RESUMEN
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by pulmonary fibroblast overactivation, resulting in the accumulation of abnormal extracellular matrix and lung parenchymal damage. Although the pathogenesis of IPF remains unclear, aging was proposed as the most prominent nongenetic risk factor. Propionate metabolism undergoes reprogramming in the aging population, leading to the accumulation of the by-product methylmalonic acid (MMA). This study aimed to explore alterations in propionate metabolism in IPF and the impact of the by-product MMA on pulmonary fibrosis. It revealed alterations in the expression of enzymes involved in propionate metabolism within IPF lung tissues, characterized by an increase in propionyl-CoA carboxylase and methylmalonyl-CoA epimerase expression, and a decrease in methylmalonyl-CoA mutase expression. Knockdown of methylmalonyl-CoA mutase, the key enzyme in propionate metabolism, induced a profibrotic phenotype and activated co-cultured fibroblasts in A549 cells. MMA exacerbated bleomycin-induced mouse lung fibrosis and induced a profibrotic phenotype in both epithelial cells and fibroblasts through activation of the canonical transforming growth factor-ß/Smad pathway. Overall, these findings unveil an alteration of propionate metabolism in IPF, leading to MMA accumulation, thus exacerbating lung fibrosis through promoting profibrotic phenotypic transitions via the canonical transforming growth factor-ß/Smad signaling pathway.
Asunto(s)
Envejecimiento , Fibrosis Pulmonar Idiopática , Ácido Metilmalónico , Animales , Humanos , Ratones , Ácido Metilmalónico/metabolismo , Envejecimiento/metabolismo , Envejecimiento/patología , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/inducido químicamente , Masculino , Fibroblastos/metabolismo , Fibroblastos/patología , Femenino , Ratones Endogámicos C57BL , Anciano , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/inducido químicamente , Persona de Mediana Edad , Células A549 , Bleomicina/efectos adversos , Pulmón/patología , Pulmón/metabolismoRESUMEN
Although both localized nuclear magnetic resonance spectroscopy (MRS) and non-localized nuclear magnetic resonance spectroscopy (NMR) generate the same information, i.e., spectra generated by various groups from the structure of metabolites, they are rarely employed in the same study or by the same research group. As our review reveals, these techniques have never been applied in the same study of methylmalonic acidemia (MMA), propionic acidemia (PA) or vitamin B12 deficiency patients. On the other hand, MRS and NMR provide complementary information which is very valuable in the assessment of the severity of disease and efficiency of its treatment. Thus, MRS provides intracellular metabolic information from localized regions of the brain, while NMR provides extracellular metabolic information from biological fluids like urine, blood or cerebrospinal fluid. This paper presents an up-to-date review of the NMR and MRS studies reported to date for methylmalonic and propionic acidemias. Vitamin B12 deficiency, although in most of its cases not inherited, shares similarities in its metabolic effects with MMA and it is also covered in this review.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos , Espectroscopía de Resonancia Magnética , Acidemia Propiónica , Humanos , Acidemia Propiónica/diagnóstico , Acidemia Propiónica/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Deficiencia de Vitamina B 12/diagnóstico , Deficiencia de Vitamina B 12/metabolismo , Ácido Metilmalónico/metabolismoRESUMEN
Combined malonic and methylmalonic aciduria is a rare genetic disorder caused by ACSF3 biallelic variants that results in impaired protein and fat metabolism and the accumulation of malonic and methylmalonic acids. A 52-day-old infant with a fever and a history of possible meningitis during the neonatal period was hospitalized. Multiple lesions of necrotizing lymphadenitis with abscesses in the left inguinal area were treated by incision and drainage along with appropriate antibiotic therapy, which revealed a methicillin-resistant Staphylococcus aureus infection. At 6 months of age, the patient was admitted with anal abscesses. Due to the increased suspicion of primary immunodeficiency disease, genetic testing was conducted, which revealed ACSF3 biallelic variants inherited from both parents. Urine organic acid analysis revealed elevated levels of malonic and methylmalonic acids. At 29 months, the patient showed normal growth and development without any dietary modifications. He had occasional colds, but severe bacterial infections were absent. The prognosis suggests a benign disease course. Here, we present the first reported case of ACSF3 compound heterozygote variants in Korea.
