RESUMEN
Propionic acidemia (PA), resulting from Pcca or Pccb gene mutations, impairs propionyl-CoA metabolism and induces metabolic alterations. While speculation exists that fasting might exacerbate metabolic crises in PA patients by accelerating the breakdown of odd-chain fatty acids and amino acids into propionyl-CoA, direct evidence is lacking. Our investigation into the metabolic effects of fasting in Pcca-/-(A138T) mice, a PA model, reveals surprising outcomes. Propionylcarnitine, a PA biomarker, decreases during fasting, along with the C3/C2 (propionylcarnitine/acetylcarnitine) ratio, ammonia, and methylcitrate. Although moderate amino acid catabolism to propionyl-CoA occurs with a 23-h fasting, a significant reduction in microbiome-produced propionate and increased fatty acid oxidation mitigate metabolic alterations by decreasing propionyl-CoA synthesis and enhancing acetyl-CoA synthesis. Fasting-induced gluconeogenesis further facilitates propionyl-CoA catabolism without changing propionyl-CoA carboxylase activity. These findings suggest that fasting may alleviate metabolic alterations in Pcca-/-(A138T) mice, prompting the need for clinical evaluation of its potential impact on PA patients.
Asunto(s)
Ayuno , Metilmalonil-CoA Descarboxilasa , Mutación , Animales , Ratones , Metilmalonil-CoA Descarboxilasa/metabolismo , Metilmalonil-CoA Descarboxilasa/genética , Acidemia Propiónica/genética , Acidemia Propiónica/metabolismo , Masculino , Ratones Noqueados , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Acilcoenzima A/metabolismoRESUMEN
In this study, peripheral blood mononuclear cells were contributed from a male infant with propionic acidemia (PA) verified by clinical and genetic diagnosis, who inherited compound heterozygous mutations in the propionyl-CoA carboxylase subunit beta (PCCB) gene. Here, this iPS was generated by non-integrated episomal vectors with SOX2, BCL-XL, OCT4, C-MYC and OCT4. Also, this iPSC line exhibited the morphology of pluripotent stem cells, upward mRNA and protein expression of pluripotency markers, conspicuous in vitro differentiation potency and regular karyotype, and carried PCCB gene mutations, which provided an excellent model for the research and drug screening of PA.
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Células Madre Pluripotentes Inducidas , Acidemia Propiónica , Lactante , Humanos , Masculino , Acidemia Propiónica/genética , Células Madre Pluripotentes Inducidas/metabolismo , Metilmalonil-CoA Descarboxilasa/genética , Metilmalonil-CoA Descarboxilasa/metabolismo , Heterocigoto , Leucocitos Mononucleares/metabolismo , Mutación/genéticaRESUMEN
Propionic acidemia (PA) is an autosomal recessive condition (OMIM #606054), wherein pathogenic variants in PCCA and PCCB impair the activity of propionyl-CoA carboxylase. PA is associated with neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorder (ASD); however, the correlates and mechanisms of these outcomes remain unknown. Using data from a subset of participants with PA enrolled in a dedicated natural history study (n = 33), we explored associations between neurodevelopmental phenotypes and laboratory parameters. Twenty (61%) participants received an ID diagnosis, and 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD. A diagnosis of ID, lower full-scale IQ (sample mean = 65 ± 26), and lower adaptive behavior composite scores (sample mean = 67 ± 23) were associated with several biomarkers. Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile. Reduced 1-13C-propionate oxidative capacity and decreased levels of plasma and urinary glutamine were also associated with a more severe ID profile. Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD. Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD. Thus, while both ID and ASD were commonly observed in our PA cohort, only ID was robustly associated with metabolic parameters. Our results suggest that disease severity and associated mitochondrial dysfunction may play a role in CNS complications of PA and identify potential biomarkers and candidate surrogate endpoints.
