Inborn
0 ‘Brien,2
of metabolism1
M. D., F.R. C.P.
Human nutrition science and practise to the outsider, at any rate, appears to emphasize the availability, procurement, preparation, and requirement of foodstuffs in man in both health and disease. Special consideration has, of course, been given to defming needs at various ages, the so-called Recommended Dietary Allowances, to the biochemistry of nutrients and to the health problems of too little and too much food. However, adequate nutrition is only achieved when nutrients complete their roles in providing energy and in intermediate metabolism. Any acquired or genetically determined aberration of these processes can thus be construed as a disorder of nutrition. For the nutritionist the special interest of these conditions undoubtedly lies in the opportunities for dietary manipulation as a means of therapy (1). In order to understand the application of dietary principles to the circumvention of inborn errors of metabolism, it must be remembered that these conditions like any other genetic abnormality represent fundamentally a change in one specific protein. The affected protein may be produced in diminished amounts, may not be produced at all or may exist in a variably altered demesne that involves either its structural role or its ability to act enzymatically in combination with its substrate or cofactor. Whether the basic defect is in a protein concerned in transport or in an enzyme acting on some nutrient pathway, therapeutic dietary regimens have a limited number of options. The ideal approach, of course, would be to restore the genetic code and some laboratories are indeed now conducting research on what is called transgenosis in which phages containing Escherichia coli derived nucleoprotein are used to try to introduce the ability to synthesize specific missing enzymes into mammalian cells. Exciting as this approach is, it has been tempered by anxieties over the possibly dangerous consequences of uncontrolled experimentation with recombi482
The American
JournalofClinical
Nutrition
nant DNA. The next best alternative is to try to replace the missing gene product. This, for example, is exactly what is done when antihemophilic globulin (AHG) is given to hemophiliacs or enteric enzymes are given orally to children with cystic fibrosis. There are obvious difficulties in this approach: the protein in question must usually be given parenterally and may not reach the locus where it is required. Repeated pulses are necessary with the consequent dangers of antibody formation. Placental glucocerebrosidase has been given intravenously to patients with Gauchers disease with transient amelioration of biochemical function. Organ transplantation is potentially another way of restoring enzyme activity in a somewhat more physiological way that has been used with occasional success with the liver in Wilson’s disease and with the kidney in cystinosis (Fig 1). Product supplementation is another approach and one that has been rather rarely used. The addition of uridine to the diet of a case of orotic aciduria is a dramatically successful instance of this and so to a lesser degree is the use of substitution therapy in inborn errors of hormone biosynthesis, e.g., thyroxin in inborn errors of tyrosyl iodination. This avenue is clearly only appropriate in situations when the abnormal phenotype is primarily characterized by the absence of the unsynthesisable gene product. Neither of the above two approaches can really be thought of as nutritional. Cofactor supplementation, however, is a third possibility which has been very much involved with nutritional considerations. The supposition is either that the defective enzyme has a structural defect on the cofactor rather than the substrate site which may be overcome in the presence of a substantial excess of cofactor molecules, or that the synthesis of the active ‘ From the University Denver, Colorado 2 Professor of Pediatrics.
32: FEBRUARY
of Colorado
1979, pp. 482-485.
Medical
Printed
Center,
in U.S.A.
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/2/482/4666301 by Boston University Libraries user on 13 January 2019
Donough
errors
REGULATOR
-
INBORN
ERRORS
)
OF
METABOLISM
OPERATOR
)STRUCTUR.AL
(1)
REPLACEMENT REPLACEMENT
(3) (4)
(5) SUBSTRATE FIG.
I . Schema
for
Nutritional
form of the cofactor is defective. Some variants ofhomocystinuria are good examples of a pyridoxine responsive apoenzyme defect, cystathionine synthase. Likewise, in certain forms of methylmalonic aciduna there is a defect in the synthesis of 5’-deoxyadenosylB12 as the cofactor for methyl malonyl-coenzyme A mutase. Clinically, this approach has again been rather sparsely useful, but it has provided the scientific basis from which has developed the whole poorly substantiated fabric of “megavitamin therapy” for mental retardation and psychiatric disorders in childhood. The last and by far the most important approach from the nutrition point of view are those conditions where the unfavorable chinical picture is an expression of the accumulation of a nonmetabolized substrate or its toxic metabolites. Phenylketonuria is the best known example of such a situation. Simple as such dietary treatment may seem in theory, however, in practice its application has many hazards and at the outset certain criteria must be assured. First, the untreated disease must be harmful; second, dietary treatment must be effective in abating these ill-effects; third, steps must be taken to ensure that the treatment is not also harmful to the patient or to others who may inappropriately adopt it; fourth, there must be adequate facilities for an impeccable confirmation of diagnosis and for suitable biochemical monitoring of the course of therapy. Because of their especial practical importance, it is appropriate at this stage to review in greater detail both the principles and practical guidelines of diets where the amino acid
CO FACTOR
COENZYME PRODUCT (2)
SUBSTRATE (4)
ENZYME PRODUCT
PROTEIN
ENZYME +
(3)
(2)
GENE
REACTION
COFACTOR SUBSTRATE
SUPPLEMENT RESTRICTIOI
LOADING
approach
to inborn
errors
of metabolism.