Asunto(s)
Staphylococcus aureus Resistente a Meticilina , Enfermedades de Inmunodeficiencia Primaria , Lactante , Recién Nacido , Masculino , Humanos , Absceso , Staphylococcus aureus Resistente a Meticilina/genética , Ácido Metilmalónico/metabolismoRESUMEN
Newborn screening (NBS) programs are effective measures of secondary prevention and have been successively extended. We aimed to evaluate NBS for methylmalonic acidurias, propionic acidemia, homocystinuria, remethylation disorders and neonatal vitamin B12 deficiency, and report on the identification of cofactor-responsive disease variants. This evaluation of the previously established combined multiple-tier NBS algorithm is part of the prospective pilot study "NGS2025" from August 2016 to September 2022. In 548,707 newborns, the combined algorithm was applied and led to positive NBS results in 458 of them. Overall, 166 newborns (prevalence 1: 3305) were confirmed (positive predictive value: 0.36); specifically, methylmalonic acidurias (N = 5), propionic acidemia (N = 4), remethylation disorders (N = 4), cystathionine beta-synthase (CBS) deficiency (N = 1) and neonatal vitamin B12 deficiency (N = 153). The majority of the identified newborns were asymptomatic at the time of the first NBS report (total: 161/166, inherited metabolic diseases: 9/14, vitamin B12 deficiency: 153/153). Three individuals were cofactor-responsive (methylmalonic acidurias: 2, CBS deficiency: 1), and could be treated by vitamin B12, vitamin B6 respectively, only. In conclusion, the combined NBS algorithm is technically feasible, allows the identification of attenuated and severe disease courses and can be considered to be evaluated for inclusion in national NBS panels.
Asunto(s)
Homocistinuria , Acidemia Propiónica , Deficiencia de Vitamina B 12 , Humanos , Recién Nacido , Homocistinuria/diagnóstico , Estudios Prospectivos , Tamizaje Neonatal/métodos , Proyectos Piloto , Vitamina B 12 , Deficiencia de Vitamina B 12/diagnóstico , Fenotipo , Ácido Metilmalónico/metabolismo , VitaminasRESUMEN
Methylmalonyl-coenzyme A (CoA) mutase (MMUT)-type methylmalonic aciduria is a rare inherited metabolic disease caused by the loss of function of the MMUT enzyme. Patients develop symptoms resembling those of primary mitochondrial disorders, but the underlying causes of mitochondrial dysfunction remain unclear. Here, we examined environmental and genetic interactions in MMUT deficiency using a combination of computational modeling and cellular models to decipher pathways interacting with MMUT. Immortalized fibroblast (hTERT BJ5ta) MMUT-KO (MUTKO) clones displayed a mild mitochondrial impairment in standard glucose-based medium, but they did not to show increased reliance on respiratory metabolism nor reduced growth or viability. Consistently, our modeling predicted MUTKO specific growth phenotypes only for lower extracellular glutamine concentrations. Indeed, two of three MMUT-deficient BJ5ta cell lines showed a reduced viability in glutamine-free medium. Further, growth on 183 different carbon and nitrogen substrates identified increased NADH (nicotinamide adenine dinucleotide) metabolism of BJ5ta and HEK293 MUTKO cells compared with controls on purine- and glutamine-based substrates. With this knowledge, our modeling predicted 13 reactions interacting with MMUT that potentiate an effect on growth, primarily those of secondary oxidation of propionyl-CoA, oxidative phosphorylation and oxygen diffusion. Of these, we validated 3-hydroxyisobutytyl-CoA hydrolase (HIBCH) in the secondary propionyl-CoA oxidation pathway. Altogether, these results suggest compensation for the loss of MMUT function by increasing anaplerosis through glutamine or by diverting flux away from MMUT through the secondary propionyl-CoA oxidation pathway, which may have therapeutic relevance.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos , Enfermedades Mitocondriales , Humanos , Células HEK293 , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Enfermedades Mitocondriales/metabolismo , Metilmalonil-CoA Mutasa , Ácido Metilmalónico/metabolismoRESUMEN
The systemic metabolic shifts that occur during aging and the local metabolic alterations of a tumor, its stroma and their communication cooperate to establish a unique tumor microenvironment (TME) fostering cancer progression. Here, we show that methylmalonic acid (MMA), an aging-increased oncometabolite also produced by aggressive cancer cells, activates fibroblasts in the TME, which reciprocally secrete IL-6 loaded extracellular vesicles (EVs) that drive cancer progression, drug resistance and metastasis. The cancer-associated fibroblast (CAF)-released EV cargo is modified as a result of reactive oxygen species (ROS) generation and activation of the canonical and noncanonical TGFß signaling pathways. EV-associated IL-6 functions as a stroma-tumor messenger, activating the JAK/STAT3 and TGFß signaling pathways in tumor cells and promoting pro-aggressive behaviors. Our findings define the role of MMA in CAF activation to drive metastatic reprogramming, unveiling potential therapeutic avenues to target MMA at the nexus of aging, the tumor microenvironment and metastasis.
