponding R 3SnCl (R = Me, Bu) and sodium ethoxide in methanol. All the complexes were characterized by elemental analysis, FT-IR, NMR ( 1H, 13C, 119Sn) spectroscopy and TGA. Except for 3, all of the complexes were also characterized by X-ray crystallography. The structural analyses reveal that complexes 1 and 5 have 2D network structures in which ( R)-(+)-methylsuccinic acid and l-(−)-malic acid act as tetradentate ligands coordinated to trimethyltin(IV) ions. Complexes 2 and 4 have 3D metal–organic framework structures in which the deprotoned acids serve as tetradentate ligands. Complex 6 adopts a 1D zigzag chain structure and forms a 2D supramolecular framework through intermolecular C–H⋯O interactions. In addition, the antitumor activities of complexes 1– 6 have been studied. We also have measured the specific rotation of the chiral dicarboxylic acids and the organotin derivatives.

Neurochemical evidence that 3-methylglutaric acid inhibits synaptic Na+,K+-ATPase activity probably through oxidative damage in brain cortex of young rats

3-Methylglutaconic aciduria (MGTA) comprehends a group of disorders biochemically characterized by accumulation of 3-methylglutaric acid (MGA), 3-methylglutaconic acid (MGT) and occasionally 3-hydroxyisovaleric acid (OHIVA). Although neurological symptoms are common in the affected individuals, the mechanisms of brain damage are poorly known. In the present study we investigated the in vitro effect MGA, MGT and OHIVA, at concentrations ranging from 0.1 to 5.0mM, on bioenergetics and oxidative stress in synaptosomal preparations isolated from cerebral cortex of young rats. MGA significantly reduced mitochondrial redox potential (25%), as determined by resazurin reduction, and inhibited the activity of Na+,K+-ATPase (30%), whereas MGT and OHIVA did not modify these parameters. Moreover, the inhibitory effect elicited by MGA on Na+,K+-ATPase activity was totally prevented by co-incubation with the scavenging antioxidants creatine and melatonin, implying a role for reactive species in this effect. MGA also increased 2′,7′-dichlorofluorescein (DCFH) oxidation (30%), reinforcing that this organic acid induces reactive species production. The present data indicate that MGA compromises mitochondrial function, elicits reactive species production and inhibits the activity of a crucial enzyme implicated in neurotransmission. It is therefore presumed that these deleterious effects may play a role in the pathophysiology of the brain damage observed in patients affected by disorders in which MGA accumulates.

Oxidation of aliphatic, branched chain, and aromatic hydrocarbons by Nocardia cyriacigeorgica isolated from oil‐polluted sand samples collected in the Saudi Arabian Desert

A soil bacterium isolated from oil-polluted sand samples collected in the Saudi Arabian Desert has been determined as Nocardia cyriacigeorgica, which has a high capacity of degrading and utilizing a broad range of hydrocarbons. The metabolic pathways of three classes of hydrocarbons were elucidated by identifying metabolites in cell-free extracts analyzed by GC/MS and HPLC/UV-Vis in comparison with standard compounds. During tetradecane oxidation, tetradecanol; tetradecanoic acid; dodecanoic acid; decanoic acid could be found as metabolites, indicating a monoterminal degradation pathway of n -alkanes. The oxidation of pristane resulted in the presence of pristanoic acid; 2-methylglutaric acid; 4,8-dimethylnonanoic acid; and 2,6-dimethylheptanoic acid, which give rise to a possible mono- and di-terminal oxidation. In case of sec -octylbenzene, eight metabolites were detected including 5-phenylhexanoic acid; 3-phenylbutyric acid; 2-phenylpropionic acid; beta -methylcinnamic acid; acetophenone; beta -hydroxy acetophenone; 2,3-dihydroxy benzoic acid and succinic acid. From these intermediates a new degradation pathway for sec -octylbenzene was investigated. Our results indicate that N. cyriacigeorgica has the ability to degrade aliphatic and branched chain alkanes as well as alkylbenzene effectively and, therefore, N. cyriacigeorgica is probably a suitable bacterium for biodegradation of oil or petroleum products in contaminated soils.

OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria

3-Methylglutaconic aciduria type III (3-MGCA type III), caused by recessive mutations in the 2-exon gene OPA3, is characterized by early-onset bilateral optic atrophy, later-onset extrapyramidal dysfunction, and increased urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid. Here we report the identification of a novel third OPA3 coding exon, the apparent product of a segmental duplication event, resulting in two gene transcripts, OPA3A and OPA3B. OPA3A deficiency (as in optic atrophy type 3) causes up-regulation of OPA3B. OPA3 protein function remains unknown, but it contains a putative mitochondrial leader sequence, mitochondrial sorting signal and a peroxisomal sorting signal. Our green fluorescent protein tagged OPA3 expression studies found its localization to be predominantly mitochondrial. These findings thus place the cellular metabolic defect of 3-MGCA type III in the mitochondrion rather than the peroxisome and implicate loss of OPA3A rather than gain of OPA3B in disease etiology.

