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-
P rn u-nics, Vol. 40, No. 2, August 1967 289
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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, 6 2 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.
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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
Di sorders 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 and translation. This dynamic ap- human inborn errors.7 Sufficient dietary proach is presently impossible and, there- supplementation with the vitamin precursor fore, “treatment” must accept as reasonable is believed to offset the unfavorable bind- goals the modification of the biochemical ing affinity and has already proven to be environment in an attempt to offset the mu- simple and effective therapy for this type of tation, and thereby restore the normal phe- hereditary metabolic disease. notype. Even under these circumstances, Replacement of Gene Product one may question whether such treatment modifies only certain biochemical derange- This is possible when natural or synthetic ments or alters the entire disease process. sources of the normal gene product are available and when it can reach the normal Limitation of Substrate site of action or, conversely, when the sub- Some abnormal and unfavorable pheno- strate can diffuse to it. The management of types may be determined predominantly by hemophilia by plasma infusion is a classical accumulation of substrate which is not example of gene product replacement. properly metabolized. Alternatively, the Other Forms of Therapy production of metabolites which are them- selves toxic and chemically related to or de- It may be impossible to offset the effect rived from the substrate may establish the of a particular hereditary metabolic disease phenotype. Dietary restriction of substrate by any of the foregoing “environmental” or its precursors should prevent or reduce approaches, and more peripheral measures accumulation and, under these circum- may be required ( the use of chelation them- stances, ameliorate the harmful phenotype. apy to remove tissue copper in Wilson’s disease, or high free-water intake in cys- Supplementation of Product tinuria to enhance urinary excretion of cys-
If the phenotype is primarily determined tine) . Direct attack on the defect in genetic by deficiency of product which cannot be coding and translation ( genetic engineer- synthesized, then appropriate supplementa- ing) should not be ignored, and advances in tion should restore biochemical relations this direction could render nutritional ma- and the normal phenotype. The inborn er- nipulations obsolete in the treatment rors of hormone biosynthesis are examples of hereditary metabolic disease. Enzyme in the category. The addition of uridine to induction8 and repression#{176}’1#{176}are already the diet in the treatment of orotic aciduria5 being evaluated, and these techniques is the most dramatic example in man of should provide increasingly important op- true auxotrophism offset by replacement portunities in the future. therapy. PROBLEMS IN DIETARY MANAGEMENT Supplementation of Coenzyme General Comments
The function of certain apoenzymes may Therapeutic regimes which involve me- be impaired by mutations compromising placement of product, coenzyme, or apoen- absorption or biosynthesis of coenzyrne. Di- zyme are usually simple; general nutri- etary supplementation of coenzyme under tional factors are not compromised and the these circumstances is analogous to “prod- efficacy of therapy is rapidly apparent. uct replacement.” Other types of mutation Greater difficulty is encountered in those may specifically alter the coenzyme binding diseases where arduous restriction of sub- site on the apoenzyme. This has been de- strate intake is required. When an essential scribed for pyridoxal phosphate binding by amino acid is involved ( Table I and Table tryptophan synthetase in a mutant strain of II ), it is difficult to devise a diet restricted Neurospora crassa;6 it is believed that a in the content of the amino acid without re- similar mechanism may underlie some course either to a mixture of pure amino
Downloaded from www.aappublications.org/news by guest on September 28, 2021 AMERICAN ACADEMY OF PEDIATRICS 293 acids prepared laboriously to specifications no benefit ( Table 11 ) and alternate methods or to the use of a specially treated protein of treatment, such as the introduction of an hydrolyzate, which is often unacceptable alternate block in the biosynthetic pathway because of unpleasant taste and smell. The of the compound,#{176} or facilitation of en- preparation of the number and the variety hanced elimination of the offending corn- of diets necessary to treat several heredi- pound in the intestine, the urine, sweat, etc. tary metabolic disorders potentially amena- may be required. ble to nutritional management represents a Regimes seeking substrate restriction major technical challenge at the present challenge the usual dietary balance; under time. these circumstances, special attention to Consumption of a diet limited in an es- nutritional aims and hazards is indicated. sential nutrient has a distinct hazard, gener- Protein ally more so for younger, more rapidly growing children than for older children or Dietary protein is the principal source of adults, for deficiency of the restricted nu- nitrogen and of essential amino acids.f trient can result if intake is too limited Non-essential amino acids can be synthe-
( Fig. 2 ) . Therefore, careful clinical evalua- sized endogenously if sufficient nitrogen is tion and frequent biochemical monitoring available and calories are adequate. An of the appropriate biological fluids must be abundant dietary intake of non-essential en11)loyed as guidelines to regulate therapy. amino acids will reduce the demand on es-
Ill SO C instances, it may be possible to restrict either pool size or concentration of 0 Therapy of oxalosis has eluded all efforts at the offending metabolite, even if the corn- treatment until now. Administration of calcium pound is formed endogenously and is not carbimide, however, prevents synthesis of the an “essential” nutrient. In some “non-essen- insoluble oxalic acid by interposing an induced artificial block in the biosynthetic pathway. Pre- tial aniino-acidopathies” ( Table II ) protein liminary results of this treatmi’nt look promising.’ r(’striction may be sufficient to achieve the I Valine, leucme, isoleucine, threonine, methio- (l(’sired effect. In other circumstances, how- nine, l)llenylalanille, lvsine, and trvptophan (pos- ‘ ‘er, rigid restriction of protein intake is of siblv histidine 111 early infancy).”