Asunto(s)
Fibroblastos Asociados al Cáncer , Vesículas Extracelulares , Neoplasias , Humanos , Fibroblastos Asociados al Cáncer/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ácido Metilmalónico/metabolismo , Interleucina-6/metabolismo , Microambiente Tumoral , Neoplasias/patología , Vesículas Extracelulares/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Methylmalonic acidemia (MMA) is a rare and severe inherited metabolic disease typically caused by mutations of the methylmalonyl-CoA mutase (MMUT) gene. Despite medical management, patients with MMA experience frequent episodes of metabolic instability, severe morbidity, and early mortality. In several preclinical studies, systemic gene therapy has demonstrated impressive improvement in biochemical and clinical phenotypes of MMA murine models. One approach uses a promoterless adeno-associated viral (AAV) vector that relies upon homologous recombination to achieve site-specific in vivo gene addition of MMUT into the last coding exon of albumin (Alb), generating a fused Alb-MMUT transcript after successful editing. We have previously demonstrated that nuclease-free AAV mediated Alb editing could effectively treat MMA mice in the neonatal period and noted that hepatocytes had a growth advantage after correction. Here, we use a transgenic knock-out mouse model of MMA that recapitulates severe clinical and biochemical symptoms to assess the benefits of Alb editing in juvenile animals. As was first noted in the neonatal gene therapy studies, we observe that gene edited hepatocytes in the MMA mice treated as juveniles exhibit a growth advantage, which allows them to repopulate the liver slowly but dramatically by 8-10 months post treatment, and subsequently manifest a biochemical and enzymatic response. In conclusion, our results suggest that the benefit of AAV mediated nuclease-free gene editing of the Alb locus to treat MMA could potentially be therapeutic for older patients.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos , Metilmalonil-CoA Mutasa , Ratones , Animales , Metilmalonil-CoA Mutasa/genética , Metilmalonil-CoA Mutasa/metabolismo , Edición Génica , Dependovirus/genética , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Ratones Noqueados , Hígado/metabolismo , Hepatocitos/metabolismo , Albúminas/genética , Albúminas/metabolismo , Ácido Metilmalónico/metabolismoRESUMEN
Methylmalonic acid (MMA) can act as a diagnosis of hereditary methylmalonic acidemia and assess the status of vitamin B12. Moreover, as a new potential biomarker, it has been widely reported to be associated with the progression and prognosis of chronic diseases such as cardiovascular events, renal insufficiency, cognitive impairment, and cancer. MMA accumulation may cause oxidative stress and impair mitochondrial function, disrupt cellular energy metabolism, and trigger cell death. This review primarily focuses on the mechanisms and epidemiology or progression in the clinical study on MMA.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos , Ácido Metilmalónico , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Humanos , Ácido Metilmalónico/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo , Deficiencia de Vitamina B 12RESUMEN
The alteration of metabolic pathways is a critical strategy for cancer cells to attain the traits necessary for metastasis in disease progression. Here, we find that dysregulation of propionate metabolism produces a pro-aggressive signature in breast and lung cancer cells, increasing their metastatic potential. This occurs through the downregulation of methylmalonyl coenzyme A epimerase (MCEE), mediated by an extracellular signal-regulated kinase 2-driven transcription factor Sp1/early growth response protein 1 transcriptional switch driven by metastatic signalling at its promoter level. The loss of MCEE results in reduced propionate-driven anaplerotic flux and intracellular and intratumoral accumulation of methylmalonic acid, a by-product of propionate metabolism that promotes cancer cell invasiveness. Altogether, we present a previously uncharacterized dysregulation of propionate metabolism as an important contributor to cancer and a valuable potential target in the therapeutic treatment of metastatic carcinomas.
