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Journal of Inherited Metabolic Disease Mar 2022There is an unmet need for the development and validation of biomarkers and surrogate endpoints for clinical trials in propionic acidemia (PA) and methylmalonic acidemia... (Review)
Review
There is an unmet need for the development and validation of biomarkers and surrogate endpoints for clinical trials in propionic acidemia (PA) and methylmalonic acidemia (MMA). This review examines the pathophysiology and clinical consequences of PA and MMA that could form the basis for potential biomarkers and surrogate endpoints. Changes in primary metabolites such as methylcitric acid (MCA), MCA:citric acid ratio, oxidation of C-propionate (exhaled CO ), and propionylcarnitine (C3) have demonstrated clinical relevance in patients with PA or MMA. Methylmalonic acid, another primary metabolite, is a potential biomarker, but only in patients with MMA. Other potential biomarkers in patients with either PA and MMA include secondary metabolites, such as ammonium, or the mitochondrial disease marker, fibroblast growth factor 21. Additional research is needed to validate these biomarkers as surrogate endpoints, and to determine whether other metabolites or markers of organ damage could also be useful biomarkers for clinical trials of investigational drug treatments in patients with PA or MMA. This review examines the evidence supporting a variety of possible biomarkers for drug development in propionic and methylmalonic acidemias.
Topics: Amino Acid Metabolism, Inborn Errors; Biomarkers; Drug Development; Humans; Methylmalonic Acid; Propionic Acidemia
PubMed: 35038174
DOI: 10.1002/jimd.12478 -
Frontiers in Neurology 2023Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are genetically and clinically variable disorders resulting from a reduction in mtDNA content in the cells, tissues,...
BACKGROUND
Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are genetically and clinically variable disorders resulting from a reduction in mtDNA content in the cells, tissues, and organ systems, leading to symptoms related to energy deficits. Deficiency of the mitochondrial succinyl-CoA ligase/synthetase enzyme secondary to pathogenic variations in the and genes is a subtype of MDDS that presents with neurological manifestations and a specific biochemical profile.
METHODS
This cross-sectional series describes five patients with MDDS secondary to pathogenic variations in the and genes from two tertiary care centers in Canada and India. Clinical data concerning the course, investigations, and outcome were gathered through chart reviews.
RESULTS
All subjects presented in early infancy with neurological manifestations, including movement disorder, psychomotor regression, developmental delay, hearing loss, behavioral issues, or a combination thereof. Elevated methylmalonic acid metabolites, an abnormal acylcarnitine profile, and lactic acidemia were noted in the biochemical profile of each patient ( = 5/5, 100%). Molecular genetic testing disclosed the presence of pathogenic homozygous mutations in four subjects and compound heterozygosity in one subject.
CONCLUSION
MDDS associated with and genes can be detected biochemically by the presence of methylmalonic aciduria besides the elevation of lactate, C3, C4DC, and C5-OH acylcarnitine. Conducting metabolic workups including MMA and acylcarnitine profiles in patients with heterogeneity of clinical symptoms associated with the presence of this biochemical marker may potentially reduce the time to diagnosis and management.
PubMed: 38073635
DOI: 10.3389/fneur.2023.1265115 -
Molecules (Basel, Switzerland) Nov 2020The paper reports on monitoring methylmalonic aciduria (MMA)-specific and non-specific metabolites via NMR urinomics. Five patients have been monitored over periods of...
The paper reports on monitoring methylmalonic aciduria (MMA)-specific and non-specific metabolites via NMR urinomics. Five patients have been monitored over periods of time; things involved were diet, medication and occasional episodes of failing to comply with prescribed diets. An extended dataset of targeted metabolites is presented, and correlations with the type of MMA are underlined. A survey of previous NMR studies on MMA is also presented.
Topics: Amino Acid Metabolism, Inborn Errors; Child; Child, Preschool; Creatinine; Female; Glycine; Humans; Infant; Infant, Newborn; Magnetic Resonance Spectroscopy; Male; Metabolomics; Time Factors
PubMed: 33202577
DOI: 10.3390/molecules25225312 -
Nature Communications Jan 2022Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic...
Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously observed in cblC, we uncovered reduced expression of target genes that encode ribosome protein subunits. We also identified specific phenotypes that we ascribe to deregulation of ribosome biogenesis impacting normal translation during development. These findings identify HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development and their mutation results in complex syndromes exhibiting aspects of both cblC and ribosomopathies.
