Fibroblast growth factor 21 as a biomarker for long‐term complications in organic acidemias

Molema, Femke; Jacobs, Ed; Onkenhout, W.; Schoonderwoerd, G.C.; Langendonk, Janneke G.; Williams, Monique

doi:10.1007/s10545-018-0244-6

Cited by 29 publications

(47 citation statements)

References 43 publications

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“…Consistent with previous studies, 8,9 we also found that FGF21 correlated with the disease burden, although the categorical clinical findings we considered to evaluate the disease burden were different from other studies.…”

Section: Discussionsupporting

confidence: 89%

“…Recently, fibroblast growth factor 21 (FGF21), a peptide hormone playing a key role in whole-body energy homeostasis and associated with mitochondrial dysfunction, 7 has been shown to be as a highly predictive biomarker for long-term complications in PA and MMA. 8,9 Thus far, MCA has been mainly considered a helpful biomarker for diagnosis of inherited disorders of propionate metabolism, but its utility in guiding the adjustment of treatment regimens and in predicting the metabolic status still needs to be established, with only a few works reporting data on urine/plasma MCA in the follow-up of PA and MMA. 5,[10][11][12][13][14][15] In this study, we have prospectively evaluated plasma concentrations of MCA and its correlations with primary and secondary biomarkers, including FGF21, in a large series of PA and MMA patients, on standard treatment and/or after transplantation, to explore the potential contribution of MCA quantification in the long-term management of organic acidemias.…”

Section: Introductionmentioning

confidence: 99%

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Plasma methylcitric acid and its correlations with other disease biomarkers: The impact in the follow up of patients with propionic and methylmalonic acidemia

Maines

Catesini

Boenzi

et al. 2020

J of Inher Metab Disea

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Methylcitric acid (MCA) analysis has been mainly utilized for the diagnosis of propionate disorders or as a second-tier test in newborn screening, but its utility for patients monitoring still needs to be established. We explored the potential contribution of MCA in the long-term management of organic acidurias. We prospectively evaluated plasma MCA and its relationship with disease biomarkers, clinical status, and disease burden in 22 patients, 13 with propionic acidemia (PA) and nine with methylmalonic acidemia (MMA) on standard treatment and/or after transplantation. Samples were collected at scheduled routine controls or during episodes of metabolic decompensation (MD), 10 patients were evaluated after transplantation (six liver, two combined liver and kidney, 2 kidney). MCA levels were higher in PA compared to MMA and its levels were not influenced by the clinical status (MD vs well state). In MMA, MCA was higher in elder patients and, along with fibroblast growth factor 21 (FGF21) and plasma methylmalonic acid, negatively correlated with GFR. In both diseases, MCA correlated with ammonia, glycine, lysine, C3, and

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Plasma methylcitric acid and its correlations with other disease biomarkers: The impact in the follow up of patients with propionic and methylmalonic acidemia

Maines

Catesini

Boenzi

et al. 2020

J of Inher Metab Disea

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“…Of great importance to the consideration of FGF21 as a hepatic biomarker for MMA patients, where renal disease directly influences the serum levels of methylmalonic acid, FGF21 concentrations did not correlate with renal disease indices, including creatinine, cystatin C, and estimated GFR, suggesting that circulating FGF21 will be a particularly useful biomarker to track hepatic mitochondrial dysfunction and response to MUT replacement therapies, independent of kidney function. A study published while the current work was under review further validates the correlations between plasma FGF21 and disease severity and lack of strong association with renal dysfunction in MMA patients (68). Because FGF21 is a pancreatic secretagogue (69) and increases bone loss (70,71), additional roles in the pathophysiology of MMA mediated by FGF21, such as the propensity toward pancreatitis and low bone density, seem likely.…”

Section: Discussionsupporting

confidence: 63%

FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia

et al. 2018

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related to MMA filed by the NIH on their behalf. Lina Li is an employee of LLN Consultant Inc. and founder of CELiD Biotechnologies Inc. GME is a consultant for Moderna Therapeutics, LogicBio Therapeutics, Horizon Pharma, and Natera; a data-monitoring committee member for BioMarin, Audentes Therapeutics, Amicus, RegenxBio, and NeuroVia; and an investigator on clinical trials for Aeglea, BioElectron, and Stealth Therapeutics. LHV is an inventor of AncAAV and other AAV technologies, which are licensed to various biotechnology and pharmaceutical entities. LHV is a consultant to a number of companies with gene therapy interest, including Selecta Biosciences and Lonza, licensees of AncAAV technology. CPV has received funding to support AAV gene therapy research for MMA from Selecta Biosciences and LogicBio Therapeutics.