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Trastorno del Espectro Autista , Biomarcadores , Discapacidad Intelectual , Mitocondrias , Acidemia Propiónica , Humanos , Acidemia Propiónica/genética , Biomarcadores/sangre , Masculino , Femenino , Niño , Discapacidad Intelectual/genética , Mitocondrias/metabolismo , Preescolar , Adolescente , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/genética , Trastorno Autístico/metabolismo , Trastorno Autístico/genética , Adulto , Metilmalonil-CoA Descarboxilasa/genética , Metilmalonil-CoA Descarboxilasa/metabolismo , Adulto Joven , Carnitina/análogos & derivados , Carnitina/metabolismo , Carnitina/sangre , CitratosRESUMEN
Propionic acidemia (PA) is an autosomal recessive metabolic disorder caused by variants in PCCA or PCCB, both sub-units of the propionyl-CoA carboxylase (PCC) enzyme. PCC is required for the catabolism of certain amino acids and odd-chain fatty acids. In its absence, the accumulated toxic metabolites cause metabolic acidosis, neurologic symptoms, multi-organ dysfunction and possible death. The clinical presentation of PA is highly variable, with typical onset in the neonatal or early infantile period. We encountered two families, whose children were diagnosed with PA. Exome sequencing (ES) failed to identify a pathogenic variant, and we proceeded with genome sequencing (GS), demonstrating homozygosity to a deep intronic PCCB variant. RNA analysis established that this variant creates a pseudoexon with a premature stop codon. The parents are variant carriers, though three of them display pseudo-homozygosity due to a common large benign intronic deletion on the second allele. The parental presumed homozygosity merits special attention, as it masked the causative variant at first, which was resolved only by RNA studies. Arriving at a rapid diagnosis, whether biochemical or genetic, can be crucial in directing lifesaving care, concluding the diagnostic odyssey, and allowing the family prenatal testing in subsequent pregnancies. This study demonstrates the power of integrative genetic studies in reaching a diagnosis, utilizing GS and RNA analysis to overcome ES limitations and define pathogenicity. Importantly, it highlights that intronic deletions should be taken into consideration when analyzing genomic data, so that pseudo-homozygosity would not be misinterpreted as true homozygosity, and pathogenic variants will not be mislabeled as benign.
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Acidemia Propiónica , Recién Nacido , Niño , Humanos , Acidemia Propiónica/genética , ARN , Metilmalonil-CoA Descarboxilasa/genética , Mutación , Codón sin SentidoRESUMEN
Propionic acidemia (PA) is a genetic metabolic disorder caused by mutations in the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), which is responsible for converting propionyl-CoA to methylmalonyl-CoA for further metabolism in the tricarboxylic acid cycle. When this process is disrupted, propionyl-CoA and its metabolites accumulate, leading to a variety of complications including life-threatening cardiac diseases and other metabolic strokes. While the clinical symptoms and diagnosis of PA are well established, the underlying pathophysiological mechanisms of PA-induced diseases are not fully understood. As a result, there are currently few effective therapies for PA beyond dietary restriction. This review focuses on the pathophysiological mechanisms of the various complications associated with PA, drawing on extensive research and clinical reports. Most research suggests that propionyl-CoA and its metabolites can impair mitochondrial energy metabolism and cause cellular damage by inducing oxidative stress. However, direct evidence from in vivo studies is still lacking. Additionally, elevated levels of ammonia can be toxic, although not all PA patients develop hyperammonemia. The discovery of pathophysiological mechanisms underlying various complications associated with PA can aid in the development of more effective therapeutic treatments. The consequences of elevated odd-chain fatty acids in lipid metabolism and potential gene expression changes mediated by histone propionylation also warrant further investigation.
