nutritional management in hereditary metabolic … · tary metabolic diseases, are in progress. as...

COMMITTEE ON NUTRITION

NUTRITIONAL MANAGEMENT IN HEREDITARYMETABOLIC DISEASE

AMERICAN ACADEMY OF PEDIATRICS

289

T HIRTEEN YEARS AGO a dietary approach

to the therapy of phenylketonuria was

proposed,I.2 and data on the usefulness as

well as the very real limitations of this pro-

gram have accumulated in the intervening

years. At the present time studies on the

application of special diets for use in this

disease, as well as for many other heredi-

tary metabolic diseases, are in progress. As

wider use is made of procedures for detec-

tion of hereditary metabolic disease in the

newborn,’ an increasingly larger number of

patients who may benefit from appropriate

nutritional therapy will be identified very

early in life. For example, calculations

based on the current birth rate and appar-

ent incidence of phenylketonuria indicate

that as many as 4,000 infants with this dis-

order in the United States alone could re-

(luire dietary therapy in the next decade.There is, therefore, a need to evaluate the

principles governing nutritional manage-

ment of hereditary metabolic disease in

order to develop optimal treatment facili-

ties for use in conjunction with new detec-

tion methods. It seems anomalous that com-

paratively little has been done either to es-

tablish good treatment practices in heredi-

tary metabolic disease or to mobilize scien-

tific resources to ensure an optimistic out-

come for therapeutic endeavors, while so

much emphasis has been placed on detec-

tion.

Dietary treatment of hereditary metabolic

disease is simple in theory; however, prac-

tical application may be unexpectedly

difficult, or even hazardous, if not carefully

supervised. It should be determined wheth-

er: (1) the untreated disease is in fact harm-

fill, ( 2 ) the treatment is useful in preventing

or reversing the unfavorable progression of

the disease, (3) the therapy may be harmful

by interfering with growth or development,

and ( 4 ) the program may be harmful to

others to whom it is inadvertently or map-

propriately given. Management begins with

confirmation of the diagnosis by methods

more specific than those used in any screen-

ing program and continues with monitoring

of the biochemical and biological response

to dietary manipulations. This memoran-

dum discusses these and other general pm-

ciples. A handbook of treatment is not in-

tended, and referral to the comprehensive

sources identified in Table I is recom-

mended for those requiring detailed infor-

mation about particular diseases.

GENERAL PRINCIPLES

The events depicted in Figure 1 underlie

all types of hereditary metabolic disease.

Mutation in the genorne, in one way or an-

other, modifies a protein gene product. The

gene product is called an apoenzyme when

the protein directs a specific biochemical

reaction. The association of a low-molecu-

lar weight compound or coenzyme ( 3 ) may

also be required by the apoprotein to

achieve optimal catalytic rates; the corn-

bined apoenzyme-coenzyme complex is

called the holoenzyme. Conversion of one

compound [substrate ( 1 ) I into another

[product ( 2 ) J, or transfer of unmodified

substrate from one side of the membrane to

the other, often against an electrochernical

gradient, constithte the principal types of

“enzymatic” activity.

The inherited disorders of cellular me-

tabolism and transport reflect alterations in

structure, activity, or amount of enzyme.

Most of the diseases exhibit simple Men-

delian inheritance and are the result of mu-

tation at a single genetic locus. Altered bio-

chemical relations and associated clinical

consequences constitute the phenotype of

such a disease. Specific phenotypes can be

described for almost all of these metabolic

diseases.

Ideal treatment would restore the normal

genetic code as �vell as subsequent tran-

P�rn�u-nics, Vol. 40, No. 2, August 1967

by guest on March 7, 2021www.aappublications.org/newsDownloaded from

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, 6�2

See also Table III 63, 64, 65

Branch-chain ketoaminoaciduria (maple

syrup urine disease) Restriction of leucine, isoleucine, and valine 39, 40Hypervalinemia 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 83Cystinuria 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 55vitamin B6 dependency and seizures 90, 90a

familial xanthurenic-aciduria 91

familial pyridoxine responsive anemia 9�

Folic acid diseasesformimino 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.


AMERICAN ACADEMY OF PEDIATRICS 291

Disorder � Therapy Which Has Been Attempted � Ref erence

Disorders of Carbohydrate Metaboli3m

Ilyperglucemia (Childhood Diabetes

Mellitus)

Hypoglucemia

toxic (EDTA, salicylates, sulphonylu-

reas, MOA inhibitors, etc.)

leucine sensitivity��

idiopathic

ketotic

deficient catecholamine# response

Ilyperinsulinism

Glycogen storage diseases (Type 1-IX)Galactosemia (4 types: see text)

Fructose intolerance

Glucose-galactose malabsorption

Fructose-galactose intolerance

True congenital disaccharidase deficiency

Acquired disaccharidase deficiency

Dietary control Insulin

Remove cause IV glucose

Protein restriction (steroids)

Steroids

Frequent feeding

Ephedrine

Diazoxide Surgery

Depends on type

Galactose restriction (need may be transient) (Preg-

nancy-special need for Rx of mother)

Restriction of fructose intake

Restriction of dietary carbohydrate

Restriction of dietary carbohydrate (excluding glu-

cose)

Long-term dietary restriction of offending disac-

charide

Temporary restriction of offending disaccharides �

95

96

97, 98101

1O�103, 10498

106

41, 107

108, 109

1 10, 111

112

113, 114,115, 116,

117118, 117

Di�sorders of Lipid Metabolism

Familial hyperlipoproteinemia-5 types:

hyperchylomicroenimia

increased fl-lipoprotein

increased pre fi and fl-Lp

increased pre fl-Lp

combined hyper �3-Lp and hypochylomi-

cronemia

Abetalipoprotenemia

High density lipoprotein deficiency (Tangier

disease)

Varies with type-includes: � 119Medium chain triglyceride supplement

�Restriction of cholesterol

Restriction of CHO

�

Polyunsaturated FA-supplement

Low fat diet 120

�

(None required usually) � 121

Miscellaneous

Gastrointestinal disorders

gluten sensitive enteropathy

cystic fibrosis (intestinal component)

trypsinogen deficiency

Disorders of mineral metabolism

idiopathic hypercalcemia

vitamin D dependency

renal phosphorus transport

Wilson’s disease

Disorders of pyrimidine metabolism

familial hyperuricemia with finger chew-

ing and MR

oroticaciduria

Gluten restriction 122, 122a

Pancreatic enzyme replacement 123

Trypsinogen replacement 125

Avoid vitamin D excess � 126

Vitamin D 50,000 units/day � 127

10 to 20 gm neutral phosphase salt solutions (+

vitamin D in some cases) � 127

D-Pencillamine 128

Prohenecid, Alkalinization 129

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}’



scription and translation. This dynamic ap-

proach is presently impossible and, there-

fore, “treatment” must accept as reasonable

goals the modification of the biochemical

environment in an attempt to offset the mu-

tation, and thereby restore the normal phe-

notype. Even under these circumstances,

one may question whether such treatment

modifies only certain biochemical derange-

ments or alters the entire disease process.

Limitation of Substrate

Some abnormal and unfavorable pheno-

types may be determined predominantly by

accumulation of substrate which is not

properly metabolized. Alternatively, the

production of metabolites which are them-

selves toxic and chemically related to or de-

rived from the substrate may establish the

phenotype. Dietary restriction of substrate

or its precursors should prevent or reduce

accumulation and, under these circum-

stances, ameliorate the harmful phenotype.

Supplementation of Product

If the phenotype is primarily determined

by deficiency of product which cannot be

synthesized, then appropriate supplementa-

tion should restore biochemical relations

and the normal phenotype. The inborn er-

rors of hormone biosynthesis are examples

in the category. The addition of uridine to

the diet in the treatment of orotic aciduria5

is the most dramatic example in man of

true auxotrophism offset by replacement

therapy.

