Nutrition therapy plays an essential role in stabilizing and restoring metabolic homeostasis in MSUD. At diagnosis or any time there is a risk of metabolic decompensation during trauma, illness, dietary non-compliance or surgery, the goals are to: closely monitor biochemical and clinical status; prevent catabolism and the accumulation of endogenous BCAA and BCKA; and provide adequate BCAA-free exogenous protein, energy, fluid, and VAL and ILE to promote anabolism. When the patient is metabolically stable, LEU requirements can be met from intact protein sources. Seriously ill individuals need aggressive treatment that may include dialysis, parenteral nutrition and/or tube feedings. Non-acutely ill individuals can often be managed with a “sick day” guideline that provides instruction for preventing catabolism and monitoring clinical status.
Provide aggressive nutrition management during illness or at first presentation to prevent or reverse catabolism and promote anabolism by supplying: adequate energy (up to 150% of usual energy intake); BCAA-free protein (increased to replace BCAA-containing intact protein); fluid (up to 150ml/kg with careful monitoring of electrolytes and possible cerebral edema); and electrolytes and insulin (if needed).
Insufficient Evidence | Consensus | Weak | Fair | Strong |
Conditional | Imperative |
The importance of increasing energy intake via calorically dense feeds is exhibited in 11 clinical studies (F.104, F.44, F.73, F.77, F.20, F.105, F.51, F.76, F.81, F.52, F.426) and 4 expert opinions (G.50, G.39, G.27, G.82). Energy recommendations indicated the following: 95 -150 Kcal/kg (neonates) (F.105, F.104, F.51, F.52), 1500 Kcal/m2 (neonates and children) (F.73), 88 Kcal/kg (children) (F.76), and 150 to 200% of calculated energy needs (F.426)
In patients with MSUD who are hospitalized due to acute illness, energy recommendations are increased to up to 150% of the amount provided to the patient when well.
Evidence: Insulin was utilized to maintain blood glucose < 150 mg/dL (F.104) or 180 to 270 mg/dL (F.86) when pushing IV glucose. Studies reported a range of 0.04 to 0.13 U insulin per hour during surgery (F.127) and 0.05 to 0.3 U per hour during acute illness (F.44, F.75, F.426).
To allow sufficient glucose infusion for anabolism, insulin may be required to prevent hyperglycemia: although 71% agreed or completely agreed with this recommendation, comments of dissenters indicated that this recommendation should be reworded to state “insulin may be needed.” Specific comments pointed out need for blood glucose monitoring and individual assessment. Another indicated that insulin would be needed when blood glucose > 150 mg/dL”.
A common finding during illness is dehydration and acid-base imbalance (F.80, F.45, F.85). A solution of 5 to 10% glucose was recommended to treat dehydration and correct acidosis (F.104, F.51, F.81) in 3 reports. A fluid intake of 150 ml/kg has been recommended (F.81). Caution must be taken to avoid fluid overload and cerebral edema by monitoring and adjusting electrolytes (F.85, F.426, F.423, G.47).
The majority of the articles cited below recommend a BCAA-free source of protein during acute illness however, recommendations vary in regard to the amount of BCAA-free protein. Age of the person, presenting symptoms and severity of symptoms seem to be determining factors. Ten clinical reports (F.104, F.44, F.45, F.73, F.20, F.105, F.51, F.76, F.75, F.426) and three expert opinions (G.50, G.39, G.82) recommend use of a BCAA-free source of protein. The total amount of BCAA-free protein ranged from 1.0 to 4 g/kg/day (F.44, F.73, F.105, F.51, F.76, F.426, F.423). Currently available BCAA-free medical foods are listed in Table TABLE #11, Classification of Medical Foods for MSUD
In patients with MSUD who are hospitalized due to acute illness, the amount of BCAA-free formula should be increased to 120-150% of the amount provided to the patient when well. The rationale for increasing BCAA-free formula is not only to replace the BCAA-containing protein (which is eliminated from the diet in acute illness) but also to maintain or increase energy intake to suppress catabolism and ketoacidosis.
Use parenteral nutrition alone (providing BCAA-free amino acids, lipids and/or glucose) or in conjunction with enteral feedings, when necessary to meet energy needs in severe illness.
Insufficient Evidence | Consensus | Weak | Fair | Strong |
Conditional | Imperative |
Route of feeding: Both enteral and parenteral nutrition are used in the acute stage and during illness to aggressively supply needed calories to minimize catabolism. Twenty clinical reports (F.104, F.44, F.80, F.45, F.73, F.79, F.20, F.93, F.105, F.51, F.76, F.81, F.52, F.75, F.426, F.423, F.86, F.92, F.66, F.83) and 5 expert opinions (G.50, G.39, G.33, G.27, G.82) use enteral nutrition or a combination of enteral and parenteral nutrition management during acute illness. The decision regarding route and composition of solution/formula is based upon severity of symptoms at initial presentation or during acute illness. Length of intravenous therapy depended on the individual’s ability to tolerate formula by mouth or nasogastric tube. Enteral nutrition using a BCAA-free formula along with parenteral glucose and lipid solutions is used until total requirements can be met enterally. Specialized BCAA-free parenteral solutions were used in 2 reports (F.104, F.51). The specialized solution in one report was 9% BCAA-free amino acids and 20 to 25% glucose or 9% BCAA-free amino acids plus 10% glucose and 10 to 20% fat emulsion (F.104).
Monitor BCAA, acid-base balance, urine α-ketoacids, blood glucose and clinical symptoms closely during illness. If hemofiltration is necessary, blood gas, hematocrit, total protein, sodium, calcium, phosphorus, urea, and creatinine should also be monitored.
