In PROP, a deficiency of propionyl CoA carboxylase (PCC) prevents further metabolism of propionate that can reach toxic levels in the cells and cause multisystem effects (F.3399, F.3403, G.20, G.19). The catabolism of VAL, ILE, MET, THR has been shown to produce approximately 50% of propionate in humans (F.252, G.80). Part of the management of individuals with PROP involves limiting the intake of complete (or intact, or natural) protein to limit the intake of these propiogenic amino acids. However, it is also important that the intake of the propiogenic amino acids be sufficient to meet the needs for growth and anabolism.

Research reports over time have shown an evolving understanding of total protein needs and how those needs were met through different proportions of complete protein and medical food.

1980's case reports of infants and toddlers described 0.55-1.5 g/kg/d complete protein restriction without PROP medical food protein equivalents with variable outcomes including decreased plasma ILE, VAL, THR concentrations and poor to adequate growth (F.516, F.256, F.255, F.513, F.253). PROP studies published in the 1990’s had larger cohorts of individuals studied. Central European countries started selected screening programs in 1985, so that individuals were being diagnosed earlier and outcomes were compared by: early onset (<1 month old) versus late onset (> 1 month old); and varied in reported nutritional intake information (F.502, F.251, F.249, F.585).  A 1994 review of 30 individuals with PROP (22 from Germany, 5 from Austria, 3 from Switzerland), diagnosed between 1975-1990, described commonalities in initial clinical presentation and diagnostic labs and outcomes. For long term therapy, the authors recommended a carefully balanced intake of natural (complete) protein according to individual  tolerance (0.7-1.5 g/kg/d; with the addition of propiogenic amino acid-free amino acid based medical food ( i.e., PROP medical food) up to the age-appropriate requirement of total protein; and high energy intake. At the time of this study, authors reported 100% survival rates after first metabolic crises in 8 individuals diagnosed via 1986 organic acidemia selective screening programs, compared to 64% in individuals diagnosed before 1986. Authors speculated that improved survival was perhaps due to adequate therapy before diagnosis and during recurrent metabolic crises (F.502).

A 1996 retrospective review of 17 French individuals (12 were early onset and 5 late onset), treated with both complete protein and propiogenic-free amino acids (from PROP medical foods), described differences in total protein intake by disease onset/severity. PROP medical food was prescribed when needed to meet the recommended daily allowance for total protein. The mean complete protein intake was found to be significantly different between the early and late onset groups; 6.3 +/- 1.5 g/d versus 17.6 +/- 5.3 g/d respectively.  Extrapolated from their data, in early onset patients, the percentage of the total protein intake that was met by the complete protein: ~ 54% in 0-6 month old infants; ~48% in 6-12 months old infants; ~41-45% in 1 to 3 year olds; ~37% in 3 to 6 year olds; and ~47% in children 6 years and older.  In late onset individuals, the percentage of total protein provided by complete protein: ~68% in 0-6 months old infants; ~61% in 6-12 month old infants;  ~ 66-69% in 1 to 3 year olds; ~ 93% in 3-4 years old children.  For 4 to 6 year old late onset children, PROP medical food was not given. All the early and late onset children were reported to have short stature. Nine of the early onset individuals and 1 late onset were treated with tube feeding. These individuals had short stature with normal weight gain. Mortality was high with 5/12 early onset and 2/5 with late onset, deceased. The authors hypothesized that the individuals’ failure to thrive and short stature were due to over restriction of complete protein in the first few years of life (F.249). 

In 2005, 29 individuals with PROP and 41 with MMA, born in France between 1990-2005, were retrospectively studied. Their long term therapy included severely restricted total protein intake of approximately 0.7-0.8 grams protein/100 kcals at any age. Patients still had poor nutritional status with growth retardation and developmental delays. But the authors noted a 25-50% decreased mortality rate compared to previous reports, perhaps due to improved neonatal management including rehydration, acid-base control, toxin removal and nutritional support (F.57). See Question #2 for more a detailed review.

In 2012, a group of healthcare providers, researchers and parents convened at the Children's National Medical Center, Washington DC, USA to review published literature and develop practice guidelines for PROP.  The chronic management group recommended that a propiogenic amino acid-restricted diet be based upon clinical and laboratory assessment and individualized based on growth and established estimated needs based on age and gender (F.3403).