Supplementation of Coenzyme

The function of certain apoenzymes may

be impaired by mutations compromising

absorption or biosynthesis of coenzyrne. Di-

etary supplementation of coenzyme under

these circumstances is analogous to “prod-

uct replacement.” Other types of mutation

may specifically alter the coenzyme binding

site on the apoenzyme. This has been de-

scribed for pyridoxal phosphate binding by

tryptophan synthetase in a mutant strain of

Neurospora crassa;6 it is believed that a

similar mechanism may underlie some

human inborn errors.7 Sufficient dietary

supplementation with the vitamin precursor

is believed to offset the unfavorable bind-

ing affinity and has already proven to be

simple and effective therapy for this type of

hereditary metabolic disease.

Replacement of Gene Product

This is possible when natural or synthetic

sources of the normal gene product are

available and when it can reach the normal

site of action or, conversely, when the sub-

strate can diffuse to it. The management of

hemophilia by plasma infusion is a classical

example of gene product replacement.

Other Forms of Therapy

It may be impossible to offset the effect

of a particular hereditary metabolic disease

by any of the foregoing “environmental”

approaches, and more peripheral measures

may be required ( the use of chelation them-

apy to remove tissue copper in Wilson’s

disease, or high free-water intake in cys-

tinuria to enhance urinary excretion of cys-

tine) . Direct attack on the defect in genetic

coding and translation ( genetic engineer-

ing) should not be ignored, and advances in

this direction could render nutritional ma-

nipulations obsolete in the treatment

of hereditary metabolic disease. Enzyme

induction8 and repression#{176}’1#{176}are already

being evaluated, and these techniques

should provide increasingly important op-

portunities in the future.

PROBLEMS IN DIETARY MANAGEMENT

General Comments

Therapeutic regimes which involve me-

placement of product, coenzyme, or apoen-

zyme are usually simple; general nutri-

tional factors are not compromised and the

efficacy of therapy is rapidly apparent.

Greater difficulty is encountered in those

diseases where arduous restriction of sub-

strate intake is required. When an essential

amino acid is involved ( Table I and Table

II ), it is difficult to devise a diet restricted

in the content of the amino acid without re-

course either to a mixture of pure amino


+

(3)

SUBSTRATE- -*PRODUCT(1) (2)

GENE

PROTEIN

COFACTOR

REACTION

(1) SUBSTRATE RESTRICTION(2) PRODUCT REPLACEMENT

(3) COENZYME (VITAMIN) SUPPLEMENT(4) ENZYME REPLACEMENT


acids prepared laboriously to specifications

or to the use of a specially treated protein

hydrolyzate, which is often unacceptable

because of unpleasant taste and smell. The

preparation of the number and the variety

of diets necessary to treat several heredi-

tary metabolic disorders potentially amena-

ble to nutritional management represents a

major technical challenge at the present

time.

Consumption of a diet limited in an es-

sential nutrient has a distinct hazard, gener-

ally more so for younger, more rapidly

growing children than for older children or

adults, for deficiency of the restricted nu-

trient can result if intake is too limited

( Fig. 2 ) . Therefore, careful clinical evalua-

tion and frequent biochemical monitoring

of the appropriate biological fluids must be

en11)loyed as guidelines to regulate therapy.

Ill SO�C instances, it may be possible to

restrict either pool size or concentration of

the offending metabolite, even if the corn-

pound is formed endogenously and is not

an “essential” nutrient. In some “non-essen-

tial aniino-acidopathies” ( Table II ) protein

r(’striction may be sufficient to achieve the

(l(’sired effect. In other circumstances, how-

‘�‘er, rigid restriction of protein intake is of

no benefit ( Table 11 ) and alternate methods

of treatment, such as the introduction of an

alternate block in the biosynthetic pathway

of the compound,#{176} or facilitation of en-

hanced elimination of the offending corn-

pound in the intestine, the urine, sweat, etc.

may be required.

Regimes seeking substrate restriction

challenge the usual dietary balance; under

these circumstances, special attention to

nutritional aims and hazards is indicated.

Protein

Dietary protein is the principal source of

nitrogen and of essential amino acids.f

Non-essential amino acids can be synthe-

sized endogenously if sufficient nitrogen is

available and calories are adequate. An

abundant dietary intake of non-essential

amino acids will reduce the demand on es-

0 Therapy of oxalosis has eluded all efforts at

treatment until now. Administration of calcium

carbimide, however, prevents synthesis of the

insoluble oxalic acid by interposing an induced

artificial block in the biosynthetic pathway. Pre-

liminary results of this treatmi’nt look promising.’�

I Valine, leucme, isoleucine, threonine, methio-

nine, l)llenylalanille, lvsine, and trvptophan (pos-

siblv histidine 111 early infancy).”

REGULATOR OPERATOR -)�STRUCTURALI 4

(4) ENZYME

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.


1)isease Nutrient Limited

Phenylalanine

Leucine, isoleucirie, and saline

Methioi,ine+ L-cystine supplement

Tyrosim�e (+ phenylala imie adjustment)

Protein

Protein

Protein

Protein

Reference

64

‘39, 40

68, 69

53, 53a

79, 131

7�

74

67

132

133

134

Protein

� Protein and ascorbate

� Protein, purines


TABLE II

ExssII’i�F� OF AMINOACIDOI’ATIIIEM IN \\EIICH SUBSTRATE LIMITATION hAS BEEN :�i’r�%II��I)

Pheiiylketonuria

Maple syrup urine (lisease

I IOIIIO(yst

Hereditary tyrositiemia and tyrosyluria

I lyperglyeinemias

IlyperlySinemia

F rea cycle (liseases

Isovalericacideinia

I IyperproliIIeIIl ill

Ilydroxyprolineinia

I Iyper-fl-alaniziemia

sential amino acids for energy purposes and

increase the availability of essential amino

acids for protein synthesis. In the normal

diets, protein should supply 10 to 20% of the

calories.

Nitrogen balance reflects intake and loss;

the latter includes urinary, fecal elimina-

tion, and epidermal replacement. The provi-

sion in the diet of an amount of protein suffi-

cient to maintain nitrogen balance will by

itself assure sustained normal growth. How-

ever, the “biological value” of the protein-

a measure of content and availability of es-

sential amino acids-must also be consid-

ered. More protein with a low biological

value is required to promote a growth rate

equivalent to that achieved with a protein

of high biological value. Figure 2 depicts

an infant who was accidentally rendered

phenvlalanine deficient while receiving an

“adequate intake” of calories and protein;

satisfactory growth occurred only when

sufficient L-phenylalanine was supplied in

the diet.

An appropriate mixture of free L-amino

acids ( not supplied as protein ) given in

adequate amount should support adequate

growth, and preliminary estimates of the

daily requirements in the human infant for

amino acid intake in this form have been

Bw(hemiral

� (‘on/mi

� With Diet

‘Yes

Yes

\es

(partial)

Yes

Yes

Partial

� Yes

Yes

No

No

No

published.” The feeding technique with

free amino acids may be of importance.

Cannon’2 demonstrated many years ago

that amino acids given separately at intcr-

vals did not support normal growth rates in

rats. Imbalance in the amino acid composi-

tion of the synthetic diet can also impair

growth.’3”4 The use of wholly synthetic

diets to supply protein needs in infants

with certain hereditary metabolic disease

(branch-chain-ketonuria below ) presents

problems, for under these conditions the

total nitrogen ( amino acid ) needs for grow-

ing subjects, the percentage of calories that

must come from amino acids, and the total

caloric needs of subjects consuming these

diets have yet to be defined.

Carbohydrate

Good nutrition can be sustained on diets

varying widely in tile content of carbohy-

drate. Under usual dietary conditions, ap-

proximately 50% of the calories consumed

come from this source. There is no require-

ment for any specific carbohydrate be-

cause protein and fat from the diet may be

converted to carbohydrate to meet the met-

abolic needs of special tissues ( brain).

