Feeding the Sick Infant, edited by Léo Stem. Nestlé Nutrition Workshop Séries, Vol. 11. Nestec Ltd, Vevey/Raven Press, New York © 1987. Nutritional Aspects of Inborn Errors of Metabolism Michel Vidailhet Department of Pediatrics 3, Hôpital d'Enfants, 54511 Vandoeuvre-lès-Nancy, France GENERALITIES Introduction Inherited metabolic disorders in volve différent nutritional aspects. On the one hand, the disease itself can impair normal nutrition. During the end of the fetal growth period and the first two years of life, the human brain grows at an impres- sive rate. This brain growth spurt period (1) is associated with a very high rate of protein synthesis that makes the central nervous system vulnérable to any interfér­ ence with protein synthesis. Biochemical insuit at this critical period may hâve a permanent effect on brain function. The accumulation of one or more substrates above an enzymatic block can af- fect normal metabolism and nutrition. For example, in amino acid disorders the high tissue levels of accumulated amino acid may competitively inhibit the trans­ port of other amino acids sharing the same transport mechanism. Amino acids in excess may interfère with the activity of enzymes involved in the metabolism of other amino acids. Short-chain fatty acids, oxo-acids, and other organic acids in- teract with ureogenesis, gluconeogenesis, pyruvate metabolism, etc. In fructose in­ tolérance, the accumulation of fructose-1-phosphate causes the trapping of inor- ganic phosphate. The fall in cellular ATP and ADP inhibits several enzymatic activities and results in altérations of energy metabolism. On the other hand, the metabolic block can induce severe deficiencies in one or more metabolites normally produced by the pathway. In ail urea cycle disorders, except arginase deficiency, arginine becomes essential; without arginine supple- mentation, stunted growth and hyperammonemia occur despite protein restriction. Undemutrition may be the conséquence of gênerai metabolic disturbances. Chrome hypoglycemia, lactic acidosis, and secondary hypercorticism explain the poor growth observed in glycogenosis type I. Severe and progressive impairments of liver function and, to a lesser degree, of rénal tubular function play a major rôle in the development of malnutrition, which appears in galactosemia, fructose intolérance, or in hereditary tyrosinosis. 205 206 INBORN ERRORS OF METABOUSM Even in lysosomal disorders, stunted growth can begin in the first few weeks of life, as in Wolman disease, probably because of the importance of the liver and small bowel lésions in this disease. In transport mechanism disorders, levels of spécifie nutrients may be decreased, with, as a conséquence, symptoms of deficiency, as in acrodermatitis enteropath- ica secondary to zinc malabsorption. On the other hand, surprisingly enough, cystinuria-lysinuria does not resuit in lysine or arginine deficiency, despite the increased rénal excrétion and the intesti­ nal malabsorption of thèse amino acids. Such an apparent contradiction is now well explained by the importance of direct intestinal absorption of di- and tripeptides. Dietetic Treatment Because of the multiplicity of inborn errors of metabolism, it is not possible to review ail their nutritional drawbacks. Some metabolic disorders are harmless variations of normal metabolism (e.g., essential fructosuria, cystathioninuria), whereas others cause severe illness or mental détérioration early in life. The latter are often treatable by means of spécial diets and their nutritional aspects appear most important for clinical practice. A block in galactose, fructose, or amino acid metabolism leads to accumulation of thèse substrates and their metabolites, which can be prevented by spécifie restricted diets. Such diets may hâve to be continued for many years, sometimes indefinitely, as in maple syrup urine disease (MSUD), urea cycle disorders, galactosemia, etc. The prolonged use of a synthetic or semisynthetic diet may hâve adverse effects if the absolute and relative amounts of the différent nutrients are not well provided. Thèse diets must provide: (a) adéquate calorie intake; (b) minimum requirements of essential amino acids and nitrogen; (c) vitamins, minerais, and trace éléments in sufficient amounts; (d) normal products of the metabolic pathway that can no longer be produced and that hâve essential functions (e.g., tyrosine in phenylketo- nuria (PKU), arginine in urea cycle disorders, cysteine in homocystinuria, free glucose in glucose-6-phosphatase deficiency). The biodisposability and intestinal absorption of several nutrients, such as vitamins or trace éléments, may be very différent between synthetic diets and normal foodstuffs. Apart from the main ef­ fects intended by the treatment, it is important to be concerned about ail nutritional problems that may resuit from the disease and its dietetic therapy. According to the type of metabolic disorder one can distinguish several kinds of dietetic manipulations. Supplementation This is the easiest to perform. An example is zinc supplementation for acroder­ matitis enteropathica. In