levels have to maintain a critical balance between what is toxic and what is insufficient for growth. An example is made of amino acid restriction: but the principles would apply as much to galactose restriction in galactosemia. The
basic
formula
The amount of restricted amino acid provided by diet must be sufficient to meet the metabolic requirements dependent on it, including the requirement for growth; yet, its intake must not permit an excess accumulation in body fluids of the amino acid or its derivatives. These requirements for adequate nutrient can be met by providing a semisynthetic diet, derived either from a modified protein hydrolysate or from a mixture of Lamino acids, so that the diet contains either an extremely low amount of the implicated amino acid or is free of it. Other dietary sources of protein can then furnish the implicated amino acid(s) in an amount sufficient to sustain normal metabolism and growth, yet low enough to avoid intoxication. Requirements for other nutrients, calories, fat, including essential fatty acids, carbohydrates, minerals, and vitamins are met either by special dietary formulations incorporated into or added to the amino acid product or by further supplementation with natural foods of known composition. The need for these special formulations is especially important in early infancy during the most active period of brain myelination. In a number of conditions, the pressure for rigid dietary management diminishes with age and a freer use can be made of natural
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/2/482/4666301 by Boston University Libraries user on 13 January 2019
TRANSPORT PROTEIN (5) e.g. B12 supplementation in transcobalamin II deficiency
0)
483
O’BRIEN
484
The
progression
to more
normal
foods.
Infants in the first six months of life traditionally receive all or most of their nutrient requirements from breast milk or infant formula. During this period it is relatively easy to meet all the nutritional needs of an infant with an inborn error of amino acid metabolism by providing the kind of semisynthetic dietary product just described. Small amounts of milk may have to be added to meet the requirements ofthe restricted amino acid(s). Other foods are introduced into the diet as the infant grows. The composition of these foods and the quantities ingested must be regulated to keep the amino acid composition of the diet under control and to assure provision of other nutritional requirements. Clearly the lower the basic semi-synthetic formulation is in the restricted nutrient(s), the greater the permitted variety of natural foods that can be used in balancing the diet. Thus, for example, Lofenelac, a complete formula containing 80 mg/lOO g of phenylalanine is suitable for the treatment of phenylketonuria in early infancy. In later months another product, Mead Johnson 3229-A, which has no phenylalanine content, permits a freer introduction to mixed feeding. Monitoring
treatment.
Careful monitoring of treatment and its course is essential throughout the period of dietary management. Total nutritional intake, including the micronutrient composition, should be known and monitored in relation to age appropriate Recommended Dietary Allowances to be certain the child is receiving a nutritionally adequate diet. The concentration of appropriate amino acids in blood should be determined often enough to assure that the level is adequate to sustain normal protein metabolism, but not high enough to be harmful. Even this surveillance is difficult because levels in plasma of the restricted amino acid may rise not only be-
cause of excess intake but also from body protein catabolism when intake is insufficient. The child must be observed frequently to be certain that nutritional deficiencies do not develop. The degree of sophistication required in laboratory monitoring is such that the American Academy of Pediatrics has stated that these patients should only be managed in specially equipped centers. It is increasingly apparent as the scope for treatment with substrate restricted diets increases that an equal degree of expertise is being demanded of nutritionists. Much can be done to facilitate a rapid, reasonably accurate and comprehensive index of total nutrition by the use of conventional data processing equipment. The
team
approach.