However, one has to consider solute load

versus a ketogenic diet if a “high protein


0 3 6 9 12MONTHS OF AGE

kg

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

Fat, an iiiiportant component of tile diet,

pr��’icles calories efficiently and ensures di-etary palatability and facilitates absorption

of the fat soluble nutrients, particularly car-

otene. Approximately 25 gm/day will

stiffice in the healthy adult. Linoleic acid is

all essential fatty acid and probably should

comprise 1% of total calories to meet re-

(juirements in maintaining growth and der-

mal integrity.’

The effect of ingestion of a supplement

of Ifle(lium-cilain triglycerides upon need

for and metabolism of polyunsaturated fatty

acids’7”� is an aspect of metabolism of cur-

rent interest. Intestinal absorption of mcdi-

urn-chain triglycerides is not associated

with significant ‘ ‘I and

under these circumstances the levels of

total lipids and cholesterol in plasma and

tissue decrease. Tile applicability of these

O1)servatiOns to the prolonged treatment of

a disease such as familial liypcr-chylomi-

cronemia is still unknown.

Vitamins and Minerals

Attention must be given to the vitamin

and tniiieral intake of children receiving

semi-synthetic or wholly synthetic diets.�#{176}’21

It is unlikely that a single proprietary

diet will meet the individual needs of all

patients, and prescription for requirements

should be calculated for each patient.

SPECIFIC ILLUSTRATIONS

The foregoing general comments can be

amplified by specific illustration. Typical

FIC. 2. An example of iatrogenic phenylalanimie

deficiency: Graph shows sveight gain of an infant

in whom the diagnosis of phenylketonuria was

confirmed at age 7 days. A low-phenylalanine dietwas prescribed on the tenth day of life (A), which

provided 180 calories, 6 gm protein, and 40 mg

L-phen�lalanine per kg daily. The total quantity

of food intake was not altered by the physician,

nor did the mother question the “standing” order.

On admission at 83�� months (B), for growth failure,the intakes of calories, protein, and phenylalanine

had declined to 100, 3.5 gm and 22 mg per kg

body weight, respectively. The plasm1�a phenyl-

alanine level svas zero. Bone changes typical of

phenylalanine deficiency were found. The mental

development was normal ( I).Q. = 105). The in-

take of L-phenylalanine alone was then increased

(B) to 75 mg/kg/day; the rate of growth increased

to 0.5 kg per week. All signs of phenylalanine de-

ficiency disappeared. Levels of phenylalanine in

blood did not rise above 8 mg/100 ml.

problems are described in the following cx-

amples. The need for continuing reapprais-

al of our current knowledge is obvious.

There is already ample indication that care-

ful monitoring of the biochemical and clini-

cal progress of the patient with a hereditary

metabolic disease is essential if untoward

or unpredicted results of management are

to be avoided.

Phenylketonuria

The most intensively studied of the

aminoacidopathies, phenylketonuria, has

served as tile prototype for the develop-


Condition

( ‘lassic�tl �)lIemlylketonuria

A tYPi(z1 1 phem�ylketoiiuria

with high PhenYlalalmine tolerance

tnt misiemit hyperphenylalamiinemnia with or

svitl,out phemiylketonuria

:�i ild pt’rsiste�it l�’perpliemiylalanimiemnia

pliemiylketonurialieterozygote (classical, under certain (on(li-

tions)

Pretiiaturity

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.


TABLE III

‘I’lIE IIYPERPIIENYLALANINEMIAS

(TENTATIVE Cm�.sss1FIcs’rloN)

Typical Plasma

Phenylaianine(‘oncent ration

mg/l()O ml

>15

>15

>15-’N

<15

N-S4-15

Dielary

Phenylalanine

Tolerated

mg/kg/day*

25 approximmiatelv

Reference

� oi, �;‘_), 63, 64

30,1� or moore �

�25----’N 133

N 136t

N 137

N �

merit of dietary management in other dis-

(‘ases . However, unanticipated problems

have arisen as the therapeutic programs

have been applied to the relatively large

numbers of affected subjects identified as a

result of the screening programs for phe-

nylketonuria. The objectives of screening

programs in the newborn period are to de-

tect the affected patient sufficiently early to

initiate treatment and to prevent the conse-

quences of the disease when possible. Hy-

perphenylalaninemia, rather than phenylke-

tonuria itself, has been chosen as the index

in most programs now screening for the

disease. However, hyperphenylalaninemia

is not synonymous with phenylketonuria.

There are several other conditions in which

hyperphenylalaninemia is also exhibited in

the newborn period (Table III ). Some of

these conditions have been recognized only

since mass screening began, and more are

probably awaiting recognition. There is no

indication at present that dietary treatment

of all forms of hyperphenylalaninemia is

indicated. Restriction of phenylalanine in-

take in the empirical manner employed for

treatment of “classical” phenylketonuria

can cause phenylalanine deficiency in pa-

tients with other forms of hyperphenylala-

ninemia22’ �‘ just as it can in “classical”

phenylketonuria. Phenylalanine deficiency,

whether in patients with phenylketonuria

or normal individuals, can cause growth

failure, rashes, alopecia, bone changes,

marrow abnormalities with anemia, gen-

eralized aminoaciduria, and even death. �

These unfortunate experiences and the con-

fusion arising from failure to distinguish a

phenocopy from the primary disease neces-

sitate considerable caution in the manage-

ment of hyperphenylalaninemia and other,

similar aminoacidopathies.

It is obvious that the specific form of the

aminoacidopathy must be identified before

treatment is begun. Simplified, but perhaps

overcategorical, guidelines have been pro-

posed for the use of low phenylalanine

diets.29 The biochemical efficacy of the di-

etary program must be monitored frequent-

ly, and any inappropriate response in levels

in the blood of the relevant metabolite or

lack of weight gain should alert the physi-



cian to the possibility of an atypical situa-

tion. Reliable techniques are available for

collection of samples in the home3032 so

that the sample may be mailed to a labora-

tory for analysis. There is, therefore, no

technical impediment to frequent monitor-

ing of dietary control.

Even careful attention to levels of phenyl-

alanine in blood cannot yet guarantee suc-

cess, since a number of patients have failed

to respond to dietary manipulations and,

more important, not all authorities agree on

the range of levels compatible with effec-

tive treatment. To add to the confusion, a

number of individuals with phenylketonuria

( typical genotypes ) who experience no

dietary manipulation have none of the neu-

rological or intellectual stigmata of the dis-

ease.

How long dietary treatment should be

continued in the lifetime of the patient is

still unknown. Homer and co-workers33 and

others3� have suggested that dietary thera-

py is probably unnecessary after the fourth

year of life. However, while this suggestion

may only reflect the greater difficulty there

is in maintaining good dietary control in

older patients, it may indeed represent a

medical fact. Nevertheless, skepticism is in-

dicated concerning a categorical statement

about early cessation of diet until more

data are available. Human brain growth is

not complete by the fourth year of life, and

a number of important functions ( Ian-

guage ) develop at a later age. The meta-

bolic processes presumably impaired in un-

treated phenylketonuria may be vulnerable

at any age, though the evidence for this is

speculative; the proposal that phenylke-

tonuric patients who discontinue use of the

diet may develop schizophrenia3� further

restricts the making of any firm mecom-

mendation on this issue.

The technique for dietary management

and its need during pregnancy for the

woman of known homozygous phenylke-

tomiric genotype needs to be assessed. Ma-

ternal hyperphenylalaninemia appears to

be harmful to the human fetus3� and is fre-

quently associated with mental retardation

in the offspring regardless of the latter’s

genotype.37 Hyperphenylalaninemia in the

pregnant experimental animal37a also

causes transplacental hyperphenylalanin-

emia and impaired postnatal performance

of the litter. On the other hand, it must be

appreciated that induction of phenylalanine

deficiency during pregnancy may be equal-

ly injurious to the fetus.