Asunto(s)
Acidemia Propiónica , Humanos , Acidemia Propiónica/complicaciones , Acidemia Propiónica/genética , Acidemia Propiónica/metabolismo , Metilmalonil-CoA Descarboxilasa/genética , Metilmalonil-CoA Descarboxilasa/metabolismo , Mutación , Metabolismo EnergéticoRESUMEN
Whole-exome sequencing (WES) is an excellent method for the diagnosis of diseases of uncertain or heterogeneous genetic origin. However, it has limitations for detecting structural variations such as InDels, which the bioinformatics analyzers must be aware of. This study aimed at using WES to evaluate the genetic cause of the metabolic crisis in a 3-day-old neonate admitted to the neonatal intensive care unit (NICU) and deceased after a few days. Tandem mass spectrometry (MS/MS) showed a significant increase in propionyl carnitine (C3), proposing methylmalonic acidemia (MMA) or propionic acidemia (PA). WES demonstrated a homozygous missense variant in exon 4 of the BTD gene (NM_000060.4(BTD):c.1330G > C), responsible for partial biotinidase deficiency. Segregation analysis of the BTD variant revealed the homozygous status of the asymptomatic mother. Furthermore, observation of the bam file, around genes responsible for PA or MMA, by Integrative Genomics Viewer (IGV) software displayed a homozygous large deletion in the PCCA gene. Comprehensive confirmatory studies identified and segregated a novel outframe deletion of 217,877 bp length, "NG_008768.1:g.185211_403087delinsTA", extended from intron 11 to 21 of the PCCA, inducing a premature termination codon and activation of nonsense-mediated mRNA decay (NMD). Homology modeling of the mutant PCCA demonstrated eliminating the protein's active site and critical functional domains. Thereupon, this novel variant is suggested as the largest deletion in the PCCA gene, causing an acute early-onset PA. These results could expand the PCCA variants spectrum, and improve the existing knowledge on the molecular basis of PA, as well as provide new evidence of pathogenicity of the variant (NM_000060.4(BTD):c.1330G > C.
Asunto(s)
Acidemia Propiónica , Humanos , Recién Nacido , Masculino , Metilmalonil-CoA Descarboxilasa/genética , Metilmalonil-CoA Descarboxilasa/metabolismo , Mutación , Acidemia Propiónica/genética , Acidemia Propiónica/diagnóstico , Espectrometría de Masas en TándemRESUMEN
Propionic acidemia (PA) is an ultrarare disorder caused by deficiency of the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), composed of PCCA and PCCB subunits. An enzyme replacement therapy is being developed using dual messenger RNA (mRNA) therapy composed of lipid nanoparticles (LNPs) encapsulating mRNAs encoding PCCA and PCCB subunits of the PCC enzyme. We herein report on development of a translational semimechanistic pharmacokinetic (PK) and PK/pharmacodynamic (PD) model to quantify the relationship between the mRNA components of mRNA-3927 (an LNP encapsulating PCCA and PCCB mRNAs) and dose levels; PCCA/B mRNA PK and PD responses were assessed as circulating levels of primary disease markers 2-methyl citrate, 3-hydroxypropionate, and propionyl carnitine normalized to acetyl carnitine (C3/C2 ratio) to inform the first-in-human dose range and regimen selection. The translational PK/PD model was developed using preclinical data available in mice with PA, Sprague Dawley rats, and cynomolgus monkeys at dose levels ranging from 0.2 to 9 mg/kg. PCCA/B mRNA PK in mice, rats, and monkeys was adequately described using allometric scaling of volume and clearance parameters. The interspecies preclinical model was scaled allometrically to humans to predict the dose-response relationship in adult and pediatric patients with PA to guide selection of dose range and regimen for the Phase 1 clinical trial (ClinicalTrials.gov Identifier NCT04159103).
