BACKGROUND: Glutaric aciduria type II (GA2) is a rare genetic disorder inherited in an autosomal recessive manner. Double dosage mutations in GA2 corresponding genes, ETFDH, ETFA, and ETFB, lead to defects in the catabolism of fatty acids, and amino acids lead to broad-spectrum phenotypes, including muscle weakness, developmental delay, and seizures. product of these three genes have crucial role in transferring electrons to the electron transport chain (ETC), but are not directly involve in ETC complexes.
METHODS: Here, by using exome sequencing, the cause of periodic cryptic gastrointestinal complications in a 19-year-old girl was resolved after years of diagnostic odyssey. Protein modeling for the novel variant served as another line of validation for it.
RESULTS: Exome Sequencing (ES) identified two variants in ETFDH: ETFDH:c.926T>G and ETFDH:c.1141G>C. These variants are likely contributing to the crisis in this case. To the best of our knowledge at the time of writing this manuscript, variant ETFDH:c.926T>G is reported here for the first time. Clinical manifestations of the case and pathological analysis are in consistent with molecular findings. Protein modeling provided another line of evidence proving the pathogenicity of the novel variant. ETFDH:c.926T>G is reported here for the first time in relation to the causation GA2.
CONCLUSIONS: Given the milder symptoms in this case, a review of GA2 cases caused by compound heterozygous mutations was conducted, highlighting the range of symptoms observed in these patients, from mild fatigue to more severe outcomes. The results underscore the importance of comprehensive genetic analysis in elucidating the spectrum of clinical presentations in GA2 and guiding personalized treatment strategies.

BACKGROUND: Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is the most common lipid storage myopathy. There are sex differences in fat metabolism and it is not known whether late-onset MADD affects men and women equally.
METHODS: In this systematic review and meta-analysis, the PubMed, Embase, Web of Science, CNKI, CBM, and Wanfang databases were searched until 01/08/2023. Studies reporting sex distribution in patients with late-onset MADD were included. Two authors independently screened studies for eligibility, extracted data, and assessed risk of bias. Pre-specified outcomes of interest were the male-to-female ratio (MFR) of patients with late-onset MADD, the differences of clinical characteristics between the sexes, and factors influencing the MFR.
RESULTS: Of 3379 identified studies, 34 met inclusion criteria, yielding a total of 609 late-onset MADD patients. The overall pooled percentage of males was 58% (95% CI, 54-63%) with low heterogeneity across studies (I2 = 2.99%; P = 0.42). The mean onset ages, diagnostic delay, serum creatine kinase (CK), and allelic frequencies of 3 hotspot variants in ETFDH gene were similar between male and female patients (P > 0.05). Meta-regressions revealed that ethnic group was associated with the MFR in late-onset MADD, and subgroup meta-analyses demonstrated that East-Asian patients had a higher percentage of male, lower CK, and higher proportion of hotspot variants in ETFDH gene than non-East-Asian patients (P < 0.05).
CONCLUSIONS: Male patients with late-onset MADD were more common than female patients. Ethnicity was proved to be a factor influencing the MFR in late-onset MADD. These findings suggest that male sex may be a risk factor for the disease.

Plant-derived insecticide-neonicotinoid insecticides (NIs) played a crucial role in the development of agriculture and food industry in recent years. Nevertheless, synthesis of these nitrogen-containing heterocyclic compounds with an effective and greener routing remains challenging especially to the notion raise of \"green chemistry\" and \"atom economy\". While bio-catalyzed methods mediated by nicotinate dehydrogenase (NDHase) then provide an alternative. The current review mainly focuses on the introduction of sources, components, structure, catalytic mechanism and applications of NDHase. Specifically, NDHase is known as nicotinic acid hydroxylase and the sources principally derived from phylum Proteobacteria. In addition, NDHase requires the participation of the electron respiratory chain system on the cell membrane. And the most important components of the electron respiratory chain are hydrogen carrier, which is mainly composed of iron-sulfur proteins (Fe-S), flavin dehydrogenase (FAD), molybdenum binding protein and cytochromes. Heterologous expression studies were hampered by the plasmid and host with high efficiency and currently only Pseudomonas entomophila L48 as well as Comamonas testosterone was successfully utilized for the expression of NDHase. Furthermore, it is speculated that the conjugate and inductive effects of the substituent group at position 3 of the substrate pyridine ring exerts a critical role in the hydroxylation reactions at position 6 concerning about the substrate molecular recognition mechanism. Finally, applications of NDHase are addressed in terms of pesticide industry and wastewater treatment. On conclusion, this critical review would not only deepen our understanding of the theory about NDHase, but also provides the guideline for future investigation of NDHase.

