-
Nutrients Jun 2024Propionate defects (PDs) mainly include methylmalonic (MMA) and propionic acidemia (PA) defects. Lifelong PD patients progress from the compensated to the decompensated...
Propionate defects (PDs) mainly include methylmalonic (MMA) and propionic acidemia (PA) defects. Lifelong PD patients progress from the compensated to the decompensated stages, the latter of which are characterized by life-threatening acidemia and hyperammonemia crises. PD patients can suffer immunocompromise, especially during the decompensation stage. There is a significant gap in the research regarding the humoral immune response in PD patients. Here, we analyzed serum immunoglobulin concentrations and hemograms across compensated and decompensated stages in PD patients. Nutritional status and crisis triggers of decompensation were also explored. Twenty patients were studied, and 25 decompensation events (DE) and 8 compensation events (CE) were recorded. Compared with those in the CE group, the IgG levels in the DE group (513.4 ± 244.5 mg/dL) were significantly lower than those in the CE group (860.8 ± 456.5 mg/dL) ( < 0.0087). The mean hemoglobin concentration was significantly lower in the DE group (11.8 g/dL) than in the CE group (13.4 g/dL) ( < 0.05). The most frequent (48%) possible decompensation trigger factor was infection. Most of the events were registered in eutrophic patients (87.9%), despite which 65.2% and 50% of patients who experienced decompensated and compensated events, respectively, presented with hypogammaglobulinemia G. These findings provide evidence of the immunodeficiency of PD patients, independent of their nutritional status. We suggest that PD patients be managed as immunocompromised independently of their nutritional status or metabolic state (compensated or decompensated).
Topics: Humans; Nutritional Status; Male; Female; Agammaglobulinemia; Middle Aged; Aged; Immunoglobulin G; Adult; Propionates; Propionic Acidemia
PubMed: 38892708
DOI: 10.3390/nu16111775 -
Frontiers in Genetics 2024Inborn errors of metabolism (IEMs) are uncommon. Although some studies have explored the distribution and characteristics of IEMs in newborns, the impact of these...
Inborn errors of metabolism (IEMs) are uncommon. Although some studies have explored the distribution and characteristics of IEMs in newborns, the impact of these disorders on hospitalized newborns remains unclear. In this study, we gathered data from 21,840 newborn patients admitted for various medical conditions at the Children's Hospital of Chongqing Medical University from January 2017 and December 2022. Liquid chromatography-tandem mass spectrometry (LC-MS/MS), gas chromatography-mass spectrometry (GC-MS/MS), and genetic analysis were used to elucidate the disease spectrum, incidence rate, and genetic characteristics of IEMs in hospitalized newborns. The results revealed that the incidence of IEMs in hospitalized newborns was 1/377 (58/21,840), with a higher incidence in full-term infants (1/428) than in premature infants (1/3,120). Among the diagnosed genetic metabolic diseases, organic acid metabolism disorders (1/662), amino acid metabolism disorders (1/950), and fatty acid oxidation disorders (1/10,920) were the most prevalent. Methylmalonic acidemia (MMA), especially the isolated form, emerged as the most common IEM, while neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and ornithine transcarbamylase deficiency (OTCD) were prevalent in premature infants. Of the 58 confirmed cases of IEMs, 72 variants were identified, of which 31.94% (23/72) had not been reported previously. This study contributes to understanding the incidence and clinical features of IEMs in hospitalized newborns, offering more efficient strategies for screening and diagnosing these disorders.
PubMed: 38863445
DOI: 10.3389/fgene.2024.1395988 -
Clinical Drug Investigation Jun 2024Novel messenger RNA (mRNA)-based therapies, currently in development, are emerging as a promising potential treatment modality for a broad range of life-threatening and...
BACKGROUND AND OBJECTIVE
Novel messenger RNA (mRNA)-based therapies, currently in development, are emerging as a promising potential treatment modality for a broad range of life-threatening and life-limiting inherited liver diseases, including methylmalonic acidemia (MMA) and propionic acidemia (PA). However, owing in part to their complexity, they are likely to come at considerable financial cost to healthcare systems. The objective of this research was to synthesize available evidence on the costs and clinical consequences associated with MMA and PA for the purpose of exploratory economic evaluation of novel mRNA-based therapies using an early cost-utility model from the United Kingdom payer perspective.
METHODS
A Markov model was constructed to simulate the costs and outcomes associated with novel mRNA therapies, compared with a combination of dietary management and organ transplantation (standard of care) among hypothetical cohorts of new-born patients with MMA and PA. Key model drivers were identified, and a price threshold analysis was performed to estimate value-based price ranges for future mRNA therapies given willingness-to-pay thresholds for orphan diseases.
