Management
Guidelines
Portal
DNDF Model
MSUD Nutrition Management Guidelines
First Edition
February 2013, v.1.50
Current version: v.1.58
Updated: August 2016
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Nutrition Recommendations
Question
2. For the individual with MSUD treated through dietary modification, what are BCAA blood levels that lead to optimal nutrition, medical and quality of life outcomes?
Conclusion Statement
Derived from evidence and consensus based clinical practice

Studies in this analysis have focused primarily on identifying plasma BCAA concentrations that result in adverse outcomes.  Elevated LEU levels are most often associated with abnormal brain morphology and cognitive impairment; impact on social and psychomotor function varies. Low plasma BCAA, particularly ILE and to a lesser extent VAL, results in severe but reversible epithelial damage to the skin, eye and gastrointestinal tract. Poor growth is reported as a result of BCAA deficiency. The goal of dietary BCAA restriction in the person with MSUD is to quickly achieve and maintain plasma BCAA concentrations as close to normal as possible while preventing and correcting BCAA deficiencies. However, reports differ in the plasma BCAA ranges that are considered acceptable but agree that biochemical monitoring is necessary to assess the effectiveness of dietary intervention. Although relaxing dietary BCAA restriction in adolescents and adults has been reported in case studies and postulated to improve quality of life, this practice poses a risk of adverse outcomes and has not been rigorously or objectively evaluated.

Summary
 
Details
Recommendation 2.1

Maintain plasma LEU, with frequent monitoring, between 75-200 µmol/L for infants and children < 5 years of age and between 75-300 µmol/L for individuals >5 years of years of age to achieve favorable cognitive outcomes.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
Impact of plasma LEU on cognition
Topic 2.1.1  Link to Topic 2.1.1 Right click and select "Copy Link Location"
Evidence
  • Delay in diet treatment in the infant with classic MSUD results in significant and irreversible cognitive impairment (F.24, F.46). Across the lifespan, adverse medical outcomes associated with elevated plasma LEU include sudden death (F.125), abnormal electroencephalogram (EEG) studies (F.614), pseudotumor cerebri spectrum (F.72), onset of neurological sequelae (F.92), and abnormal brain morphology that may not always correlate with acute neurotoxicity symptoms, IQ, or CNS function (F.46, F.65, F.125).
  • In three studies, elevated long-term plasma LEU levels were associated with impaired cognitive outcome in patients with classic MSUD, as measured by reductions in IQ (F.69, F.612, F.37).
  • The results of one attempt to quantify the impact of long-term LEU level on IQ in children suggest that for each 76 µmol/L increase in LEU concentration, IQ decreases by 3.22 points (F.69). 
  • In another study, long-term medians of semi-annual plasma LEU concentrations were shown to be predictors of non-verbal IQ, with a decrease of 10 IQ points for each 100 µmol/L of average increase in plasma LEU in the first three years of life (F.612).
  • In a retrospective review of patients with classic MSUD, median plasma LEU concentrations during the first six years of life were indirectly correlated with IQ at 6 years of age, leading the researchers to suggest a plasma LEU level of <200 µmol/L as optimal in infants and preschool children to achieve best possible IQ scores (F.37).
  • Conversely, one study (F.24) concluded long-term blood leucine did not correlate with IQ, but four of the 14 subjects were “too neurologically damaged” to measure IQ and one patient “did not attend for testing.” Several studies (F.46, F.21, F.91) reported plasma BCAA levels and IQ but did not attempt to statistically correlate the two.
Consensus based on clinical practice
  • LEU as marker for control: 70% agreed or completely agreed that plasma LEU should be routinely monitored as the best marker of BCAA control in metabolically stable individuals.
  • 84% agreed that 200 µM was an appropriate upper limit for those ≤ 5 years of age, while 68% agreed that individuals >5 years of age could maintain good control at an upper limit of 300µM. for LEU.
  • 84% agreed that the lower limit for LEU should be 75-100 µM, or the lab’s definition of lower the normal range.
Recommendation 2.2