Multiple-acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessive disorder which can be split into three types. Type III MADD is associated with acute or subacute proximal muscle weakness and other variable non-specific features making it a challenging diagnosis for the clinician. This case report describes MADD in a 64 year-old lady, thought to be one of the latest first presentations of the disease. Unusually for this condition, the initial presentation was with dyspnoea. Furthermore, since this case provides further evidence that gene variants can predict age of onset, we advocate for further subclassification of type III MADD into late onset MADD (LO-MADD) when homozygous gene variants are present and very LO-MADD when heterozygous gene variants are found.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism affecting fatty acid, amino acid, and choline metabolism. The clinical manifestation of MADD is heterogeneous, from severe neonatal forms to mild late-onset forms.
UNASSIGNED: Here, we report a patient who presented with severe hypoglycemia and exercise intolerance suggestive of MADD. Serum tandem mass spectrometry analysis indicated elevated levels of various acyl carnitines at 25 days of age. Exome sequencing of the proband revealed compound heterozygous mutations, c. 413T>G (p.Leu138Arg) and c.1667C > G (p.Pro556Arg), in the ETFDH gene as the probable causative mutations.
UNASSIGNED: Based on the patient\'s clinical presentation and test results, the patient was diagnosed with MADD.
METHODS: A high-calorie and reduced-fat diet was given together with oral supplements of L-carnitine (150 mg/day).
RESULTS: He passed away at the age of 4 months because of severe respiratory distress accompanied by muscle weakness.
CONCLUSIONS: He passed away at the age of 4 months because of severe respiratory distress accompanied by muscle weakness. Clinicians should consider MADD in the differential diagnosis when patients present with muscle weakness and biochemical abnormalities. Gene testing plays a critical role in confirming the diagnosis of MADD and may not only prevent the need for invasive testing but also allow for timely initiation of treatment.

Alzheimer\'s, a degenerative cause of the brain cells, is called as a progressive neurodegenerative disease and appears to have a heterogeneous etiology with main emphasis on amyloid-cascade and hyperphosphorylated tau-cascade hypotheses, that are directly linked with macromolecules called enzymes such as β- & γ-secretases, colinesterases, transglutaminases, and glycogen synthase kinase (GSK-3), cyclin-dependent kinase (cdk-5), microtubule affinity-regulating kinase (MARK). The catalytic activity of the above enzymes is the result of cognitive deficits, memory impairment and synaptic dysfunction and loss, and ultimately neuronal death. However, some other enzymes also lead to these dysfunctional events when reduced to their normal activities and levels in the brain, such as α- secretase, protein kinase C, phosphatases etc; metabolized to neurotransmitters, enzymes like monoamine oxidase (MAO), catechol-O-methyltransferase (COMT) etc. or these abnormalities can occur when enzymes act by other mechanisms such as phosphodiesterase reduces brain nucleotides (cGMP and cAMP) levels, phospholipase A2: PLA2 is associated with reactive oxygen species (ROS) production etc. On therapeutic fronts, several significant clinical trials are underway by targeting different enzymes for development of new therapeutics to treat Alzheimer\'s, such as inhibitors for β-secretase, GSK-3, MAO, phosphodiesterase, PLA2, cholinesterases etc, modulators of α- & γ-secretase activities and activators for protein kinase C, sirtuins etc. The last decades have perceived an increasing focus on findings and search for new putative and novel enzymatic targets for Alzheimer\'s. Here, we review the functions, pathological roles, and worth of almost all the Alzheimer\'s associated enzymes that address to therapeutic strategies and preventive approaches for treatment of Alzheimer\'s.

After the initial use of anti-folates for treatment of malignancies, folate metabolism has emerged as a rational diagnostic and therapeutic target in gastrointestinal cancer. The one-carbon metabolic pathway, which comprises three critical reactions (i.e., folate and methionine cycles), underlies this effect in conjunction with the trans-sulfuration pathway. Understanding of the one-carbon metabolism pathway has served to unravel the link between the causes and effects of cancer phenotypes leading to several seminal discoveries such as that of diadenosine tri-phosphate hydrolase, microRNAs, 5-FU and, more recently, trifluridine. In the folate cycle, glycine and serine fuel the mitochondrial enzymes SHMT2, MTHFD2 and ALDH1L2, which play critical roles in the cancer survival and proliferation presumably through purine production. In the methionine cycle, S-adenocyl methionine serves hydrocarbons and polyamines that are critical for the epigenetic controls. The trans-sulfuration pathway is a critical component in the synthesis of glutathione, which is involved in the production of reactive oxygen species in cancer stem cells. Therefore, characterization of one-carbon metabolism is indispensable to the development of precision medicine in the context of cancer diagnostics and therapeutics. In the present study, we review the historical issues associated with one-carbon metabolism and highlight the recent advances in cancer research.