Asunto(s)
Neoplasias , Propionatos , Humanos , Ácido Metilmalónico/metabolismo , Fenotipo , Propionatos/farmacología , Transducción de SeñalRESUMEN
Methylmalonic acidemia (MMA) due to methylmalonyl-CoA mutase deficiency (OMIM #251,000) is an autosomal recessive disorder of organic acid metabolism associated with life-threatening acute metabolic decompensations and significant neuropsychological deficits. "Isolated" MMA refers to the presence of excess methylmalonic acid without homocysteine elevation. Belonging to this class of disorders are those that involve complete deficiency (mut0) and partial deficiency (mut-) of the methylmalonyl-CoA mutase enzyme and other disorders causing excess methylmalonic acid excretion. These other disorders include enzymatic subtypes related to cobalamin A defect (cblA) (OMIM #25,110), cobalamin B defect (cblB) (OMIM #251,110) and related conditions. Neuropsychological attributes associated with isolated MMA have become more relevant as survival rates increased following improved diagnostic and treatment strategies. Children with this disorder still are at risk for developmental delay, cognitive difficulties and progressive declines in functioning. Mean IQ for all types apart from cblA defect enzymatic subtype is rarely above 85 and much lower for mut0 enzymatic subtype. Identifying psychological domains responsive to improvements in biochemical status is important. This review suggests that processing speed, working memory, language, attention, and quality of life may be sensitive to fluctuations in metabolite levels while IQ and motor skills may be less amenable to change. Due to slower developmental trajectories, Growth Scale Values, Projected Retained Ability Scores and other indices of change need to be incorporated into clinical trial study protocols. Neuropsychologists are uniquely qualified to provide a differentiated picture of cognitive, behavioral and emotional consequences of MMA and analyze benefits or shortcomings of novel treatments.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos , Metilmalonil-CoA Mutasa , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Niño , Humanos , Ácido Metilmalónico/metabolismo , Metilmalonil-CoA Mutasa/genética , Mutación , Calidad de Vida , Vitamina B 12RESUMEN
Combined methylmalonic aciduria with homocystinuria (cblC type) is a rare disease caused by mutations in the MMACHC gene. MMACHC encodes an enzyme crucial for intracellular vitamin B12 metabolism, leading to the accumulation of toxic metabolites e.g. methylmalonic acid (MMA) and homocysteine (Hcy), and secondary disturbances in folate and one-carbon metabolism when not fully functional. Patients with cblC deficiency often present in the neonatal or early childhood period with a severe multisystem pathology, which comprises a broad spectrum of treatment-resistant ophthalmological phenotypes, including retinal degeneration, impaired vision, and vascular changes. To examine the potential function of MMACHC in the retina and how its loss may impact disease, we performed gene expression studies in human and mouse, which showed that local expression of MMACHC in the retina and retinal pigment epithelium is relatively stable over time. To study whether functional MMACHC is required for retinal function and tissue integrity, we generated a transgenic mouse lacking Mmachc expression in cells of the peripheral retina. Characterization of this mouse revealed accumulation of cblC disease related metabolites, including MMA and the folate-dependent purine synthesis intermediates AICA-riboside and SAICA-riboside in the retina. Nevertheless, fundus appearance, morphology, vasculature, and cellular composition of the retina, as well as ocular function, remained normal in mice up to 6 or 12 months of age. Our data indicates that peripheral retinal neurons do not require intrinsic expression of Mmachc for survival and function and questions whether a local MMACHC deficiency is responsible for the retinal phenotypes in patients.