Asunto(s)
Acidemia Propiónica , Adulto , Humanos , Niño , Ratones , Ratas , Animales , Acidemia Propiónica/tratamiento farmacológico , Acidemia Propiónica/genética , Mutación , ARN Mensajero/genética , Ratas Sprague-Dawley , Metilmalonil-CoA Descarboxilasa/genéticaRESUMEN
Propionic acidemia (PA) is an autosomal recessive inheritable metabolic disease caused by mutations in the propionyl CoA carboxylase gene (PCC) that affects multiple systems of the human body. Here, we report neuropathological findings of a PA patient. The patient was a male infant who presented with increasing lethargy and poor feeding from four days postpartum. He gradually became comatose and died from complications after liver transplantation at three months old. The results of laboratory examination were consistent with PA, and genetic analysis revealed compound heterozygous mutations in the gene for PCC subunit beta: c.838dupC (rs769968548) and c.1127G>T (rs142982097). Brain-restricted autopsy was performed 23 h after his death, and the neuropathological examination revealed distinct astrocytosis, oligodendrocytic loss, neuronal loss, and demyelination across the brainstem, motor cortex, basal ganglia, and thalamus. Spongiosis, vacuolization, and the appearance of Alzheimer type II astrocytes and activated microglia were observed as well. This is the first brain autopsy report of PA with a clear genetic cause.
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Acidemia Propiónica , Lactante , Femenino , Humanos , Masculino , Acidemia Propiónica/diagnóstico , Acidemia Propiónica/genética , Metilmalonil-CoA Descarboxilasa/genética , Metilmalonil-CoA Descarboxilasa/metabolismo , Mutación , Tálamo/metabolismo , NeuropatologíaRESUMEN
Propionic acidemia (PA, OMIM 606054) is a devastating inborn error of metabolism arising from mutations that reduce the activity of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). The defects in PCC reduce the concentrations of nonesterified coenzyme A (CoASH), thus compromising mitochondrial function and disrupting intermediary metabolism. Here, we use a hypomorphic PA mouse model to test the effectiveness of BBP-671 in correcting the metabolic imbalances in PA. BBP-671 is a high-affinity allosteric pantothenate kinase activator that counteracts feedback inhibition of the enzyme to increase the intracellular concentration of CoA. Liver CoASH and acetyl-CoA are depressed in PA mice and BBP-671 treatment normalizes the cellular concentrations of these two key cofactors. Hepatic propionyl-CoA is also reduced by BBP-671 leading to an improved intracellular C3:C2-CoA ratio. Elevated plasma C3:C2-carnitine ratio and methylcitrate, hallmark biomarkers of PA, are significantly reduced by BBP-671. The large elevations of malate and α-ketoglutarate in the urine of PA mice are biomarkers for compromised tricarboxylic acid cycle activity and BBP-671 therapy reduces the amounts of both metabolites. Furthermore, the low survival of PA mice is restored to normal by BBP-671. These data show that BBP-671 relieves CoA sequestration, improves mitochondrial function, reduces plasma PA biomarkers, and extends the lifespan of PA mice, providing the preclinical foundation for the therapeutic potential of BBP-671.
Asunto(s)
Acidemia Propiónica , Ratones , Animales , Acidemia Propiónica/genética , Metilmalonil-CoA Descarboxilasa/genética , Metilmalonil-CoA Descarboxilasa/metabolismo , Modelos Animales de Enfermedad , Mitocondrias/metabolismo , CarnitinaRESUMEN
Objective: Propionic acidemia is a rare inherited metabolic disorder caused by propionyl CoA carboxylase (PCC) deficiency. This study aims to analyze the clinical characteristics and gene variations of Chinese patients with propionic acidemia, and to explore the correlation between clinical phenotypes and genotypes. Methods: Single-center, retrospective and observational study. Seventy-eight patients of propionic acidemia (46 males and 32 females) from 20 provinces and autonomous regions were admitted from January 2007 to April 2022. Their age of initial diagnosis ranged from 7 days to 15 years. The clinical manifestations, biochemical and metabolic abnormalities, genetic variations, diagnosis, treatment and outcome were studied. Chi-Square test or Mann-Whitney U test were used for statistical analysis. Results: Among 78 cases, 6 (7.7%) were identified by newborn screening; 72 (92.3%) were clinically diagnosed after onset, and the age of onset was 2 hours after birth to 15 years old; 32 cases had early-onset disease and 40 cases had late-onset disease. The initial manifestations included lethargy, hypotonia, vomiting, feeding difficulties, developmental delay, epilepsy, and coma. Among the 74 cases who accepted gene analysis, 35 (47.3%) had PCCA variants and 39 (52.7%) had PCCB variants. A total of 39 PCCA variants and 32 PCCB variants were detected, among which c.2002G>A and c.229C>T in PCCA and c.838dupC and c.1087T>C in PCCB were the most common variants in this cohort. The variants c.1228C>T and c.1283C>T in PCCB may be related to early-onset type. The variants c.838dupC, c.1127G>T and c.1316A>G in PCCB, and c.2002G>A in PCCA may be related to late-onset disease. Six patients detected by newborn screening and treated at asymptomatic stage developed normal. The clinically diagnosed 72 cases had varied complications. 10 (12.8%) cases of them died. 62 patients improved after metabolic therapy by L-carnitine and diet. Six patients received liver transplantation because of recurrent metabolic crisis. Their clinical symptoms were markedly improved. Conclusion: The clinical manifestations of propionic acidemia are complex and lack of specificity. Newborn screening and high-risk screening are keys for early treatment and better outcome. The correlation between the genotype and phenotype of propionic acidemia is unclear, but certain variants may be associated with early-onset or late-onset propionic acidemia.