Menkes disease parenteral supplementation with copper gives much less satisfactory results. A particular group of inherited metabolic diseases is the group of vitamin- INBORN ERRORS OF METABOUSM 207 dépendent disorders. Several amino acidemias and organic acidemias are com- pletely or partially cured by large doses of vitamins that are the precursors of spé­ cifie cofactors involved in defective enzymatic reactions. Table 1 lists thèse dis- eases. According to the kind of enzymatic deficiency, a metabolic disorder, as methylmalonic acidemia, may be fully or partially responsive or unresponsive to B12 vitamin therapy. In every instance it is important to try such cofactor therapy, which is easier to apply than restricted diets. Exclusion Such diets can be proposed when the nutrient to be excluded is not an essential one. This is the case for galactose (galactosemia, galactokinase deficiency, glyco- genosis type I) and for fructose (fructose intolérance, fructose-1, 6-diphosphatase deficiency, glycogenosis type I). Restriction In disorders involving an essential amino acid, the diet must supply the minimal requirement for this amino acid that is restricted relative to the total protein intake. Most of the natural protein is replaced by a protein substitute deprived of this amino acid (Tables 2 and 3). TABLE 1. Amino acid and organic acid disorders that may be responsive to vitamin therapy Disease Vitamin Dose Homocystinuria (cystathionine synthetase deficiency) Cystathioninuria Pyridoxine 100-150 mg/day Hyperoxaluria Xanthurenic aciduria Methylmalonic acidemia (MMA) (mutase deficiency) B 0.25-1 mg/day Homocystinuria + MMA + hypomethioninemia 12 Homocystinuria + hypomethioninemia Folie acid 10-50 mg/day Maple syrup urine disease Lactic acidosis (pyruvate dehydrogenâte [PDH] Thiamin 10-20 mg/day deficiency) Dicarboxylic aciduria Riboflavin 100 mg/day Type 2 glutaric aciduria Hartnup disease Niacin 50-200 mg/day Hyperphenylalaninemia with dihydropterin synthetase BH„* 3-5 mg/kg deficiency Tyrosinemia C 50-100 mg/day Multiple carboxylase deficiency (3-methylcrotonylglycine, Biotin 10 mg/day propionic, lactic acids) "Cofactor φ + + + ο ο + + c 1 ε + +-Q.+ + +00 + + ! (0 Ο) Φ Ο ΟΟ ΝΜΙΟΟΟΟΙΟ in r» ΙΟΜΧΟΟΙΟΜ S ° *ί C0 C0 CM 0J τ!· -«t CO F5 ! <ο •S οο Ο υ Φ .C C •S φ S •c (Ο τ- Q. II h- m 00SSOOO01 ο ΙΟ ΙΟ ϋ φ ι§ ο ο ο ο ο ο ο 8 s: σ> Φ Ι 5 ç σ> "5 Φ ο Ρ° ιη ο Ο Ο Ο Ο Ο Ο CD ω trooooonio «0 Φ < τ- m Φ â .»"§ î?s c °> II Ο) fc i- (β ο ^ C φ Φ Ο Ο Ο Ο Ο Ο Ο Ο Ο Φ Ε 1° 00 τ- CM UJOOÇ •ses. IE f Ρ α. flffilîîîj CM § 1 Sx Τ3 3 φ ?Ζ, ε α. ζ _J < 1 û. D. < CL Σ 1 1NBORN ERRORS OF METABOUSM 209 TABLE 3. Low amino acid and galactose-free substitutes Disorder Substrate lowered Name of Product Cystinosis cystine (0.5 g/100 g) Albumaid X Cysf Maple syrup urine disease Branched-chain amino M.S.U.D. Aid· acids Leucidonfc M.S.U.D. 1 and 2e Homocystinuria (classical Methionine Albumaid X Meth* form) Methionaid" Hom 1 and 2e Tyrosinosis Phenylalanine and tyrosine Albumaid X Tyr* Tyrosinaid* Tyrosidon" Tyr 1 and 2e Histidinemia Histidine Histinaid* Histidon" Hist 1 and 2e Hyperlysinemia Lysine Lys 1 and 2e Urea cycle disorders Nonessential amino acids Essential Amino Acid Mixture* U.C.D. 1 and 2e Nitrogen Ketosteril" Propionic and Isoleucine, methionine, OS 1 and 2e Methylmalonic acidemias threonine, valine Galactosemia Galactose Galactomin 19* Nutramigen" Pregestimil· Isomil' Prosobee" Vegelact9 •Scientific Hospital Supplies (England) •"Nutricia (The Netherlands) cMilupa (Fédéral Republic of Germany) ''Fresenius (Fédéral Republic of Germany) "Mead-Johnson (United States) 'Ross (United States) «Gallia (France) For PKU, see Table 2. A major danger of such diets is the occurrence of nutritional deficiencies, partic- ularly a deficiency in the restricted amino acid. Phenylalanine deficiency owing to overtreatment of PKU has been well described. The baby fails to gain weight; de- velops a severe, red, cutaneous rash starting in the napkin région; vomits; becomes anorexie and léthargie; and may develop alopecia, edema, and fréquent infections. Death or définitive mental retardation may ensue. Deficiency of other essential amino acids has the same gênerai effect. In several diseases such as MSUD, propionic acidemia (PA), B12 unresponsive methylmalonic acidemia (MMA), and infantile tyrosinosis, the borderline between deficiency and excess is narrow, and monitoring is more difficult than in PKU. Low protein diets, in which total protein is restricted and replaced by nonprotein calories, are necessary in several diseases such as urea cycle disorders. They give 210 INBORN ERRORS OF METABOUSM way to protein lack and sometimes necessitate the use of an essential amino acid mixture or of keto- and hydroxy-analogues of essential amino acids. Emergency Conditions Some of the diseases manifest themselves in severe acute forms, particularly in the neonatal period. This is the case for several amino acid disorders like MSUD, urea cycle disorders, MMA, PA, and isovaleric acidemia (IVA). Certain clinical findings are suggestive of a hereditary metabolic disease that frequently mimics neonatal sepsis.