In 2014, European MMA and PROP diagnosis and management guidelines were developed and published from a series of meetings of metabolic clinicians from 12 European countries and the US who met to gather, evaluate, and score evidence according to the SIGN evidence system and make conclusion statements supported by evidence. This guideline suggested to: aim for metabolic stability and normal growth; monitor plasma amino acids, individualize protein intake based on adequate energy; avoid prolonged fasting; reduce intake of propiogenic amino acids with a protein restricted diet. When total protein intake is exclusively from complete  protein, the FAO/WHO/UNU (2007) safe levels of protein intake should be the goal. The authors recommended that the biological quality be considered in these calculations if fruits, cereals and/or vegetables are the only sources of complete protein being consumed, as additional protein may be required to compensate (F.3399).

Delphi 2:

There was not consensus among all respondents (83% of RD respondents agreed or strongly agreed, but only 64% of MD respondents somewhat to strongly agreed) to provide 60-100% of DRI for total protein from sources of intact protein to meet ILE, VAL, MET, and THR recommendations. 

Comments:  MD: would agree if the statement had said “if tolerated"; otherwise too much risk that a guideline would push us to keep trying to reach a goal that is not achievable.RD: would depend on patient and circumstances as not all patients tolerate that much. RD: We don’t expect to achieve 100% DRI from intact protein; often we don’t even achieve 60%.

There was consensus (100% agreement among all RD and MD respondents) to adjust the percentage of total protein from intact protein sources based on individual tolerance, age, growth, disease severity, and clinical status.

Comments: One MD stated that he/she was a big fan of natural protein, and has come to realize that we have restricted our patients too enthusiastically at times; we see this in the slow growth of some of our patients.

Reviews published after 2000 showed that metabolic centers differed in their use of PROP medical food and restriction of complete protein to meet individual daily protein requirements.

In 2003, 13 individuals with PROP and 3 infants and toddlers with MMA were studied in a 6 month multicenter trial with a PROP medical food. Nine of the 13 with PROP were diagnosed prior to 1 mo of age, 3 prior to 1 year old, and one diagnosed at 1.04 years old.  Seven of the total subjects, who had increased length percentiles at the end of study, had a mean intake of 98% DRI for energy and 115% of 1985 FAO/WHO/UNU recommended total protein intake.  This contrasted to the 9 patients who either remained the same (n=3) or decreased their length percentile (n=6) and had mean dietary intake of 87% DRI for energy and 104% DRI for protein. Extrapolation from their data showed that baseline complete protein intake ranged from 61% (< 6 mo old), 65% (6<12 mo old), to 67.4% (1<4 years old) of total protein. During the study, mean complete protein intake ranged from 64% (<6 mo old), 63% (6<12 mo old), to 68% (1<4 years old) of total protein intake (F.55) with remaining protein consumed from PROP medical food.

Summarized in a 2004 report, data from 49 individuals with PROP were collected by questionnaire from 18 metabolic centers in Austria, Belgium, Czech Republic, Germany, Netherlands and Switzerland from June 1998 to April 1999. Treatment strategies to reduce the precursor substrates of PCC were different.  Protein restriction to the “minimum safe recommended protein intake” per age was attempted in almost all patients after diagnosis. The authors did not define the ‘minimum safe recommended protein intake’ in this report. This goal was achieved in some centers by just restricting complete protein intake in a subgroup of mildly affected patients. More severely affected individuals were restricted to approximately 2/3 of their minimum safe protein intake taken as complete protein with the remaining 1/3 derived from PROP medical food. Authors could verify no differences regarding outcome of the patients on different degrees of complete protein restriction. In five late-onset individuals (presenting with clinical symptoms at >3months of age) dietary restrictions appeared to be less strict. PROP medical foods were either not taken regularly or not at all by these individuals in contrast to the early onset individuals (presenting with clinical symptoms <3 months of age). Outcomes showed a tendency for decreased body length and head circumference, but BMI was not decreased.  Also, mild cognitive and neurologic impairment, measured at a median age of 3.5 years was noted. Compared to earlier studies, their data indicated that a relatively higher total protein intake from a combination of both PROP medical food and complete protein had no negative effect on outcome and may even have been beneficial. In addition the authors made dietary protein intake recommendations based on their clinical experience (F.3492). In the first year of life, they recommended a combination of 0.7-1.5 g/kg body weight/day complete protein and 1.5-0.7 g/kg body weight/d of PROP medical food for a total protein of 1.8-2.2 g/kg/day. For individuals aged 1 to 4 years, they recommended a combination of 1-1.5 g/kg/d complete protein and 1-0.5 g/kg/d PROP medical food for a total protein of 1.5-2 g/kg/d. For individuals aged 4-7 years old, they recommended a combination of 1-1.5 g/kg/d complete protein and 0.5-0.2 g/kg/d PROP medical food for a total protein of 1.2-1.5 g/kg/d. Finally for individuals greater than 7 years old, they recommended a combination of 0.8-1.2 g/kg/d complete protein and 0.4-0 g/kg/d PROP medical food for a total protein of 1.2-1.5 g/kg/d (F.3492).

