Metabolism of 1-13C-Propionate In Vivo in Patients with Disorders of Propionate Metabolism

Abstract

ABSTRAa. Metabolism of propionate in human subjects was studied using bolus administration of l-'3C-propionate i.v. or orally. The study population consisted of five patients with propionic acidemia (PA), eight with methylmalonic acidemia (MMA, four responsive to vitamin BIZ), one each with multiple carboxylase deficiency and transcobalamin-I1 deficiency, and five healthy volunteers. Concentrations of I-I3C-propionate were measured in blood in three patients with PA, two with MMA, and two controls. Breath samples were obtained at intervals during 3 h after the dose, isotopic enrichment of I3CO2 was measured, and the cumulative percentage of recovery of I3C was calculated from the individual's predicted resting energy expenditure. Recovery of I3CO2 and half-time of I-I3C-propionate in PA were significantly less than normal. The same parameters in MMA were below normal, but significantly greater than in PA. Recovery of I3CO2 was well correlated with clinical severity in PA, but did not correlate in MMA. Differences between MMA and PA may indicate different distribution of propionate pools, differences in inducibility of residual enzyme activities, or an alternate pathway for decarboxylation of propionate available in MMA but not PA. Only one patient with PA demonstrated increased 13C02 production during biotin treatment. In a B12-responsive MMA patient, no differences were noted within 2 d of initiating treatment with BIZ, but there was an increase in I3CO2 production after 4 mo. Recovery of I3CO2 was normal in the patient with transcobalamin-I1 deficiency before and after treatment with vitamin B17. In the ~a t i e n t with muletiple carboxylase deficiency, 13C02 generation was nearly normal while he was receiving his maintenance dose of biotin, and was not significantly changed after 3 and 7 d without biotin treatment, despite a decrease of 30% in lymphocyte propionyl-CoA carboxylase activity. (Pediatr Res 30: [15][16][17][18][19][20][21][22]1991)

Gene therapy in a murine model of methylmalonic acidemia using rAAV9-mediated gene delivery

“…Methylmalonic acid concentrations in plasma were measured by gas chromatography-mass spectrometry [41, 42]. To determine 1- 13 C-propionate oxidation in vivo , mice were placed into a respiratory chamber after intraperitoneal injection of 200 μg of 1- 13 C-sodium propionate [22, 43]. Breath samples from mutant, control, and treated mice were collected at 5, 15, and 25 minutes after injection and the isotope ratio ( 13 C/ 12 C) of the expired gas was measured with a gas isotope ratio mass spectrometer (Metabolic Solutions, Nashua, NH).…”

Propionyl-CoA carboxylase – A review

“…However, molecular genetics studies should be undertaken to attempt to predictt disease severity, but also genetic testing is useful for carrier detection among family members and precise genetic counselling [1]. A marker of oxidation, exhaled carbon dioxide (CO2) when using stable isotope labeled propionate has been noted to be lower in individuals with severe PA, but this does not have any clinical utility at this time since few centers can do these studies currently [111, 112]. …”

Late‐onset holocarboxylase synthetase deficiency

“…Hypoglycaemia is a common feature of isolated deficiency of MCC, but it could also reflect the deficiency of PC. PC appeared to be the first carboxylase to lose activity during a brief withdrawal of biotin in a patient with HCS deficiency (Barshop et al 1991), although MCC was the most severely affected carboxylase in our patient. Differential response to oral biotin (10-100mg/day) has been noted in HCS-deficient patients (Fuchshuber et al 1993;Dabbagh et al 1994;Livne et al 1994;Wolf 1995), In a patient receiving 100rag/day, biochemical and enzymatic abnormalities did not completely resolve.…”