Costeff optic atrophy syndrome: New clinical case and novel molecular findings

3-Methylglutaconic aciduria (MGA) encompasses a heterogeneous group of disorders, often coinciding with elevated levels of urinary 3-methylglutaric acid. Type I MGA is a disorder of leucine metabolism, while the biological basis for the MGA is unclear for the other types (MGA types II-V). MGA type III (Costeff optic atrophy syndrome, autosomal recessive optic atrophy-3 or optic atrophy plus syndrome, OMIM 258501) is distinguished by early bilateral optic atrophy, later-onset spasticity, extrapyramidal dysfunction, ataxia, and occasional cognitive deficits. It is caused by homozygous mutations in the optic atrophy 3 gene (OPA3). We present a case of a patient with MGA who has infantile-onset optic atrophy, ataxia, extrapyramidal movements and spasticity, but with normal intellect. Sequencing of the patient's DNA revealed a homozygous nonsense mutation c.415C>T (p.Q139X) in exon 2 of transcript 2 of the OPA3 gene, as well as a common silent polymorphism c.231T>C in the same exon. This is the first nonsense mutation found in OPA3. The molecular findings in OPA3 are also reviewed, including mutations in OPA3 that result in autosomal dominant optic atrophy and cataract (ADOAC). The recessive mode of inheritance of MGA type III as a result of the p.Q139X mutation is supported by the carrier status of the unaffected father.

3-Methylglutaconic Aciduria Type 4 Manifesting as Leigh Syndrome in 2 Siblings

The authors report the case of a pair of siblings with 3-methylglutaconic aciduria type 4 manifesting as Leigh syndrome. Disease progression was monitored from birth until the present. Both patients fulfilled the diagnostic criteria for Leigh syndrome along with increased urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid (biochemical markers of methylglutaric acid) in several determinations. No mitochondrial respiratory chain defects in muscle biopsy were detected. Although mitochondrial abnormalities are the most common known cause of Leigh syndrome, there have been several reports of links with nonmitochondrial metabolic disorders. Descriptions of 3-methylglutaric acid type 4 associated with Leigh syndrome are rare.

3-Methylglutaconic aciduria type I causes leukoencephalopathy of adult onset

3-Methylglutaconic amino aciduria (MGA) is characterized by an increased urinary excretion of 3-methylclutaconic acid and 3-methylglutaric acid.1 Four distinct forms are currently recognized: type I (MGA1), 3-methylglutaconyl-CoA hydratase deficiency caused by mutations of the AUH gene1–7; type II, caused by mutations in the tafazzin gene; type III, occurring in a genetic isolate of Iraqi Jews (causative gene has been recently isolated); and type IV, a heterogeneous group. The symptoms usually appear in the first decade of life.1–7 We herein report MGA1 presenting with progressive leukoencephalopathy in late adulthood. A 55–year-old woman was referred to us for an evaluation of progressive forgetfulness and an unsteady gait since age 53. Urinary incontinence also appeared at age 52. She easily tripped and fell, resulting in a fracture of her right clavicle. Her parents were first cousins. She had no serious illnesses during her childhood, graduated from a junior college, got married at age 23, and gave birth to two healthy children. …

3-Methylglutaric acid as a 13C solid-state NMR standard

The calibration of a solid-state NMR spectrometer requires setting the magic angle, setting the reference and decoupler frequencies, ensuring that the magnetic field is homogeneous across the sample volume, optimizing the signal-to-noise ratio, determining the π/2 pulse durations, and optimizing the Hartman–Hahn matching condition. Each task has one or more widely accepted standards, such as potassium bromide for setting the magic angle, adamantane for optimizing magnet homogeneity, and hexamethylbenzene or glycine for measuring the signal-to-noise ratio. We show that all of these tasks can be performed using 3-methylglutaric acid (MGA). In the case of high-powered decoupling, the CH 2 and CH carbon peaks of MGA provide an opportunity to evaluate the decoupling in a manner that is superior to any of the commonly used standard compounds. Thus, MGA can be used as a single solid-state NMR standard compound to perform all calibration steps except for magnet shimming.

Biochemical characterization of human 3‐methylglutaconyl‐CoA hydratase and its role in leucine metabolism

The metabolic disease 3-methylglutaconic aciduria type I (MGA1) is characterized by an abnormal organic acid profile in which there is excessive urinary excretion of 3-methylglutaconic acid, 3-methylglutaric acid and 3-hydroxyisovaleric acid. Affected individuals display variable clinical manifestations ranging from mildly delayed speech development to severe psychomotor retardation with neurological handicap. MGA1 is caused by reduced or absent 3-methylglutaconyl-coenzyme A (3-MG-CoA) hydratase activity within the leucine degradation pathway. The human AUH gene has been reported to encode for a bifunctional enzyme with both RNA-binding and enoyl-CoA-hydratase activity. In addition, it was shown that mutations in the AUH gene are linked to MGA1. Here we present kinetic data of the purified gene product of AUH using different CoA-substrates. The best substrates were (E)-3-MG-CoA (V(max) = 3.9 U.mg(-1), K(m) = 8.3 microM, k(cat) = 5.1 s(-1)) and (E)-glutaconyl-CoA (V(max) = 1.1 U.mg(-1), K(m) = 2.4 microM, k(cat) = 1.4 s(-1)) giving strong evidence that the AUH gene encodes for the major human 3-MG-CoA hydratase in leucine degradation. Based on these results, a new assay for AUH activity in fibroblast homogenates was developed. The only missense mutation found in MGA1 phenotypes, c.719C>T, leading to the amino acid exchange A240V, produces an enzyme with only 9% of the wild-type 3-MG-CoA hydratase activity.