RESULTS
mRNA therapy was associated with an additional 5.7 and 1.3 quality-adjusted life-years (QALYs) gained per patient lifetime among patients with MMA and PA, respectively. Key drivers of cost-effectiveness were relative improvement in utility among patients who receive mRNA-based therapy and transplantation, and the cost of mRNA therapy. Assuming a willingness to pay range of £100,000-£300,000 per QALY gained, the model demonstrated mRNA therapy to be cost-effective in MMA and PA at an annual treatment cost of £70,452-£94,575 and £31,313-£36,695, respectively.
CONCLUSIONS
Despite the lack of a strong evidence base in MMA and PA, this model provides a useful tool to estimate the cost-effectiveness, and inform value-based pricing, of new mRNA-based therapies. Our analyses also identified areas for research that will have the greatest value in reducing uncertainty in future health economic evaluations of such treatments.
Topics: Propionic Acidemia; Humans; Amino Acid Metabolism, Inborn Errors; Cost-Benefit Analysis; United Kingdom; RNA, Messenger; Markov Chains; Quality-Adjusted Life Years; Models, Economic; Genetic Therapy
PubMed: 38796677
DOI: 10.1007/s40261-024-01363-1 -
Biomolecules Apr 2024Although both localized nuclear magnetic resonance spectroscopy (MRS) and non-localized nuclear magnetic resonance spectroscopy (NMR) generate the same information,... (Review)
Review
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 B 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 B 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.
Topics: Humans; Propionic Acidemia; Amino Acid Metabolism, Inborn Errors; Magnetic Resonance Spectroscopy; Vitamin B 12 Deficiency; Methylmalonic Acid
PubMed: 38785935
DOI: 10.3390/biom14050528 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Jun 2024To investigate the clinical features and outcomes of adolescence-onset methylmalonic acidemia (MMA) and explore preventive strategies. This was a retrospective case...
To investigate the clinical features and outcomes of adolescence-onset methylmalonic acidemia (MMA) and explore preventive strategies. This was a retrospective case analysis of the phenotypes, genotypes and prognoses of adolescence-onset MMA patients. There were 55 patients diagnosed in Peking University First Hospital from January 2002 to June 2023, the data of symptoms, signs, laboratory results, gene variations, and outcomes was collected. The follow-ups were done through WeChat, telephone, or clinic visits every 3 to 6 months. Among the 55 patients, 31 were males and 24 were females. The age of onset was 12 years old (range 10-18 years old). They visited clinics at Tanner stages 2 to 5 with typical secondary sexual characteristics. Nine cases (16%) were trigged by infection and 5 cases (9%) were triggered by insidious exercises. The period from onset to diagnosis was between 2 months and 6 years. Forty-five cases (82%) had neuropsychiatric symptoms as the main symptoms, followed by cardiovascular symptoms in 12 cases (22%), kidney damage in 7 cases (13%), and eye disease in 12 cases (22%). Fifty-four cases (98%) had the biochemical characteristics of methylmalonic acidemia combined with homocysteinemia, and 1 case (2%) had the isolated methylmalonic acidemia. Genetic diagnosis was obtained in 54 cases, with 20 variants identified in MMACHC gene and 2 in MMUT gene. In 53 children with MMACHC gene mutation,1 case had dual gene variants of PRDX1 and MMACHC, with 105 alleles. The top 5 frequent variants in MMACHC were c.482G>A in 39 alleles (37%), c.609G>A in 17 alleles (16%), c.658_660delAAG in 11 alleles (10%), c.80A>G in 10 alleles (10%), c.567dupT and c.394C>T both are 4 alleles (4%). All patients recovered using cobalamin, L-carnitine, betaine, and symptomatic therapy, and 54 patients (98%) returned to school or work. Patients with adolescence-onset MMA may triggered by fatigue or infection. The diagnosis is often delayed due to non-specific symptoms. Metabolic and genetic tests are crucial for a definite diagnosis. Treatment with cobalamin, L-carnitine, and betaine can effectively reverse the prognosis of MMA in adolescence-onset patients.
Topics: Humans; Male; Female; Amino Acid Metabolism, Inborn Errors; Adolescent; Retrospective Studies; Child; Follow-Up Studies; Mutation; Age of Onset; Phenotype; Genotype; Prognosis; Methylmalonic Acid; Vitamin B 12; Oxidoreductases
PubMed: 38763872
DOI: 10.3760/cma.j.cn112140-20240130-00083 -
Cell & Bioscience May 2024Methylmalonic acidemia (MMA) is a rare inborn error of propionate metabolism caused by deficiency of the mitochondrial methylmalonyl-CoA mutase (MUT) enzyme. As matter...
