AMERICAN ACADEMY OF PEDIATRICS COMMITTEE ON NUTRITION NUTRITIONAL MANAGEMENT IN HEREDITARY METABOLIC DISEASE T HIRTEEN YEARS AGO a dietary approach propriately given. Management begins with to the therapy of phenylketonuria was confirmation of the diagnosis by methods proposed,I.2 and data on the usefulness as more specific than those used in any screen- well as the very real limitations of this pro- ing program and continues with monitoring gram have accumulated in the intervening of the biochemical and biological response years. At the present time studies on the to dietary manipulations. This memoran- application of special diets for use in this dum discusses these and other general pm- disease, as well as for many other heredi- ciples. A handbook of treatment is not in- tary metabolic diseases, are in progress. As tended, and referral to the comprehensive wider use is made of procedures for detec- sources identified in Table I is recom- tion of hereditary metabolic disease in the mended for those requiring detailed infor- newborn,’ an increasingly larger number of mation about particular diseases. patients who may benefit from appropriate nutritional therapy will be identified very GENERAL PRINCIPLES early in life. For example, calculations The events depicted in Figure 1 underlie based on the current birth rate and appar- all types of hereditary metabolic disease. ent incidence of phenylketonuria indicate Mutation in the genorne, in one way or an- that as many as 4,000 infants with this dis- other, modifies a protein gene product. The order in the United States alone could re- gene product is called an apoenzyme when (luire dietary therapy in the next decade. the protein directs a specific biochemical There is, therefore, a need to evaluate the reaction. The association of a low-molecu- principles governing nutritional manage- lar weight compound or coenzyme ( 3 ) may ment of hereditary metabolic disease in also be required by the apoprotein to order to develop optimal treatment facili- achieve optimal catalytic rates; the corn- ties for use in conjunction with new detec- bined apoenzyme-coenzyme complex is tion methods. It seems anomalous that com- called the holoenzyme. Conversion of one paratively little has been done either to es- compound [substrate ( 1 )I into another tablish good treatment practices in heredi- [product ( 2 ) J, or transfer of unmodified tary metabolic disease or to mobilize scien- substrate from one side of the membrane to tific resources to ensure an optimistic out- the other, often against an electrochernical come for therapeutic endeavors, while so gradient, constithte the principal types of much emphasis has been placed on detec- “enzymatic” activity. tion. The inherited disorders of cellular me- Dietary treatment of hereditary metabolic tabolism and transport reflect alterations in disease is simple in theory; however, prac- structure, activity, or amount of enzyme. tical application may be unexpectedly Most of the diseases exhibit simple Men- difficult, or even hazardous, if not carefully delian inheritance and are the result of mu- supervised. It should be determined wheth- tation at a single genetic locus. Altered bio- er: (1) the untreated disease is in fact harm- chemical relations and associated clinical fill, ( 2 ) the treatment is useful in preventing consequences constitute the phenotype of or reversing the unfavorable progression of such a disease. Specific phenotypes can be the disease, (3) the therapy may be harmful described for almost all of these metabolic by interfering with growth or development, diseases. and ( 4 ) the program may be harmful to Ideal treatment would restore the normal others to whom it is inadvertently or map- genetic code as vell as subsequent tran- Prnu-nics, Vol. 40, No. 2, August 1967 289 Downloaded from www.aappublications.org/news by guest on September 28, 2021 290 NUTRITION IN METABOLIC DISEASE TABLE I TYPES OF HEREDITARY METABOLIC DISEASE APPARENTLY AMENABLE TO THERAPY Disorder Therapy Which Has Been Attempted Reference* Disorder8 of Amino Acid Meiabolism Essential Amino Acids Phenylketonuria (classical) Phenylalanine restriction 61, 62 See also Table III 63, 64, 65 Branch-chain ketoaminoaciduria (maple syrup urine disease) Restriction of leucine, isoleucine, and valine 39, 40 Hypervalinemia Valine restriction 66 Isovalericacidemiat (“sweaty-feet” syndrome) Protein restriction 67 Homocystinuria, with methioninemia Methionine restriction and cystine supplementation 68, 69, 69a Hi.stidinemia Early histidine restriction (?) 