Topics: Amino Acid Metabolism, Inborn Errors; Animals; Disease Models, Animal; Embryo, Mammalian; Female; Gene Expression Regulation, Developmental; Homocystinuria; Host Cell Factor C1; Humans; Male; Mice; Mice, Knockout; Mutation; Organelle Biogenesis; Oxidoreductases; Protein Biosynthesis; Protein Subunits; Repressor Proteins; Ribosomal Proteins; Ribosomes; Vitamin B 12; Vitamin B 12 Deficiency
PubMed: 35013307
DOI: 10.1038/s41467-021-27759-7 -
Orphanet Journal of Rare Diseases Jan 2020Combined malonic and methylmalonic aciduria (CMAMMA) is an inborn error of metabolism which has been proposed being a benign condition. However, older patients may...
Combined malonic and methylmalonic aciduria (CMAMMA) is an inborn error of metabolism which has been proposed being a benign condition. However, older patients may present with neurological manifestations such as seizures, memory problems, psychiatric problems and/ or cognitive decline. In fibroblasts from CMAMMA patients we have recently demonstrated a dysregulation of energy metabolism with increased dependency on β-oxidation for energy production. Because of the inability of the brain to rely efficiently on this pathway to retrieve the required energy to a great extent, we hypothesize an alternative disease-causing mechanism that does not only include the accumulation of the metabolites malonic and methylmalonic acids. Here, we suggest a novel hypothesis on the possible pathophysiological mechanism responsible for the development of neurological symptoms in the long-run.
Topics: Amino Acid Metabolism, Inborn Errors; Brain; Humans; Metabolism, Inborn Errors; Methylmalonic Acid
PubMed: 31969167
DOI: 10.1186/s13023-020-1299-7 -
Clinical Genetics Jun 2015Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene, which codes for the enzyme adenosine triphosphate (ATP): cobalamin adenosyltransferase...
Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene, which codes for the enzyme adenosine triphosphate (ATP): cobalamin adenosyltransferase (ATR). This study reports differences in the metabolic and disease outcomes of two pairs of siblings with MMA cblB type, respectively harbouring the novel changes p.His183Leu/p.Arg190dup (P1 and P2) and the previously described mutations p.Ile96Thr/p.Ser174fs (P3 and P4). Expression analysis showed p.His183Leu and p.Arg190dup to be destabilizing mutations. Both were associated with reduced ATR stability and a shorter half-life than wild-type ATR. Analysis of several parameters related to oxidative stress and mitochondrial function showed an increase in reactive oxygen species (ROS) content, a decrease in mitochondrial respiration and changes in mitochondria morphology and structure in patient-derived fibroblasts compared to control cells. The impairment in energy production and the presence of oxidative stress and fission of the mitochondrial reticulum suggested mitochondrial dysfunction in cblB patients' fibroblasts. The recovery of mitochondrial function should be a goal in efforts to improve the clinical outcome of MMA cblB type.
Topics: Alkyl and Aryl Transferases; Alleles; Amino Acid Metabolism, Inborn Errors; Amino Acid Substitution; Fibroblasts; Humans; Intracellular Space; Mitochondria; Mutation; Outcome Assessment, Health Care; Oxidative Stress; Reactive Oxygen Species; Siblings
PubMed: 24813872
DOI: 10.1111/cge.12426 -
Frontiers in Pediatrics 2021Combined malonic and methylmalonic aciduria (CMAMMA) is a rare metabolic disease caused by biallelic variants in gene. The clinical phenotype is highly heterogeneous...
Combined malonic and methylmalonic aciduria (CMAMMA) is a rare metabolic disease caused by biallelic variants in gene. The clinical phenotype is highly heterogeneous in this disorder, ranging from asymptomatic to severe symptoms. No cases with CMAMMA were reported in China. In this study, three Chinese pediatric patients were diagnosed with CMAMMA unexpectedly while being treated for other ailments. To better characterize CMAMMA in a Chinese population, we made a multidimensional analysis with detailed clinical phenotype, semi-quantitative detection of urine organic acid, and analysis of gene variants. The clinical presentation of these patients is quite different; their main complaints were anemia, jaundice, or abnormal urine test, respectively. They showed no symptoms of the classic methylmalonic academia, but urine organic acid analysis showed elevated malonic acid and methylmalonic acid in all the patients repeatedly. Variants were found at four sites in gene. Patient 1 carried the compound heterogeneous variant c.689G> A (p.Trp230)/c.1456G> A (p.Ala486Thr). A compound heterozygous variant c.473C> T (p.Pro158Leu)/c.1456G> A (p.Ala486Thr) was identified in patient 2. Patient 3 harbored a novel homozygous variant c.1447A> G (p.Lys483Glu). Three Chinese patients were diagnosed with CMAMMA caused by variants. Their clinical course revealed that CMAMMA can be a benign condition that does not affect individual growth and development, but severe clinical phenotype may appear when other triggers exist. This study systematically elaborates CMAMMA in a Chinese population for the first time, broadens the spectrum of gene variant, and provides a strong basis for the etiological study of this disorder.
