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Indian Journal of Psychological Medicine May 2023
PubMed: 37152389
DOI: 10.1177/02537176231159916 -
Metabolites Apr 2023Organic acidurias are a heterogeneous group of rare inherited metabolic disorders (IMDs) caused by a deficiency of an enzyme or a transport protein involved in the... (Review)
Review
Organic acidurias are a heterogeneous group of rare inherited metabolic disorders (IMDs) caused by a deficiency of an enzyme or a transport protein involved in the intermediary metabolic pathways. These enzymatic defects lead to an accumulation of organic acids in different tissues and their subsequent excretion in urine. Organic acidurias include maple syrup urine disease, propionic aciduria, methylmalonic aciduria, isovaleric aciduria, and glutaric aciduria type 1. Clinical features vary between different organic acid disorders and may present with severe complications. An increasing number of women with rare IMDs are reporting successful pregnancy outcomes. Normal pregnancy causes profound anatomical, biochemical and physiological changes. Significant changes in metabolism and nutritional requirements take place during different stages of pregnancy in IMDs. Foetal demands increase with the progression of pregnancy, representing a challenging biological stressor in patients with organic acidurias as well as catabolic states post-delivery. In this work, we present an overview of metabolic considerations for pregnancy in patients with organic acidurias.
PubMed: 37110176
DOI: 10.3390/metabo13040518 -
Journal of Inherited Metabolic Disease May 2023Methylmalonic acidemia (MMA) is a severe inborn error of metabolism that is characterized by pleiotropic metabolic perturbations and multiorgan pathology. Treatment... (Review)
Review
Methylmalonic acidemia (MMA) is a severe inborn error of metabolism that is characterized by pleiotropic metabolic perturbations and multiorgan pathology. Treatment options are limited and non-curative as the underlying causative molecular mechanisms remain unknown. While earlier studies have focused on the potential direct toxicity of metabolites such as methylmalonic and propionic acid as a mechanism to explain disease pathophysiology, new observations have revealed that aberrant acylation, specifically methylmalonylation, is a characteristic feature of MMA. The mitochondrial sirtuin enzyme SIRT5 is capable of recognizing and removing this PTM, however, reduced protein levels of SIRT5 along with other mitochondrial SIRTs 3 and 4 in MMA and potentially reduced function of all three indicates aberrant acylation may require clinical intervention. Therefore, targeting posttranslational modifications may represent a new therapeutic approach to treat MMA and related organic acidemias.
Topics: Humans; Amino Acid Metabolism, Inborn Errors; Mitochondria; Methylmalonyl-CoA Mutase; Methylmalonic Acid; Propionic Acidemia
PubMed: 37078237
DOI: 10.1002/jimd.12617 -
Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B delivery and repair.BioRxiv : the Preprint Server For... Mar 2023G-proteins function as molecular switches to power cofactor translocation and confer fidelity in metal trafficking. MMAA, a G-protein motor, together with MMAB, an...
G-proteins function as molecular switches to power cofactor translocation and confer fidelity in metal trafficking. MMAA, a G-protein motor, together with MMAB, an adenosyltransferase, orchestrate cofactor delivery and repair of B -dependent human methylmalonyl-CoA mutase (MMUT). The mechanism by which the motor assembles and moves a >1300 Da cargo, or fails in disease, are poorly understood. Herein, we report the crystal structure of the human MMUT-MMAA nanomotor assembly, which reveals a dramatic 180° rotation of the B domain, exposing it to solvent. The nanomotor complex, stabilized by MMAA wedging between two MMUT domains, leads to ordering of the switch I and III loops, revealing the molecular basis of mutase-dependent GTPase activation. The structure explains the biochemical penalties incurred by methylmalonic aciduria-causing mutations that reside at the newly identified MMAA-MMUT interfaces.
PubMed: 36993209
DOI: 10.1101/2023.03.23.533963 -
Intractable & Rare Diseases Research Feb 2023Methylmalonic acidemia with homocystinuria (MMA-cblC) is an autosomal recessive genetic disorder of organic acid metabolism. Shandong, a northern province of China, has...