In 2006, nutritional data was studied for 39 French individuals with severe forms of their disorder (17 PROP and 22 MMA) followed from 1988 to 2005. Some of these individuals were part of the authors’ 2005 study previously reported (F.57). Authors adjusted intake from complete protein, for each individual, by measuring and monitoring urinary urea and organic acid excretion. This method was based upon the principle that urea excretion reflects protein catabolism, therefore they were able to increase protein as long as urea excretion remained low. They tried to maintain a urea: creatinine ratio between 10-20 during the first 3 years of life and between 5-10 for those 3 years and older without giving medical food. Most individuals taking PROP medical food had higher urea: creatinine ratios suggesting that some the medical food protein was not utilized but catabolized to urea. Based upon these findings, they gave approximately  0.8-0.9 g/kg/d from complete protein and no PROP medical food  for most children between 0-3 years of age. Protein intakes were compared at 3 years, 6 years and 11 years of age. At 3 years, 41% (9 with PROP and 7 MMA) were given PROP medical food, with complete protein providing 58% total protein (1.29 g/kg/d) At 6 and 11 years, 50% (1.17 g/kg/d total protein) were given PROP medical food ( 7 PROP and 7 MMA). At 6 years, complete protein provided 63% the total protein. At 11 years (6 PROP and 2 MMA), complete protein provided 61% of total protein.  Compared to same age groups given only complete protein, the 3, 6, and 11 year old individuals who were given both complete protein and PROP medical food had median higher total protein intakes (42%, 48%, and 16% more, respectively) but lower complete protein (22%, 5%, and 30% less, respectively) and total energy intakes (8%, 13%, and 21% less, respectively). At 3 years of age, most patients showed low or very low plasma VAL and ILE concentrations, less than 2 SD below the mean laboratory value for age, with or without PROP medical food. At 3 years of age, plasma LEU and PHE were also below the mean normal values, close to 2 SD below the normal range. Similar trends were observed in 6 and 11 year olds. Growth and other nutritional lab results were not compared between those taking or not taking medical foods (F.56).

The clinical course and outcome data of 55 individuals with PROP from 16 European centers was collected in 2007-2008 and retrospectively evaluated in a 2013 report. 35 individuals were diagnosed by selective metabolic screening and 20 individuals via newborn screening. The median age was 5.2 years (ranging from 5 days to 18.6 years). Greater than 85% of individuals presented in the neonatal period with metabolic decompensation, 73% were symptomatic within the first 5 days of life, and only 7% (4 individuals) had no acute symptoms by the writing of this report. Within the first 5 years of life, median intake of complete protein ranged from 0.8 to 1.1 g/kg/d. The authors reported a ‘majority’ of patients (actual number not reported) were supplemented with propiogenic amino acid-free medical food to meet age appropriate protein intake recommendations.  Medical food was administered in doses ranging from 0.1-4.1 g/kg body weight/day (median intake of 0.7-0.9 g/kg/d) at different ages within the first 5 years of life. Energy intake was not described. BMI at age3 months and 2 years did not correlate with daily protein intake. About 50% received tube feedings due to feeding problems starting at median age 2 years (range 6 months to 7 years old); 15% were exclusively tube-fed.  The authors noted improved survival rates compared to past reports but continued unsatisfactory neurologic outcomes with approximately 75% of individuals with cognitive delays with a median IQ of 55. They also had early onset, progressive growth retardation (F.2807). 