Asunto(s)
Oxidorreductasas/metabolismo , Retina/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Animales , Femenino , Homocisteína/metabolismo , Homocistinuria/metabolismo , Humanos , Masculino , Ácido Metilmalónico/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Mutación/genética , Oxidorreductasas/genética , Fenotipo , Degeneración Retiniana/genética , Degeneración Retiniana/metabolismo , Vitamina B 12/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Elevated plasma homocysteine has been found to be associated with an increased risk of osteoporosis, especially hip and vertebral fractures. The plasma concentration of homocysteine is dependent on the activities of several B vitamin-dependent enzymes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and cystathionine ß-synthase (CBS). OBJECTIVES: We investigated whether genetic variants in some of the genes involved in 1 carbon metabolism modify the association of B vitamin-related measures with bone mineral density (BMD) and strength. METHODS: We measured several B vitamins and biomarkers in participants of the Framingham Offspring Study, and performed analyses of methylmalonic acid (MMA) continuously and <210 nmol/L; pyridoxal-5'-phosphate; vitamin B-12 continuously and ≥258 pmol/L; and folate. The outcomes of interest included areal and volumetric BMD, measured by DXA and quantitative computed tomography (QCT), respectively. We evaluated associations between the bone measures and interactions of single nucleotide polymorphism with a B vitamin or biomarker in Framingham participants (n = 4310 for DXA and n = 3127 for QCT). For analysis of DXA, we validated the association results in the B-PROOF cohort (n = 1072). Bonferroni-corrected locus-wide significant thresholds were defined to account for multiple testing. RESULTS: The interactions between rs2274976 and vitamin B-12 and rs34671784 and MMA <210 nmol/L were associated with lumbar spine BMD, and the interaction between rs6586281 and vitamin B-12 ≥258 pmol/L was associated with femoral neck BMD. For QCT-derived traits, 62 interactions between genetic variants and B vitamins and biomarkers were identified. CONCLUSIONS: Some genetic variants in the 1-carbon methylation pathway modify the association of B vitamin and biomarker concentrations with bone density and strength. These interactions require further replication and functional validation for a mechanistic understanding of the role of the 1-carbon metabolism pathway on BMD and risks of fracture.
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Densidad Ósea/fisiología , Variación Genética , Ácido Metilmalónico/sangre , Complejo Vitamínico B/sangre , Adolescente , Adulto , Anciano , Densidad Ósea/genética , Niño , Preescolar , Femenino , Ácido Fólico/sangre , Ácido Fólico/metabolismo , Genotipo , Humanos , Masculino , Ácido Metilmalónico/metabolismo , Persona de Mediana Edad , Vitamina B 12/sangre , Vitamina B 12/metabolismo , Vitamina B 6/sangre , Vitamina B 6/metabolismo , Complejo Vitamínico B/metabolismo , Adulto JovenRESUMEN
BACKGROUND: The association of moderate hyperhomocysteinemia (HHcy) (15-30 µmol/L) with cardiovascular diseases (CVD) has been challenged by the lack of benefit of vitamin supplementation to lowering homocysteine. Consequently, the results of interventional studies have confused the debate regarding the management of patients with intermediate/severe HHcy. OBJECTIVE: We sought to evaluate the association of intermediate (30-100 µmol/L) and severe (>100 µmol/L) HHcy related to vitamin deficiencies and/or inherited disorders with CVD outcomes. METHODS: We performed a retrospective cross-sectional study on consecutive patients who underwent a homocysteine assay in a French University Regional Hospital Center. Patients with CVD outcomes were assessed for vitamin B12, folate, Hcy, methylmalonic acid, and next-generation clinical exome sequencing. RESULTS: We evaluated 165 patients hospitalized for thromboembolic and other cardiovascular (CV) manifestations among 1006 patients consecutively recruited. Among them, 84% (138/165) had Hcy >30 µmol/L, 27% Hcy >50 µmol/L (44/165) and 3% Hcy >100 µmol/L (5/165). HHcy was related to vitamin B12 and/or folate deficiency in 55% (87/165), mutations in one or more genes of one-carbon and/or vitamin B12 metabolisms in 11% (19/165), and severe renal failure in 15% (21/141) of the studied patients. HHcy was the single vascular risk retrieved in almost 9% (15/165) of patients. Sixty % (101/165) of patients received a supplementation to treat HHcy, with a significant decrease in median Hcy from 41 to 17 µmol/L (IQR: 33.6-60.4 compared with 12.1-28). No recurrence of thromboembolic manifestations was observed after supplementation and antithrombotic treatment of patients who had HHcy as a single risk, after â¼4 y of follow-up. CONCLUSION: The high frequency of intermediate/severe HHcy differs from the frequent moderate HHcy reported in previous observational studies of patients with pre-existing CVD. Our study points out the importance of diagnosing and treating nutritional deficiencies and inherited disorders to reverse intermediate/severe HHcy associated with CVD outcomes.