Dietary constraints of the type required for treatment of the inborn errors of amino acid metabolism can engender difficulties for patient and family. Frequent and open communication between parents and physician in this difficult area can be aided by the recruitment of allied health personnel, e.g., nutritionists, social workers, genetic counselors, and nurses. The competence and availability of these health workers are essential to help parents implement the dietary prescriptions. Applied to diseases such as phenylketonuria or maple syrup urine disease, these general rules may have a dramatically successful impact. Biochemical control, however, is not always with direct influence on the clinical situation as shown in the case of disease such as histidinemia and homocystinuria. Substrate reduction in the instances given above involve a specific amino acid and applies to disorders of essential amino acids. Where, however, the amino acid can be synthesized in the body such as specific approach, is not possible. In these cases there is, nonetheless, an advantage to restricting the total protein in the diet. This is the basis of therapy in the hyperammonemias and if the needs for special products in these conditions is less immediate the meticulous demand for careful nutritional monitoring remains. The genetic defects and their nutritional remedies that have been so far discussed are instructive but decidedly uncdmmon. Their study has, however, illuminated one basic
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/2/482/4666301 by Boston University Libraries user on 13 January 2019
foods. This is not always the case, however. For example, in branched-chain ketoaciduria the need to restrict leucine, isoleucine and valine is life long: a considerable challenge to sustain with conventional eating patterns.
INBORN
ERRORS
METABOLISM
485
derstanding of these less severe genetic variants and their nutrition needs, especially in populations with marginal availability of foodstuffs, promises to be an area of interesting future research. It has already been shown to be so in veterinary science.
[3
References I . Nutritional Management in Hereditary Metabolic Disease. American Academy of Pediatrics, Committee on Nutrition. Pediatrics 40: 289, 1976. 2. Special Diets for Infant with Inborn Errors of Metabolism. American Academy of Pediatrics, Committee on Nutrition. Pediatrics 57: 783, 1976.
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/2/482/4666301 by Boston University Libraries user on 13 January 2019
factor of genetic disease that is that of heterogenity. Put another way, in the production of any one given protein, there is a potential for functional variation that ranges all the way from incompetence to a negligible difference from the normal. The relevance of this to the state of nutrition in a population is obvious: it is that figures like Recommended Dietary Allowances can only be approximations and that there will always be some people who from genetic variation will require more or less of any given nutrient for optimal physiological performance. The un-
OF
0 ‘Brien,2
of metabolism1
M. D., F.R. C.P.
Human nutrition science and practise to the outsider, at any rate, appears to emphasize the availability, procurement, preparation, and requirement of foodstuffs in man in both health and disease. Special consideration has, of course, been given to defming needs at various ages, the so-called Recommended Dietary Allowances, to the biochemistry of nutrients and to the health problems of too little and too much food. However, adequate nutrition is only achieved when nutrients complete their roles in providing energy and in intermediate metabolism. Any acquired or genetically determined aberration of these processes can thus be construed as a disorder of nutrition. For the nutritionist the special interest of these conditions undoubtedly lies in the opportunities for dietary manipulation as a means of therapy (1). In order to understand the application of dietary principles to the circumvention of inborn errors of metabolism, it must be remembered that these conditions like any other genetic abnormality represent fundamentally a change in one specific protein. The affected protein may be produced in diminished amounts, may not be produced at all or may exist in a variably altered demesne that involves either its structural role or its ability to act enzymatically in combination with its substrate or cofactor. Whether the basic defect is in a protein concerned in transport or in an enzyme acting on some nutrient pathway, therapeutic dietary regimens have a limited number of options. The ideal approach, of course, would be to restore the genetic code and some laboratories are indeed now conducting research on what is called transgenosis in which phages containing Escherichia coli derived nucleoprotein are used to try to introduce the ability to synthesize specific missing enzymes into mammalian cells. Exciting as this approach is, it has been tempered by anxieties over the possibly dangerous consequences of uncontrolled experimentation with recombi482
The American
JournalofClinical
Nutrition
nant DNA. The next best alternative is to try to replace the missing gene product. This, for example, is exactly what is done when antihemophilic globulin (AHG) is given to hemophiliacs or enteric enzymes are given orally to children with cystic fibrosis. There are obvious difficulties in this approach: the protein in question must usually be given parenterally and may not reach the locus where it is required. Repeated pulses are necessary with the consequent dangers of antibody formation. Placental glucocerebrosidase has been given intravenously to patients with Gauchers disease with transient amelioration of biochemical function. Organ transplantation is potentially another way of restoring enzyme activity in a somewhat more physiological way that has been used with occasional success with the liver in Wilson’s disease and with the kidney in cystinosis (Fig 1). Product supplementation is another approach and one that has been rather rarely used. The addition of uridine to the diet of a case of orotic aciduria is a dramatically successful instance of this and so to a lesser degree is the use of substitution therapy in inborn errors of hormone biosynthesis, e.g., thyroxin in inborn errors of tyrosyl iodination. This avenue is clearly only appropriate in situations when the abnormal phenotype is primarily characterized by the absence of the unsynthesisable gene product. Neither of the above two approaches can really be thought of as nutritional. Cofactor supplementation, however, is a third possibility which has been very much involved with nutritional considerations. The supposition is either that the defective enzyme has a structural defect on the cofactor rather than the substrate site which may be overcome in the presence of a substantial excess of cofactor molecules, or that the synthesis of the active ‘ From the University Denver, Colorado 2 Professor of Pediatrics.