70 Hyperlysinemia Protein restriction 1.5 gm/kg/day (see also diseases of urea cycle) 71, 7, 73 Non-Essential Amino Acids Tyrosinemia hereditary form Tyrosine restriction and phenylalanine adjustment 53, 53a transient neonatal form Protein restriction 1-ascorbic acid 75 to 100 mg/day 45,46 Diseases of urea cycle Protein restriction for control of NH5 intoxication 74 hyperammonemia carbamyiphosphate synthetase deficiency Protein restriction for control of NH3 intoxication 75 ornithine transcarbamylase deficiency Protein restriction for control of NH3 intoxication 76 citrullinemia Protein restriction for control of NH3 intoxication 77 argininosuccirncaciduria Arginine supplementation in early infancy (?) protein restriction 78 The hyperglyeinemias acetolluric form Protein restriction (about 1 gm/kg/day) 79 bypo-oxaluric form Protein restriction? 80 Disorders of Amino Acid Transport Hartnup disease Nicotinic acid supplements; good general nutrition 81, 8 Tryptophanuria Nicotinic acid 83 Cystinuria Water; D-penicillamine 84, 85 with malabsorption or protein into1erance Variable 86,87 Methionine malabsorption Protein restriction 88 Tryptophan malabsorption (blue diaper syndrome) . Protein restriction 89 Miscellaneous Problems Vitamin B6 dependency syndromes Pyridoxine HC1 (10 mg/day or more) 7 cystathioninuria 55 vitamin B6 dependency and seizures 90, 90a familial xanthurenic-aciduria 91 familial pyridoxine responsive anemia 9 Folic acid diseases formimino transferase deficiency None known Histidine restriction? 93 FIGLU’uria, MD magaloblastic anemia and ataxia Folic acid 94 S Citation is either to a recent article, review, or “classical” paper, whichever provides the most useful informa- tion and bibliography concerning treatment. t L-valme metabolism per se is Ilot abnormal in this disorder affecting the degradation of the equivalent hydroxy acid. This may be a disorder of tryptophan pyrollase activity, and hence classified under essential amino acids. § Whether this constitutes disease separate from the three genotypes of cystinurias or is merely interesting associative phenomena is not clear. Downloaded from www.aappublications.org/news by guest on September 28, 2021 AMERICAN ACADEMY OF PEDIATRICS 291 Disorder Therapy Which Has Been Attempted Ref erence Disorders of Carbohydrate Metaboli3m Ilyperglucemia (Childhood Diabetes Mellitus) Dietary control Insulin 95 Hypoglucemia toxic (EDTA, salicylates, sulphonylu- reas, MOA inhibitors, etc.) Remove cause IV glucose 96 leucine sensitivity Protein restriction (steroids) 97, 98 idiopathic Steroids 101 ketotic Frequent feeding 1O deficient catecholamine# response Ephedrine 103, 104 Ilyperinsulinism Diazoxide Surgery 98 Glycogen storage diseases (Type 1-IX) Depends on type 106 Galactosemia (4 types: see text) Galactose restriction (need may be transient) (Preg- nancy-special need for Rx of mother) 41, 107 Fructose intolerance Restriction of fructose intake 108, 109 Glucose-galactose malabsorption Restriction of dietary carbohydrate 1 10, 111 Fructose-galactose intolerance Restriction of dietary carbohydrate (excluding glu- cose) 112 True congenital disaccharidase deficiency Long-term dietary restriction of offending disac- charide 113, 114, 115, 116, 117 Acquired disaccharidase deficiency Temporary restriction of offending disaccharides 118, 117 Disorders of Lipid Metabolism Familial hyperlipoproteinemia-5 types: Varies with type-includes: 119 hyperchylomicroenimia Medium chain triglyceride supplement increased fl-lipoprotein increased pre fi and fl-Lp Restriction of cholesterol increased pre fl-Lp Restriction of CHO combined hyper 3-Lp and hypochylomi- cronemia Polyunsaturated FA-supplement Abetalipoprotenemia Low fat diet 120 High density lipoprotein deficiency (Tangier disease) (None required usually) 121 Miscellaneous Gastrointestinal disorders gluten sensitive enteropathy Gluten restriction 122, 122a cystic fibrosis (intestinal component) Pancreatic enzyme replacement 123 trypsinogen deficiency Trypsinogen replacement 125 Disorders of mineral metabolism idiopathic hypercalcemia Avoid vitamin D excess 126 vitamin D dependency Vitamin D 50,000 units/day 127 renal phosphorus transport 10 to 20 gm neutral phosphase salt solutions (+ vitamin D in some cases) 127 Wilson’s disease D-Pencillamine 128 Disorders of pyrimidine metabolism familial hyperuricemia with finger chew- ing and MR Prohenecid, Alkalinization 129 oroticaciduria Uridine p.o. 150 mg every 4 to 6 hours 130, 5 This abnormality probably reflects aII exaggeration of a normal mechanism reducing hepatic glucose produc- tion rather than a genetically controlled metabolic abnormality.99100 # There is no evidence that the abnormality in adrenalin production in certain patients results from an hereditary enzymatic defect. Rather, it probably results from exhaustion of tile chromaffin system.1#{176}’ Downloaded from www.aappublications.org/news by guest on September 28, 2021 292 NUTRITION IN METABOLIC DISEASE scription