BACKGROUND
Methylmalonic acidemia (MMA) is a rare inborn error of propionate metabolism caused by deficiency of the mitochondrial methylmalonyl-CoA mutase (MUT) enzyme. As matter of fact, MMA patients manifest impairment of the primary metabolic network with profound damages that involve several cell components, many of which have not been discovered yet. We employed cellular models and patients-derived fibroblasts to refine and uncover new pathologic mechanisms connected with MUT deficiency through the combination of multi-proteomics and bioinformatics approaches.
RESULTS
Our data show that MUT deficiency is connected with profound proteome dysregulations, revealing molecular actors involved in lysosome and autophagy functioning. To elucidate the effects of defective MUT on lysosomal and autophagy regulation, we analyzed the morphology and functionality of MMA-lysosomes that showed deep alterations, thus corroborating omics data. Lysosomes of MMA cells present as enlarged vacuoles with low degradative capabilities. Notwithstanding, treatment with an anti-propionigenic drug is capable of totally rescuing lysosomal morphology and functional activity in MUT-deficient cells. These results indicate a strict connection between MUT deficiency and lysosomal-autophagy dysfunction, providing promising therapeutic perspectives for MMA.
CONCLUSIONS
Defective homeostatic mechanisms in the regulation of autophagy and lysosome functions have been demonstrated in MUT-deficient cells. Our data prove that MMA triggers such dysfunctions impacting on autophagosome-lysosome fusion and lysosomal activity.
PubMed: 38760822
DOI: 10.1186/s13578-024-01245-1 -
Transplantation Jun 2024Split liver transplantation is a valuable means of mitigating organ scarcity but requires significant surgical and logistical effort. Ex vivo splitting is associated...
BACKGROUND
Split liver transplantation is a valuable means of mitigating organ scarcity but requires significant surgical and logistical effort. Ex vivo splitting is associated with prolonged cold ischemia, with potentially negative effects on organ viability. Machine perfusion can mitigate the effects of ischemia-reperfusion injury by restoring cellular energy and improving outcomes.
METHODS
We describe a novel technique of full-left/full-right liver splitting, with splitting and reconstruction of the vena cava and middle hepatic vein, with dual arterial and portal hypothermic oxygenated machine perfusion. The accompanying video depicts the main surgical passages, notably the splitting of the vena cava and middle hepatic vein, the parenchymal transection, and the venous reconstruction.
RESULTS
The left graft was allocated to a pediatric patient having methylmalonic aciduria, whereas the right graft was allocated to an adult patient affected by hepatocellular carcinoma and cirrhosis.
CONCLUSIONS
This technique allows ex situ splitting, counterbalancing prolonged ischemia with the positive effects of hypothermic oxygenated machine perfusion on graft viability. The venous outflow is preserved, safeguarding both grafts from venous congestion; all reconstructions can be performed ex situ, minimizing warm ischemia. Moreover, there is no need for highly skilled surgeons to reach the donor hospital, thereby simplifying logistical aspects.
Topics: Humans; Hepatic Veins; Liver Transplantation; Perfusion; Liver Neoplasms; Liver; Organ Preservation; Carcinoma, Hepatocellular; Male; Treatment Outcome; Cold Ischemia; Reperfusion Injury; Adult; Liver Cirrhosis; Hypothermia, Induced
PubMed: 38755751
DOI: 10.1097/TP.0000000000005039 -
Orphanet Journal of Rare Diseases May 2024Methylmalonic aciduria (MMA) is a group of rare genetic metabolic disorders resulting from defects in methylmalonyl coenzyme A mutase (MCM) or intracellular cobalamin...
BACKGROUND
Methylmalonic aciduria (MMA) is a group of rare genetic metabolic disorders resulting from defects in methylmalonyl coenzyme A mutase (MCM) or intracellular cobalamin (cbl) metabolism. MMA patients show diverse clinical and genetic features across different subtypes and populations.
METHODS
We retrospectively recruited 60 MMA patients from a single center and diagnosed them based on their clinical manifestations and biochemical assays. We then performed genetic analysis to confirm the diagnosis and identify the causal variants.
RESULTS
We confirmed the common clinical manifestations of MMA reported previously. We also described four rare MMA cases with unusual symptoms or genetic variants, such as pulmonary hypertension or limb weakness in late-onset patients. We identified 15 MMACHC and 26 MMUT variants in 57 patients, including 6 novel MMUT variants. Two patients had only one MMAA variant each, and one patient had mild MMA due to mitochondrial DNA depletion syndrome caused by a SUCLA2 variant. Among 12 critically ill patients, isolated MMA was associated with higher C3, blood ammonia, and acidosis, while combined MMA was linked to hydrocephalus on skull MRI. MMACHC c.658-660delAAG and MMUT c.1280G > A variants were correlated with more severe phenotypes.