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Deficiencia de Ácido Fólico/complicaciones , Ácido Fólico/uso terapéutico , Hiperhomocisteinemia/complicaciones , Errores Innatos del Metabolismo/sangre , Adulto , Preescolar , Estudios Transversales , Femenino , Homocisteína/sangre , Homocisteína/metabolismo , Humanos , Masculino , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Ácido Metilmalónico/sangre , Ácido Metilmalónico/metabolismo , Persona de Mediana Edad , Estudios Retrospectivos , Vitamina B 12/sangre , Vitamina B 12/metabolismoRESUMEN
Cobalamin J disease (CblJ) is an ultra-rare autosomal recessive disorder of intracellular cobalamin metabolism associated with combined methylmalonic acidemia and homocystinuria. It is caused by pathogenic variants in ABCD4, which encodes an ATP-binding cassette (ABC) transporter that affects the lysosomal release of cobalamin (Cbl) into the cytoplasm. Only six cases of CblJ have been reported in the literature. Described clinical features include feeding difficulties, failure to thrive, hypotonia, seizures, developmental delay, and hematological abnormalities. Information on clinical outcomes is extremely limited, and no cases of presymptomatic diagnosis have been reported. We describe a now 17-month-old male with CblJ detected by newborn screening and confirmed by biochemical, molecular, and complementation studies. With early detection and initiation of treatment, this patient has remained asymptomatic with normal growth parameters and neurodevelopmental function. To the best of our knowledge, this report represents the first asymptomatic and neurotypical patient with CblJ.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/genética , Deficiencia de Vitamina B 12/diagnóstico , Vitamina B 12/genética , Errores Innatos del Metabolismo de los Aminoácidos/patología , Femenino , Predisposición Genética a la Enfermedad , Homocistinuria/diagnóstico , Homocistinuria/genética , Homocistinuria/patología , Humanos , Lactante , Recién Nacido , Masculino , Ácido Metilmalónico/metabolismo , Mutación/genética , Tamizaje Neonatal , Vitamina B 12/metabolismo , Deficiencia de Vitamina B 12/genética , Deficiencia de Vitamina B 12/patologíaRESUMEN
Cobalamin C defect is caused by pathogenic variants in the MMACHC gene leading to impaired conversion of dietary vitamin B12 into methylcobalamin and adenosylcobalamin. Variants in the MMACHC gene cause accumulation of methylmalonic acid and homocysteine along with decreased methionine synthesis. The spectrum of MMACHC gene variants differs in various populations. A total of 19 North Indian children (age 0-18 years) with elevated methylmalonic acid and homocysteine were included in the study, and their DNA samples were subjected to Sanger sequencing of coding exons with flanking intronic regions of MMACHC gene. The genetic analysis resulted in the identification of a common pathogenic nonsense mutation, c.394C > T (R132*) in 85.7% of the unrelated cases with suspected cobalamin C defect. Two other known mutations c.347T > C (7%) and c.316G > A were also detected. Plasma homocysteine was significantly elevated (> 100 µmol/L) in 75% of the cases and methionine was decreased in 81% of the cases. Propionyl (C3)-carnitine, the primary marker for cobalamin C defect, was found to be elevated in only 43.75% of cases. However, the secondary markers such as C3/C2 and C3/C16 ratios were elevated in 87.5% and 100% of the cases, respectively. Neurological manifestations were the most common in our cohort. Our findings of the high frequency of a single MMACHC R132* mutation in cases with combined homocystinuria and methylmalonic aciduria may be proven helpful in designing a cost-effective and time-saving diagnostic strategy for resource-constraint settings. Since the R132* mutation is located near the last exon-exon junction, this is a potential target for the read-through therapeutics.
