The majority of studies were performed using L-carnitine doses of 50-100 mg/kg/d. L-carnitine conjugates with propionic acid to form propionylcarnitine. In PROP, supplementation with L-carnitine reduces the accumulation of free propionic acid and prevents secondary carnitine deficiency. Low levels of carnitine have been found in the muscle and liver (F.510), as well as heart (F.59) of patients with PROP.  L-carnitine is a widely used supplement in both the acute and chronic treatment of PROP.  Survey data indicated that patients are prescribed L-carnitine from 80 to nearly 95% of the time (F.3382, F.2807, F.3318). Eight research articles (F.574, F.2738, F.530, F.3387, F.3264, F.3179, F.510, F.575) including 37 patients with PROP reported better outcomes for patients receiving L-carnitine. Several reports were case studies or case series where L-carnitine was given in combination with diet therapy and other interventions, making it difficult to attribute the benefit to L-carnitine alone (F.2738, F.3387, F.3264, F.3179,F.575). Reported benefits of L-carnitine supplementation, ranging from 25-100 mg/kg/d, included: lower mortality when compared to cohort of patients treated prior to L-carnitine therapy (F.57); improved nutritional status and decreased incidence of metabolic decompensation (F.3264); better intellectual outcome (F.575); and better ability to tolerate stress caused by fasting, fever, viral infection or excessive protein loading (F.530); reduced ketogenesis (G.80) and less constipation (G.80). An in vitro study of leukocytes, from healthy volunteers, incubated with propionic acid and L-carnitine, found that L-carnitine reduced the markers of DNA damage in a concentration-dependent manner (F.521).  Conversely, 2 studies (F.485, F.503) found no direct benefit of L-carnitine supplementation. The first (F.485) showed no consistent effect of L-carnitine (100 mg/kg/d divided in 2-3 doses) on ¹³CO₂ production in 3 patients with PROP given carnitine and labeled sodium propionate. The second (F.503) was a study of patients with organic acidemias, including 1 patient with PROP. Patients were given their typical dose of L-carnitine (50-100 mg/kg/day) for at least 3 months prior to being admitted to the clinical research center for 4-6 day carnitine withdrawal study.  Initial carnitine concentrations (µmol/L) were: total-106, free-49 and acyl-57) that decreased to: total-53, free-11, acyl-42 after the withdrawal period with no adverse clinical outcome.  Both time periods represented carnitine concentrations in the patients that were different from control.  The authors suggested that the ability of the kidneys to conserve carnitine is impaired in patients with acyl CoA enzyme deficiencies.  L-carnitine supplementation increased plasma free carnitine (F.510) and decreased plasma glycine concentrations (F.510). Biochemical changes seen in urine included lowered urinary lactate and propionylglycine and increased 3-hydroxypropionate and methylcitrate (F.575). 

Delphi 2:

There was consensus (86% of MD and 75% of RD respondents agreed) that the dose of L-carnitine should be adjusted to maintain plasma free carnitine in the normal range.

There was not consensus about the dose to use when starting an individual with PROP on carnitine therapy. Responses ranged from 50 to 200 mg/kg/day (43% of MD respondents agreed with 50-100 mg/kg/d and 43% t agreed with 100-200 mg/kg/d).

There was also not a consensus about carnitine dosage during illness - approximately 50% of the total respondents agreed that carnitine dosage is typically increased during illness.

Eleven formal review articles (F.526, F.3109, F.3273, F.3403, F.521, F.3399, F.241, F.3382, F.2807, F.485, F.3318) and 9 grey literature articles (G.20, G.17,G.18, G.19, G.51, G.65, G.76, G.78, G.80) on PROP treatment recommended L-carnitine supplementation for both chronic and acute management. Recommended doses for acutely ill patients ranged from 200-400 mg/kg/d divided into 2-4 doses (often administered intravenously) and for chronic management range from 50-200 mg/kg/d divided into 2-3 doses. European Consensus recommended 200 mg/kg/d in acute illness and 100-200 mg/kg/d in 2-4 doses per day (F.3399). US Consensus recommended 200-300 mg/kg/d divided into 2-3 doses per day; and for patients with acute hyperammonemia or recurrent metabolic decompensations, doses at high end of the range or IV delivery. (F.3403). The amount of L-carnitine in medical food should be considered when dosing (F.3403). Dosing is adjusted individually based on monitoring of plasma total, free and esterified (acyl) carnitine with the goal of maintaining plasma free carnitine above 30 µmol/L (G.78).