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“…Mitochondrial dysfunction plays an important role in the pathophysiology of MMA, and FGF‐21 is a biomarker for mitochondrial dysfunction. Clearly increased FGF‐21 levels have been described in MMA . We confirmed the severe initial decrease of FGF‐21 after transplantation as recently reported by Manoli et al in our two case reports.…”

Section: Discussionsupporting

confidence: 92%

“…Clearly increased FGF-21 levels have been described in MMA. 22,[39][40][41][42] We confirmed the severe initial decrease of FGF-21 after transplantation as recently reported by Manoli et al 43 in our two case reports. However, we also showed an increase in FGF-21 plasma levels in case 1 at the time of neurological symptoms due to CNI-induced PRES with a decrease in FGF-21 with improvement of symptoms and brain MRI-scan findings.…”

Section: Outcomesupporting

confidence: 91%

Neurotoxicity including posterior reversible encephalopathy syndrome after initiation of calcineurin inhibitors in transplanted methylmalonic acidemia patients: Two case reports and review of the literature

Molema¹,

Williams²,

Langendonk

et al. 2020

JIMD Reports

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Introduction New neurological symptoms in methylmalonic acidemia (MMA) patients after liver and/or kidney transplantation (LKT) are often described as metabolic stroke‐like‐events. Since calcineurin inhibitors (CNIs) are a well‐known cause of new neurological symptoms in non‐MMA transplanted patients, we investigated the incidence of CNI‐induced neurotoxicity including posterior reversible encephalopathy syndrome (PRES) in post‐transplanted MMA patients. Methods We report the two MMA patients treated with LKT in our center. Additionally, we performed a systematic review of case reports/series of post‐transplanted MMA patients and determined if CNI‐induced neurotoxicity/PRES was a likely cause of new neurological symptoms. Definite CNI‐induced neurotoxicity was defined as new neurological symptoms during CNI treatment with symptom improvement after CNI dose reduction/discontinuation. PRES was defined as CNI‐induced neurotoxicity with signs of vasogenic edema on brain magnetic resonance imaging (MRI)‐scan post‐transplantation. Results Our two MMA patients both developed CNI‐induced neurotoxicity, one had PRES. In literature, 230 transplanted MMA patients were identified. Neurological follow‐up was reported in 54 of them, of which 24 were excluded from analysis since no anti‐rejection medication was reported. Thirty patients, all using CNI, were included. Sixteen patients (53%) had no new neurological symptoms post‐transplantation and five patients (17%) had definite CNI neurotoxicity of whom two had PRES. Including our cases this results in a pooled incidence of 22% (7/32) definite CNI neurotoxicity and 9% PRES (3/32) in post‐transplanted MMA patients on CNI. Conclusion In MMA post‐transplanted patients with new neurological symptoms CNI‐induced neurotoxicity/PRES should be considered. Early recognition of CNI‐induced neurotoxicity is essential to initiate dose reduction/discontinuation of CNI to minimize persistent neurologic damage and improve outcome. Concise one sentence take home message In all post‐transplanted MMA patients with new neurological symptoms CNI‐induced neurotoxicity/PRES should be considered, and directly reducing the dose/discontinuation of CNI is essential.

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Fibroblast growth factor 21 as a biomarker for long‐term complications in organic acidemias

Abstract: This study demonstrates the potential role of FGF-21 as a biomarker for long-term complications in classical organic acidemias, attributed to mitochondrial dysfunction.

Cited by 29 publications

References 43 publications

Plasma methylcitric acid and its correlations with other disease biomarkers: The impact in the follow up of patients with propionic and methylmalonic acidemia

Plasma methylcitric acid and its correlations with other disease biomarkers: The impact in the follow up of patients with propionic and methylmalonic acidemia

FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia

Neurotoxicity including posterior reversible encephalopathy syndrome after initiation of calcineurin inhibitors in transplanted methylmalonic acidemia patients: Two case reports and review of the literature

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