REGULATOR OPERATOR -) STRUCTURAL GENE I 4
(4) ENZYME PROTEIN
+
(3) COFACTOR
SUBSTRATE- -*PRODUCT REACTION (1) (2)
(1) SUBSTRATE RESTRICTION (3) COENZYME (VITAMIN) SUPPLEMENT (2) PRODUCT REPLACEMENT (4) ENZYME REPLACEMENT
Fic. 1. A simple scheme depicting the sequence linking the gene to a specific cellular biochemical reaction. A change in genetic information (mu- tation) may alter the reaction rate. The equilibrium is therefore changed; product deficiency and/or substrate accumulation will occur, either one of which may be important determinants of the total clinical phenotype. Treat- ment usually includes one of the four basic approaches indicated here; other measures may also be required.
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TABLE II
ExssII’i F OF AMINOACIDOI’ATIIIEM IN \\EIICH SUBSTRATE LIMITATION hAS BEEN : i’r %II I)
Bw(hemiral 1)isease Nutrient Limited (‘on/mi Reference With Diet
Pheiiylketonuria Phenylalanine ‘Yes 64 Maple syrup urine (lisease Leucine, isoleucirie, and saline Yes ‘39, 40 I IOIIIO(yst Methioi,ine+ L-cystine supplement \es 68, 69 (partial) Hereditary tyrositiemia and tyrosyluria Tyrosim e (+ phenylala imie adjustment) 53, 53a Yes
I lyperglyeinemias Protein Yes 79, 131 IlyperlySinemia Protein Partial 7 F rea cycle (liseases Protein Yes 74 Isovalericacideinia Protein Yes 67
I IyperproliIIeIIl ill Protein No 132 Ilydroxyprolineinia Protein and ascorbate No 133 I Iyper-fl-alaniziemia Protein, purines No 134
sential amino acids for energy purposes and published.” The feeding technique with increase the availability of essential amino free amino acids may be of importance. acids for protein synthesis. In the normal Cannon’2 demonstrated many years ago diets, protein should supply 10 to 20% of the that amino acids given separately at intcr- calories. vals did not support normal growth rates in Nitrogen balance reflects intake and loss; rats. Imbalance in the amino acid composi- the latter includes urinary, fecal elimina- tion of the synthetic diet can also impair tion, and epidermal replacement. The provi- growth.’3”4 The use of wholly synthetic sion in the diet of an amount of protein suffi- diets to supply protein needs in infants cient to maintain nitrogen balance will by with certain hereditary metabolic disease itself assure sustained normal growth. How- (branch-chain-ketonuria below ) presents ever, the “biological value” of the protein- problems, for under these conditions the a measure of content and availability of es- total nitrogen ( amino acid ) needs for grow- sential amino acids-must also be consid- ing subjects, the percentage of calories that ered. More protein with a low biological must come from amino acids, and the total value is required to promote a growth rate caloric needs of subjects consuming these equivalent to that achieved with a protein diets have yet to be defined. of high biological value. Figure 2 depicts Carbohydrate an infant who was accidentally rendered phenvlalanine deficient while receiving an Good nutrition can be sustained on diets “adequate intake” of calories and protein; varying widely in tile content of carbohy- satisfactory growth occurred only when drate. Under usual dietary conditions, ap- sufficient L-phenylalanine was supplied in proximately 50% of the calories consumed the diet. come from this source. There is no require- An appropriate mixture of free L-amino ment for any specific carbohydrate be- acids ( not supplied as protein ) given in cause protein and fat from the diet may be adequate amount should support adequate converted to carbohydrate to meet the met- growth, and preliminary estimates of the abolic needs of special tissues ( brain). daily requirements in the human infant for However, one has to consider solute load amino acid intake in this form have been versus a ketogenic diet if a “high protein