Asunto(s)
Acidemia Propiónica , Carnitina , Femenino , Genotipo , Humanos , Masculino , Metilmalonil-CoA Descarboxilasa/genética , Metilmalonil-CoA Descarboxilasa/metabolismo , Mutación , Fenotipo , Acidemia Propiónica/genética , Estudios RetrospectivosRESUMEN
BACKGROUND: Propionic acidemia (PA) is a rare autosomal recessive disorder of metabolism caused by mutations in the PCCA or PCCB gene, leading to propionyl CoA carboxylase (PCC) enzyme deficiencies. Most PA patients present variable clinical phenotypes and severity in the neonatal or infant period, with only a few developing symptoms after infancy. This report describes a PA patient with an adult-onset phenotype and a novel compound heterozygous mutation in the PCCB gene. To further explore the genotype-phenotype correlations in late-onset PA, we performed a literature review focusing on and summarizing 11 patients with PCC gene mutations who had the first onset and/or the definite diagnosis after infancy. CASE PRESENTATION: A 21-year-old PA patient presented with weakness of four limbs, gait abnormalities, two episodes of seizures, mental and behavior disorders after severe vomiting. Magnetic Resonance Imaging (MRI) demonstrated sustained bilateral caudate head and putamen symmetrical hyperintensity. Biochemical investigations revealed plasma amino and urine values correlating with a PA profile. Genetic analysis confirmed novel compound heterozygous variants in PCCB, with a newly-found pathogenic mutation (c.467T>C) and the c.1316A>G mutation associated with pathogenicity. CONCLUSION: We identified a novel compound heterozygous mutation in the PCCB gene causing late-onset PA. Patients carrying mutations in the PCCB gene tend to develop late-onset PA and present neuropsychiatric symptoms and/or signs. Further molecular biological research is needed to explore the genotype-phenotype correlations of PA.
