Organic Acid Analysis

Hoffmann, Georg F.; Feyh, Patrik

doi:10.1007/978-3-642-55878-8_3

Cited by 16 publications

(6 citation statements)

References 15 publications

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“…MMA and PA should be considered in any newborn/child (whether critically ill or not) with unexplained Metabolic acidosis (with elevated anion gap) Elevated lactate Hyperammonemia Leukopenia, thrombocytopenia, anemia [ 27 ] and/or Urine ketone bodies (acetoacetate, dipstick) [ 80 ] …”

Section: Methodology and Objectivesmentioning

confidence: 99%

Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia

Baumgartner

Hörster

Dionisi‐Vici

et al. 2014

Orphanet J Rare Dis

541

788

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Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100’000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity.These guidelines aim to provide a trans-European consensus to guide practitioners, set standards of care and to help to raise awareness. To achieve these goals, the guidelines were developed using the SIGN methodology by having professionals on MMA/PA across twelve European countries and the U.S. gather all the existing evidence, score it according to the SIGN evidence level system and make a series of conclusive statements supported by an associated level of evidence. Although the degree of evidence rarely exceeds level C (evidence from non-analytical studies like case reports and series), the guideline should provide a firm and critical basis to guide practice on both acute and chronic presentations, and to address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Furthermore, these guidelines highlight gaps in knowledge that must be filled by future research. We consider that these guidelines will help to harmonize practice, set common standards and spread good practices, with a positive impact on the outcomes of MMA/PA patients.

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Section: Methodology and Objectivesmentioning

confidence: 99%

Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia

Baumgartner

Hörster

Dionisi‐Vici

et al. 2014

Orphanet J Rare Dis

541

788

View full text Add to dashboard Cite

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“…Organic acids were extracted with ethyl acetate and diethyl ether (Sigma) and derivatized with bis(trimethyl-silyl)trifluoro-acetamide (BSTFA) (Sigma) [ 101 ]. The trimethylsilyl derivatives obtained were separated by gas chromatography (Agilent 7890A) and detected in a mass spectrometer (Agilent 5975C).…”

Section: Methodsmentioning

confidence: 99%

Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition

et al. 2021

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The mitochondrial ATP synthase emerges as key hub of cellular functions controlling the production of ATP, cellular signaling, and fate. It is regulated by the ATPase inhibitory factor 1 (IF1), which is highly abundant in neurons. Herein, we ablated or overexpressed IF1 in mouse neurons to show that IF1 dose defines the fraction of active/inactive enzyme in vivo, thereby controlling mitochondrial function and the production of mitochondrial reactive oxygen species (mtROS). Transcriptomic, proteomic, and metabolomic analyses indicate that IF1 dose regulates mitochondrial metabolism, synaptic function, and cognition. Ablation of IF1 impairs memory, whereas synaptic transmission and learning are enhanced by IF1 overexpression. Mechanistically, quenching the IF1-mediated increase in mtROS production in mice overexpressing IF1 reduces the increased synaptic transmission and obliterates the learning advantage afforded by the higher IF1 content. Overall, IF1 plays a key role in neuronal function by regulating the fraction of ATP synthase responsible for mitohormetic mtROS signaling.

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“…Organic acids were extracted in fibroblasts as previously reported 18 . The trimethylsilyl derivatives obtained were separated by gas chromatography (Agilent 7890A, Wilmington, DE, USA) and detected in a mass spectrometer (Agilent 5975C, Wilmington, DE, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Organic acids were extracted in fibroblasts as previously reported. 18 The trimethylsilyl derivatives obtained were separated by gas chromatography (Agilent 7890A, Wilmington, DE, USA) and detected in a mass spectrometer (Agilent 5975C, Wilmington, DE, USA). Amino acids were quantified in fibroblasts by ultra‐performance liquid chromatography coupled to tandem mass spectrometry, as previously reported.…”

Section: Methodsmentioning

confidence: 99%

Unravelling inclusion body myositis using a patient‐derived fibroblast model

Cantó-Santos

Valls-Roca

Tobías

et al. 2023

J cachexia sarcopenia muscle

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Background Inclusion body myositis (IBM) is an inflammatory myopathy clinically characterized by proximal and distal muscle weakness, with inflammatory infiltrates, rimmed vacuoles and mitochondrial changes in muscle histopathology. There is scarce knowledge on IBM aetiology, and non‐established biomarkers or effective treatments are available, partly due to the lack of validated disease models. Methods We have performed transcriptomics and functional validation of IBM muscle pathological hallmarks in fibroblasts from IBM patients (n = 14) and healthy controls (n = 12), paired by age and sex. The results comprise an mRNA‐seq, together with functional inflammatory, autophagy, mitochondrial and metabolic changes between patients and controls. Results Gene expression profile of IBM vs control fibroblasts revealed 778 differentially expressed genes (P‐value adj < 0.05) related to inflammation, mitochondria, cell cycle regulation and metabolism. Functionally, an increased inflammatory profile was observed in IBM fibroblasts with higher supernatant cytokine secretion (three‐fold increase). Autophagy was reduced considering basal protein mediators (18.4% reduced), time‐course autophagosome formation (LC3BII 39% reduced, P‐value < 0.05), and autophagosome microscopic evaluation. Mitochondria displayed reduced genetic content (by 33.9%, P‐value < 0.05) and function (30.2%‐decrease in respiration, 45.6%‐decline in enzymatic activity (P‐value < 0.001), 14.3%‐higher oxidative stress, 135.2%‐increased antioxidant defence (P‐value < 0.05), 11.6%‐reduced mitochondrial membrane potential (P‐value < 0.05) and 42.8%‐reduced mitochondrial elongation (P‐value < 0.05)). In accordance, at the metabolite level, organic acid showed a 1.8‐fold change increase, with conserved amino acid profile. Correlating to disease evolution, oxidative stress and inflammation emerge as potential markers of prognosis. Conclusions These findings confirm the presence of molecular disturbances in peripheral tissues from IBM patients and prompt patients' derived fibroblasts as a promising disease model, which may eventually be exported to other neuromuscular disorders. We additionally identify new molecular players in IBM associated with disease progression, setting the path to deepen in disease aetiology, in the identification of novel biomarkers or in the standardization of biomimetic platforms to assay new therapeutic strategies for preclinical studies.

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Organic Acid Analysis

Cited by 16 publications

References 15 publications

Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia

Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia

Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition

Unravelling inclusion body myositis using a patient‐derived fibroblast model

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