Downloaded from www.aappublications.org/news by guest on September 28, 2021 AMERiCAN ACADEMY OF PEDIATRICS 295 low fat” or a ‘high fat low proteiii” diet is utilized. Specific attention to the type of carbohy- drate dIl(l carl)Ohydrate cont( ut of the diet is important in disorders involving metab- OIiSITI of monosaccharides and disaccharides (Table I). Data on disaccharide content, in particular of table foods, are unfortunately difficult to obtain because of tile variable coiit#{128}’nt associated with different growth conditions of the plants and differences ill manufacturing processes . ‘
Fats kg Fat, an iiiiportant component of tile diet, 0 3 6 9 12 pr ’icles calories efficiently and ensures di- MONTHS OF AGE etary palatability and facilitates absorption FIC. 2. An example of iatrogenic phenylalanimie of the fat soluble nutrients, particularly car- deficiency: Graph shows sveight gain of an infant otene. Approximately 25 gm/day will in whom the diagnosis of phenylketonuria was stiffice in the healthy adult. Linoleic acid is confirmed at age 7 days. A low-phenylalanine diet all essential fatty acid and probably should was prescribed on the tenth day of life (A), which comprise 1% of total calories to meet re- provided 180 calories, 6 gm protein, and 40 mg L-phen lalanine per kg daily. The total quantity (juirements in maintaining growth and der- of food intake was not altered by the physician, mal integrity.’ nor did the mother question the “standing” order. The effect of ingestion of a supplement On admission at 83 months (B), for growth failure, of Ifle(lium-cilain triglycerides upon need the intakes of calories, protein, and phenylalanine for and metabolism of polyunsaturated fatty had declined to 100, 3.5 gm and 22 mg per kg body weight, respectively. The plasm1 a phenyl- acids’7” is an aspect of metabolism of cur- alanine level svas zero. Bone changes typical of rent interest. Intestinal absorption of mcdi- phenylalanine deficiency were found. The mental urn-chain triglycerides is not associated development was normal ( I).Q. = 105). The in- with significant ‘ ‘I and take of L-phenylalanine alone was then increased (B) to 75 mg/kg/day; the rate of growth increased under these circumstances the levels of to 0.5 kg per week. All signs of phenylalanine de- total lipids and cholesterol in plasma and ficiency disappeared. Levels of phenylalanine in tissue decrease. Tile applicability of these blood did not rise above 8 mg/100 ml. O1)servatiOns to the prolonged treatment of a disease such as familial liypcr-chylomi- cronemia is still unknown. problems are described in the following cx- amples. The need for continuing reapprais- Vitamins and Minerals al of our current knowledge is obvious. Attention must be given to the vitamin There is already ample indication that care- and tniiieral intake of children receiving ful monitoring of the biochemical and clini- semi-synthetic or wholly synthetic diets. #{176}’21 cal progress of the patient with a hereditary It is unlikely that a single proprietary metabolic disease is essential if untoward diet will meet the individual needs of all or unpredicted results of management are patients, and prescription for requirements to be avoided. should be calculated for each patient. Phenylketonuria
SPECIFIC ILLUSTRATIONS The most intensively studied of the The foregoing general comments can be aminoacidopathies, phenylketonuria, has amplified by specific illustration. Typical served as tile prototype for the develop-
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TABLE III
‘I’lIE IIYPERPIIENYLALANINEMIAS
(TENTATIVE Cm .sss1FIcs’rloN)
Typical Plasma Dielary Phenylaianine Phenylalanine Condition Reference (‘oncent ration Tolerated mg/l()O ml mg/kg/day*
( ‘lassic tl )lIemlylketonuria >15 25 approximmiatelv oi, ;‘_), 63, 64 A tYPi(z1 1 phem ylketoiiuria with high PhenYlalalmine tolerance >15 30,1 or moore tnt misiemit hyperphenylalamiinemnia with or svitl,out phemiylketonuria >15-’N 25----’N 133 : i ild pt’rsiste it l ’perpliemiylalanimiemnia pliemiylketonuria <15 N 136t lieterozygote (classical, under certain (on(li- tions) N-S N 137 Pretiiaturity 4-15 N Iechm,ical artefact
* For mature infant; requiremnem ts are higher for all periods (luring greater growth.