Asunto(s)
Oxidorreductasas/genética , Mutación Puntual , Deficiencia de Vitamina B 12/genética , Vitamina B 12/metabolismo , Adolescente , Niño , Preescolar , Exones , Femenino , Homocisteína/metabolismo , Humanos , India , Lactante , Recién Nacido , Masculino , Ácido Metilmalónico/metabolismo , Oxidorreductasas/metabolismo , Vitamina B 12/análogos & derivados , Deficiencia de Vitamina B 12/metabolismoRESUMEN
OBJECTIVE: Discovery of specific markers that reflect altered hepatic fatty acid oxidation could help to detect an individual's risk of fatty liver, type 2 diabetes and cardiovascular disease at an early stage. Lipid and protein metabolism are intimately linked, but our understanding of this crosstalk remains limited. METHODS: In male Wistar rats, we used synthetic fatty acid analogues (3-thia fatty acids) as a tool to induce hepatic fatty acid oxidation and mitochondrial biogenesis, to gain new insight into the link between fatty acid oxidation, amino acid metabolism and TCA cycle-related intermediate metabolites in liver and plasma. RESULTS: Rats treated with 3-thia fatty acids had 3-fold higher hepatic, but not adipose and skeletal muscle, expression of the thioesterase 3-hydroxyisobutyryl-CoA hydrolase (Hibch), which controls the formation of 3-hydroxyisobutyrate (3-HIB) in the valine degradation pathway. Consequently, 3-thia fatty acid-stimulated hepatic fatty acid oxidation and ketogenesis was accompanied by decreased plasma 3-HIB and increased methylmalonic acid (MMA) concentrations further downstream in BCAA catabolism. The higher plasma MMA corresponded to higher MMA-CoA hydrolase activity and hepatic expression of GTP-specific succinyl-CoA synthase (Suclg2) and succinate dehydrogenase (Sdhb), and lower MMA-CoA mutase activity. Plasma 3-HIB correlated positively to plasma and hepatic concentrations of TAG, plasma total fatty acids, plasma NEFA and insulin/glucose ratio, while the reverse correlations were seen for MMA. CONCLUSION: Our study provides new insight into TCA cycle-related metabolic changes associated with altered hepatic fatty acid flux, and identifies 3-HIB and MMA as novel circulating markers reflective of mitochondrial ß-oxidation in male Wistar rats.
Asunto(s)
Ácidos Grasos/metabolismo , Hidroxibutiratos/sangre , Ácido Metilmalónico/sangre , Mitocondrias Hepáticas/metabolismo , Animales , Hidroxibutiratos/metabolismo , Resistencia a la Insulina , Masculino , Ácido Metilmalónico/metabolismo , Oxidación-Reducción , Ratas WistarRESUMEN
Metformin-treated diabetics (MTD) showed a decrease in cobalamin, a rise in homocysteine, and methylmalonic acid, leading to accentuated diabetic peripheral neuropathy (DPN). This study aimed to determine whether or not metformin is a risk factor for DPN. We compared MTD to non-metformin-treated diabetics (NMTD) clinically using the Toronto Clinical Scoring System (TCSS), laboratory (methylmalonic acid, cobalamin, and homocysteine), and electrophysiological studies. Median homocysteine and methylmalonic acid levels in MTD vs. NMTD were 15.3 vs. 9.6 µmol/l; P < 0.001 and 0.25 vs. 0.13 µmol/l; P = 0.02, respectively with high statistical significance in MTD. There was a significantly lower plasma level of cobalamin in MTD than NMTD. Spearman's correlation showed a significant negative correlation between cobalamin and increased dose of metformin and a significant positive correlation between TCSS and increased dose of metformin. Logistic regression analysis showed that MTD had significantly longer metformin use duration, higher metformin dose > 2 g, higher TCSS, lower plasma cobalamin, and significant higher homocysteine. Diabetics treated with metformin for prolonged duration and higher doses were associated with lower cobalamin and more severe DPN.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Neuropatías Diabéticas/tratamiento farmacológico , Metformina/administración & dosificación , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/patología , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/patología , Femenino , Homocisteína/sangre , Humanos , Masculino , Metformina/efectos adversos , Ácido Metilmalónico/metabolismo , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Periférico/sangre , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/patología , Factores de Riesgo , Vitamina B 12/sangreRESUMEN