Nanotechnology for cancer gene therapy is an emerging field. Nucleic acids, polyamine analogues and cytotoxic products of polyamine oxidation, generated in situ by an enzyme-catalyzed reaction, can be developed for nanotechnology-based cancer therapeutics with reduced systemic toxicity and improved therapeutic efficacy. Nucleic acid-based gene therapy approaches depend on the compaction of DNA/RNA to nanoparticles and polyamine analogues are excellent agents for the condensation of nucleic acids to nanoparticles. Polyamines and amine oxidases are found in higher levels in tumours compared to that of normal tissues. Therefore, the metabolism of polyamines spermidine and spermine, and their diamine precursor, putrescine, can be targets for antineoplastic therapy since these naturally occurring alkylamines are essential for normal mammalian cell growth. Intracellular polyamine concentrations are maintained at a cell type-specific set point through the coordinated and highly regulated interplay between biosynthesis, transport, and catabolism. In particular, polyamine catabolism involves copper-containing amine oxidases. Several studies showed an important role of these enzymes in developmental and disease-related processes in animals through the control of polyamine homeostasis in response to normal cellular signals, drug treatment, and environmental and/or cellular stress. The production of toxic aldehydes and reactive oxygen species (ROS), H2O2 in particular, by these oxidases suggests a mechanism by which amine oxidases can be exploited as antineoplastic drug targets. The combination of bovine serum amine oxidase (BSAO) and polyamines prevents tumour growth, particularly well if the enzyme has been conjugated with a biocompatible hydrogel polymer. The findings described herein suggest that enzymatically formed cytotoxic agents activate stress signal transduction pathways, leading to apoptotic cell death. Consequently, superparamagnetic nanoparticles or other advanced nanosystem based on directed nucleic acid assemblies, polyamine-induced DNA condensation, and bovine serum amine oxidase may be proposed for futuristic anticancer therapy utilizing nucleic acids, polyamines and BSAO. BSAO based nanoparticles can be employed for the generation of cytotoxic polyamine metabolites.

Multiple Acyl-CoA dehydrogenation deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation and amino-acid metabolism. Most patients with late-onset MADD are well responsive to treatment with riboflavin, which is also termed as riboflavin-responsive MADD (RR-MADD). In this study, we summarized the clinical profiles and genetic features of 13 Chinese patients with RR-MADD and reanalyzed the existing data on RR-MADD patients in Mainland China. In a cohort comprising 13 patients, all were seen to present with severe muscular symptoms occasionally accompanied with mild involvements of extramuscular organs. A total of 18 mutations (13 reported and 5 novel) of the ETFDH gene were identified in this series of patients. Exon deletion/duplication was not found in all patients. ETF:QO expression from the muscle specimens was significantly decreased in all patients. At the time of this study the total number of RR-MADD cases had reached 148 in Mainland China since 2009. The muscle symptoms in Mainland China were similar to those in other regions. However, the common extramuscular symptoms were fatty liver and recurrent vomiting in mainland Chinese patients rather than encephalopathy found in Caucasian patients. A total of 68 mutations had been identified in 148 patients with RR-MADD. The c.250G>A had a high mutation frequency in Southern China, whereas c.770A>G and c.1227A>C were more geographically widespread hot spot mutations in Mainland China.

The identification of increased polyamine concentrations in a variety of diseases from cancer and psoriasis to parasitic infections has led to the hypothesis that manipulation of polyamine metabolism is a realistic target for therapeutic or preventative intervention in the treatment of certain diseases. The early development of polyamine biosynthetic single enzyme inhibitors such as alpha-difluoromethylornithine (DFMO) and methylglyoxal bis(guanylhydrazone) showed some interesting early promise as anticancer drugs, but ultimately failed in vivo. Despite this, DFMO is currently in use as an effective anti-parasitic agent and has recently also been shown to have further potential as a chemopreventative agent in colorectal cancer. The initial promise in vitro led to the development and testing of other potential inhibitors of the pathway namely the polyamine analogues. The analogues have met with greater success than the single enzyme inhibitors possibly due to their multiple targets. These include down regulation of polyamine biosynthesis through inhibition of ornithine decarboxylase and S-adenosylmethionine decarboxylase and decreased polyamine uptake. This coupled with increased activity of the catabolic enzymes, polyamine oxidase and spermidine/spermine N1-acetyltransferase, and increased polyamine export has made the analogues more effective in depleting polyamine pools. Recently, the identification of a new oxidase (PAO-h1/SMO) in polyamine catabolism and evidence of induction of both PAO and PAO-h1/SMO in response to polyamine analogue treatment, suggests the analogues may become an important part of future chemotherapeutic and/or chemopreventative regimens.