Branch-Chain Ketonuria

(Maple Syrup Urine Disease)

The principles of dietary management

illustrated by phenylketonuria may also

apply to branch-chain ketonuria. The ap-

parent rarity of the disease and high mom-

tality among the affected, in addition to the

difficulties in preparing what is believed to

be the appropriate diet, have made the col-

lection of information about treatment

difficult. The experiences of Westall3#{176} and

of Holt and Snyderman�#{176} represent the

most complete documentation presently

available and indicate the potential useful-

ness of special diets in this disease. Two

particular features concerning dietary man-

agement merit comment. Growth failure

occurred in most patients fed the totally

synthetic diet,4#{176}even though all nutrients

were apparently present in adequate

amounts. Growth improved when yeast was

added to the diet. The possibility that a mel-

ative methionine deficiency caused the

growth failure has been considered. The

difficulties in defining a “completely ade-

quate” synthetic diet are evident in this sit-

uation.

This disease presents a special problem

since theme is a rapid reappearance of neu-

mological symptoms when patients develop

an abrupt rise in plasma concentration of

branch-chain amino acids, particularly if

initiated by infection.13� Early detection of

the biochemical deterioration by the use of

monitoring techniques would provide a

better opportunity to maintain biochemical

homeostasis.

Galactosemia

This disease is another example of the

efficacy of substrate restriction as a mode of



therapy; long-term therapy is indicated for

the typical patient. However, it is now ap-

parent that abnormal “galactosemia” is not

a homogeneous mutant phenotype or geno-

type. In addition to the classical disease,��

there are at least three phenocopies of

galactosemia caused by a mild (Durate)

variant,42 a “mosaic” type of transferase

deficiency,’3 and by galactokinase deficien-

cy.’4 The precise mole of dietary therapy in

the latter three diseases is unknown at pres-

ent. The precautions presented in detail for

the management of hypemphenylalaninemia

would also apply to patients with galacto-

semia if they received a wholly or partially

synthetic diet. There is no reason to believe

that a galactose-fmee diet per se presents

any hazard, since this sugar is synthesized

by the human.

Tyrosinemia

Tyrosinemia is the most common ami-

noacidopathy occurring in man.4548 A tran-

sient form of tyrosinemia is common in the

newborn, in whom manifestation is depen-

dent upon the intake of protein, as well as of

ascorbic acid, and on gestational age of the

infant. This form of tyrosinemia may be as-

sociated with levels of tyrosine in plasma

manyfold above normal and yet is not

known to he harmful to the infant.�� The

condition is related to delayed develop-

ment of the pamahydroxyphenylpymuvic acid

oxidizing system which results in tyrosyl-

uria (the only manifestation of the disorder)

and can be reversed either by temporarily

reducing the intake of protein or by in-

creasing the intake of a reducing agent

such as 1-ascorbic acid.

A second less common form of tyrosin-

emia associated with tymosyluria is now

being recognized throughout the world

and may be at least as common as phenyl-

ketoniiria.453 The condition is hereditary

and is persistent postnatally, and it cannot

l)e ameliorated by ascorbic acid or by mod-

est protein restriction. Only stringent re-

stmiction of tyrosine and phenylalanine in-

take by dietary control beginning early in

life can prevent development of hepatic and

renal damage and begin to restore a normal

biochemical phenotype.

Vitamin Dependencies

There are at least two types of vitamin

dependencies; one group involves vitamin

B6 and the other vitamin D5. These dis-

eases manifest no evidence of deficient in-

take nor of aberrations in endogenous me-

tabolism of the particular vitamin. How-

ever, an augmented daily intake of vitamin

is required to maintain a normal pheno-

ty pe. Occurrence of the diseases is often fa-

milial in a pattern indicative of Mendelian

inheritance.

The vitamin B6-dependency syndromes

are the best studied. � ‘� There are four rec-

ognized syndromes affecting independently

cerebral metabolism, blood formation, cys-

tathionine metabolism, and tryptophan me-

tabolism. In each syndrome it has been hy-

pothesized that the abnormal vitamin me-

quimement may be attributed to a genetic

modification of coenzyme binding by the

pertinent apoenzyme. Evidence in support

of this hypothesis has been found in the

case of cystathioninuria.��

The term, vitamin D dependency, is now

being proposed to describe a hereditary

form of vitamin D responsive rickets associ-

ated with hypocalcemia, hypophosphate-

mia, and, in most cases, hypemaminoacidu-

na.56’57 The daily requirement of vitamin D:

is 100 times the normal in this disease. Evi-

dence for vitamin D responsive impairment

of calcium transport in the intestine is pres-

ent. Treatment is simple and, at least with

respect to most of the stigmata, effective;

but, the dependency appears to be perma-

nent.

Enzyme Replacement

Diseases such as cystic fibrosis of the

pancreas, trypsmogen deficiency, and the

hemophilias have th(.� advantage that natsi-

ral SOU�CCS of the gene product are avail-

able and can he delivered to their normal

site of action. In diseases such as diabetes

mellitus and diabetes insipidus, the ap-

propmiate protein hormones are adminis-



tered to maintain homeostasis; replacement

of the hormone in these instances is analo-

gous to replacement of enzyme.

Many technical advances will be me-

quired before this direct approach to thera-

py may be applied in other hereditary met-

abolic diseases. The production of synthetic

enzymes will require a knowledge of their

primary structure. Experience gained from

resolving the structures of hemoglobin, of

insulin, of ribonuclease, and of other pro-

teins suggests that the structure of many

proteins, including enzymes, may soon be

known. When this information is available,

it should be possible to consider biochemi-

cal synthesis of these proteins, a task which

might be facilitated by the new techniques

of automated polypeptide synthesis.58 The

effective use of such enzymes will then de-

pend upon achieving contact with sub-

strate. Tile use of semipermeable microcap-

sules to contain the enzyme in the vas-

cular compartment is currently under

investigation.59 Finally, transplantation of

an organ or of cultured normal human cells

must be considered as a possible sustained

source of natural enzymes. Prospects for

direct attack on the genetic apparatus at

ofle point or another9” are also of interest,

hut discussion in this area is beyond the

scope of this memorandum.

PRESENT AND FUTURE

The impact of screening programs upon

diagnostic and therapeutic resources repre-

sents a problem of increasing magnitude.

Patients with neonatal biochemical imbal-

alice requiring no treatment must be segre-

gated from infants with the permanent he-

reditary conditions who do require treat-

ment and identification. Only when pheno-

copies of the �)rimamy diseases are distin-

guisliable will it be possil)le to identify the

s1)ecifics of any treatment reginw. More-

over, W(’ C�1H l)erc(�i�’(’ tile niost likely out-

(‘011W of Ollr efforts at treatment in only a

few of the hereditary metabolic diseases; in

many others we are either ignorant of what

to do or we lack the resources to do what

might be done. Treatment centers may

have to be organized in order to gather

sufficient information quickly and accurate-

ly before treatment of most hereditary met-

abolic diseases can become a feature of

medical practice. A cooperative spirit

throughout the scientific community is

sential to meet this challenge.

One of the legacies of any current suc-

cess in screening the treatment of people

with hereditary metabolic diseases will be a

large population of healthy, but mutant,

homozygous women. These women will

surely want to bear children; therefore, ma-

temnal screening and treatment of some of

the diseases throughout pregnancy will

emerge as a new challenge to guarantee the

offspring a normal intra-uterine environ-

ment in which to develop.

In the future, technical advances in the

medical sciences may radically alter our

present approach to the management of pa-

tients with hereditary metabolic diseases.