Delphi 2:

There was a trend toward the practice of increasing the L-carnitine dose during illness, but no consensus. 63% of MD respondents agreed (28% strongly agreeing) that L-carnitine should be increased during illness.

Comments: usual recommended doses ranged from 100-300 mg/kg/d IV L-carnitine. Some double the oral dose of L-carnitine when a patient is ill at home.

L-carnitine is usually well-tolerated (F.3399). When given by mouth or gastrostomy tube, about one quarter of the amount is absorbed (G.65). High doses (defined as above 60-100 mg/kg/d (G.17) or >200 mg/kg/d (G.65)) when given by mouth or by gastrostomy tubes often cause diarrhea, but otherwise toxicity has not been encountered.  Higher doses can be given intravenously without producing diarrhea. Intravenous carnitine is fully absorbed and is preferred in acutely ill patients (G.65). Besides gastrointestinal distress, doses >200 mg/kg/d are associated with a fishy odor caused by the production of triethylamine  by certain gut bacteria (G.65). Reported frequency of side effects were vomiting 37%, diarrhea 23%, abdominal pain 12%, fishy odor 12%, rash 4% (G.70)

L-carnitine supplementation leads to accumulation of trimethylamine N-oxide (TMAO) in the plasma of patients with IEMs, including patients with PROP (L. article here). Since TMAO has been implicated in artherosclerosis and patients with PROP are living longer, additional studies on the safety and efficacy of this treatment is needed. A statement prepared by several professional societies, including GMDI and the Society for Inherited Metabolic Disorders, urged patients with inherited metabolic disorder and their caregivers to consider that L-carnitine therapy is prescribed in an effort to protect patients from various severe consequences of their underlying medical condition and it should not be discontinued without having a discussion of the risks and benefits of L-carnitine therapy with the prescribing physician (Y article).

Delphi 1 and 2:

There were not specific statements about the upper limit of L-carnitine intake, however, responses about appropriate L-carnitine doses in well and sick individuals ranged from 50-300 mg/kg/d.

Propionyl Co-A carboxylase (PCC) is a biotin dependent enzyme, therefore 5-20 mg/d biotin supplementation has often been recommended as part of therapy. This is due to the fact that PCC is one of four enzymes in multiple carboxylase deficiency (MCC), a disorder that is biotin-dependent. Therefore, while a definitive diagnosis of PROP is being made, biotin is often provided to make certain that MCC is not overlooked. However, once the diagnosis of PROP is confirmed, the benefit of further supplementation is questionable.

Two case studies included biotin supplementation as part of treatment for PROP. (F.2738, F.3179) but the role of biotin in improved outcome was not provided. Another case study (F.525) showed no reduction in methylcitrate concentration when the patient was given 5 mg biotin for 3 days. Other evidence for lack of an effect of biotin supplementation was a study of 3 individuals with PROP who were given labeled sodium propionate and the resulting ¹³ CO ₂ was measured. There was no difference in the concentration of propionate in blood or half life of 1-¹³C-propionate with or without supplementation with 10 mg/d biotin. However, in the same study PCC activity was measured in lymphocytes and 1 out of 3 individuals (who had mild PROP) showed improved PCC activity when given biotin. Similarly, (F.486) showed that 5-10 mg /d of biotin given for 10 days was associated with significant increase in PCC activity in the white cells in 7 out of 8 individuals with PROP.

While 5-20 mg of biotin has traditionally been used in PROP, review articles suggest that no one with PROP has ever been responsive (F.3109, F.3403, F.58). One recommended that biotin should not be part of standard therapy (F.3109), while another suggested considering 5 mg/d of supplemental biotin but discontinuing it if there is no reduction in plasma propionylcarnitine (F.3403). Gray literature articles acknowledged the lack biotin responders in PROP (G.18,G.20, G.51), but recommended a trial of 10-20 mg/d of biotin (G.51) or 5-10 mg/d in patients with residual PCC activity (G19). Biotin is considered safe, even in large doses (F.3403). Biotin is part of therapy in 20% of patients in Saudi Arabia (F.3382).