#{149}1#{149}Few pul)li(atiomls yet ; verbal con ruuiiication.s fromi mmiamiy centers, smmd l)ersonal ol)servatiomls by the (‘omnn it- tee on Nutrition suggest this condition may not he UIieomnnion. There is ito good evi(lemlce- that the l)leml tYPe is lieterozygous for the classical condition.
N = Normal amount.
merit of dietary management in other dis- treatment of “classical” phenylketonuria
(‘ases . However, unanticipated problems can cause phenylalanine deficiency in pa- have arisen as the therapeutic programs tients with other forms of hyperphenylala- have been applied to the relatively large ninemia22’ ‘ just as it can in “classical” numbers of affected subjects identified as a phenylketonuria. Phenylalanine deficiency, result of the screening programs for phe- whether in patients with phenylketonuria nylketonuria. The objectives of screening or normal individuals, can cause growth programs in the newborn period are to de- failure, rashes, alopecia, bone changes, tect the affected patient sufficiently early to marrow abnormalities with anemia, gen- initiate treatment and to prevent the conse- eralized aminoaciduria, and even death. quences of the disease when possible. Hy- These unfortunate experiences and the con- perphenylalaninemia, rather than phenylke- fusion arising from failure to distinguish a tonuria itself, has been chosen as the index phenocopy from the primary disease neces- in most programs now screening for the sitate considerable caution in the manage- disease. However, hyperphenylalaninemia ment of hyperphenylalaninemia and other, is not synonymous with phenylketonuria. similar aminoacidopathies. There are several other conditions in which It is obvious that the specific form of the hyperphenylalaninemia is also exhibited in aminoacidopathy must be identified before the newborn period (Table III ). Some of treatment is begun. Simplified, but perhaps these conditions have been recognized only overcategorical, guidelines have been pro- since mass screening began, and more are posed for the use of low phenylalanine probably awaiting recognition. There is no diets.29 The biochemical efficacy of the di- indication at present that dietary treatment etary program must be monitored frequent- of all forms of hyperphenylalaninemia is ly, and any inappropriate response in levels indicated. Restriction of phenylalanine in- in the blood of the relevant metabolite or take in the empirical manner employed for lack of weight gain should alert the physi-
Downloaded from www.aappublications.org/news by guest on September 28, 2021 AMERICAN ACADEMY OF PEDIATRICS 297 cian to the possibility of an atypical situa- genotype.37 Hyperphenylalaninemia in the tion. Reliable techniques are available for pregnant experimental animal37a also collection of samples in the home3032 so causes transplacental hyperphenylalanin- that the sample may be mailed to a labora- emia and impaired postnatal performance tory for analysis. There is, therefore, no of the litter. On the other hand, it must be technical impediment to frequent monitor- appreciated that induction of phenylalanine ing of dietary control. deficiency during pregnancy may be equal- Even careful attention to levels of phenyl- ly injurious to the fetus. alanine in blood cannot yet guarantee suc- cess, since a number of patients have failed Branch-Chain Ketonuria to respond to dietary manipulations and, (Maple Syrup Urine Disease) more important, not all authorities agree on The principles of dietary management the range of levels compatible with effec- illustrated by phenylketonuria may also tive treatment. To add to the confusion, a apply to branch-chain ketonuria. The ap- number of individuals with phenylketonuria parent rarity of the disease and high mom- (typical genotypes ) who experience no tality among the affected, in addition to the dietary manipulation have none of the neu- difficulties in preparing what is believed to rological or intellectual stigmata of the dis- be the appropriate diet, have made the col- ease. lection of information about treatment How long dietary treatment should be difficult. The experiences of Westall3#{176} and continued in the lifetime of the patient is of Holt and Snyderman #{176} represent the still unknown. Homer and co-workers33 and most complete documentation presently others3 have suggested that dietary thera- available and indicate the potential useful- py is probably unnecessary after the fourth ness of special diets in this disease. Two year of life. However, while this suggestion particular features concerning dietary man- may only reflect the greater difficulty there agement merit comment. Growth failure is in maintaining good dietary control in occurred in most patients fed the totally older patients, it may indeed represent a synthetic diet,4#{176}even though all nutrients medical fact. Nevertheless, skepticism is in- were apparently present in adequate dicated concerning a categorical statement amounts. Growth improved when yeast was about early cessation of diet until more