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Trastornos Mentales , Acidemia Propiónica , Humanos , Metilmalonil-CoA Descarboxilasa/genética , Mutación , Fenotipo , Acidemia Propiónica/complicaciones , Acidemia Propiónica/genéticaAsunto(s)
Proteínas Bacterianas/genética , Eubacterium/crecimiento & desarrollo , Perfilación de la Expresión Génica/métodos , Ácido Láctico/metabolismo , Acil-CoA Deshidrogenasa/genética , Butiril-CoA Deshidrogenasa/genética , Eubacterium/genética , Microbioma Gastrointestinal , Regulación Bacteriana de la Expresión Génica , Hexosas/metabolismo , Humanos , Metilmalonil-CoA Descarboxilasa/genética , Familia de MultigenesRESUMEN
Propionic acidemia (PA) is a severe autosomal recessive metabolic disease caused by deficiency of propionyl-CoA carboxylase (PCC). We studied PA transgenic (Pat) mice that lack endogenous PCC but express a hypoactive human PCCA cDNA, permitting their survival. Pat cohorts followed from 3 to 20 weeks of age showed growth failure and lethal crises of lethargy and hyperammonemia, commoner in males (27/50, 54%) than in females (11/52, 21%) and occurring mainly in Pat mice with the most severe growth deficiency. Groups of Pat mice were studied under basal conditions (P-Ba mice) and during acute crises (P-Ac). Plasma acylcarnitines in P-Ba mice, compared to controls, showed markedly elevated C3- and low C2-carnitine, with a further decrease in C2-carnitine in P-Ac mice. These clinical and biochemical findings resemble those of human PA patients. Liver acyl-CoA measurements showed that propionyl-CoA was a minor species in controls (propionyl-CoA/acetyl-CoA ratio, 0.09). In contrast, in P-Ba liver the ratio was 1.4 and in P-Ac liver, 13, with concurrent reductions of the levels of acetyl-CoA and other acyl-CoAs. Plasma ammonia levels in control, P-Ba and P-Ac mice were 109 ± 10, 311 ± 48 and 551 ± 61 µmol/L respectively. Four-week administration to Pat mice, of carglumate (N-carbamyl-L-glutamic acid), an analogue of N-carbamylglutamate, the product of the only acyl-CoA-requiring reaction directly related to the urea cycle, was associated with increased food consumption, improved growth and absence of fatal crises. Pat mice showed many similarities to human PA patients and provide a useful model for studying tissue pathophysiology and treatment outcomes.
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Hiperamonemia , Acidemia Propiónica , Acetilcoenzima A/metabolismo , Animales , Femenino , Humanos , Hiperamonemia/genética , Hiperamonemia/metabolismo , Hígado/metabolismo , Masculino , Metilmalonil-CoA Descarboxilasa/genética , Metilmalonil-CoA Descarboxilasa/metabolismo , Ratones , Acidemia Propiónica/tratamiento farmacológicoRESUMEN
Propionic acidemia (PA) is an autosomal recessive metabolic disorder after gene encoding propionyl-CoA carboxylase, Pcca or Pccb, is mutated. This genetic disorder could develop various complications which are ascribed to dysregulated propionyl-CoA metabolism in organs. However, the effect of attenuated PCC on propionyl-CoA metabolism in different organs remains to be fully understood. We investigated metabolic perturbations in organs of Pcca-/-(A138T) mice (a mouse model of PA) under chow diet and acute administration of [13C3]propionate to gain insight into pathological mechanisms of PA. With chow diet, the metabolic alteration is organ dependent. l-Carnitine reduction induced by propionylcarnitine accumulation only occurs in lung and liver of Pcca-/- (A138T) mice. [13C3]Propionate tracing data demonstrated that PCC activity was dramatically reduced in Pcca-/-(A138T) brain, lung, liver, kidney, and adipose tissues, but not significantly changed in Pcca-/-(A138T) muscles (heart and skeletal muscles) and pancreas, which was largely supported by PCCA expression data. The largest expansion of propionylcarnitine in Pcca-/-(A138T) heart after acute administration of propionate indicated the vulnerability of heart to high circulating propionate. The overwhelming propionate in blood also stimulated ketone production from the increased fatty acid oxidation in Pcca-/-(A138T) liver by lowering malonyl-CoA, which has been observed in cases where metabolic decompensation occurs in PA patients. This work shed light on organ-specific metabolic alternations under varying severities of PA.
