Metabolic changes associated with hyperammonemia in patients with propionic acidemia

Filipowicz, Heather R.; Ernst, Sharon L.; Ashurst, Carrie L.; Pasquali, Marzia; Longo, Nicola

doi:10.1016/j.ymgme.2005.11.016

Cited by 81 publications

(101 citation statements)

References 30 publications

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“…During propionic acidemia the accumulated propionyl-CoA can combine with oxaloacetate leading to methylcitric acid, which can affect cellular metabolism (38). However, addition of purified 2-methylcitric acid did not affect MICA/B induction by propionate or FR901228 (data not shown), suggesting that propionate-induced MICA/B expression is not caused by methylcitric acid production.…”

Section: Discussionmentioning

confidence: 90%

Propionic Acid Secreted from Propionibacteria Induces NKG2D Ligand Expression on Human-Activated T Lymphocytes and Cancer Cells

Andresen¹,

Hansen²,

Jensen³

et al. 2009

The Journal of Immunology

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We found that propionic acid secreted from propionibacteria induces expression of the NKG2D ligands MICA/B on activated T lymphocytes and different cancer cells, without affecting MICA/B expression on resting peripheral blood cells. Growth supernatant from propionibacteria or propionate alone could directly stimulate functional MICA/B surface expression and MICA promoter activity by a mechanism dependent on intracellular calcium. Deletion and point mutations further demonstrated that a GC-box motif around −110 from the MICA transcription start site is essential for propionate-mediated MICA promoter activity. Other short-chain fatty acids such as lactate, acetate, and butyrate could also induce MICA/B expression. We observed a striking difference in the molecular signaling pathways that regulate MICA/B. A functional glycolytic pathway was essential for MICA/B expression after exposure to propionate and CMV. In contrast, compounds with histone deacetylase-inhibitory activity such as butyrate and FR901228 stimulated MICA/B expression through a pathway that was not affected by inhibition of glycolysis, clearly suggesting that MICA/B is regulated through different molecular mechanisms. We propose that propionate, produced either by bacteria or during cellular metabolism, has significant immunoregulatory function and may be cancer prophylactic.

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Section: Discussionmentioning

confidence: 90%

Propionic Acid Secreted from Propionibacteria Induces NKG2D Ligand Expression on Human-Activated T Lymphocytes and Cancer Cells

Andresen¹,

Hansen²,

Jensen³

et al. 2009

The Journal of Immunology

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“…2. Severe hyperammonemia in PA is explained by several complex mechanisms [1,7]. PropionylCoA competitively inhibits N-acetyl glutamate synthase, the allosteric activator of carbamoyl phosphate synthase, the rate limiting enzyme of urea cycle resulting in hyperammonemia.…”

Section: Discussionmentioning

confidence: 99%

Biochemical Basis of Heterogeneity in Acute Presentations of Propionic Acidemia

et al. 2012

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“…However in all reports, including ours, evaluation of NCG efficacy remains limited by concomitant dialysis and /or the co-administration of ammonia scavenger drugs. The efficacy of ammonia scavengers for controlling hyperammonemia in organic acidurias also remains controversial, given the low or normal glutamine plasma levels typically found in PA patients (Al-Hassnan et al 2003;Filipowicz et al 2006). Indeed, glutamine was not elevated in three of our four patients.…”

Section: Discussionmentioning

confidence: 99%

“…Other mechanisms have been proposed to explain hyperammonemia in organic aciduria including depletion of Krebs cycle intermediates, resulting in reduced alphaketoglutarate for glutamate and glutamine production, leading to altered synthesis of N-acetylglutamate. Indeed, glutamate and glutamine levels are reduced in PA (AlHassnan et al 2003;Filipowicz et al 2006). If the ammonia toxicity has a significant impact on the neurological outcomes of PA patients, then decreasing the hyperammonemia by NCG supplementation could reduce associated morbidity.…”

Section: Introductionmentioning

confidence: 99%

Short-Term Outcome of Propionic Aciduria Treated at Presentation with N-Carbamylglutamate: A Retrospective Review of Four Patients

et al. 2011

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N-carbamylglutamate (NCG) has been reported to decrease ammonia levels in patients with propionic aciduria (PA) and methylmalonic aciduria (MMA), but reports on clinical outcomes remain scant. Here, we report a retrospective series of four patients with neonatal PA treated with NCG at presentation. Patients presented between 2 and 9 days of age and peak plasma ammonia ranged from 524 to 1,572 mM. Patients received bolus (30-200 mg/kg) and sustaining (115-300 mg/kg per day) doses of NCG in addition to a standard treatment regimen that included ammonia scavenger drugs. Ammonia levels decreased significantly in three of the four cases within 2 h after administration of NCG and fell below 100 mM in all within 12-29 h. Two patients received NCG (bolus 200 mg/kg) while ammonia was above 500 mM (740 and 1,572) and their levels fell below 500 mM by 4 and 8 h post-treatment, respectively. Outcomes of these NGC-treated patients were not improved over previously reported PA patients who did not receive NCG: two died during the initial episode and one after his third metabolic decompensation at 46 days. The survivor is now 3 years old and has a well-controlled seizure disorder and a mild developmental delay mostly in language. We conclude that despite a trial of NCG and a rapid fall in plasma ammonia, the short-term outcome of these patients was not improved.

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Metabolic changes associated with hyperammonemia in patients with propionic acidemia

Cited by 81 publications

References 30 publications

Propionic Acid Secreted from Propionibacteria Induces NKG2D Ligand Expression on Human-Activated T Lymphocytes and Cancer Cells

Propionic Acid Secreted from Propionibacteria Induces NKG2D Ligand Expression on Human-Activated T Lymphocytes and Cancer Cells

Biochemical Basis of Heterogeneity in Acute Presentations of Propionic Acidemia

Short-Term Outcome of Propionic Aciduria Treated at Presentation with N-Carbamylglutamate: A Retrospective Review of Four Patients

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