One can also predict that increasing inter-

est in eugenic procedures will probably

stimulate efforts at segregation and manip-

ulation of mutant genotypes.�”#{176} However,

it is likely that environmental modification

by dietary and pharmacological means will

be the mainstay of treatment for this group

of diseases for many years to come.

CHARLES U. LOWE, Chairman

DAVID BAIRD COURSIN

FELIX P. HEALD

MALCOLM A. HOLLIDAY

DONOUGH O’BRIEN

GEORGE M. OWEN

HOWARD A. PEARSON

CHARLES R. Sciuvi�ii

L. J. FILER, JR., Con�tultant

0. L. KLINE, Consultant

REFERENCES

1. Bickel, II., Cerrard, J., and llickmans, E. M.:

Influence of phenylalanim�e intake on the

chemistry ,lml(1 behaviour of a phenylketo-

ntmric (‘hil(l. Act,t P�Lv(liat. Scamid., 43:6.1,

1954.

2. Armstrong, I’d. 1)., amid Tyler, F. 11.: Studies

on phenylketontiria. I. Restricted phenyl-

alanine intake in phenylketonuria. J. Clin.

Invest., 34:565, 1955.

3. Scriver, C. R. : Screening nesvborns for hered-



itary metabolic disease. Pediat. Clin. N.

Amer., 12:807, 1965.

4. Hoagland, M. B. : Coding, information trans-

fer, and protein synthesis. In Stanbury,

J. B., Wyngaarden, J. B., and Fredrickson,

D. S., ed : The Metabolic Basis of In-

herited Disease. New York: McGraw-Hill

Book Co., p. 21, 1966.

5. Smith, L. H., Jr. : Hereditary oroticaciduria

-pyrimidine auxotrophism in man. Amer.

J. Med., 38:1, 1965.6. Bonner, D. M., Suyama, Y., and Demoss,

J. A. : Genetic fine structure and enzyme

formation. Fed. Proc., 19:926, 1960.

7. Scriver, C. R. : Vitamin B0 dependency syn-

dromes : Their larger significance. PEDI-

ATRICS, 37:553, 1966.

8. Yaffe, S. J., Levy, C., and Matsuzawa, T.:

Enhancement of glucuronide conjugating

capacity in a hyperbilirubinemic infant.

New Eng. J. Med., in press.

9. Wolstenholme, G., ed. : Man and his future.

Ciba Foundation Symposium. Boston : Lit-

tIe, Brown and Co., 1962.10. Sonneborn, T. M., ed. : Control of human

heredity and evolution. New York: The

Macmillan Co., 1965.

1 1. 1-bIt, L. E., Cyorgy, P., Pratt, E. L., Snyder-

man, S. E., and Wallace, W. Mc. : Protein

and amino acid requirements in early life.New York : New York University Press,

p. 33, 1960.

12. Cannon, P. R. : Some Pathological Conse-

quences of Protein and Amino Acid Dc-

ficiencies. Springfield, Illinois: Charles C

Thomas, p. 34, 1948.

13. Elvehjem, C. A. : In Cole, W. H., ed. : Aspects

of Amino Acid Supplementation. Bruns-

wick, New Jersey: Rutgers University

Press, p. 22, 1956.

14. Yoshida, A., Leung, P., Rogers, Q. R., and

Harper, A. E. : Effect of amino acid fin-

balance on the fate of the limiting amino

acid. J. Nutr., 89:80, 1966.

15. Hardinge, M. C., Swarner, J. B., and Crooks,H. : Carbohydrates in foods. J. Amer. Diet.Ass., 46:197, 1965.

16. Hansen, H. E., Wiese, H. F., Boelsche, A. N.,

Haggard, M. E., Adam, D. J. D., andDavis, H. : Role of linoleic acid in infant

nutrition. PEDIATRICS, 31 : 171, 1963.

17. Playoust, M. R., and Isselbacher, K. J.:Studies on the intestinal absorption and in-

tramucosal lipolysis of a medium chain tn-

glyceride. J. Clin. Invest., 43:878, 1964.

18. Kuo, P. T., and Huang, N. N. : The effect of

medium chain triglyceride upon fat ab-

sorption and plasma lipid and depot fat of

children with cystic fibrosis of the pan-

creas. J. Clin. Invest., 44: 1924, 1965.

19. Isselbacher, K. J., and Senior, j. R. : The

intestinal absorption of carbohydrate and

fat. Gastroenterologv, 46:287, 1964.

20. Council on Foods and Nutrition of the Amen-

ican Medical Association : Vitamin prepara-

lions as dietary supplements and as thera-

peutie agents. J.A.M.A., 169:41, 1959.

21. Report of the Food and Nutrition Board of

the National Academy of Science and Na-

tional Research, Council on RecommendedDaily Allowances. Publication No. 1146,sixth revised ed. Washington, D. C. : 1964.

22. Allen, R. J., Heffelfinger, J. C., Masotti,

R. F., and Tsan, M. U. : Phenylalaninc

hydroxylase activity in newborn infants.

PEDIATRICS, 33:512, 1964.

23. Rouse, B. M. : Phenylalanine deficiency syn-

drome. J. Pediat., 69:246, 1966.

24. Snyderman, S. E., Pratt, E. L., Chang.M. W., Norton, P., and Holt, L. E. : The

phenylalanine requirement of the normal

infant. J. Nutn., 56:253, 1955.

25. Wilson, M. and Clayton, B. : Special diets

in the treatment of biochemical disorders

of mental handicap. In Allan, J. D., andHolt, K. S., ed. : Biochemical Approaches

to Mental Handicap in Childhood. Balti-

more: Williams and Wilkins Co., 1965.

26. Bnimblecombe, F. S. W., Blainey, J. D.,

Stoneman, M. E. R., and Wood, B. S. B.:

Dietary and biochemical control of P.K.U.

Bnit. Med. J., 2:793, 1961.27. Moncnief, A., and Wilkinson, B. 11. : Further

experiences in the treatment of phenyl-

ketonunia. Bnit. Med. J., 1 :763, 1961.

28. Wilson, K. M., and Clayton, B. E. : Im-

portance of choline during growth with

particular reference to synthetic diets in

P.K.U. Arch. Dis. Child., 37:565, 1962.29. Berry, H. K., Sutherland, B. S., and Um-

banger, B. : Diagnosis and treatment: In-

terpretation of results of blood screening

studies for detection of phenylketonunia.

PEDIATRICS, 37: 102, 1966.

30. Efnon, M. L., Young, D., Moser, H. \V., and

MacCready, R. A. : A simple chromato-

graphic screening test for the detection of

disorders of amino acid metabolism; a

technique using whole blood or urine col-

lected on filter paper. New Eng. J. Med.,

270:1378, 1964.

31. Scniver, C. R., Davies, E., and Cullen,

A. M. : Application of a simple micro-

method to the screening of plasma for a

variety of aminoacidopathies. Lancet,

2:230, 1964.

32. Umbargen, B., Berry, H. K., and Sutherland,

B. S. : Advances in the management of pa-

tients with phenylketonuna. J.A.M.A.,

193:784, 1965.


AMERICAN ACADEMY OF PEDIATEIC5� :301

�33. Homer, F. A., Streamer, C. W., Alejandnino,

L. L., Reed, L. H., and Ibbott, F. : Ten-

mination of dietary treatment of phenylke-

tonunia. New Eng. J. Med., 266:79,

1962.

34. Vandeman, P. R. : Termination of dietary

treatment for phenylketonuria. Amen. J.Dis. Child., 106:492, 1963.

35. Woolley, D. W. : Senotonin deficiencies in

relation to mental defect of phenylketo-

miuria and galactosemia. In Proceedings of

(onference on Nutrition and the Inherited

Diseases of Man as Related to Public

Health. Minneapolis, Minnesota: State De-

partment of Health, 1966.36. Fisck, R. 0., Walker, W. A., and Anderson,

J. A. : Prenatal and postnatal developmental

consequences of maternal phenylketonuria.

