TABLE 5.12. Recommendations for BCAA in MSUD
Objetive, µmol/l (mg/dl)
Leucine 200-700 (2.6-9.2)
Isoleucine 100-400 (1.3-5.2)
Valine 100-400 (1.1-4.4)
TABLE 5.13. Vegetables and fruits with lower content in leucine Vegetables with < 50 mg Egg plant, beets, carrots, celery, chicory, leucine/100 ga green spotted zucchini (squash), cucumber,
onion, peppers, radishes, sweet potatoes, tomato, pumpkin, cabbage
Fruits with < 30 mg Apple, apple juice, apricot, cherries, oranges, leucine/100 gb orange juice, grapefruit, tangerine, lemons,
grapes, guava, peach, plums, strawberries, pears, passion fruit, melon, raspberry, blueberry
aThe protein content ranges from 0.5-1 g/100 g. The new varieties, in gene-ral, contain less leucine than the old ones. bThe protein content ranges from 0.3-1 g/100 g.
Given that isoleucine and valine levels in foods are always lower than that of leucine and their daily requirements are also lower, leucine restricted diets normally contain sufficient quantities of isoleucine and valine. However, if a significant decline in their levels is observed in periodic testing, diet supplements must be included so that insufficient levels of these amino acids do not limit protein synthesis.
A starting dose of 50-100 mg/day diluted in water is normally used. This should be divided into 2-3 daily doses to be taken and can be increased depending on plasma levels.
The drastic limitation of natural proteins in the diet requires BCAA free protein supplements to ensure adequate protein intake to sustain adequate growth and development. The majority of these preparations contain vitamins and minerals that meet the patient’s daily requirements according to age. A thiamine supplement of 5 mg/kg/day is recommended for all forms of this disease as it can improve the tolerance to BCAA in some patients(43). Forms that are sensitive to thiamine require a dose of between 10-1000 mg/day.
Metabolic decompensation crisis
During intercurrent infections or other processes that increase energy demands, a rapid increase in BCAA levels is seen, especially of leucine levels. Thus, it is necessary to suppress the intake of foods containing protein and start an emergency dietary plan including glucose polymers in conjunction with BCAA free protein preparations in order to stimulate protein synthesis and supply adequate caloric intake.
Isovaleric acidemia (IVA)- Propionic acidemia (PPA).
Methylmalonic acidemia (MMA)
The deficiency of enzymes employed at distinct steps in the metabolism of branched amino acids (Fig. 5.5) result in organic acidemias, of which the most frequent are:
• Isovaleric acidemia (IVA): This condition is caused by a deficiency in isovaleryl-CoA deshydrogenase (step 2 in figure 5.5).
• Propionic acidemia (PPA): This disease is caused by a deficiency in propionyl-CoA carboxylase, a biotin-dependent mitochondrial enzyme necessary for the metabolism of propionyl-CoA (step 3 in figure 5.5).
• Methylmalonic acidemia (MMA): This is a result of a deficiency in the mitochondrial enzyme methylmalonyl-CoA mutase, which requires the cofactor adenosyl-cobalamine and catalizes the step of methyl-malonyl-CoA to succinyl-CoA (step 4 in figure 5.5).
There are other acidemias caused by deficiencies in enzymes required for the metabolism of leucine (methylcrotonylglycinuria, type I and IV methylglutaconic, mevalonic, etc.), of valine (deficiencies of isobutiryl-CoA-DH, 3-OH-isobutiryl-CoA desacylase, etc.), as well as multiple carboxylase deficiencies. The three most frequent acidemias, IVA, PPA and MMA, are inherited in an autosomal recessive manner and have the common characteristics of intense acidosis (pH <7.25, bicarbonate <15), ketonemia and ketonuria, hyperammonemia of varying intensity, with normal or high glucemia and lactate. They tend to have an increased anion gap and pancytopenia.
The most frequent form of presentation is the severe neonatal form, where after a symptom-free period, the patient begins with an intoxication-type neurological picture including food refusal, vomiting, rapid dehydration, hypotonia, convulsions, apnea crises, coma and death. In IVA there is a characteristic smell of sweaty feet.
Less frequently there may be a a late onset form (even in the adult) characterized by acute recurrent symptoms that may be the result of a precipitating factor (fasting, intercurrent diseases) and a chronic progressive form where symptoms tend to be intense anorexia, failure to thrive and vomiting in conjunction with neurological signs (pyramidal and extrapyramidal, psychomotor delay). There may be clinical complications such as pancreatitis, 99 Treatment of the Inborn Errors of Metabolism
myocardiopathy, cutaneous lesions, progressive renal dysfunction, etc. (Tables 5.14 and 5.15).
The diagnosis is made by testing for organic acids in biological fluids using gas chromatography/mass spectrometry, where the diagnostic metabolites of each acidemia can be identified. Fibroblasts can be used to determine the corresponding enzymatic deficiency.
In the following two tables a summary of these clinical entities is shown. In one table IVA is presented, while PPA and MMA are present together in the other table due to their clinical similarities.
Treatment of the organic acidemias IVA, PPA and MMA have many common elements, for this reason they are present together(41).
Acute initial phase
This generally effects newborns suffering from acute and severe intoxication-type clinical symptoms where the treatment priorities will be(45-48):
TABLE 5.14. IEM of amino acids and proteins. Organic acidemias. Isovaleric
Isovaleric aciduria (IVA)(41,44,45) (↓ Isovaleryl- CoA- dehydrogenase) Pathophysiological group • Type II
Incidence (cases/NB) • Unknown as it is not in neonatal screening programs and is underdiagnosed
Debut • Neonatal
Age • Late infancy
Clinical aspects • Neonatal: general toxic syndrome
• Late infancy: development and mental retardation, acidosis during decompensations, pancytopenia Treatment • Diet low in proteins and leucine
• L-glycine and carnitine supplements Prognosis and complications • Good prognosis with early diagnosis and
treatment
• Poor prognosis with later diagnosis in neonatal forms
• Maintain the vital signs and rapidly eliminate the toxic substrate:
– Admission and monitoring in the ICU.
– Correction of the severe acidosis.
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