CONCLUSIONS
Our study demonstrates the clinical and genotypic heterogeneity of MMA patients and indicates that metabolic screening and genetic analysis are useful tools to identify rare cases.
Topics: Humans; Retrospective Studies; Amino Acid Metabolism, Inborn Errors; Female; Male; China; Methylmalonyl-CoA Mutase; Child, Preschool; Infant; Child; Adolescent; Vitamin B 12; Genetic Testing; Mutation; Infant, Newborn
PubMed: 38750596
DOI: 10.1186/s13023-024-03210-0 -
Nature Communications May 2024Messenger RNA (mRNA) therapeutics delivered via lipid nanoparticles hold the potential to treat metabolic diseases caused by protein deficiency, including propionic...
Messenger RNA (mRNA) therapeutics delivered via lipid nanoparticles hold the potential to treat metabolic diseases caused by protein deficiency, including propionic acidemia (PA), methylmalonic acidemia (MMA), and phenylketonuria (PKU). Herein we report results from multiple independent preclinical studies of mRNA-3927 (an investigational treatment for PA), mRNA-3705 (an investigational treatment for MMA), and mRNA-3210 (an investigational treatment for PKU) in murine models of each disease. All 3 mRNA therapeutics exhibited pharmacokinetic/pharmacodynamic (PK/PD) responses in their respective murine model by driving mRNA, protein, and/or protein activity responses, as well as by decreasing levels of the relevant biomarker(s) when compared to control-treated animals. These preclinical data were then used to develop translational PK/PD models, which were scaled allometrically to humans to predict starting doses for first-in-human clinical studies for each disease. The predicted first-in-human doses for mRNA-3927, mRNA-3705, and mRNA-3210 were determined to be 0.3, 0.1, and 0.4 mg/kg, respectively.
Topics: Propionic Acidemia; Animals; Phenylketonurias; RNA, Messenger; Amino Acid Metabolism, Inborn Errors; Mice; Humans; Disease Models, Animal; Male; Female; Nanoparticles; Mice, Inbred C57BL; Liposomes
PubMed: 38714648
DOI: 10.1038/s41467-024-47460-9 -
Orphanet Journal of Rare Diseases Apr 2024Clinicians traditionally aim to identify a singular explanation for the clinical presentation of a patient; however, in some cases, the diagnosis may remain elusive or...
BACKGROUND
Clinicians traditionally aim to identify a singular explanation for the clinical presentation of a patient; however, in some cases, the diagnosis may remain elusive or fail to comprehensively explain the clinical findings. In recent years, advancements in next-generation sequencing, including whole-exome sequencing, have led to the incidental identification of dual diagnoses in patients. Herein we present the cases of five pediatric patients diagnosed with dual rare genetic diseases. Their natural history and diagnostic process were explored, and lessons learned from utilizing next-generation diagnostic technologies have been reported.
RESULTS
Five pediatric cases (3 boys, 2 girls) with dual diagnoses were reported. The age at diagnosis was from 3 months to 10 years. The main clinical presentations were psychomotor retardation and increased muscular tension, some accompanied with liver dysfunction, abnormal appearance, precocious puberty, dorsiflexion restriction and varus of both feet, etc. After whole-exome sequencing, nine diseases were confirmed in these patients: Angelman syndrome and Krabbe disease in case 1, Citrin deficiency and Kabuki syndrome in case 2, Homocysteinemia type 2 and Copy number variant in case 3, Isolated methylmalonic acidemia and Niemann-Pick disease type B in case 4, Isolated methylmalonic acidemia and 21-hydroxylase deficiency in case 5. Fifteen gene mutations and 2 CNVs were identified. Four novel mutations were observed, including c.15292de1A in KMT2D, c.159_164inv and c.1427G > A in SLC25A13, and c.591 C > G in MTHFR.
CONCLUSIONS
Our findings underscore the importance of clinicians being vigilant about the significance of historical and physical examination. Comprehensive clinical experience is crucial for identifying atypical clinical features, particularly in cases involving dual rare genetic diseases.
Topics: Male; Female; Humans; Child; Citrullinemia; Amino Acid Metabolism, Inborn Errors; Abnormalities, Multiple; Angelman Syndrome; Mitochondrial Membrane Transport Proteins
PubMed: 38610036
DOI: 10.1186/s13023-024-03148-3