PimIATRIcs, 37:979, 1966.

:37. Mabry, C. C., Denniston, J. C., and Cald-

well, J. G. : Mental retardation in children

of �)henylketOnunic mothers. New Eng. J.Med., 275:1331, 1966.

37:t. Kerr, C. R., and Waismnan, H. A. : Phenyl-

alanine : Tnansplacental concentrations in

Rhesus monkeys. Science, 151:824, 1966.

38. Thompson, W. R., and Kano, K. : Effects on

rat offspring of maternal phenylalanine

diet during pregnancy. J. Psychiat. Res.,

3:91, 1965.39. \Vestall, R. G. : Dietary therapy of a child

with maple syrup urine disease (branched

chain ketoacidunia). Arch. Dis. Child., 38:

485, 1963.

40. Snyderman, S. E., Norton, P. M., Roitman,

E., and Holt, L. E., Jr. : Maple syrup urine

disease, with particular reference to dieto-

tlwrapy. PEDIATRICS, 34:454, 1964.41 . Isselbachen, K. J. : Galactosemia. In Stan-

bury, J. B., Wyngaarden, J. B., and Fred-nickson, D. S., ed. : The Metabolic Basis

of Inherited Disease. New York : McGraw-

Hill Book Co., p. 178, 1966.

42. Beutler, E., Baluda, M. C., Sturgeon, P.,

and Day, R. : A new genetic abnormality

resulting in galactose-1-phosphate unidyl-

transferase deficiency. Lancet, 1 :353, 1965.43. Segal, S., Blair, A., and Roth, H. : The

metabolism of galactose by patients with

congenital galactosemia. Amer. J. Med.,38:62, 1965.

44. Gitzelmann, R. : Deficiency of erythnocyte

galactokinase in a patient with galactose

diabetes. Lancet, 2:670, 1965.

45. Levine, S. Z. : Tynosine and phenylalanine

metabolism in infants and the role of

vitamin C. Harvey Lect., Series 42, 303,

1946-47.

46. Menkes, J., and Avery, M. E. : The metab-olism of phenylalanine and tyrosine in the

premature infant. Bull. Hopkins Hosp.,

113:301, 1963.

47. La Du, B. N., Howell, R. R., Michael, P. J.,and Sober, E. K. : A quantitative micro-

method for the determination of phenyl-alanine and tvrosine in blood and its ap-plication in the diagnosis of phenylke�

tonuria in infants. PEDL&ThJCS, 31:39,1963.

48. Avery, M. E., Clow, C. L., Menkes, J. Fl.,Ramos, A., Scniver, C. R., Stern, L., andWasserman, B. P. : Transient tyrosineimmia

of the newborn: Dietary and clinical as-

pects. PEDIATRICS, 39:378, 1967.49. Gentz, J., Jagenbung, R., Zetterstrom, R.:

Tyrosinemia. J. Pediat., 66:670, 1965.

50. Baber, M. D. : A case of congenital cirrhosis

of the liver with renal tubular defects akin

to those in the Fanconi syndrome. Arch.Dis. Child., 31:335, 1956.

51. Sakai, K., and Kitagawa, T.: An atypical

case of tvnosinosis (1 -para-hydnoxyphe-

nylactic acidunia). I. Clinical and biochemi-

cal findings. II. A research on the metabolic

block. Jikeikai Med. J., 4: 1, 1957.52. Jagenburg, R. : The effect of low tyrosine and

low phenylalanine diet on the amino acid

metabolism in a case of tynosinemia. InGjessing, L. R., ed. : Symposium on Tyno-

sinosis, Oslo: Univensitetsfonlaget, 1966.

53. Halvorsen, S., Paide, H., L#{248}ken, A. C., and

Gjessing, L. B. : Tyrosinosis: a study of

six cases. Arch. Dis. Child, 41:238, 1966.

53a. Halvonsen, S. : Dietary treatment of tynosino-

sis. Amer. J. Dis. Child., 113:38, 1967.54. Committee on Nutrition, American Academy

of Pediatrics : Vitamin B6 requirements in

man. PEDIATRICS, 38: 1068, 1966.55. Frimpten, G. : Cystathioninunia; nature of the

defect. Science, 149: 1095, 1965.56. Fraser, D., and Salter, R. B. : The diagnosis

and management of the various types of

rickets. Pediat. Clin. N. Amen., 417, 19�8.

57. Pnaden, Von A., Illig, R., and Heienli, E.:

Eine Besonders form den pnim#{228}ren Vita-

min-D-nesistenten Rachitis mit Hypocal-

c#{228}mie und autosomal-dominantem Erb-

gang; die heredit#{228}ne Pseudo-Mangelnachi-

tis. Helv. Paediat. Acta, 16:452, 1961.58. Merrifield, R. B. : Automated synthesis of

peptides. Science, 150: 178, 1965.

59. Chang, T. M. S. : Semipermeable aqueous

microcapsules (“artificial cells”) with em-phasis on experiments in an extraconporeal

shunt system. Trans. Amer. Soc. Artif.

Intern. Organs, 12: 13, 1966.

60. Perry, T. L., and Tischler, B. : Phenylketo-

nunia in a woman of normal intelligenceand her child. New Eng. J. Med.,274:1018, 1966.



61. Knox, W. E.: An evaluation of the treatment

of phenyilcetonunia with diets low in

phenylalanine. PEDIATRICS, 26: 1, 1960.62. Moncnieff, A., et a!.: Treatment of phe-

nylketonunia. Report to the Medical Re-

search Council on the conference on phe-

nylketonunia. Brit. Med. J., 1:1691, 1963.

63. Kang, E. S.. Kennedy, J. L., Jr., Gates, L.,

Burwash, I., and McKinnon, A. : Clinical

observations in phenylketonunia. PEDI-

ATRICS, 35:932, 1965.64. Knox, W. E. : Phenylketonunia. In Stanbuny,

J. B., Wyngaanden, J. B., and Fredrick-

son, D. S., ed. : The Metabolic Basis of

Inherited Disease. New York: McGraw-

Hill Book Co., p. 258, 1966.65. Anderson, J. A., and Swaiman, K. F., ed:

Proceedings of a conference on phenyl-

ketonuria and allied disorders. Unpub-

lished manuscript.66. Wada, Y., Tada, K., Minagawa, A., Yo-

shida, T., Monikawa, T., and Okamura,

T. : Idiopathic valinemia. Tohoku J. Exp.

Med., 81:46, 1963.67. Tanaka, K., Budd, M. A., Efron, M. L., and

Isselbacher, K. j. : Isovalericacidemia; a

new genetic defect of leucine metabo-

lism. Proc. Nat. Acad. Sci., 56:236, 1966.

68. Perry, T. L., Dunn, H. G., Hanson, S., Mac-

Dougall, L., and Wannington, P. D.:

Early diagnosis and treatment of homo-

cystinuria. PEDIATRICS, 37:502, 1966.

69. Brenton, D. P., Cusworth, D. C., Dent,C. E., and Jones, E. E. : Homocystinunia.

Clinical and dietary studies. Quart. J.Med., 35:325, 1966.

69a. Komrower, G. M., Lambert, A. M., Gus-

worth, D. C., and Westall, R. G.: Dietary

treatment of homocystinuria. Arch. Dis.

Child., 41:666, 1966.

70. La Du, B. N. : Histidinemia. In Stanbuny,

J. B., Wyngaarden, J. B., and Frednick-son, D. S., ed : The Metabolic Basis of

Inherited Disease, ed. 2. New York: Mc-

Gnaw-Hill Book Co., p. 366, 1966.71 . Woody, N. C. : Hyperlysinemia. Amer. J.