Methylmalonic acidemia with homocystinuria (MMA-cblC) is an autosomal recessive genetic disorder of organic acid metabolism. Shandong, a northern province of China, has a significantly high incidence of about 1/4,000, suggesting a high carrying rate among the local population. The current study established a PCR technique involving high-resolution melting (HRM) to screen for carriers based on hotspot mutation analysis to further develop a preventive strategy to reduce the local incidence of this rare disease. Whole-exome sequencing of 22 families with MMA-cblC and a comprehensive literature review were used to identify MMACHC hotspot mutations in Shandong Province. Subsequently, a PCR-HRM assay based on the selected mutations was established and optimized for large-scale hotspot mutation screening. The accuracy and efficiency of the screening technique was validated using samples from 69 individuals with MMA-cblC and 1,000 healthy volunteers. Six hotspot mutations in the MMACHC gene (c.609G>A, c.658_660delAAG, c.80A>G, c.217C>T, c.567dupT and c.482G>A), which account for 74% of the alleles associated with MMA-cblC, were used to establish a screening technique. The established PCR-HRM assay detected 88 MMACHC mutation alleles in a validation study with 100% accuracy. In the general population in Shandong, the carrying rate of 6 MMACHC hotspot mutations was 3.4%. In conclusion, the 6 hotspots identified cover the majority of the MMACHC mutation spectrum, and the Shandong population has a particularly high carrying rate of MMACHC mutations. The PCR-HRM assay is highly accurate, cost-effective, and easy to use, making it an ideal choice for mass carrier screening.
PubMed: 36873673
DOI: 10.5582/irdr.2023.01016 -
Molecular Genetics & Genomic Medicine Jun 2023The incidence of inborn errors of metabolism (IEM) varies across countries and areas. Currently, there are no studies on IEM using newborn screening (NBS) in eastern...
BACKGROUND
The incidence of inborn errors of metabolism (IEM) varies across countries and areas. Currently, there are no studies on IEM using newborn screening (NBS) in eastern coastal areas of China. We aimed to estimate the incidence and genetic variants of IEM and understand the spectrum of diseases caused by IEM and variants among them in this area.
METHODS
The NBS performed by tandem mass spectrometry (MS/MS) from 2016 to 2021 was retrospectively reviewed. Heel blood was collected from all newborns 72 h after birth. Targeted massively parallel sequencing was performed for genetic analysis.
RESULTS
Among 245,194 newborns, 95 were diagnosed with IEM, the overall incidence observed was-IEM: 1/2581; amino acid metabolism disorder: 1/4715; organic acid metabolism disorder: 1/11676; and fatty acid metabolism disorder: 1/11145. The incidence of different IEM was in the range of 1/245194 to 1/6452. Phenylketonuria (PKU, 1/7211) was the most common IEM, followed by methylmalonic acidemia (MMA, 1/27244), short-chain acyl-CoA dehydrogenase deficiency (SCADD, 1/30649), and citrin deficiency (CD, 1/35028). For genetic variants, the common hotspot variants found were-PAH gene for PKU: c.728G > A, c.442-1G > A, c.611A > G, c.721C > T; PTS gene for non-classical PKU: c.259C > T; MMACHC gene for MMA: c.658_660delAAG, c.609G > A; MMUT gene for MMA: c.1663G > A; ACADS gene for SCADD: c.1031A > G and c.1130C > T; and SLC25A13 gene for CD: c.1638_1660dup, c.852_855del.
CONCLUSION
This study displayed the diseases and varied spectrum of IEM in eastern coastal areas of China. Implementing NBS for IEM by MS/MS combined with massively parallel sequencing can offer an improved plan for NBS to detect IEM.
Topics: Infant, Newborn; Humans; Neonatal Screening; Tandem Mass Spectrometry; Incidence; Retrospective Studies; Citrullinemia; Metabolism, Inborn Errors; Phenylketonurias; China; Mitochondrial Membrane Transport Proteins; Oxidoreductases
PubMed: 36787440
DOI: 10.1002/mgg3.2152 -
Proceedings of the National Academy of... Feb 2023G-protein metallochaperone MeaB in bacteria [methylmalonic aciduria type A (MMAA) in humans] is responsible for facilitating the delivery of adenosylcobalamin (AdoCbl)...
G-protein metallochaperone MeaB in bacteria [methylmalonic aciduria type A (MMAA) in humans] is responsible for facilitating the delivery of adenosylcobalamin (AdoCbl) to methylmalonyl-CoA mutase (MCM), the only AdoCbl-dependent enzyme in humans. Genetic defects in the switch III region of MMAA lead to the genetic disorder methylmalonic aciduria in which the body is unable to process certain lipids. Here, we present a crystal structure of MeaB bound to a nonhydrolyzable guanosine triphosphate (GTP) analog guanosine-5'-[(β,γ)-methyleno]triphosphate (GMPPCP) with the Cbl-binding domain of its target mutase enzyme (MCM). This structure provides an explanation for the stimulation of the GTP hydrolyase activity of MeaB afforded by target protein binding. We find that upon MCM association, one protomer of the MeaB dimer rotates ~180°, such that the inactive state of MeaB is converted to an active state in which the nucleotide substrate is now surrounded by catalytic residues. Importantly, it is the switch III region that undergoes the largest change, rearranging to make direct contacts with the terminal phosphate of GMPPCP. These structural data additionally provide insights into the molecular basis by which this metallochaperone contributes to AdoCbl delivery without directly binding the cofactor. Our data suggest a model in which GTP-bound MeaB stabilizes a conformation of MCM that is open for AdoCbl insertion, and GTP hydrolysis, as signaled by switch III residues, allows MCM to close and trap its cofactor. Substitutions of switch III residues destabilize the active state of MeaB through loss of protein:nucleotide and protein:protein interactions at the dimer interface, thus uncoupling GTP hydrolysis from AdoCbl delivery.