Delphi I:

All respondents disagreed with the statement that only the protein derived from PROP medical food (propiogenic amino acid-free amino acid mix) should be used to determine adequacy of dietary protein intake.

Comments: Three RD respondents commented on the need to consider both sources of complete (intact) protein AND medical food to determine total protein intake.

There was not consensus (46% of all respondents agreed) that meeting age appropriate DRI for protein (sum of free amino acids, medical food and intact protein) should be sufficient.

Comments: one RD respondent commented that she/he usually gives amounts above DRIs, another RD gives more than DRI to achieve metabolic balance, and another RD commented that DRI might be too low if on medical food. Another RD commented that it varies slightly between patients: if patient has good growth and normal plasma amino acids without meeting the DRI, then won’t push to achieve a number.  Another RD commented that depending on linear growth, aim for 10-15%, with a maximum of 20% of total energy from protein.

There was consensus (82% of all respondents agreed) that the recommended amount of total protein in the diet should be above the DRI when the majority of protein is provided by medical food.

Comments: one MD commented most individuals get a substantial amount of intact protein. Another MD commented that toxicity of excessive protein intake needs further study.

There was no consensus that the recommendation for the amount of protein in the diet should be based on ideal body weight for age. While MD respondents agreed with this, the  RD respondents advocated for consideration of individual weight status.

Comments: one RD commented that protein intake should be based on actual weight. Two RD commented that for overweight/obese individuals, they use actual or adjusted weight, while one RD commented that for underweight individuals she/he uses ideal body weight.

Delphi 2:

There was consensus (92% among all RD and MD respondents agreed and strongly agreed) for individuals tolerating less than 100% DRI for total protein from intact protein alone, add PROP medical food to provide 100-120% DRI for total protein.

There was also consensus (85% of all RD and MD respondents somewhat to strongly agreed) that, to assure adequate protein when using an amino-acid based medical food, provide up to 120% of the DRI for protein to account for the rapid oxidation of the free amino acids compared to intact protein

ILE and VAL are two propiogenic amino acids limited in the treatment of PROP. Some individuals, treated with a protein-restricted diet and/or medical food, have been noted to have low plasma ILE concentrations (F.536). See Question #4 Topic 4.4.1 for further monitoring information.  A case report described a 2-month old infant on an intake of 0.8 g/kg/d PRO with PROP-medical food, had low plasma concentrations of ILE and developed skin lesions (F.500). Some recommend that ILE and VAL can be added back as individual amino acids, starting at doses of 100 mg/d (F.242, G.51, G.18).  However, there are no studies on the safety and efficacy of the combination of medical food and ILE or VAL supplements (F.3399). 

Delphi 1:

There was not consensus among the MD and RD respondents with the statement that if plasma levels are less than desired ranges, ILE and VAL should be supplemented by using solutions/powders of individual L-amino acids added to PROP medical food. 

Comments: One MD respondent would increase complete protein first, may consider adding individual ILE or VAL if can’t get levels in normal range. Another MD commented that the propiogenic amino acids may be low even in well-controlled individuals. Another RD noted that she considers ILE the sentinel amino acid to determine intake and would add food if ILE is low. One RD mentioned considering other amino acid levels and pre-albumin; and patients may require supplemental VAL, but ILE needs are typically met with food. One RD noted that this doesn’t work, look at symptoms as well as numbers. She/he had trouble with insurance reimbursement for individual amino acids. One RD indicated she/he would try adding intact protein first.

There was consensus (89% RDs strongly agreed and 100% of MDs agreed) that if VAL, ILE, MET, THR are all more than 10% below normal levels, more intact protein should be added to the diet.

Comments:one RD commented that s/he preferred this method rather than adding individual amino acids.

There was not consensus among all respondents that propiogenic amino acids can be somewhat above the normal range to avoid deficiencies.

Comments: One MD commented that they are usually not increased and another MD commented that s/he worried about creating imbalance of amino acids. One RD commented that s/he had never seen this, another RD generally aims for low-mid-normal levels, while another RD commented that if there is a deficiency it means they aren’t ingesting adequate amounts. 

Delphi 2:

There was consensus (81% of RD and MD respondents agreed) that when plasma concentrations of propiogenic amino acids are low, increasing intact protein is preferred over providing individual L-amino acids.