Asunto(s)
Acilcoenzima A/análisis , Propionatos/metabolismo , Acidemia Propiónica/fisiopatología , Alimentación Animal , Animales , Modelos Animales de Enfermedad , Corazón/fisiopatología , Hígado/química , Hígado/fisiopatología , Pulmón/química , Pulmón/fisiopatología , Masculino , Análisis de Flujos Metabólicos , Metabolómica , Metilmalonil-CoA Descarboxilasa/genética , Ratones , Propionatos/sangreRESUMEN
Propionic aciduria (PA) is caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). Due to inefficient propionate catabolism patients are endangered by life-threatening ketoacidotic crisis. Protein and amino acid restriction are major therapeutic pillars. However, long-term complications like neurological deterioration and cardiac abnormalities cannot be prevented. Chronic kidney disease (CKD), which is a well-known characteristic of methylmalonic aciduria two enzymatic steps downstream from PCC, has been recognized as a novel late-onset complication in PA. The pathophysiology of CKD in PA is unclear. We investigated mitochondrial structure and metabolism in human renal tubular cells of healthy controls and PA patients. The cells were exposed to either standard cell culture conditions (NT), high protein (HP) or high concentrations of isoleucine and valine (I/V). Mitochondrial morphology changed to condensed, fractured morphology in PA cells irrespective of the cell culture medium. HP and I/V exposure, however, potentiated oxidative stress in PA cells. Mitochondrial mass was enriched in PA cells, and further increased by HP and I/V exposure suggesting a need for compensation. Alterations in the tricarboxylic acid cycle intermediates and accumulation of medium- and long-chain acylcarnitines pointed to altered mitochondrial energy metabolism. Mitophagy was silenced while autophagy as cellular defense mechanisms was highly active in PA cells. The data demonstrate that PA is associated with renal mitochondrial damage which is aggravated by protein and I/V load. Preservation of mitochondrial energy homeostasis in renal cells may be a potential future therapeutic target.
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Errores Innatos del Metabolismo de los Aminoácidos/patología , Metilmalonil-CoA Descarboxilasa/genética , Mitocondrias/metabolismo , Acidemia Propiónica/genética , Insuficiencia Renal Crónica/patología , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Estudios de Casos y Controles , Línea Celular , Ciclo del Ácido Cítrico , Metabolismo Energético/genética , Células Epiteliales/metabolismo , Humanos , Metilmalonil-CoA Descarboxilasa/metabolismo , Mitocondrias/patología , Estrés Oxidativo/genética , Acidemia Propiónica/enzimología , Insuficiencia Renal Crónica/complicacionesRESUMEN
Propionic acidemia is an inborn error of metabolism characterized by accumulation of propionic acid due to deficiency of propionyl-CoA carboxylase. Main stay of treatment focuses on reducing dietary protein. However, orthotropic liver transplantation decreases the frequency of metabolic decompensations and improves life expectancy. We report a case of a 4-year-old boy undergoing orthotropic liver transplantation to treat propionic acidemia. This case highlights the use of intraoperative monitoring of metabolic markers like urine ketones, arterial ammonia, and lactate levels as these patients are at risk for hyperammonemia and metabolic acidosis. Also, the relevance in outcomes when performing early extubation in fast-tracking recovery.
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Anestésicos , Trasplante de Hígado , Acidemia Propiónica , Niño , Preescolar , Humanos , Masculino , Metilmalonil-CoA Descarboxilasa/genética , Acidemia Propiónica/complicacionesRESUMEN
BACKGROUND AND AIMS: Propionic acidemia (PA) is an autosomal recessive metabolic disorder caused by a deficiency of propionyl-CoA carboxylase and mutations in the PCCA and PCCB genes. In this study, we investigated the clinical characteristics of individuals with PA and conducted genetic analyses to provide new genetic evidence for the diagnosis of PA. MATERIALS AND METHODS: We conducted whole-exome sequencing and Sanger sequencing in four individuals with PA from three unrelated Chinese families. We also performed a structural analysis of the PCCB protein variants. Couples from the three families included in our study underwent in vitro fertilization with preimplantation genetic testing. RESULTS: We found five variants of PCCB. These biallelic variants were inherited from heterozygous parental carriers and were located in the functional domain, absent in human population genome datasets, and predicted to be deleterious. These findings indicate that the variants might be responsible for the clinical features observed in these particular patients with PA. Through successful embryo transfer and implantation, one of the couples fortunately gave birth to a healthy child. CONCLUSION: Overall, our study can expand the mutation spectrum of PCCB and provide useful information for the prenatal diagnosis of PA and genetic counseling for affected individuals.