Delphi 1:

There was consensus (100% of all respondents strongly agreed) that individuals with PROP should be evaluated for responsiveness to biotin. And, 82% strongly agreed that the trial dose of biotin should be 10mg/day.

There was not consensus (only 11% of RD and 0% of MD respondents agreed) that individuals should be maintained long term on a biotin dose of 10 mg/day.

Because of the strong consensus about biotin supplementation, this question was not further explored in the Nominal group or Delphi 2 survey.

Metronidazole is an antibiotic that is used as an adjunct therapy in PROP to reduce propionic acid production by gut bacteria (F.3109). Studies have shown a 43% reduction in fecal propionate production within 24 hours of administration of metronidazole, followed by a sustained 25% reduction for 3 weeks (F.573). Another study showed an average of 33.5% increase in urinary propionate production in 4 individuals with PROP who were well and on a stable diet and given 10-20 mg/kg/d (divided into 3 doses) for 5 days, followed by 10 mg/kg/d for the remainder of a 2 week study. While several research articles included the use of metronidazole as part of PROP therapy in chronic (F.57, F.573) and acute management (F.2738), none compared clinical outcomes of patients with or without metronidazole. One study of two individuals with PROP found no difference in propionylcarnitine or propionate production when 20 mg of metronidazole was given for 5 days (F.591).

Many review articles (F.526, F.3109, F.3273, F.3403, F.573, F.58, F.3399, F.3382, and F.2807) and gray literature (G.17, G.19, G.20, G.51, G.78) on PROP management suggested that 10-20 mg/kg/d metronidazole be considered as a treatment option. When metronidazole was given in a cyclical fashion; a frequently prescribed regimen was 20 mg/kg/d in 2-3 doses for 1-2 weeks alternating with 2-3 weeks off or alternating every month with other antibiotics, such as colistin (F.3273,F.2807). Metronizadole has not universally been used as part of therapy; for example, in one survey from Saudi Arabia, it was used 13% of the time (F.3382).

Delphi 2:

There was not a consensus (66% of all respondents agreed) for metronidazole use in individuals with PROP. Approximately 66% of all respondents felt that the use of metronidazole was beneficial, but only in selected individuals with PROP when well but not in the other proposed patient populations (e.g,all patients with PROP, acutely ill patients with PROP). 

Comments: One respondent did not believe there was benefit to using metronidazole and one commented that it might be harmful.

Metronidazle has been associated with fewer side effects compared to other antibiotics (F.505). Reports of possible negative effects of metronidazole therapy included anorexia (F.58) and risk of dystonia with toxicity (F.3403). Another stated concern was that complete removal of gut bacteria would potentially be harmful as gut mucosal cells depend on short chain fatty acids for energy (F.505).

Delphi 2:

Several respondents commented that they did not believe there was benefit to using metronidazole and one commented that it might be harmful.

Hyperammonemia in PROP is caused by the inhibition of N-acetylglutamate synthetase (NAGS) by  elevated propionyl CoA. This results in diminished N-acetylglutamate that impacts hepatic urea cycle function. Nine case reports or case-series involving 25 patients investigated the effect of carbamylglutamate therapy on reducing secondary hyperammonemia in PROP (F.522, F.550. F.2630. F.2741, F.523, F.525, F.2859, F.458, F.2982, F.519). The doses provided ranged from 25 to 250 mg/kg. Because carbamylglutamate was given in conjunction with standard acute management strategies/therapies, it was difficult to attribute reduction in hyperammonemia solely to carbamylglutamate. However, in most cases the authors stated that the reduction in ammonia was more rapid with the medication than they would have otherwise expected.

