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Molecular Therapy. Methods & Clinical... Sep 2023Propionic acidemia (PA) is rare autosomal recessive metabolic disorder caused by defects in the mitochondrially localized enzyme propionyl-coenzyme A (CoA) carboxylase....
Propionic acidemia (PA) is rare autosomal recessive metabolic disorder caused by defects in the mitochondrially localized enzyme propionyl-coenzyme A (CoA) carboxylase. Patients with PA can suffer from lethal metabolic decompensation and cardiomyopathy despite current medical management, which has led to the pursuit of gene therapy as a new treatment option for patients. Here we assess the therapeutic efficacy of a recently described adeno-associated virus (AAV) capsid, AAV44.9, to deliver a therapeutic transgene in a new mouse model of propionyl-CoA carboxylase α (PCCA) deficiency generated by genome editing. mice recapitulate the severe neonatal presentation of PA and manifest uniform neonatal lethality, absent PCCA expression, and increased 2-methylcitrate. A single injection of the AAV44.9 PCCA vector in the immediate newborn period, systemically delivered at a dose of 1e11 vector genome (vg)/pup but not 1e10 vg/pup, increased survival, reduced plasma methylcitrate, and resulted in high levels of transgene expression in the liver and heart in treated mice. Our studies not only establish a versatile and accurate new mouse model of PA but further demonstrate that the AAV44.9 vectors may be suitable for treatment of many metabolic disorders where hepato-cardiac transduction following systemic delivery is desired, such as PA, and, by extension, fatty acid oxidation defects and glycogen storage disorders.
PubMed: 37746248
DOI: 10.1016/j.omtm.2023.06.008 -
Clinical Case Reports Sep 2023Methylmalonic acidemia (MMA) combined with hyperhomocysteinemia is an autosomal recessive genetic disease which can lead to metabolic acidosis, elevated lactate, and...
Methylmalonic acidemia (MMA) combined with hyperhomocysteinemia is an autosomal recessive genetic disease which can lead to metabolic acidosis, elevated lactate, and high blood ammonia level. This anesthetic management was mainly how to maintain the stable state of perioperative physiological metabolism of such patients.
PubMed: 37744624
DOI: 10.1002/ccr3.7924 -
Nutrients Jul 2023Newborn screening (NBS) programs are effective measures of secondary prevention and have been successively extended. We aimed to evaluate NBS for methylmalonic...
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 B 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 B 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 B deficiency: 153/153). Three individuals were cofactor-responsive (methylmalonic acidurias: 2, CBS deficiency: 1), and could be treated by vitamin B, vitamin B 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.
Topics: Humans; Infant, Newborn; Homocystinuria; Propionic Acidemia; Prospective Studies; Neonatal Screening; Pilot Projects; Vitamin B 12; Vitamin B 12 Deficiency; Phenotype; Methylmalonic Acid; Vitamins
PubMed: 37571294
DOI: 10.3390/nu15153355 -
Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B delivery and repair.Nature Communications Jul 2023G-proteins function as molecular switches to power cofactor translocation and confer fidelity in metal trafficking. The G-protein, MMAA, together with MMAB, an...
G-proteins function as molecular switches to power cofactor translocation and confer fidelity in metal trafficking. The G-protein, MMAA, together with MMAB, an adenosyltransferase, orchestrate cofactor delivery and repair of B-dependent human methylmalonyl-CoA mutase (MMUT). The mechanism by which the complex 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 nano-assembly, which reveals a dramatic 180° rotation of the B domain, exposing it to solvent. The 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 MMAA-MMUT interfaces we identify here.
Topics: Humans; Methylmalonyl-CoA Mutase; Mutation; Amino Acid Metabolism, Inborn Errors; GTP-Binding Proteins; GTP Phosphohydrolases; Intramolecular Transferases
PubMed: 37468522
DOI: 10.1038/s41467-023-40077-4 -
Journal of Medical Case Reports Jul 2023Persistent pulmonary hypertension of the newborn manifesting with refractory and severe cyanosis is the consequence of high pulmonary vascular resistance causing... (Review)
Review
BACKGROUND
Persistent pulmonary hypertension of the newborn manifesting with refractory and severe cyanosis is the consequence of high pulmonary vascular resistance causing extrapulmonary right-to-left shunt. Acidosis and hypoxemia produce pulmonary vasoconstriction. Persistent pulmonary hypertension of the newborn occurs due to numerous disorders and has been rarely reported as a manifestation of methylmalonic acidemia. We report a newborn with methylmalonic acidemia who presented with persistent pulmonary hypertension of the newborn.
