The outcome of 41 Late-Diagnosed Turkish GA-1 Patients: A Candidate for the Turkish NBS

Background Glutaric aciduria type 1(GA-1) is an inherited cerebral organic aciduria. Untreated patients with GA-1 have a risk of acute encephalopathic crises during the first 6 years of life. In so far as GA-1 desperately does not exist in Turkish newborn screening (NBS) program, most patients in our study were late-diagnosed. Method This study included 41 patients diagnosed with acylcarnitine profile, urinary organic acids, mutation analyses in the symptomatic period. We presented with clinical, neuroradiological, and molecular data of our 41 patients. Results The mean age at diagnosis was 14.8 ± 13.9 (15 days to 72 months) and, high blood glutaconic acid, glutarylcarnitine and urinary glutaric acid (GA) levels in 41 patients were revealed. Seventeen different mutations in the glutaryl-CoA dehydrogenase gene were identified, five of which were novel. The patients, most of whom were late-diagnosed, had a poor neurological outcome. Treatment strategies made a little improvement in dystonia and the frequency of encephalopathic attacks. Conclusion All GA-1 patients in our study were severely affected since they were late-diagnosed, while others show that GA-1 is a treatable metabolic disorder if it is diagnosed with NBS. This study provides an essential perspective of the severe impact on GA-1 patients unless it is diagnosed with NBS. We immediately advocate GA-1 to be included in the Turkish NBS.

Flexible Entry into 3-Arylpent-2-enedioic Acids via Heck–Matsuda Arylation of Dimethyl Glutaconate with Arenediazonium Tosylates

For the preparation of compound libraries of Michael acceptors with tunable reactivity toward nuclophilic selenocysteine residue of thioredoxin reductase, a range of 3-arylglutaconic acids were required. The existing methods at the time had limited scope or involved several steps. A hitherto undescribed protocol for direct palladium(II) acetate-catalyzed arylation of glutaconic acid dimethyl ester at position 3 has been developed with a diverse set of arenediazonium tosylates followed by hydrolysis. This generally good-yielding two-step sequence displayed a propensity to deliver E-configured coupling products while compounds mostly featured in the literature were predominantly Z-configured. The possibility for preparing a library of 4-arylpyridine-2,6(1H,3H)-diones has been exemplified.

SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family

ObjectiveTo demonstrate that mutations in the phosphatidylglycerol remodelling enzyme SERAC1 can cause juvenile-onset complicated hereditary spastic paraplegia (cHSP) clusters, thus adding SERAC1 to the increasing number of complex lipid cHSP genes.MethodsCombined genomic and functional validation studies (whole-exome sequencing, mRNA, cDNA and protein), biomarker investigations (3-methyl-glutaconic acid, filipin staining and phosphatidylglycerols PG34:1/PG36:1), and clinical and imaging phenotyping were performed in six affected subjects from two different branches of a large consanguineous family.Results5 of 6 affected subjects shared cHSP as a common disease phenotype. Three subjects presented with juvenile-onset oligosystemic cHSP, still able to walk several miles at age >10–20 years. This benign phenotypic cluster and disease progression is strikingly divergent to the severe infantile phenotype of all SERAC1 cases reported so far. Two family members showed a more multisystemic juvenile-onset cHSP, indicating an intermediate phenotype between the benign oligosystemic cHSP and the classic infantile SERAC1 cluster. The homozygous splice mutation led to loss of the full-length SERAC1 protein and impaired phosphatidylglycerol PG34:1/PG36:1 remodelling. These phosphatidylglycerol changes, however, were milder than in classic infantile-onset SERAC1 cases, which might partially explain the milder SERAC1 phenotype.ConclusionsOur findings add SERAC1 to the increasing list of complex lipid cHSP genes. At the same time they redefine the phenotypic spectrum of SERAC1 deficiency. It is associated not only with the severe infantile-onset ‘Methylglutaconic aciduria, Deafness, Encephalopathy, Leigh-like’ syndrome (MEGDEL syndrome), but also with oligosystemic juvenile-onset cHSP as part of the now unfolding SERAC1 deficiency spectrum.

Glutaric Aciduria Type I

Glutaric Aciduria type I is a recessive inborn error of metabolism caused by deficiency of glutaryl-CoA dehydrogenase. This enzyme is responsible for catabolism of L-lysine, L-hydroxylysine, and L-tryptophan. Deficiency of this enzyme leads to abnormal accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine. Untreated individuals are at extremely high risk for encephalopathic crisis, usually triggered by an intercurrent illness or other stressor, and typically occurring between 3 and 36 months of age. This crisis classically results in bilateral striatal injury. Treatment, which can help to prevent encephalopathic crises, includes dietary lysine restriction, carnitine supplementation, and careful metabolic management during intercurrent illness.

Adiabatic quantum computing with spin qubits hosted by molecules

Molecular spin QCs for adiabatic quantum computing: a phthalocyanine derivative with three electron qubits and a glutaconic acid radical with one electron bus qubit and two nuclear client qubits.

Neurotoxic Effects oftrans-Glutaconic Acid in Rats

trans-Glutaconic acid (tGA) is an unsaturated C5-dicarboxylic acid which may be found accumulated in glutaric aciduria type I, whose pathophysiology is still uncertain. In the present work it was investigated thein vitroeffect of increasingtGA concentrations on neurochemical and oxidative stress parameters in rat cerebral cortex. We observed that Na+, K+-ATPase activity was reduced bytGA, but not creatine kinase, respiratory chain complex IV, and ATP synthase activities. On the other hand,tGA significantly increased lipid peroxidation (thiobarbituric acid-reactive species levels and spontaneous chemiluminescence), as well as protein oxidative damage (oxidation of sulfhydryl groups).tGA also significantly decreased nonenzymatic antioxidant defenses (TRAP and reduced glutathione levels). Our data suggest thattGA may be neurotoxic in rat brain.

Production of Glutaconic Acid in a RecombinantEscherichia coliStrain

ABSTRACTThe assembly of six genes that encode enzymes from glutamate-fermenting bacteria convertedEscherichia coliinto a glutaconate producer when grown anaerobically on a complex medium. The new anaerobic pathway starts with 2-oxoglutarate from general metabolism and proceeds via (R)-2-hydroxyglutarate, (R)-2-hydroxyglutaryl-coenzyme A (CoA), and (E)-glutaconyl-CoA to yield 2.7 ± 0.2 mM (E)-glutaconate in the medium.