Dis. Child., 108:543, 1964.72. Chadimi, H., Binnington, V. L., and Fe-

cura, P. : Hyperlysinemia associated with

mental retardation. New Eng. J. Med.,273:723, 1965.

73. Colombo, J. P., Richtenich, R., Donath, A.,

Spahr, A., and Rossi, E. : Congenital ly-

sine inheritance with periodic ammonia

intoxication. Lancet, 1:1014, 1964.

74. Efron, M. : Diseases of the urea cycle. in

Stanbury, J. B., Wyngaarden, J. B., andFredrickson, D. S., ed. : The MetabolicBasis of Inherited Disease. New York:

McGraw-Hill Book Co., p. 393, 1966.

75. Freeman, J. M., Nicholson, J. F., Masland,

W. S., Rowland, L. P., and Carter, S.:

Ammonia intoxication due to a congeni-

till defect ill tir�a synthesis. j. Pediat., 65:

1039, 1964.

76. Russell, A., Levin, B., Obenholzer, V. C.,

and Sinclair, L. : I lyperamnionaeinia : a

new instance of an inborn enzymatic de-

feet of the biosynthesis of urea. Lancet,

2:699, 1962.

77. McMurray, W. C., Rathburn, J. C., Moh-

vuddin, F., and Koegler, S. J. : Citrul-

linemia. PEDIATRICS, 32:347, 1963.78. Westall, R. G. : Angininosuccinicaciduria.

Biochem. J., 77:135, 1960.79. Childs, B., and Nyhan, W. L. : Further oh-

senvations of a patient with hypenglycin-emia. PEDIATRICS, 33:402, 1964.

80. Gerritsen, T., Kaveggia, E., and Waisman,

H. A. : A new type of idiopathic hyper-

glycinemia with hypo-oxalunia. PEDIATRICS,

36:882, 1965.

81. Seniver, C. R.: Hartnup disease: a geneticmodification of intestinal and renal trans-

port of certain neutral alpha-amino acids.New Eng. J. Med., 273:530, 1965.

82. Jepson, J. B. : Hartnup disease. In Stanbury,

J. B., Wyngaarden, J. B., and Fredrick-

son, D. S., ed. : The Metabolic Basis of

Inherited Disease. New York : McGraw-

Hill Book Co., p. 1283, 1966.

83. Tada, K., Ito, H., Wada, Y., and Arakawa,

T. : Congenital tryptophanunia with dwarf-

ism: H-disease-like clinical features with-

out indicenunia and generalized amino-

aciduria. Tohoku J. Exp. Med., 80:118,1963.

84. Dent, C. E., Friedman, M., Green, H., and

Watson, L. C. A. : Treatment of cystin-

unia. Bnit. Med. J., 1:403, 1965.85. McDonald, J. E., and Henneman, P. H.:

Stone dissolution in vivo and control of

cystinuria with D-penicillamine. New

Eng. J. Med., 273:578, 1965.

86. Fleming, W. H., Avery, C. B., Morgan,R. I., and Cone, T. C. : Gastrointestinal

malabsorption associated with cystinuria.

Report of a case in a Negro. PEDIATRICS,

32:358, 1963.

87. Perheentupa, J., and Visakorpi, J. K. : Pro-tein intolerance with deficient transport

of basic amino acids. Lancet, 2:813, 1965.

88. Hooft, C., Timmenmans, J., Snoeck, J., An-

tenen, I., Oyaent, W., and Van den Hende,C. : Methionine malabsorption syndrome.

Ann. Paediat., 205:73, 1965.89. Drummond, K. N., Michael, A. F., Ulstrom,

R. A., and Good, R. A.: Blue diaper syn-



drome : familial hypercalcemia with neph-

rocalcinosis and indicanuria. Amer. J.Me(l., 37:928, 1964.

90. Bessey, 0. A., Adams, I). j. D., and han-

5(11, A. l . : Intake of vitamin B6 and in-

faiitil, con�’i ilsions : first approximation of

re(Iuirvment of pyridoxine in infants. PEn!-

ATIIICS, 20::33, 1957.90a. Gartv, H., Yonis, Z., Braham, J., and Stein-

it7., K. : Pyridoxine-dependent convulsions

in an infant. Arch. Dis. Child., 37:21,

1962.

91. Knapp, A. : Uher eine neue hereditare von

vitamin B� al)hangige st#{246}nung im Tr�pto-

phan Stoffwechsel. Gun. Chim. Acta, 5:6,1960.

92. Ilorrigan, D. D., and Harris, j. W. : Pyni-

(loxine-responsive anemia : Analysis of sixty-

one cases. Advances Intern. Med., 12:103,

1964.

93. Arakawa, T. S., Ohara, K., Takahashi, Y.,

Ogasawara, J., Hayashi, T., Chiba, R.,

Wada, Y., Tada, K., Mizuno, T., Okamura,

T., and Yoshida, T. : Rormimino transfer-

ase deficiency syndrome: A new inborn

error of folic acid metabolism. Ann.

Pediat., 205:1, 1965.

94. Luhhv, A. L., Cooperman, J. NI., and Pesci-

Bourd, A. : A new inborn error of metab-

olism. Folic acid responsive megaloblastic

anemia, ataxia, mental retardation and con-

vulsions. Proc. Amen. Ped. Soc. Seventy-

fifth Annual Meeting, p. 42, 1965.

95. O’Brien, D. : Childhood diabetes: a con-temporary re-evaluation . Clin. Pediat.,

5:21, 1966.96. O’Brien, D., Ibbot, F. A., and Rodgerson, D.:

Recent advances in clinical biochemistryof diseases of childhood. In Stefanini, M.,

ed. : Progress in Clinical Pathology. New

York: Grune and Stratton, p. 512, 1966.

97. Cochrane, W. A. : Idiopathic infantile hypo-

glycemia and leucine sensitivity. Metab-

olism, 9:386, 1960.98. Drash, A., and Wolff, F. : Drug therapy in

leucine-sensitive hypoglycemia. Metabo-

lism, 13:487, 1964.

99. Reaven, G., and Greenberg, R. E. : Experi-mental leucine-induced hypoglycemia inmice. Metabolism, 14:625, 1965.

100. Greenberg, R., and Reaven, C. : The effect

of L-Leucine on hepatic glucose forma-tion. PEDIATRICS, 37:934, 1966.

101. Ilaworth, J. C., and Ardin, F. J. : Idiopathic

spontaneous hypoglycemia in children. PE-

DIATRICS, 25:748, 1960.102. Colle, E., and Ulstrom, R. A. : Ketotic hypo-

glycemia. J. Pediat., 64:632, 1964.

103. Brobenger, 0., and Zettenstrom, R. : Hypogly-

cemia with an inability to increase the

epinephrine secretion in insulin-induced

h�pogl�cemia. A further report. J. Pediat.,

59:215, 1961.104. Brunjes, S., Hodgman, J., Nowack, J., and

J ohns, V., Jr. : Adrenal medullary function

in idiopathic spontaneous hypoglycemia

of infancy and childhood. Amer. J. Med.,

34:168, 1963.

105. Broberger, 0. : Personal communication.

106. Cornblath, M., and Schwarz, R. : Disorders

of Carbohydrate Metabolism in Infancy.Philadelphia: \V. B. Saunders, 1966.

107. California State Department of Public Health.Calactose free diet for professional use

(c/o 2151 Berkeley Way, Berkeley 4,

California).108. Fnoesch, E. R., Wolf, H. P., Bait.sch, H.,

Prader, A., and Labhart, A. : Hereditary

fructose intolerance. An inborn defect of

hepatic fructose-i-phosphate splitting aldo-lase. Amer. J. Med., 34: 151, 1963.

109. Gomblath, M., Rosenthal, I. M., Reisnen,S. H., Wybregt, S. H., and Grane, R. K.:

Hereditary fructose intolerance. New Eng.