Organic acidurias (OADs) comprise a biochemically defined group of inherited metabolic diseases. Increasing awareness, reliable diagnostic work-up, newborn screening programs for some OADs, optimized neonatal and intensive care, and the development of evidence-based recommendations have improved neonatal survival and short-term outcome of affected individuals. However, chronic progression of organ dysfunction in an aging patient population cannot be reliably prevented with traditional therapeutic measures. Evidence is increasing that disease progression might be best explained by mitochondrial dysfunction. Previous studies have demonstrated that some toxic metabolites target mitochondrial proteins inducing synergistic bioenergetic impairment. Although these potentially reversible mechanisms help to understand the development of acute metabolic decompensations during catabolic state, they currently cannot completely explain disease progression with age. Recent studies identified unbalanced autophagy as a novel mechanism in the renal pathology of methylmalonic aciduria, resulting in impaired quality control of organelles, mitochondrial aging and, subsequently, progressive organ dysfunction. In addition, the discovery of post-translational short-chain lysine acylation of histones and mitochondrial enzymes helps to understand how intracellular key metabolites modulate gene expression and enzyme function. While acylation is considered an important mechanism for metabolic adaptation, the chronic accumulation of potential substrates of short-chain lysine acylation in inherited metabolic diseases might exert the opposite effect, in the long run. Recently, changed glutarylation patterns of mitochondrial proteins have been demonstrated in glutaric aciduria type 1. These new insights might bridge the gap between natural history and pathophysiology in OADs, and their exploitation for the development of targeted therapies seems promising.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Encefalopatías Metabólicas Innatas/metabolismo , Encefalopatías Metabólicas Innatas/patología , Metabolismo Energético , Humanos , Recién Nacido , Ácido Metilmalónico/metabolismo , Tamizaje NeonatalRESUMEN
BACKGROUND: Methylmalonic acid (MMA) is best known for its use as a functional marker of vitamin B12 deficiency. However, MMA concentrations not only depend on adequate vitamin B12 status, but also relate to renal function and endogenous production of propionic acid. Hence, we aimed to investigate to what extent variation in MMA levels is explained by vitamin B12 and eGFR and whether MMA levels are associated with mortality if vitamin B12 and eGFR are taken into account. METHODS: A total of 1533 individuals (aged 60-75 years, 50% male) were included from the Lifelines Cohort and Biobank Study. Individuals were included between 2006 and 2013, and the total follow-up time was 8.5 years. RESULTS: Median [IQR] age of the study population was 65 [62-69] years, 50% was male. At baseline, median MMA concentration was 170 [138-216] nmol/L, vitamin B12 290 [224-362] pmol/L, and eGFR 84 [74-91] mL/min/1.73 m2. Log2 vitamin B12, log2 eGFR, age, and sex were significantly associated with log2 MMA in multivariable linear regression analyses (model R2 = 0.22). After a total follow-up time of 8.5 years, 72 individuals had died. Log2 MMA levels were significantly associated with mortality (hazard ratio [HR] 1.67 [95% CI 1.25-2.22], P < 0.001). Moreover, we found a significant interaction between MMA and eGFR with respect to mortality (Pinteraction < 0.001). CONCLUSIONS: Only 22% of variation in MMA levels was explained by vitamin B12, eGFR, age, and sex, indicating that a large part of variation in MMA levels is attributable to other factors (e.g., catabolism, dietary components, or gut microbial production). Higher MMA levels are associated with an increased risk for mortality, independent of vitamin B12, eGFR, and sex. This association was more pronounced in individuals with impaired renal function.
Asunto(s)
Pruebas de Función Renal/métodos , Riñón/patología , Ácido Metilmalónico/metabolismo , Mortalidad/tendencias , Deficiencia de Vitamina B 12/complicaciones , Vitamina B 12/uso terapéutico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Vitamina B 12/farmacologíaRESUMEN
The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards1-6. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy2,3,7,8. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing9-12. Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.