Topics: Humans; Metallochaperones; Molecular Chaperones; Methylmalonyl-CoA Mutase; Nucleotides; Guanosine Triphosphate
PubMed: 36787360
DOI: 10.1073/pnas.2214085120 -
Frontiers in Neuroscience 2023Methylmalonic acidemia (MMA) is a genetic disease of abnormal organic acid metabolism, which is one of the important factors affecting the survival rate and quality of... (Review)
Review
Methylmalonic acidemia (MMA) is a genetic disease of abnormal organic acid metabolism, which is one of the important factors affecting the survival rate and quality of life of newborns or infants. Early detection and diagnosis are particularly important. The diagnosis of MMA mainly depends on clinical symptoms, newborn screening, biochemical detection, gene sequencing and neuroimaging diagnosis. The accumulation of methylmalonic acid and other metabolites in the body of patients causes brain tissue damage, which can manifest as various degrees of intellectual disability and severe neurological dysfunction. Neuroimaging examination has important clinical significance in the diagnosis and prognosis of MMA. This review mainly reviews the etiology, pathogenesis, and nervous system development, especially the neuroimaging features of MMA.
PubMed: 36777632
DOI: 10.3389/fnins.2023.1110942 -
Analytical Chemistry Feb 2023First-tier MS-based newborn screening by flow injection analysis can have high presumptive positive rates, often due to isomeric/isobaric compounds or poor biomarker...
First-tier MS-based newborn screening by flow injection analysis can have high presumptive positive rates, often due to isomeric/isobaric compounds or poor biomarker specificity. These presumptive positive samples can be analyzed by second-tier screening assays employing separations such as liquid chromatography-mass spectrometry (LC-MS/MS), which increases test specificity and drastically reduces false positive referrals. The ability to screen for multiple disorders in a single multiplexed test simplifies workflows and maximizes public health laboratories' resources. In this study, we developed and validated a highly multiplexed second-tier method for dried blood spots using a hydrophilic interaction liquid chromatography (HILIC) column coupled to an MS/MS system. The LC-MS/MS method was capable of simultaneously detecting second-tier biomarkers for maple syrup urine disease, homocystinuria, methylmalonic acidemia, propionic acidemia, glutaric acidemia type 1, glutaric acidemia type 2, guanidinoacetate methyltransferase deficiency, short-chain acyl-CoA dehydrogenase deficiency, adrenoleukodystrophy, and Pompe disease.
Topics: Infant, Newborn; Humans; Amino Acids; Neonatal Screening; Chromatography, Liquid; Lysophosphatidylcholines; Tandem Mass Spectrometry; Propionic Acidemia; Organic Chemicals; Antifibrinolytic Agents; Biomarkers
PubMed: 36724346
DOI: 10.1021/acs.analchem.2c03098 -
Nature Metabolism Jan 2023Methylmalonic aciduria (MMA) is an inborn error of metabolism with multiple monogenic causes and a poorly understood pathogenesis, leading to the absence of effective...
Methylmalonic aciduria (MMA) is an inborn error of metabolism with multiple monogenic causes and a poorly understood pathogenesis, leading to the absence of effective causal treatments. Here we employ multi-layered omics profiling combined with biochemical and clinical features of individuals with MMA to reveal a molecular diagnosis for 177 out of 210 (84%) cases, the majority (148) of whom display pathogenic variants in methylmalonyl-CoA mutase (MMUT). Stratification of these data layers by disease severity shows dysregulation of the tricarboxylic acid cycle and its replenishment (anaplerosis) by glutamine. The relevance of these disturbances is evidenced by multi-organ metabolomics of a hemizygous Mmut mouse model as well as through identification of physical interactions between MMUT and glutamine anaplerotic enzymes. Using stable-isotope tracing, we find that treatment with dimethyl-oxoglutarate restores deficient tricarboxylic acid cycling. Our work highlights glutamine anaplerosis as a potential therapeutic intervention point in MMA.
Topics: Mice; Animals; Methylmalonyl-CoA Mutase; Glutamine; Multiomics; Metabolism, Inborn Errors
PubMed: 36717752
DOI: 10.1038/s42255-022-00720-8