Maintain plasma ILE and VAL concentrations between 200-400 µmol/L (or slightly above the normal ranges) in individuals with MSUD to avoid metabolic instability and BCAA deficiencies.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
Impact of plasma ILE and VAL on epithelial integrity
Topic 2.2.1  Link to Topic 2.2.1 Right click and select "Copy Link Location"
Evidence
  • Eighteen case reports on 14 infants with MSUD show that low plasma BCAA, particularly ILE and to a lesser extent VAL, can result in severe but reversible epithelial damage to the skin, eye and gastrointestinal tract.
  • Symptoms were reported in conjunction with low plasma ILE levels in 15 case reports. In eight case reports, ILE levels were between 1.9 and 48 µmol/L (F.100, F.68, F.67, F.71, F.122, F.92, F.96); in seven case reports, plasma ILE was described as “low” (F.28). Plasma ILE was normal (102.2 µmol/L) in one case (F.67), mildly elevated (180 µmol/L) in one case (F.68) and not reported in one case (F.426).
  • Symptoms were reported in conjunction with low plasma VAL in eight case reports. In seven case reports, ILE levels ranged from 40 to 100 µmol/L (F.68, F.67, F.122, F.100); in one case, plasma VAL level was reported as “low” (F.426). Plasma VAL was elevated (320-360 µmol/L) in three cases (F.68, F.71, F.96). Plasma VAL was not reported in seven cases (F.28, F.92).
  • Skin lesions are a hallmark sign of BCAA deficiency and may be accompanied by diarrhea (F.71, F.96, F.100, F.122), alopecia (F.68, F.71), anemia (F.100, F.426, F.122), edema (F.100, F.122), and in one case, near-total de-epithelialization of the cornea (F.96). Manifestation may mimic erythema multiforme (F.67), or an acrodermatitis-enteropathica-like eruption (AELE) with normal plasma zinc levels (F.100, F.68, F.67, F.71, F.28, F.122, F.92). All studies reported rapid and marked improvement within 2 to 10 days of BCAA supplementation. Specific post-treatment BCAA levels were not reported, although some reports (F.100, F.68, F.71) stated that levels normalized. Supplementation of parenteral ILE (85-90 mg/kg), VAL (85-100 mg/kg) and in one case LEU (115 mg/kg) resulted in resolved symptoms (F.100, F.122), while enteral supplements of 35 mg ILE/kg and 40 mg VAL/kg did not (F.68).
Consensus based on clinical practice
  • Control of plasma ILE and VAL levels: 84% agreed that ILE and VAL values should be at the upper limit, or slightly above the upper limit of the lab’s definition of the normal range to prevent deficiencies with 200-400 µmol/L as a satisfactory goal.
Impact of plasma ILE and VAL on growth
Topic 2.2.2  Link to Topic 2.2.2 Right click and select "Copy Link Location"
Evidence
  • Growth was measured in five studies. When plasma BCAA levels are largely kept in desirable ranges, growth is reported to follow expected curves in children ages 1 – 3 years except during times of illness (F.43, F.126, F.426, F.614), including those fed both formula and breast milk. Poor growth in MSUD has been reported as a result of BCAA deficiency (F.613), and catch-up growth occurs once the deficiency is corrected. The gray literature also reports poor growth in relationship to BCAA deficiency (G.50, G.43, G.39, G.5).
Consensus based on clinical practice
  • Control of plasma ILE and VAL levels: 84% agreed that ILE and VAL values should be at the upper limit, or slightly above the upper limit of the lab’s definition of the normal range to prevent deficiencies with 200-400 µmol/L as a satisfactory goal.
Recommendation 2.3

Maintain plasma BCAA within the recommended ranges throughout life.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
Lifetime dietary treatment
Topic 2.3.1  Link to Topic 2.3.1 Right click and select "Copy Link Location"
Evidence
  •  A relaxed dietary BCAA restriction in older children and adults has been postulated to improve quality of life without detrimental effects, although the definition of “detrimental” is not always clearly defined, and quality of life is not objectively measured. A handful of studies report a small number of adolescent and adult individuals with MSUD are able to tolerate plasma LEU levels of 500-2000 µmol/L without obvious effects on cognition or social functioning (F.24, F.26, F.46). One group of researchers reversed their stance on relaxing the BCAA restriction following the unexpected death of a school-aged patient and MRI findings of severe and diffuse dysmyelination in other patients (F.125). Nevertheless, one family was reluctant to resume a strict diet in a 12-year-old boy without major symptoms or EEG abnormalities despite brain changes on MRI and plasma LEU levels between 1000 to >2000 µmol/L (F.65)
  • Persons with mild variant MSUD may require less stringent dietary BCAA restriction when well, but stringent dietary BCAA restriction during illness (F.21, G.50, G.3, G.4, G.6). 
  • Deficiency syndromes can be prevented by supplementing BCAA as soon as plasma concentrations reach the upper limit of the treatment range, or within 1-4 days of starting nutrition support (G.39, G.7).
  • If plasma ILE or LEU concentrations fall below 50 µmol/L or plasma VAL concentration below 95 μmol/L on full, supplemented feedings, the BCAA prescription should be increased by at least 5% to 10% (25% if BCAA undetectable) and plasma level rechecked in 1 week (3 days if BCAA undetectable) (G.39, G.7).
  • The addition of a small amount of low-LEU formula containing normal amounts of ILE and VAL (typically used to treat disorders of LEU metabolism) has been proposed as a practical way to supplement ILE and VAL without increasing plasma LEU (G.7, G.50).
Consensus based on clinical practice
  • Intact protein as BCAA source: 82% agreed that if offending amino acids (VAL, ILE, LEU) are >10% below normal levels, more intact protein should be added to the diet.
Recommendation 2.4

Employ MSUD-specific dietary management stratagies to achieve recommended BCAA levels. See TABLE #4, Recommended Daily Nutrient Intakes of BCAA, PRO, ENERGY and Fluids for Infants, Children and Adults with MSUD (when well), and TABLE #5, Protein Recommendations during Pregnancy for MSUD.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
Dietary management
Topic 2.4.1  Link to Topic 2.4.1 Right click and select "Copy Link Location"
Evidence
  • Without adequate dietary management, the newly diagnosed infant with classic MSUD is at risk for death or for significant and irreversible cognitive impairment (F.24, F.46). Across the lifespan, adverse medical outcomes associated with elevated plasma LEU include sudden death (F.125), abnormal electroencephalogram (EEG) studies (F.614), pseudotumor cerebri spectrum (F.72), onset of neurological sequelae (F.92), and abnormal brain morphology that may not always correlate with acute neurotoxicity symptoms, IQ, or CNS function (F.46, F.65, F.125)
  • The goal of dietary BCAA restriction in the person with MSUD is to achieve and maintain plasma BCAA concentrations as close to normal as possible while preventing and correcting BCAA deficiencies (F.47, G.39, G.49, G.50). 
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