PubMed: 34900860
DOI: 10.3389/fped.2021.751895 -
Nutricion Hospitalaria Jul 2021Introduction: cobalamin C (Cbl C) deficiency is the most common defect in intracellular cobalamin metabolism, associated with methylmalonic acidemia and homocystinuria....
Introduction: cobalamin C (Cbl C) deficiency is the most common defect in intracellular cobalamin metabolism, associated with methylmalonic acidemia and homocystinuria. Its late clinical presentation is heterogeneous and may lead to a diagnostic delay. Case report: we report the case of a 45-year-old man with a 20-year history of chronic kidney disease and recently diagnosed spastic paraparesis, both of unknown origin. Metabolic studies revealed elevated levels of homocysteine and methylmalonic acid in the blood and urine. A genetic study confirmed cobalamin C deficiency. Treatment with hydroxocobalamin, betaine, carnitine, and folic acid was started. The patient eventually received a kidney transplant. Discussion: early diagnosis and appropriate treatment improve the clinical evolution of patients with Cbl C deficiency. Determination of homocysteine, organic acids, and other amino acids should be included in the differential diagnosis of patients with nephrological-neurological symptoms without a clear etiology.
Topics: Delayed Diagnosis; Homocystinuria; Humans; Hyperhomocysteinemia; Male; Middle Aged; Renal Insufficiency, Chronic; Vitamin B 12 Deficiency
PubMed: 34132563
DOI: 10.20960/nh.03623 -
Human Molecular Genetics Aug 2023Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria, present unique challenges to energetic homeostasis by disrupting...
Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria, present unique challenges to energetic homeostasis by disrupting energy-producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut)-type methylmalonic aciduria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared with littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator-activated receptor and Fgf21-controlled pathways. Together, these shed light on the mechanisms and adaptations behind energy imbalance in methylmalonic aciduria and provide insight into metabolic responses to chronic energy shortage, which may have important implications for disease understanding and patient management.
Topics: Mice; Animals; Amino Acid Metabolism, Inborn Errors; Energy Metabolism; Liver
PubMed: 37369025
DOI: 10.1093/hmg/ddad100 -
Orphanet Journal of Rare Diseases Jan 2024Combined methylmalonic acidemia and homocystinuria, cblC type is an inborn error of intracellular cobalamin metabolism and the most common one. The age of onset ranges... (Review)
Review
INTRODUCTION
Combined methylmalonic acidemia and homocystinuria, cblC type is an inborn error of intracellular cobalamin metabolism and the most common one. The age of onset ranges from prenatal to adult. The disease is characterised by an elevation of methylmalonic acid (MMA) and homocysteine and a decreased production of methionine. The aim is to review existing scientific literature of all late onset cblC patients in terms of clinical symptoms, diagnosis, and outcome.
METHODS
A bibliographic database search was undertaken in PubMed (MEDLINE) complemented by a reference list search. We combined search terms regarding cblC disease and late onset. Two review authors performed the study selection, data extraction and quality assessment.
RESULTS
Of the sixty-five articles included in this systematic review, we collected a total of 199 patients. The most frequent clinical symptoms were neuropathy/myelopathy, encephalopathy, psychiatric symptoms, thrombotic microangiopathy, seizures, kidney disease, mild to severe pulmonary hypertension with heart failure and thrombotic phenomena. There were different forms of supplementation used in the different studies collected and, within these studies, some patients received several treatments sequentially and/or concomitantly. The general outcome was: 64 patients recovered, 78 patients improved, 4 patients did not improve, or the disease progressed, and 12 patients died.
CONCLUSIONS
Most scientific literature regarding the late onset cblC disease comes from case reports and case series. In most cases treatment initiation led to an improvement and even recovery of some patients. The lack of complete recovery underlines the necessity for increased vigilance in unclear clinical symptoms for cblC disease.
Topics: Adult; Female; Pregnancy; Humans; Amino Acid Metabolism, Inborn Errors; Hyperhomocysteinemia; Homocystinuria; Methylmalonic Acid; Vitamin B 12
PubMed: 38245797
DOI: 10.1186/s13023-024-03021-3