CASE PRESENTATION
A 1-day-old Iranian girl presented with respiratory distress and refractory metabolic acidosis. She was born at 39 + 5 weeks gestational age with Apgar scores of 8 and 9 in the 1st and 5th minutes, respectively, and was in good condition up to 10 hours of life. After that, she presented with cyanosis, tachypnea, retraction, and hypotonia. Despite receiving oxygen, she had low oxygen saturation. Echocardiography revealed severe pulmonary hypertension and right-to-left shunt through patent ductus arteriosus and foramen ovale. Her acidosis worsened despite receiving full support and medical therapy. So, she was started on peritoneal dialysis. Unfortunately, she did not respond to treatment, and after she had died, biochemical tests confirmed methylmalonic acidemia.
CONCLUSION
Persistent pulmonary hypertension of the newborn is a very rare manifestation of methylmalonic acidemia. Severe inborn errors of metabolism may cause irreversible damage with adverse lifelong morbidity, and early diagnosis may help to prevent such complications. Furthermore, diagnosis of these disorders aids in prenatal diagnosis through the use of cultured amniocytes or chorionic villi to detect gene mutations, as well as biochemical analyses of amniotic fluid for subsequent pregnancies.
Topics: Female; Infant, Newborn; Pregnancy; Humans; Hypertension, Pulmonary; Iran; Amino Acid Metabolism, Inborn Errors; Cyanosis
PubMed: 37430309
DOI: 10.1186/s13256-023-04031-8 -
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 -
Frontiers in Nutrition 2023The most common disorder of the intracellular cobalamin metabolism pathway is the combined methylmalonic acidemia and homocysteinemia, cblC type (cblC). There is a...
BACKGROUND
The most common disorder of the intracellular cobalamin metabolism pathway is the combined methylmalonic acidemia and homocysteinemia, cblC type (cblC). There is a variation in its clinical spectrum ranging from severe neonatal-onset forms that are highly fatal to later-onset forms which are milder. In this study, the first case of an asymptomatic Chinese woman with a defect in congenital cobalamin (cblC type) metabolism at prenatal diagnosis due to elevated homocysteine level is identified.
CASE PRESENTATION
The proband, a male child born to a 29-year-old G1P0 mother, admitted to local hospital with feeding disorder, intellectual disability, seizures, microcephaly, as well as heterophthalmos. The level of the urine methylmalonic was elevated. Equally found were increased blood propionylcarnitine (C3) and propionylcarnitine/free carnitine ratio (C3/C0) and decreased methionine levels. The plasma total homocysteine level was elevated at 101.04 μmol/L (normal < 15 μmol/L). The clinical diagnosis of combined methylmalonic acidemia and homocysteinemia was supported. Four years later, the mother of the boy married again and came to us for prenatal diagnosis exactly 15 weeks after her last menstrual period. Subsequently, there is an increase in the amniotic fluid methylmalonate. The level of the amniotic fluid total homocysteine was marginally high. A considerably elevated amniotic fluid C3 was equally observed. In addition, there is a respective significant increase in the plasma and urine total homocysteine at 31.96 and 39.35 μmol/L. After the sequencing of MMACHC genes, it is found that the boy, a proband carried a homozygous mutation of the at c.658_660delAAG. While the boy's mother, she carries two mutations in : c.658_660delAAG and c.617G>A. The fetus is a carrier of the gene. Following the administration of routine treatment, the mother remained symptom-free in the course of pregnancy, and she gave birth to a healthy boy.
CONCLUSION
Variable and nonspecific symptoms characterized the cblC type of methylmalonic acidemia combined with homocysteinemia. Both biochemical assays and mutation analysis are recommended as crucial complementary techniques.
PubMed: 37252234
DOI: 10.3389/fnut.2023.1124387 -
Hereditas May 2023Methylmalonic acidemia (MMA) is a rare metabolic disorder resulting from functional defects in methylmalonyl-CoA mutase. Mutations in the MMAB gene are responsible for...
BACKGROUND
Methylmalonic acidemia (MMA) is a rare metabolic disorder resulting from functional defects in methylmalonyl-CoA mutase. Mutations in the MMAB gene are responsible for the cblB type of vitamin B12-responsive MMA.