Insufficient Evidence | Consensus | Weak | Fair | Strong |
Conditional | Imperative |
For individuals with MSUD who are at risk for metabolic crisis, it is important that access to stat monitoring for acid-base balance (F.104), blood glucose (F.104), and indicators of cerebral edema be available (F.51, G.35, G.43, G.44)). There should be access for rapid turnaround for plasma amino acid analyses to follow BCAA (F.75, F.104) and frequent monitoring of urinary α-ketoacids (G.44). Although there is no published evidence for optimal intervals for monitoring, there are recommendations for every 2-24 hours for plasma BCAA (F.104), every 30-60 minutes for glucose when insulin is being given (F.104), every 6-24 hours for α- ketoacids (G.38). If hemofiltration is necessary, blood gas, hematocrit, total protein, sodium, calcium, phosphorus, urea, and creatinine should be monitored every 3-6 hours and amino acids every 12 hours (F.73). Inpatient treatment with possible admission to the critical care unit can facilitate monitoring of clinical signs as well as biochemical markers during serious catabolic illnesses
Consensus through both Delphi surveys and the Nominal Group stress the need for frequent clinical assessment and biomarker monitoring during catabolic illness.
Include nutritional intervention when dialysis, hemoperfusion or similar treatment is necessary to lower plasma BCAA and remove toxic metabolites.
Insufficient Evidence | Consensus | Weak | Fair | Strong |
Conditional | Imperative |
Add ILE and VAL, even if they are already in the 200-400 µmol/L range, to help lower elevated plasma LEU into the treatment range.
Insufficient Evidence | Consensus | Weak | Fair | Strong |
Conditional | Imperative |
There was strong agreement that ILE and VAL supplementation should be used to help decrease LEU levels during illness. If patients normally receive supplementation, this should be continued, and may be increased during illness.
Reintroduce intact protein (or complete amino acid mixtures) when elevated plasma LEU approaches the upper limit of the treatment range: 200 µmol/L for infants and children ≤ 5 years of age and 300 µmol/L for individuals > 5 years of age.
Insufficient Evidence | Consensus | Weak | Fair | Strong |
Conditional | Imperative |
Reintroduction of dietary intact protein (or LEU source): LEU is typically stopped during initial presentation and acute illness depending on symptoms. Seven clinical studies (F.104, F.105, F.51, F.426, F.83, F.75, F.44) and 3 expert opinions (G.50, G.39, G.33) recommend to reintroduce dietary LEU when plasma LEU reaches the upper level of treatment range or when metabolic decompensation is abated. This can usually be accomplished within 48-72 hours (F.104, F.51). Minimal details are provided that recommend the amount of dietary LEU that should be introduced. Recommended ranges of protein, energy and BCAA are found in TABLE #3, Nutrient Recommended Intake and Sources in the Dietary Treatment of Well Individuals with MSUD.
Consider use of breast milk (mean LEU concentration of 1 mg/mL) as a source of intact protein (and BCAA) in the dietary management of infants with MSUD if there is frequent anthropometric, clinical, and laboratory monitoring of the infant, and mother has adequate milk production.See TABLE #7, Recommendations for the Nutritional Monitoring of Individuals with MSUD.
Insufficient Evidence | Consensus | Weak | Fair | Strong |
Conditional | Imperative |
Although the use of human breast milk has been reported in the dietary management of a number of IMD, there are only two publications (F.664, F.663) that provide any outcome data for infants with MSUD. One study reports the results of a survey of 27 IMD centers in 15 countries (caring for over 8000 patients with IMD treated through dietary intervention). Successful demand feeding was reported in 17 infants with MSUD. The study did not report the percentage of breast feeding failures, but listed the most common problems incurred for the total population of IMD cases attempting breast feeding. The authors recommended strict monitoring, but did not feel their data suggested what the appropriate monitoring intervals should be (F.664). Another study reported the experience of breast milk feeding among seven patients with IMD, including a single patient with MSUD. Expressed breast milk was used for 2 months. Then, after one week of on-demand feeding, plasma BCAA levels were too high. On-demand breast feeding was attempted again at 3 months with good control, but was terminated because of the stress of frequent monitoring (F.663).
Mature human breast milk with approximately 1 mg LEU/mL is an appropriate source of intact protein for infants with MSUD: 100% agreement among RDs, 83% among MDs
Bottle feeding a combination of expressed breast milk and BCAA-free medical food requires determining the requirements for PRO, BCAA, energy and fluid for the infant with MSUD, and adjusting the mixture frequently based on anthropometric and biochemical monitoring: 100% agreement among both RDs and MDs
Alternating between feeding at the breast and from the bottle (containing the BCAA-free medical food and any additional supplemental VAL, ILE and energy) can be successful if the infant with MSUD has close biochemical and anthropometric monitoring: 92% agreement among RDs, 67% among MDs.
Manage mild illnesses with patient-specific sick-day instructions to include: reduction of intact PRO by 50-100% for 24-48 hours by replacement with additional BCAA-free medical food; adequate hydration; addition of non-protein energy sources; and close monitoring.
Insufficient Evidence | Consensus | Weak | Fair | Strong |
Conditional | Imperative |
Two reports (F.20, F.426), one review (F.83) and four expert opinions, (G.26, G.33, G.44, G.27) provided interventions to be used in non-critical illness. Sick day regimens included removal of natural protein for 1- 2 days with gradual increase to 1 g/kg plus energy intake of 100 to 170 kcal/kg (F.20, F.426). Oral glucose solutions are recommended to increase energy intake. The use of nasogastric feeding is recommended if the individual is unable to consume adequate intake orally (F.83). Specific emergency guidance for caregivers and ED personnel are also recommended (G.44)