J. Med., 269:1271, 1963.1 10. Schneider, A. J., Kinter, W. B., and Stirling,

C. E. : Glucose-galactose malabsonption.New Eng. J. Med., 274:305, 1966.

111. Marks, J. F., Norton, J. B., and Fondtran,

J. S. : Glucose-galactose malabsorption. J.Pediat., 69:225, 1966.

1 12. Dormandy, T. L., and Porter, R. J. : Familial

fructose and galactose intolerance. Lancet,

1:1189, 1961.

113. Burgess, E. A., Levin, B., Mahalanabis, D.,

and Tonge, R. E. : Hereditary sucrose in-tolerance: Levels of sucrase activity injejunal mucosa. Arch. Dis. Child., 39:431,1964.

1 14. Prader, A., and Aunicchio, S. : Defects ofintestinal disaccharide absorption. Ann.

Rev. Med., 16:345, 1965.1 15. Aunicchio, S., Rubino, A., Praden, A., Rev,

J., Jos, J., Fr#{233}zal,J., and Davidson, M.:

Intestinal glucosidase activities in congeni-

tal malabsonption of disaccharides. J.Pediat., 66:555, 1965.

1 16. Lifshitz, F. : Congenital lactase deficiency.

J. Pediat., 69:229, 1966.

1 17. Dahlquist, A.: Disaccharide intolerance.J.A.M.A., 195:225, 1966.

118. Sunshine, P., and Kretchmer, N.: Studies

of small intestine during development. III.

Infantile diarrhea associated with intoler-

ance to disaccharides. PEDIATRICS, 34:38,1964.

119. Fredrickson, D. S., and Lees, R. S.: Familial

hypenlipoproteinemia. In Stanbuny, J. B.,



Wyngaarden, J. B., and Fredrickson, D. S.,ed. : The Metabolic Basis of Inherited Dis-ease. New York: McGraw-Hill Book Co.,

p. 429, 1966.

120. Farquhar, J. W., and Ways, P. : Abetalipo-

proteinemia. In Stanbury, J. B., Wyngaan-den, J. B., and Fredrickson, D. S., ed.:

The Metabolic Basis of Inherited Disease.New York: McGraw-Hill Book Co., p. 509,1966.

I 21 . Fredrickson, D. S. : Familial high-density

lipopnotein deficiency: Tangier disease. In

Stanbury, J. B., Wyngaanden, J. B., and

Fredrickson, D. S., ed : The Metabolic

Basis of Inherited Disease. New York: Mc-

Gnaw-Hill Book Co., p. 486, 1966.122. Weijens, H. A., Van Dc Kramer, J. H., and

Dicke, W. K. : Geliac disease. AdvancesPediat., 4:227, 1957.

122a. di Sant’Agnese, PA., and Jones, W. 0.:

The celiac syndrome ( malabsorption ) in

pediatrics. J.A.M.A., 180:308, 1962.

123. \Iatthe�vs, L. W., Doenshuk, C. F., Wise, M.,

Eddy, C., Nudelinan, H., and Spector, S.:A therapeutic regimen for patients withcystic fibrosis. J. Pediat., 65:558, 1964.

124. Lowe, C. U., and Pessin, V. : Metabolic con-

sequences of pancreatic insufficiency incystic fibrosis of the pancreas: A statistical

analysis. PEDIATRICS, 23:738, 1959.125. Townes, P. L. : Trypsinogen deficiency dis-

ease. J. Pediat., 66:275, 1965.126. O’Brien, D. : Idiopathic hypencalcemia of

infancy. PEDIATRICS, 23:640, 1959.127. Fraser, D. : Rickets. In Conn, H. F., Clohecy,

R. J., and Conn, R. B., ed. : Current

Diagnosis. Philadelphia: W. B. Saunders,

p. 391, 1966.

128. Beam, A. G. : Wilson’s disease. In Stanbury,

J. B., Wyngaarden, J. B., and Fred-rickson, D. S., ed. : The Metabolic Basis

of Inherited Disease. New York: McGraw-lull Book Co., p. 761, 1966.

129. Lesch, M., and Nyhan, W. L. : A familial

disorder of uric acid metabolism and cen-

tral nervous system function. Amen. J.Med., 36:561, 1964.

130. Becroft, D. M., and Phillips, L. I. : Henedi-tary oroticacidunia and megaloblastie ane-

mia: A second case with response to un-

dine. Bnit. Med. J., 1:547, 1965.

131. Nyhan, W. L., and Tocci, P. : Aminoacidunia.

Ann. Rev. Med., 17:133, 1966.

132. Schafer, I. A., Scniven, C. R., and Efron,

M. L. : Familial hypenprolinemia, cerebral

dysfunction and renal anomalies occurring

in a family with hereditary nephropathy

and deafness. New Eng. J. Med., 267:51,1962.

133. Efnon, M. L. : Treatment of hydroxyprolin-

emia and hypenprolinemia. In The Treat-

ment of Inborn Errors of Amino Acid

Metabolism. Am. J. Dis. Child, in press.

134. Scriver, C. R., Pueschel, S., Davies, E.:

Hypen-�-alaninemia associated with �-

aminoacidunia and ?-aminobutynicacidunia,

somnolence and seizures. New Eng. J.Med., 274:636, 1966.

135. Ouellette, E. M., Mosco, H. W., Cresson,

0. C., and Efron, M. L. : The clinical

problem of atypical phenylketonunia: Ap-

parent biochemical remission in a se-

venely retarded patient. New Eng. J. Med.,in press.

136. Anderson, J. A., Fisch, R., Miller, E., and

Doeden, D. : Atypical phenylketonunic

heterozygote. Deficiency in phenylalanine

hydroxylase and transaminase activity. J.Pediat., 68:351, 1966.

137. Kang, E., and Paine, R. S. : Elevation of

plasma phenylalanine during pregnancies

of women hetenozygous for phenylketo-nuria. J. Pediat., 63:283, 1963.

138. Solomons, C., Goodman, S., and Riley, C.:

Calcium carbimide in treatment of primary

hyperoxaluria. 276:207, 1966.

139. Westall, R. G. Personal communication, 1966.


1967;40;289Pediatrics CHARLES R. SCRIVER, L. J. FILER, JR. and O. L. KLINE

HOLLIDAY, DONOUGH O'BRIEN, GEORGE M. OWEN, HOWARD A. PEARSON, CHARLES U. LOWE, DAVID BAIRD COURSIN, FELIX P. HEALD, MALCOLM A.

HEREDITARY METABOLIC DISEASECOMMITTEE ON NUTRITION: NUTRITIONAL MANAGEMENT IN

ServicesUpdated Information &

http://pediatrics.aappublications.org/content/40/2/289including high resolution figures, can be found at:

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtmlentirety can be found online at: Information about reproducing this article in parts (figures, tables) or in its

Reprintshttp://www.aappublications.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:


http://http://pediatrics.aappublications.org/content/40/2/289

http://www.aappublications.org/site/misc/Permissions.xhtml

http://www.aappublications.org/site/misc/reprints.xhtml

1967;40;289Pediatrics CHARLES R. SCRIVER, L. J. FILER, JR. and O. L. KLINE

HOLLIDAY, DONOUGH O'BRIEN, GEORGE M. OWEN, HOWARD A. PEARSON, CHARLES U. LOWE, DAVID BAIRD COURSIN, FELIX P. HEALD, MALCOLM A.

HEREDITARY METABOLIC DISEASECOMMITTEE ON NUTRITION: NUTRITIONAL MANAGEMENT IN

http://pediatrics.aappublications.org/content/40/2/289the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397. American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1967 by thebeen published continuously since 1948. Pediatrics is owned, published, and trademarked by the Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has


http://pediatrics.aappublications.org/content/40/2/289

nutritional management in hereditary metabolic … · tary metabolic diseases, are in progress. as...

Documents