RESULTS
This study used Whole-exome sequencing (WES), Sanger sequencing, linkage analysis, and in-silico evaluation of the variants' effect on protein structure and function to confirm their pathogenicity in a 2-day-old neonate presenting an early-onset metabolic crisis and death. WES revealed a homozygous missense variant on chromosome 12, the NM_052845.4 (MMAB):c.557G > A, p.Arg186Gln, in exon 7, a highly conserved and hot spot region for pathogenic variants. After being confirmed by Sanger sequencing, the wild-type and mutant proteins' structure and function were modeled and examined using in-silico bioinformatics tools and compared to the variant NM_052845.4 (MMAB):c.556C > T, p.Arg186Trp, a known pathogenic variant at the same position. Comprehensive bioinformatics analysis showed a significant reduction in the stability of variants and changes in protein-protein and ligand-protein interactions. Interestingly, the variant c.557G > A, p.Arg186Gln depicted more variations in the secondary structure and less binding to the ATP and B12 ligands compared to the c.556C > T, p.Arg186Trp, the known pathogenic variant.
CONCLUSION
This study succeeded in expanding the variant spectra of the MMAB, forasmuch as the variant c.557G > A, p.Arg186Gln is suggested as a pathogenic variant and the cause of severe MMA and neonatal death. These results benefit the prenatal diagnosis of MMA in the subsequent pregnancies and carrier screening of the family members. Furthermore, as an auxiliary technique, homology modeling and protein structure and function evaluations could provide geneticists with a more accurate interpretation of variants' pathogenicity.
Topics: Infant, Newborn; Humans; Amino Acid Metabolism, Inborn Errors; Mutation; Methylmalonyl-CoA Mutase; Exons
PubMed: 37248539
DOI: 10.1186/s41065-023-00281-0 -
Molecular Genetics and Metabolism Jul 2023Clinical trial development in rare diseases poses significant study design and methodology challenges, such as disease heterogeneity and appropriate patient selection,... (Review)
Review
Clinical trial development in rare diseases poses significant study design and methodology challenges, such as disease heterogeneity and appropriate patient selection, identification and selection of key endpoints, decisions on study duration, choice of control groups, selection of appropriate statistical analyses, and patient recruitment. Therapeutic development in organic acidemias (OAs) shares many challenges with other inborn errors of metabolism, such as incomplete understanding of natural history, heterogenous disease presentations, requirement for sensitive outcome measures and difficulties recruiting a small sample of participants. Here, we review strategies for the successful development of a clinical trial to evaluate treatment response in propionic and methylmalonic acidemias. Specifically, we discuss crucial decisions that may significantly impact success of the study, including patient selection, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families.
Topics: Humans; Propionic Acidemia; Rare Diseases; Amino Acid Metabolism, Inborn Errors; Research Design; Methylmalonic Acid
PubMed: 37245378
DOI: 10.1016/j.ymgme.2023.107612 -
Scientific Reports May 2023Methylmalonic aciduria (MMA-uria) is caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). MUT deficiency hampers energy generation from...
Methylmalonic aciduria (MMA-uria) is caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT). MUT deficiency hampers energy generation from specific amino acids, odd-chain fatty acids and cholesterol. Chronic kidney disease (CKD) is a well-known long-term complication. We exposed human renal epithelial cells from healthy controls and MMA-uria patients to different culture conditions (normal treatment (NT), high protein (HP) and isoleucine/valine (I/V)) to test the effect of metabolic stressors on renal mitochondrial energy metabolism. Creatinine levels were increased and antioxidant stress defense was severely comprised in MMA-uria cells. Alterations in mitochondrial homeostasis were observed. Changes in tricarboxylic acid cycle metabolites and impaired energy generation from fatty acid oxidation were detected. Methylcitrate as potentially toxic, disease-specific metabolite was increased by HP and I/V load. Mitophagy was disabled in MMA-uria cells, while autophagy was highly active particularly under HP and I/V conditions. Mitochondrial dynamics were shifted towards fission. Sirtuin1, a stress-resistance protein, was down-regulated by HP and I/V exposure in MMA-uria cells. Taken together, both interventions aggravated metabolic fingerprints observed in MMA-uria cells at baseline. The results point to protein toxicity in MMA-uria and lead to a better understanding, how the accumulating, potentially toxic organic acids might trigger CKD.
Topics: Humans; Amino Acid Metabolism, Inborn Errors; Homeostasis; Methylmalonyl-CoA Mutase; Renal Insufficiency, Chronic; Epithelial Cells
PubMed: 37169781
DOI: 10.1038/s41598-023-34373-8