Dosages of carbamylglutamate and outcomes in individuals who also received standard acute management and hemodialysis were also reported. Two individuals, given 400 mg/kg at 10 hrs after elevation in ammonia was noted, and then 200 mg every 6 hours (in one) and every 12 hours (in the other) had a decrease in ammonia in 4 to 8 hours from a peak of 1569 µmol/L in the former and in 8 to 22 hrs from a peak of 4700 µmol/L in the latter (F.523). One individual receiving peritoneal dialysis, who was given a single dose of 100 mg/kg via NG tube, had a decrease in ammonia concentration from 1187 to 267 µg/dL in 24 hours and an improvement in metabolic acidosis (F.2741). Four individuals received 30-200mg/kg/d bolus followed by 115-300 mg/kg and 3 of them demonstrated rapid and sustained reduction in ammonia (F.2982). Two individuals (3 admissions) received 25-250 mg/kg; in one of these, ammonia remained above 1000 µmol/L until carbamylglutamate was added and in the other, the dose of 25 mg was not effective in reducing ammonia (F.519). Outcomes of individuals receiving carbamylglutamate in addition to treatment with IV glucose and L-carnitine have been reported. Two patients, given 200 mg/kg/d, showed normalization of ammonia in 6 hours (of note, one individual initially did not receive carbamylglutamate but it was added to therapy after ammonia continued to rise, lending support to the reduction of ammonia being due to carbamylglutamate) (F.525). Two individuals given loading dose of 150 mg/kg followed by 100 mg/kg starting at day 3 or 4 of life and discontinued at age 10 days showed reduction in ammonia from 680 to 210 µg/dL in 8 hours in one infant and from 732 to 254 µg/dL in 8 hours in the other (F.522).  One individual given 100 mg/kg loading dose followed by 70 mg/kg for 48 hours normalized ammonia within 36 hours; however methylcitrate concentration remained elevated (F.550). Three individuals (8 admissions) given 21-80 mg/kg/d divided into 2-6 doses per day demonstrated a reduction in ammonia from 2 hours after the first dose to below 100 µmol/L within 6-19 hours (F.2630). In one study, carbamylglutamate was given 150 mg/kg  along with sodium benzoate and arginine HCl  the ammonia was reduced from 750 to 250 in 12 hours (without dialysis) (F.2859). In one infant presenting with illness and hyperammonemia, 200 mg/kg carbamylglutamate was mixed into formula and ammonia was reduced from 451 µg/dL to 68 µg/dL over a 6 day period in an outpatient setting (F.458). 

Two studies investigated the fate of labeled acetate with and without carbamylglutamate (F.548, F.2840). In one study, 7 individuals received 100 mg/kg or 2.2 g/M²/d if >25 kg and were their own controls. Carbamylglutamate resulted in significantly greater ureagenesis in clinically well PROP individuals with concurrent significant reduction in ammonia, glutamine and alanine (F.2840). The second study, one individual with PROP was compared to 17 controls and showed a rise of radio-labeled urea synthesis after carbamylglutamate treatment (F.548).

Two studies investigated the fate of labeled acetate with and without carbamylglutamate (F.548, F.2840). In one study, 7 individuals received 100 mg/kg or 2.2 g/M²/d if >25 kg BW and were their own controls. Carbamylglutamate resulted in significantly greater ureagenesis in individuals with PROP when well with concurrent significant reduction in ammonia, glutamine and alanine (F.2840). The second study, one individual with PROP was compared to 17 controls and showed a rise of radio-labeled urea synthesis after carbamylglutamate treatment (F.548).

Review articles have recognized the potential of carbamylglutamate to reduce secondary hyperammonemia in PROP (F.3109, F.535, F.3399, F.3273), and one suggested that more research was needed (F.3109). The suggested dose in one report was 100 mg/kg bolus followed by 25-62 mg/kg every 6 hours  (F.3399). Side effects included vomiting, abdominal pain, pyrexia, tonsillitis, anemia, ear infection, diarrhea, nasopharyngitis, and headache. Carbamylglutamate was tolerated without significant adverse effects in newborns (F.535).

Delphi 2:

Consensus was not quite reached concerning the use of carglumic acid or Ammonul to treat hyperammonemia in individuals with PROP. 79% of MD respondents agreed that it is appropriate to manage hyperammonemia using carbamylglutamate (carglumic acid). The question did not address specific dose.  79% of MD respondents also agreed with the the use of Ammonul to manage hyperammonemia. 

The RD respondents neither agreed nor disagreed about how to manage hyperammonemia, with some commenting that management of hyperammonemia is not within their scope of practice.

Prebiotics are non-digestible substances in food (usually fibers) that promote the growth of beneficial gut flora. The use of prebiotics in individuals with PROP has been controversial because of the concern that they may promote the growth of bacteria that enhance production of short chain fatty acids, including propionic acid. There is no direct evidence of the effect of prebiotic use in PROP, however there is indirect evidence that their use is safe and possibly beneficial. 