added to the diet. The possibility that a mel- data are available. Human brain growth is ative methionine deficiency caused the not complete by the fourth year of life, and growth failure has been considered. The a number of important functions ( Ian- difficulties in defining a “completely ade- guage ) develop at a later age. The meta- quate” synthetic diet are evident in this sit- bolic processes presumably impaired in un- uation. treated phenylketonuria may be vulnerable This disease presents a special problem at any age, though the evidence for this is since theme is a rapid reappearance of neu- speculative; the proposal that phenylke- mological symptoms when patients develop tonuric patients who discontinue use of the an abrupt rise in plasma concentration of diet may develop schizophrenia3 further branch-chain amino acids, particularly if restricts the making of any firm mecom- initiated by infection.13 Early detection of mendation on this issue. the biochemical deterioration by the use of The technique for dietary management monitoring techniques would provide a and its need during pregnancy for the better opportunity to maintain biochemical woman of known homozygous phenylke- homeostasis. tomiric genotype needs to be assessed. Ma- ternal hyperphenylalaninemia appears to be harmful to the human fetus3 and is fre- Galactosemia quently associated with mental retardation This disease is another example of the in the offspring regardless of the latter’s efficacy of substrate restriction as a mode of
Downloaded from www.aappublications.org/news by guest on September 28, 2021 298 NUTRITION IN METABOLIC DISEASE therapy; long-term therapy is indicated for renal damage and begin to restore a normal the typical patient. However, it is now ap- biochemical phenotype. parent that abnormal “galactosemia” is not a homogeneous mutant phenotype or geno- Vitamin Dependencies type. In addition to the classical disease, There are at least two types of vitamin there are at least three phenocopies of dependencies; one group involves vitamin galactosemia caused by a mild (Durate) B6 and the other vitamin D5. These dis- variant,42 a “mosaic” type of transferase eases manifest no evidence of deficient in- deficiency,’3 and by galactokinase deficien- take nor of aberrations in endogenous me- cy.’4 The precise mole of dietary therapy in tabolism of the particular vitamin. How- the latter three diseases is unknown at pres- ever, an augmented daily intake of vitamin ent. The precautions presented in detail for is required to maintain a normal pheno- the management of hypemphenylalaninemia ty pe. Occurrence of the diseases is often fa- would also apply to patients with galacto- milial in a pattern indicative of Mendelian semia if they received a wholly or partially inheritance. synthetic diet. There is no reason to believe The vitamin B6-dependency syndromes that a galactose-fmee diet per se presents are the best studied. ‘ There are four rec- any hazard, since this sugar is synthesized ognized syndromes affecting independently by the human. cerebral metabolism, blood formation, cys- tathionine metabolism, and tryptophan me- Tyrosinemia tabolism. In each syndrome it has been hy- Tyrosinemia is the most common ami- pothesized that the abnormal vitamin me- noacidopathy occurring in man.4548 A tran- quimement may be attributed to a genetic sient form of tyrosinemia is common in the modification of coenzyme binding by the newborn, in whom manifestation is depen- pertinent apoenzyme. Evidence in support dent upon the intake of protein, as well as of of this hypothesis has been found in the ascorbic acid, and on gestational age of the case of cystathioninuria. infant. This form of tyrosinemia may be as- The term, vitamin D dependency, is now sociated with levels of tyrosine in plasma being proposed to describe a hereditary manyfold above normal and yet is not form of vitamin D responsive rickets associ- known to he harmful to the infant. The ated with hypocalcemia, hypophosphate- condition is related to delayed develop- mia, and, in most cases, hypemaminoacidu- ment of the pamahydroxyphenylpymuvic acid na.56’57 The daily requirement of vitamin D: oxidizing system which results in tyrosyl- is 100 times the normal in this disease. Evi- uria (the only manifestation of the disorder) dence for vitamin D responsive impairment and can be reversed either by temporarily of calcium transport in the intestine is pres- reducing the intake of protein or by in- ent. Treatment is simple and, at least with creasing the intake of a reducing agent respect to most of the stigmata, effective; such as 1-ascorbic acid. but, the dependency appears to be perma- A second less common form of tyrosin- nent. emia associated with tymosyluria is now being recognized throughout the world Enzyme Replacement and may be at least as common as phenyl- Diseases such as cystic fibrosis of the ketoniiria.453 The condition is hereditary pancreas, trypsmogen deficiency, and the and is persistent postnatally, and it cannot hemophilias have th(. advantage that natsi- l)e ameliorated by ascorbic acid or by mod- ral SOU CCS of the gene product are avail- est protein restriction. Only stringent re- able and can he delivered to their normal stmiction of tyrosine and phenylalanine in- site of action. In diseases such as diabetes take by dietary control beginning early in mellitus and diabetes insipidus, the ap- life can prevent development of hepatic and propmiate protein hormones are adminis-