32: FEBRUARY
of Colorado
1979, pp. 482-485.
Medical
Printed
Center,
in U.S.A.
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/2/482/4666301 by Boston University Libraries user on 13 January 2019
Donough
errors
REGULATOR
-
INBORN
ERRORS
)
OF
METABOLISM
OPERATOR
)STRUCTUR.AL
(1)
REPLACEMENT REPLACEMENT
(3) (4)
(5) SUBSTRATE FIG.
I . Schema
for
Nutritional
form of the cofactor is defective. Some variants ofhomocystinuria are good examples of a pyridoxine responsive apoenzyme defect, cystathionine synthase. Likewise, in certain forms of methylmalonic aciduna there is a defect in the synthesis of 5’-deoxyadenosylB12 as the cofactor for methyl malonyl-coenzyme A mutase. Clinically, this approach has again been rather sparsely useful, but it has provided the scientific basis from which has developed the whole poorly substantiated fabric of “megavitamin therapy” for mental retardation and psychiatric disorders in childhood. The last and by far the most important approach from the nutrition point of view are those conditions where the unfavorable chinical picture is an expression of the accumulation of a nonmetabolized substrate or its toxic metabolites. Phenylketonuria is the best known example of such a situation. Simple as such dietary treatment may seem in theory, however, in practice its application has many hazards and at the outset certain criteria must be assured. First, the untreated disease must be harmful; second, dietary treatment must be effective in abating these ill-effects; third, steps must be taken to ensure that the treatment is not also harmful to the patient or to others who may inappropriately adopt it; fourth, there must be adequate facilities for an impeccable confirmation of diagnosis and for suitable biochemical monitoring of the course of therapy. Because of their especial practical importance, it is appropriate at this stage to review in greater detail both the principles and practical guidelines of diets where the amino acid
CO FACTOR
COENZYME PRODUCT (2)
SUBSTRATE (4)
ENZYME PRODUCT
PROTEIN
ENZYME +
(3)
(2)
GENE
REACTION
COFACTOR SUBSTRATE
SUPPLEMENT RESTRICTIOI
LOADING
approach
to inborn
errors
of metabolism.
levels have to maintain a critical balance between what is toxic and what is insufficient for growth. An example is made of amino acid restriction: but the principles would apply as much to galactose restriction in galactosemia. The
basic
formula
The amount of restricted amino acid provided by diet must be sufficient to meet the metabolic requirements dependent on it, including the requirement for growth; yet, its intake must not permit an excess accumulation in body fluids of the amino acid or its derivatives. These requirements for adequate nutrient can be met by providing a semisynthetic diet, derived either from a modified protein hydrolysate or from a mixture of Lamino acids, so that the diet contains either an extremely low amount of the implicated amino acid or is free of it. Other dietary sources of protein can then furnish the implicated amino acid(s) in an amount sufficient to sustain normal metabolism and growth, yet low enough to avoid intoxication. Requirements for other nutrients, calories, fat, including essential fatty acids, carbohydrates, minerals, and vitamins are met either by special dietary formulations incorporated into or added to the amino acid product or by further supplementation with natural foods of known composition. The need for these special formulations is especially important in early infancy during the most active period of brain myelination. In a number of conditions, the pressure for rigid dietary management diminishes with age and a freer use can be made of natural
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/2/482/4666301 by Boston University Libraries user on 13 January 2019
TRANSPORT PROTEIN (5) e.g. B12 supplementation in transcobalamin II deficiency
0)
483
O’BRIEN
484
The
progression
to more
normal
foods.