The oligosaccharides in human milk are an example of prebiotics. Fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) are examples of prebiotics added to some medical foods for PROP and have been well tolerated (G.114). FOS/GOS have been shown to produce higher acetate and lower propionate in healthy infants (L.285). FOS/GOS stimulated bifidobacteria, which in turn produced more acetate and lowered the pH, and made the colon less hospitable to pathogens. At a higher pH, propionate production was higher (L.286). Prebiotics soften stool and may help support increased transit time and lower colon pH.

Delphi 2:

There was consensus (81% of all respondents agreed) that, if taken by individuals with PROP, prebiotic supplement products should be used with medical supervision as part of the management plan.

There was not consensus about prebiotic use. About half of the respondents agreed that their use should be avoided until more research is available.There was no consensus about certain prebiotic fibers that should be used and an apparent lack of knowledge about prebiotic use, as judged by a widespread agreement and disagreement with several questions related to prebioitc use

Supplements aimed at increasing mitochondrial energy production and/or reducing the accumulation of reactive oxidative species (ROS) have been given to individuals with PROP.  A case study showed reversal of cardiomyopathy (as evidenced by improvement in pro b-type natriuretic peptide) when the patient was given: D,L hydroxybutyrate at 200 mg/kg/day, riboflavin 200 mg/day, thiamin 200 mg/day, mg/kg/day, and CoQ10 1.5 mg/kg/day). When low levels of myocardial CoQ10 were detected, the CoQ10 was increased to 25 mg/kg/day (F.3457). L-arginine, metronidazole, L-carnitine and vitamin D were also given.  Studies in fibroblasts of 10 individuals with PROP showed reduction in ROS when the following antioxidants were provided in the incubation solution at the indicated concentrations: tiron (40mM for 18 h), resveratrol (1mM for 3 h), trolox (a vitamin E analog given at 1mM for 72 h, MitoQ (200nM for 24 h), N-acetyl-L-cysteine (NAC) (1-10mM for 1-4 h), vit E (30µM for 18h) (F.3461). Supplemental alpha-tocopherol, creatine, co-enzyme Q, mitochondria-targeted peptides, and ornithine alpha-ketogluatarate have been used to reduce oxidative stress in disorders of branched chain amino acids and keto acids, but this article did not provide doses and was not specific to PROP (F.534). One study found that patients with inborn errors of metabolism, including one individual with PROP, have low tocopherol concentrations despite adequate amounts in medical food that were normalized by vitamin E supplementation at100-300 mg/day (F.586).

Delphi 2:

Because of the lack of literature evidence to support use of supplements to enhance mitochondrial energy production, the survey questions posed to get clarification about practice on this statement were slightly different than other questions where respondents agreed or disagreed with practice statements.

For this question, a list of possible supplements (CoQ10, riboflavin, thiamin, vitamin E, N-acetyl L-cysteine, L-malate, L-hydroxybutyrate, L creatine, peptides, mitochondrial "cocktails", and other) was provided and the respondents stated if:

(1) they were aware of self-prescription by individuals with PROP

(2) their clinic or center prescribed these

(3) they had observed any positive results from supplement use.  

In all cases, except for L-hydroxybutyrate, the percent of respondents who were aware of self prescription by individuals with PROP was greater than the percent of respondents who prescribed the supplement.

The most commonly prescribed supplements by respondents included CoQ10 (10/20), thiamin and vitamin E (6/12)  and mitochondrial cocktails (5/12).

25% or fewer of respondents stated that they had observed benefits from any prescribed mitochondrial supplements, except one respondent mentioned that (s)he had found benefit in giving thiamin prior to transplantation in order to make sure stores were adequate. Five respondents commented that they do not use these supplements for PROP.

Propionic acid sequesters oxaloacetate from the Krebs cycle to form methylcitric acid which, in turn, leads to a deficiency of Krebs cycle intermediates.  Anaplerosis, the supplementation of Krebs cycle intermediates, may improve the energy deficit in propionic acidemia but more studies are needed (F.3109, F.534). The addition of L-malate to rat mitochondrial matrix stimulated succinate efflux and reduced the concentration of propionyl-CoA (F.603). In a case study of a 6 year old girl with PROP in metabolic crisis, the use of citric acid (1200 mg K-Na-H citrate TID for 7 days) along with standard acute management strategies led to clinical improvement (F.3405).

See consensus statements for topic 3.7.1.