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Ligasas de Carbono-Carbono/genética , Acidemia Propiónica , China , Femenino , Heterocigoto , Humanos , Metilmalonil-CoA Descarboxilasa/genética , Mutación , Embarazo , Acidemia Propiónica/genéticaRESUMEN
Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA) are inborn errors of metabolism affecting the catabolism of valine, isoleucine, methionine, threonine and odd-chain fatty acids. These are multi-organ disorders caused by the enzymatic deficiency of propionyl-CoA carboxylase (PCC) or methylmalonyl-CoA mutase (MUT), resulting in the accumulation of propionyl-coenzyme A (P-CoA) and methylmalonyl-CoA (M-CoA in MMA only). Primary metabolites of these CoA esters include 2-methylcitric acid (MCA), propionyl-carnitine (C3), and 3-hydroxypropionic acid, which are detectable in both PA and MMA, and methylmalonic acid, which is detectable in MMA patients only (Chapman et al., 2012). We deployed liver cell-based models that utilized PA and MMA patient-derived primary hepatocytes to validate a small molecule therapy for PA and MMA patients. The small molecule, HST5040, resulted in a dose-dependent reduction in the levels of P-CoA, M-CoA (in MMA) and the disease-relevant biomarkers C3, MCA, and methylmalonic acid (in MMA). A putative working model of how HST5040 reduces the P-CoA and its derived metabolites involves the conversion of HST5040 to HST5040-CoA driving the redistribution of free and conjugated CoA pools, resulting in the differential reduction of the aberrantly high P-CoA and M-CoA. The reduction of P-CoA and M-CoA, either by slowing production (due to increased demands on the free CoA (CoASH) pool) or enhancing clearance (to replenish the CoASH pool), results in a net decrease in the CoA-derived metabolites (C3, MCA and MMA (MMA only)). A Phase 2 study in PA and MMA patients will be initiated in the United States.
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Errores Innatos del Metabolismo de los Aminoácidos/tratamiento farmacológico , Metilmalonil-CoA Descarboxilasa/genética , Metilmalonil-CoA Mutasa/genética , Acidemia Propiónica/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/farmacología , Acilcoenzima A/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/patología , Carnitina/metabolismo , Línea Celular , Citratos/metabolismo , Hepatocitos/efectos de los fármacos , Humanos , Metilmalonil-CoA Mutasa/deficiencia , Acidemia Propiónica/genética , Acidemia Propiónica/patologíaRESUMEN
ABSTRACT: Propionic acidemia is associated with pathogenic variants in PCCA or PCCB gene. We investigated the potential pathogenic variants in PCCA or PCCB genes in Fujian Han population.Two probands and their families of Han ethnicity containing two generations were subject to newborn screening using tandem mass spectrometry, followed by diagnosis using urine gas chromatography mass spectrometry. Sanger sequencing was used to identify potential mutations in PCCA and PCCB genes.Compound heterozygous variants were identified in PCCB gene in two siblings of the first family, the youngest girl showed a novel missense variant c.1381G>C (p.Ala461Pro) in exon 13 and a heterozygous missense variant c.1301C>T (p.Ala434Val) in exon 13, which were inherited respectively from their parents. The oldest boy is a carrier with a novel missense variant c.1381G>C (p.Ala461Pro) in exon 13 which were inherited from his father. In the second family, c.1535G>A homozygous mutations were identified in the baby girl, which were inherited respectively from their parents. In silico analysis, several different types of bioinformatic software were utilized, which predicted that the novel variant c.1381G>C in PCCB gene was damaged. According to ACMG principle, the missense variant c.1381G>C (p.Ala461Pro) in exon 13 was a Variant of Undetermined Significance (VUS).One novel missense variant and two missense variants in PCCB gene were identified in the study. The novel variant of PCCB gene identified VUS was identified for the first time in the Chinese population, which enriched the mutational spectrum of PCCB gene.