Comments: one RD commented that it depends on how many are low, if just one is low then may use individual amino acids, one MD commented that if two of the four are low and two are high, then he/she doesn’t feel he can increase the intact protein; so he/she agrees with ‘preferred’ but there has to be recognition of the possibility that they don’t track completely together.

There was no consensus among RD and MD respondents for the practice of adjusing dietary intact protein to maintain a plasma ratio for VAL:ILE:LEU of approximately 3:1:1. 

Comments: one MD agreed, but suggested that one recognize that there may be some limitation in ability to get there.  One MD suggested that rather than a strict ratio for branched chain amino acids, sufficient amounts to maintain normal range as much as possible from intact protein. Another MD preferred a 3:2:1 ratio or a 2:2:1 ratio  One RD commented that the above ratio depended depend on pt and circumstances; have not used a ratio with PROP, just with MSUD.  Another RD stated that she/he had not considered this practice; but aimed for plasma level within normal lab reference ranges.

Studies comparing protein tolerance of early onset to late onset patients showed a spectrum of protein tolerance in breastfed infants with PROP (F.249, F.251). In a 1994 review of 30 individuals with PROP, 80% of whom were breastfed, no precipitating factors for metabolic decompensation were noted (F.502).  According to the 2014 European management guidelines, the consensus was that human breast milk (from feeding at the breast or using expressed breastmilk) may be considered as a source of complete protein for an infant diagnosed with PROP if used with careful monitoring (F.3399).

Delphi 2:

There was consensus (92% of both RD and MD respondents agreed) for considering use of breast milk as source of intact protein in infants with PROP.

Comments: one MD commented some babies maybe too brittle to tolerate uncertainty in content, some moms may not be able to pump well, one RD commented that he/she would advise use of expressed breast milk (rather than feeding at the breast) unless the infant has mild PROP

In one study, 3 healthy individuals with PROP and 11 with MMA were tested for resting energy expenditure (REE) with indirect calorimetry and results were compared to a theoretical REE using Schofield height, weight, age and activity calculation. Individuals with PROP on 0.9-1.2 g protein/kg/d without PROP medical food had lower weight and height z-scores compared to normal UK reference growth standards. REE was 20% lower and not correlated with protein intakes. According to study authors, calculated REE should be adjusted for clinical status changes such as catabolic illness (F.437). Energy requirement should be individually determined and balanced between promoting anabolism while avoiding overfeeding especially for less physically active individuals (F.3399, G.18, G.19, G.78, G.80). Refer to Question 2 Recommendation 2.1 for energy requirements during illness.

Delphi 1:

There was consensus (82% of respondents agreed) that meeting the age appropriate DRI for energy should be appropriate.

Comments: RD comments underscored the need to individualize caloric needs. Two RD respondents commented that they individualize energy and monitor patients’ growth, weight changes, clinical status. Two RD commented that some patients require more/ do better with a bit more than DRIs for energy.  One RD commented to increase energy at times of crises. Two RDs commented that some patients require less than DRIs for energy.

Delphi 2:                                                                    

There was also consensus (82% of all RD and MD respondents agreed to strongly agreed) to provide PROP individuals with 80-120% of the total energy requirement (DRI) for age.

Comments: One MD commented that s/he had data that the resting metabolic rate (RMR) is not necessarily lower in the organic acidemias when measured. One RD commented that it depends on the individual, if quite compromised, as one of her/his patients was, may need fewer calories. Another RD commented that s/he had needed to go lower when a patient was proven to be a low energy user

There was also consensus (92% of all RD and MD respondents somewhat to strongly agreed) that the energy needs of some individuals with PROP may be lower than the DRI due to lower resting energy expenditure (REE) or physical inactivity.

Comments: One MD commented that some of her/his patients have become overweight, even when calories were intentionally limited.  S/he didn't know if it could be due to low activity, or perhaps altered/different gut flora.

There was not consensus ( 67% of RD and 71% of MD respondents agreed) that an increase of up to 120% of the DRI for energy may be necessary to achieve or maintain normal growth.

Comments: One RD commented that in her/his experience, energy requirements were increased (up to 120 - 130% REE) during illness/decompensation.  Another RD commented that this has never been her/his experience.