Downloaded from www.aappublications.org/news by guest on September 28, 2021 AMERICAN ACADEMY OF PEDIATRICS 299 tered to maintain homeostasis; replacement have to be organized in order to gather of the hormone in these instances is analo- sufficient information quickly and accurate- gous to replacement of enzyme. ly before treatment of most hereditary met- Many technical advances will be me- abolic diseases can become a feature of quired before this direct approach to thera- medical practice. A cooperative spirit py may be applied in other hereditary met- throughout the scientific community is abolic diseases. The production of synthetic sential to meet this challenge. enzymes will require a knowledge of their One of the legacies of any current suc- primary structure. Experience gained from cess in screening the treatment of people resolving the structures of hemoglobin, of with hereditary metabolic diseases will be a insulin, of ribonuclease, and of other pro- large population of healthy, but mutant, teins suggests that the structure of many homozygous women. These women will proteins, including enzymes, may soon be surely want to bear children; therefore, ma- known. When this information is available, temnal screening and treatment of some of it should be possible to consider biochemi- the diseases throughout pregnancy will cal synthesis of these proteins, a task which emerge as a new challenge to guarantee the might be facilitated by the new techniques offspring a normal intra-uterine environ- of automated polypeptide synthesis.58 The ment in which to develop. effective use of such enzymes will then de- In the future, technical advances in the pend upon achieving contact with sub- medical sciences may radically alter our strate. Tile use of semipermeable microcap- present approach to the management of pa- sules to contain the enzyme in the vas- tients with hereditary metabolic diseases. cular compartment is currently under One can also predict that increasing inter- investigation.59 Finally, transplantation of est in eugenic procedures will probably an organ or of cultured normal human cells stimulate efforts at segregation and manip- must be considered as a possible sustained ulation of mutant genotypes. ”#{176} However, source of natural enzymes. Prospects for it is likely that environmental modification direct attack on the genetic apparatus at by dietary and pharmacological means will ofle point or another9” are also of interest, be the mainstay of treatment for this group hut discussion in this area is beyond the of diseases for many years to come. scope of this memorandum. CHARLES U. LOWE, Chairman DAVID BAIRD COURSIN PRESENT AND FUTURE FELIX P. HEALD
The impact of screening programs upon MALCOLM A. HOLLIDAY diagnostic and therapeutic resources repre- DONOUGH O’BRIEN sents a problem of increasing magnitude. GEORGE M. OWEN Patients with neonatal biochemical imbal- HOWARD A. PEARSON alice requiring no treatment must be segre- CHARLES R. Sciuvi ii gated from infants with the permanent he- L. J. FILER, JR., Con tultant reditary conditions who do require treat- 0. L. KLINE, Consultant ment and identification. Only when pheno- REFERENCES copies of the )rimamy diseases are distin- 1. Bickel, II., Cerrard, J., and llickmans, E. M.: guisliable will it be possil)le to identify the Influence of phenylalanim e intake on the s1)ecifics of any treatment reginw. More- chemistry ,lml(1 behaviour of a phenylketo- over, W(’ C 1H l)erc( i ’(’ tile niost likely out- ntmric (‘hil(l. Act,t P Lv(liat. Scamid., 43:6.1,
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Downloaded from www.aappublications.org/news by guest on September 28, 2021 COMMITTEE ON NUTRITION: NUTRITIONAL MANAGEMENT IN HEREDITARY METABOLIC DISEASE CHARLES U. LOWE, DAVID BAIRD COURSIN, FELIX P. HEALD, MALCOLM A. HOLLIDAY, DONOUGH O'BRIEN, GEORGE M. OWEN, HOWARD A. PEARSON, CHARLES R. SCRIVER, L. J. FILER, JR. and O. L. KLINE Pediatrics 1967;40;289
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Downloaded from www.aappublications.org/news by guest on September 28, 2021 COMMITTEE ON NUTRITION: NUTRITIONAL MANAGEMENT IN HEREDITARY METABOLIC DISEASE CHARLES U. LOWE, DAVID BAIRD COURSIN, FELIX P. HEALD, MALCOLM A. HOLLIDAY, DONOUGH O'BRIEN, GEORGE M. OWEN, HOWARD A. PEARSON, CHARLES R. SCRIVER, L. J. FILER, JR. and O. L. KLINE Pediatrics 1967;40;289
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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1967 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.
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