Infants in the first six months of life traditionally receive all or most of their nutrient requirements from breast milk or infant formula. During this period it is relatively easy to meet all the nutritional needs of an infant with an inborn error of amino acid metabolism by providing the kind of semisynthetic dietary product just described. Small amounts of milk may have to be added to meet the requirements ofthe restricted amino acid(s). Other foods are introduced into the diet as the infant grows. The composition of these foods and the quantities ingested must be regulated to keep the amino acid composition of the diet under control and to assure provision of other nutritional requirements. Clearly the lower the basic semi-synthetic formulation is in the restricted nutrient(s), the greater the permitted variety of natural foods that can be used in balancing the diet. Thus, for example, Lofenelac, a complete formula containing 80 mg/lOO g of phenylalanine is suitable for the treatment of phenylketonuria in early infancy. In later months another product, Mead Johnson 3229-A, which has no phenylalanine content, permits a freer introduction to mixed feeding. Monitoring
treatment.
Careful monitoring of treatment and its course is essential throughout the period of dietary management. Total nutritional intake, including the micronutrient composition, should be known and monitored in relation to age appropriate Recommended Dietary Allowances to be certain the child is receiving a nutritionally adequate diet. The concentration of appropriate amino acids in blood should be determined often enough to assure that the level is adequate to sustain normal protein metabolism, but not high enough to be harmful. Even this surveillance is difficult because levels in plasma of the restricted amino acid may rise not only be-
cause of excess intake but also from body protein catabolism when intake is insufficient. The child must be observed frequently to be certain that nutritional deficiencies do not develop. The degree of sophistication required in laboratory monitoring is such that the American Academy of Pediatrics has stated that these patients should only be managed in specially equipped centers. It is increasingly apparent as the scope for treatment with substrate restricted diets increases that an equal degree of expertise is being demanded of nutritionists. Much can be done to facilitate a rapid, reasonably accurate and comprehensive index of total nutrition by the use of conventional data processing equipment. The
team
approach.
Dietary constraints of the type required for treatment of the inborn errors of amino acid metabolism can engender difficulties for patient and family. Frequent and open communication between parents and physician in this difficult area can be aided by the recruitment of allied health personnel, e.g., nutritionists, social workers, genetic counselors, and nurses. The competence and availability of these health workers are essential to help parents implement the dietary prescriptions. Applied to diseases such as phenylketonuria or maple syrup urine disease, these general rules may have a dramatically successful impact. Biochemical control, however, is not always with direct influence on the clinical situation as shown in the case of disease such as histidinemia and homocystinuria. Substrate reduction in the instances given above involve a specific amino acid and applies to disorders of essential amino acids. Where, however, the amino acid can be synthesized in the body such as specific approach, is not possible. In these cases there is, nonetheless, an advantage to restricting the total protein in the diet. This is the basis of therapy in the hyperammonemias and if the needs for special products in these conditions is less immediate the meticulous demand for careful nutritional monitoring remains. The genetic defects and their nutritional remedies that have been so far discussed are instructive but decidedly uncdmmon. Their study has, however, illuminated one basic
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/2/482/4666301 by Boston University Libraries user on 13 January 2019
foods. This is not always the case, however. For example, in branched-chain ketoaciduria the need to restrict leucine, isoleucine and valine is life long: a considerable challenge to sustain with conventional eating patterns.
INBORN
ERRORS
METABOLISM
485
derstanding of these less severe genetic variants and their nutrition needs, especially in populations with marginal availability of foodstuffs, promises to be an area of interesting future research. It has already been shown to be so in veterinary science.
[3
References I . Nutritional Management in Hereditary Metabolic Disease. American Academy of Pediatrics, Committee on Nutrition. Pediatrics 40: 289, 1976. 2. Special Diets for Infant with Inborn Errors of Metabolism. American Academy of Pediatrics, Committee on Nutrition. Pediatrics 57: 783, 1976.
Downloaded from https://academic.oup.com/ajcn/article-abstract/32/2/482/4666301 by Boston University Libraries user on 13 January 2019
factor of genetic disease that is that of heterogenity. Put another way, in the production of any one given protein, there is a potential for functional variation that ranges all the way from incompetence to a negligible difference from the normal. The relevance of this to the state of nutrition in a population is obvious: it is that figures like Recommended Dietary Allowances can only be approximations and that there will always be some people who from genetic variation will require more or less of any given nutrient for optimal physiological performance. The un-
OF