NMR spectroscopic studies on the late onset form of 3‐methylglutaconic aciduria type I and other defects in leucine metabolism

A diagnosis of 3-methylglutaconic aciduria type I (OMIM: 250950) based on elevated urinary excretion of 3-methylglutaconic acid (3MGA), 3-methylglutaric acid (3MG) and 3-hydroxyisovaleric acid (3HIVA) was made in a 61-year-old female patient presenting with leukoencephalopathy slowly progressing over more than 30 years. The diagnosis was confirmed at the enzymatic and molecular level. In vivo brain MR spectroscopic imaging (MRSI) was performed at 3.0 T, and one-dimensional and two-dimensional in vitro NMR spectroscopy of body fluids of the patient was performed at 11.7 T. Additionally, we measured 1D (1)H-NMR spectra of urine of seven patients with a total of four different inborn errors of leucine metabolism. Increased concentrations of 3HIVA, 3MGA (cis and trans) and 3MG were observed in the NMR spectra of the patient's urine. In the cerebrospinal fluid, the 3HIVA concentration was 10 times higher than in the plasma of the patient and only the cis isomer of 3MGA was observed. In vivo brain MRSI showed an abnormal resonance at 1.28 ppm that may be caused by 3HIVA. Comparison of (1)H-NMR spectra of urine samples from all eight patients studied, representing five different inborn errors of leucine metabolism, showed that each disease has typical NMR characteristics. Our leukoencephalopathy patient suffers from a late-onset form of 3-methylglutaconic aciduria type I. In the literature, only very few adult patients with this conditions have been described, and 3HIVA accumulation in white matter in the brain has not been presented before in these patients. Our data demonstrate that (1)H-NMR spectroscopy of urine can easily discriminate between the known inborn errors of leucine metabolism and provide the correct diagnosis.

Structural investigation of the nickel 3-methylglutarate from powder diffraction demonstrating adaptability of the inorganic skeleton of MIL-77

Ni20[(C6H8O4)20(H2O)8]∙33H2O, a new nickel(II) 3-methylglutarate, was prepared hydrothermally (180 °C, 48 h, autogenous pressure) from a 1:1.5:2:180 mixture of nickel (II) sulphate hexahydrate, 3-methylglutaric acid, sodium hydroxide, and water. It crystallizes in the cubic system (space group P4332, Z=1) with a=16.8488(5) Å and V=4783.1(4) Å3. Its structure was solved from conventional X-ray powder diffraction data. It presents a three-dimensional network of edge-sharing nickel octahedra, lined by deprotonated organic anions. This remarkable oxide network with corrugated 20-membered rings is constructed from homochiral helices. The rings intersect each other to generate large crossing channels full of water along [111].

One‐Pot Synthesis of Helical Aromatics: Stereoselectivity, Stability Against Racemization, and Assignment of Absolute Configuration Assisted by Experimental and Theoretical Circular Dichroism.

AbstractFor Abstract see ChemInform Abstract in Full Text.

らせん不斉を有する縮合芳香族分子の簡便な合成法および理論円二色性スペクトルを用いた絶対配置決定法

Helical aromatics possessing a diazapentaphene skeleton were synthesized via one step in good quantity by solvent-free condensation reaction of N, N'-diphenyl-p-phenylenediamine and various carboxylic acids in the presence of a Lewis acid. Microwave irradiation greatly facilitated the condensation to furnish a helical aromatic with a 100% diastereo- and a 50% enantioselectivity, when a chiral carboxylic acid was utilized. The aromatic derived from 2-methylglutaric acid was quite stable, with no racemization taking place even at 200 °C. The assignment of the absolute configurations to the helical aromatics has been achieved by theoretical CD spectra calculated by time-dependent density functional theory.

One-Pot Synthesis of Helical Aromatics: Stereoselectivity, Stability against Racemization, and Assignment of Absolute Configuration Assisted by Experimental and Theoretical Circular Dichroism

Helical aromatics (1) were synthesized via one step in good quantity by solvent-free condensation of N,N'-p-phenylenediamine (2) and various carboxylic acids in the presence of a Lewis acid. Microwave irradiation greatly facilitated the condensation reaction to furnish 1 with a 100% diastereo- and a 50% enantioselectivity, when a chiral carboxylic acid was utilized. 1f, derived from 2-methylglutaric acid, was quite stable, no racemization taking place even at 200 degrees C. The assignment of the absolute configurations to the helical aromatics has been achieved by experimental and theoretical CD spectra calculated by time-dependent density functional theory.