Abstract
BackgroundThere is increasing evidence that long-term complications in organic acidemias are caused by impaired mitochondrial metabolism. Currently, there is no specific biomarker to monitor mitochondrial dysfunction in organic acidemias. Serum fibroblast growth factor 21 (FGF-21) is a biomarker for mitochondrial disease and could be a candidate to monitor mitochondrial function in the deleterious course of disease.MethodsData of 17 patients with classical organic acidemias (11 propionic acidemia (PA), four methylmalonic acidemia (MMA) and two isovaleric acidemia (IVA) patients) were included. The clinical course was evaluated; metabolic decompensations and long-term complications were correlated with plasma FGF-21 levels. Cardiomyopathy, prolonged QT interval, renal failure, and optic neuropathy were defined as long-term complications.ResultsPatients ages ranged from 16 months up to 32 years. Serious long-term complications occurred in eight patients (five PA and three MMA patients). In MMA and PA patients plasma FGF-21 levels during stable metabolic periods were significantly higher in patients with long-term complications (Mdn = 2556.0 pg/ml) compared to patients without (Mdn = 287.0 pg/ml). A median plasma FGF-21 level above 1500 pg/ml during a stable metabolic period, measured before the occurrence of long-term complications, had a positive predictive value of 0.83 and a negative predictive value of 1.00 on long-term complications in MMA and PA patients.ConclusionThis study demonstrates the potential role of FGF-21 as a biomarker for long-term complications in classical organic acidemias, attributed to mitochondrial dysfunction.
Highlights
The branched chain amino acids isoleucine, valine, and leucine are essential nutrients for human growth and development (Adibi 1976)
We studied the potential of serum fibroblast growth factor 21 (FGF-21) measured in the stable metabolic period as a biomarker for long-term complications, attributed to mitochondrial failure, in patients with organic acidemias
This study demonstrates that FGF-21 can be a biomarker for long-term complications, attributed to mitochondrial dysfunction, in classic organic acidemia patients
Summary
The branched chain amino acids isoleucine, valine, and leucine are essential nutrients for human growth and development (Adibi 1976). The enzymes methylmalonylCoA mutase, propionyl-CoA carboxylase, and isovaleryl-CoA dehydrogenase play pivotal roles in the metabolism of these amino acids. Deficiencies of these enzymes result in three classic organic acidemias, methylmalonic acidemia (MMA; OMIM #251000, #251100, #251110, #277400, #277410), propionic acidemia (PA; OMIM #606054), and isovaleric acidemia (IVA; OMIM #243500). Occurrence of mental retardation is most likely multifactorial, for example cerebral damage during decompensations with metabolic encephalopathy (Kölker et al 2006a, cerebral accumulation of toxic metabolites (Kölker et al 2006b; Harting et al 2008) and presumably mitochondrial dysfunction (Melo et al 2011; Wajner and Goodman 2011). Cardiomyopathy, prolonged QT interval, renal failure, and optic neuropathy were defined as long-term complications
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