A report of five individuals with PROP, who had a mean complete  protein intake of 1.4 g/kg/d  and a mean protein equivalent intake of 0.2 g/kg/d  from propiogenic amino acid-free medical food were assessed for their plasma fatty acid profiles.  No dietary fat, energy intake, nor energy distribution information was provided. Elevated odd chain fatty acids were detected in all plasma samples from the individuals with PROP, compared to controls. However, no significant differences were found in the levels of saturated fatty acids, mono- or polyunsaturated fatty acid precursors or intermediary metabolites ARA and DHA (F.585). There is no evidence that individuals with PROP need supplemental essential fatty acids, assuming their diets are sufficient in linoleic and alpha linolenic acid.  See Question 2  topic 2.6.3 for more information on odd chain fats.

Delphi 1:

There was no consensus (43% of respondents did not agree or disagree) that DHA should be supplemented.

Comments: MD: DHA is not added to prop medical foods (for now) we don't add additional unless fatty acid profile indicate problems. MD: Depends on age - infants, yes.  If on low fat formula, likely.  Will monitor EFA profiles to determine. RD: We have never supplemented DHA to this population.  We do, however, supplement with LA and ALA (walnut and flax seed oil). RD: Yes, when tested and found to be low. RD: through metabolic formula 

There was no consensus (64% of respondents completely disagreed(7.1), disagreed(28.6), somewhat disagreed (28.6)) that polyunsaturated fats are restricted in the PROP diet

Comments: MD: we don't worry so much about this. RD: Have not seen any evidence to suggest diet with PUFA's has led to metabolic instability. RD Sometimes. RD: I suppose if they are eating.

Maintaining adequate hydration is essential in individuals with PROP to prevent dehydration and constipation, and promote excretion of offending metabolites. Additional water has been shown to be required during intermittent febrile illnesses and when there were increased fluid losses due to vomiting and/or diarrhea (F.3399, G.51, G.79, G.64, G.18). Hyperosmolarity of formulas should be avoided unless providing sufficient additional  fluids (G.19, G.51).  

Delphi 1:

There was consensus regarding fluid requirements:

82% of respondents agreed with calculating fluid maintenance requirements using the Holliday-Segar method for infants weighing 0-10 kg: 100 ml/kg/d.

91% agreed with each of the other statements regarding fluids: Children 11-20 kg: 1000ml/d + 50 ml/kg/d for each kg over; children>20 kg: 1500 ml/d + 20 ml/kg/d for each kg over 20 kg; and adults: 30-35 ml/kg body weight. 

Comments: one RD commented using 150 ml/kg fluids for stable infants given standard dilutions of medical food to meet energy needs. Another RD commented the use of 1.5 x fluid maintenance needs for vomiting/diarrhea, fever or very hot weather.  Another RD commented using BSA x 1500 to calculate maintenance fluid needs.

Alopecia in PROP had been reported due to a selenium deficiency (F.502).  Osteopenia or osteoporosis was also noted in retrospective reviews of individuals with PROP (F.502).  One adult woman presented with severe osteoporosis on a vegetarian low protein diet of 0.69 g/kg/d, 36 g/d complete protein without PROP medical food. She received supplements of calcium and vitamin D and monthly infusions of bisphosphonates. In spite of treatment, she had two spinal fractures resulting from a fall with myoclonic jerks. She improved her bone mineral density with treatment (F.248). See Question 4 topic 4.5.3 to monitor bone indices. Studies of individuals with PROP and reviews of the disorder have recommended that diet treatment must provide sufficient vitamins, minerals and micronutrients (F.57, F.58, F.256, G.51, G.64). As long as diet intake provides age appropriate DRIs for vitamins and minerals below DRI Upper Limits; in a well individual there is a lack of evidence to support additional supplementation. For more information on other PROP specific nutrients such as carnitine, biotin see Question 3 Recommendations 3.1 (carnitine) and 3.2 (biotin) for evidence and recommendations.

Delphi 2:

There was lack of consensus (only 62% of all participants "somewhat" to "strongly" agreed) with the statement that the needs for all other nutrients (beyond protein and energy) are the same for individuals with PROP as for individuals without PROP.

Comments: one RD suggested that vit D and Ca needs may be higher in individuals with PROP. One MD stated that carnitine needs are higher (note: this is covered in another section of the guideline); another suggested that micronutrient recommendations need further study.