Reports of delay in dietary treatment in the infant with classic MSUD have described significant and irreversible cognitive impairment (F.24, F.46). Across the lifespan, adverse medical outcomes associated with elevated plasma LEU included 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 of individuals with classic MSUD, elevated long-term plasma LEU levels were associated with impaired cognitive outcome, 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 suggested 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.

Delphi 1:

There was consensus (100% of RD and 82% MD respondents agreed) that plasma LEU should be routinely monitored as the best marker of BCAA control in metabolically stable individuals.

Delphi 2:

There was consensus (100% of RD and 71% of MD respondents agreed) that 200 µM was an appropriate upper limit for those ≤ 5 years of age, when well. 

There was no consensus (75% of RD and 57% MD respondents agreed) that that individuals >5 years of age could maintain good control at an upper limit of 300µM for LEU when well.

Comments: there should be similar recommendations for those both younger than and older than 5 years of age.

There was consensus (84% of both RD and MD respondents agreed) that the lower limit for LEU should be 75-100 µM, or the lab’s definition of lower the normal range.

Comments: normal ranges may differ from lab to lab.

Eighteen case reports on 14 infants with MSUD showed 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 were shown to be a hallmark 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. Parenteral supplementation of 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).

Delphi 1:

There was consensus (91% of RD and 83% of MD respondents 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 defictencies, with 200-400 µmol/L as a satisfactory goal.

Growth was measured in five studies. When plasma BCAA levels were largely kept in desirable ranges, growth was 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 a combination of formula and breast milk. Poor growth in MSUD has been reported as a result of BCAA deficiency (F.613), while catch-up growth occured once the deficiency was corrected. The gray literature also reported poor growth in relationship to BCAA deficiency (G.50, G.43, G.39, G.5).

Delphi 1:

There was consensus (91% of RD and 83% MD 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.

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” was not always clearly defined, and quality of life was not objectively measured. A handful of studies reported a small number of adolescent and adult individuals with MSUD able to tolerate plasma LEU concentrations 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 concentrations between 1000 to >2000 µmol/L (F.65). Individuals 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). When plasma ILE or LEU concentrations fell below 50 µmol/L or plasma VAL concentration below 95 μmol/L on full, supplemented feedings, the BCAA prescription was 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 (medical food) 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).

Delphi 1:

There was consensus (100% of all respondents agreed) that if offending amino acids (VAL, ILE, LEU) are >10% below normal levels, more intact protein should be added to the diet.

Without adequate dietary management, the newly diagnosed infant with classic MSUD has been shown to be 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) and onset of neurological sequelae (F.92). Abnormal brain morphology has not always correlated with acute neurotoxicity symptoms, IQ, or CNS function (F.46, F.65, F.125). Dietary BCAA restriction in the person with MSUD has been shown to achieve and maintain plasma BCAA concentrations as close to normal as possible and prevent and correct BCAA deficiencies (F.47, G.39, G.49, G.50). 

There were no statements in the Delphi surveys that addressed lifelong dietary management.