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INBORN ERRORS OF METABOLISM | Overview
3262 INBORN ERRORS OF METABOLISM/Overview
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The authors thank the following agencies for supporting the research program in Dr. Scott’s laboratory: Juvenile Diabetes Research Foundation (JDF), Canadian Inistitutes of Health Research (CIHR), Ontario Research and Development Challenge Fund, Canada Founation for Innovation, Health Canada. Karolina Burghardt was the recipient of a scholarship from the Diabetic Childrens Foundation and the CIHR. See also: Anemia (Anaemia): Iron-deficiency Anemia; Copper: Properties and Determination; Physiology; Essential Fatty Acids; Fats: Classification; Food Intolerance: Types; Food Allergies; Milk Allergy; Lactose Intolerance; Elimination Diets; Garlic; Infants: Breastand Bottle-feeding; Nutrition Education; Selenium: Properties and Determination; Zinc: Deficiency
Further Reading Brandtzaeg P (1998) Development and basic mechanisms of human gut immunity. Nutrition Reviews 56: S5–S18. Cousins RJ (1999) Nutritional regulation of gene expression. American Journal of Medicine 106(1A): 20S–23S. Cunningham-Rundles S (2001) Nutrition and the mucosal immune system. Current Opinion in Gastroenterology 17: 171–176. Hanson LA (1999) Human milk and host defense: immediate and long-term effects. Acta Paediatrica 88(430) (Suppl.): 42–46. Hesketh JE, Vasconcelos MH and Bermano G (1998) Regulatory signals in messenger RNA: determinants of
nutrient–gene interaction and metabolic compartmentation. British Journal of Nutrition 80: 307–321. Heyman M (1999) Evaluation of the impact of food technology on the allergenicity of cow’s milk proteins. Proceedings of Nutritional Society 58: 587–592. Koletzko B, Aggett PJ, Bindels JG et al. (1998) Growth, development and differentiation: a functional food science approach. British Journal of Nutrition 80(suppl. 1): S5–S45. Lamm DL and Riggs DR (2001) Enhanced immunocompetence by garlic: role in bladder cancer and other malignancies. Journal of Nutrition 131: 1067S–1070S. Scott FW (1996) Food induced Type 1 diabetes in the BB rat. Diabetes Metabolism Reviews 12: 341–359. Smith KM, Eaton AD, Finlayson LM and Garside P (2000) Oral tolerance. American Journal of Respiratory Critical Care Medicine 162: S175–S178. Strobel S and Mowat AM (1998) Immune responses to dietary antigens: oral tolerance. Immunology Today 19: 173–181. Voelker R (2000) The hygiene hypothesis. Journal of the American Medical Association 283: 1282. Weindruch R, Kayo T, Lee CK and Prolla TA (2001) Microarray profiling of gene expression in aging and its alteration by caloric restriction in mice. Journal of Nutrition 131: 918S–923S. Williams RJ (1956) Biochemical variations; its significance in biology and medicine. In: Biochemical Individuality, pp. 1–7. New York: Wiley. Ziboh VA (2000) Nutritional modulation of inflammation by polyunsaturated fatty acids/eicosanoids. In: Gershwin ME, German JB and Keen CL (eds) Nutrition and Immunology: Principles and Practice, pp. 157–167. Totowa, NJ: Humana Press.
INBORN ERRORS OF METABOLISM Overview K de Meer, Vrije Universiteit Medical Center, Amsterdam, The Netherlands Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Scope 0001
In clinical medicine and food science, metabolic disorders form a small but important field. Removal of nutrients which can have a critical effect on development of toxic crises or irreversible detrimental effect on organ function is a potentially simple and sometimes life-saving treatment. Simple measures, such as avoidance of prolonged fasting, can be very effective in selected cases. Special diets and costly supplements
are necessary in others. Although inborn errors of metabolism are collectively numerous, most disorders are individually rare. Clinical presentation can vary substantially over the spectrum of inborn errors of metabolism and patients can be seen at any age by pediatricians, neurologists, cardiologists, immunologists, hepatologists, dermatologists, and gynecologists. There is no common single test to screen for the whole group of diseases. Collaboration between specialized clinicians and biochemists, metabolic laboratories, and the food industry is required for adequate procedures in the diagnostic work-up and for proper treatment. Much expert and scientific information on individual genetic variation in relation to human disease is available online (Table 1). This article offers a
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Table 1 Inborn errors of metabolism: online information sources OMIM (Johns Hopkins University, Baltimore) Extensive information on clinical and molecular topics of inborn errors of metabolism and other inherited diseases is available from www.ncbi.nlm.nih.gov in the Online Mendelian Inheritance in Man (OMIM) library. It combines the human gene map with a morbidity map. The OMIM database assigns a code (MIM) number, gives the locus symbol, and provides a complete list of clinical phenotypes for each disease entity. Experts also describe the clinical picture. OMIM provides a morbidity search machine for differential diagnosis on the basis of clinical symptoms and signs. At present, the number of gene loci with an associated clinical disease entity exceed 1700, and more than 2250 human phenotypes have been mapped on the genome. In more than 70% of these disease phenotypes, the molecular basis has been defined. The National Center of Biomedical Information (NCBI) website of the National Library of Medicine at the National Institute of Health also hosts the medical scientific literature (PubMed) and human genome (GenBank) library databases. Together these resources provide an intertwined and up-to-date online source for practitioners and scientists HUGO Mutation Database Initiative (University of Melbourne) The website ariel.ucs.unimelb.edu.au/*cotton/mdi.htm provides a list of locus-specific databases according to gene designation, available from university and research institute sources around the world. Connected by the MIM number of each locus, the information from OMIM is only one click away. The drawback is that the visitor should already know the locus lettercode prior to starting up the link. HUGO also lists patient information sites. Information on nonhuman genetic variation is also available
conceptual approach to the field, and describes a selection of diseases in which nutritional intervention is possible.
Genetics and Inborn Errors of Metabolism 0003
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Inherited metabolic diseases cause structural changes or metabolic derangements in the body. The term ‘inborn error of metabolism’ was presented by John Garrow in 1906 in a lecture about alcaptonuria, in which he also hypothesized the theory of one gene, one protein as its cause. Although the concept of inborn error of metabolism implies that a deficiency of a single enzyme is present, the term has also come into use to describe inherited disorders in proteins not involved in metabolism. Mutated genes and their translation products, proteins, can cause derangements during body and tissue formation, and can also be present as abnormal structural proteins and diminished enzyme activity in a wide range of processes. Autosomal recessive inheritance is the most common form of inheritance encountered in inborn errors of metabolism, but not all affected individuals necessarily have symptoms and other inheritance patterns are all but rare. Mutations in the estimated 30 000 human genes can in principle cause a very large number of diseases. More than 2200 disease loci are now known. In the human genome, mutations in a number of genes are not compatible with survival at the time the embryo develops. In some cases the same mutation in an allele is known to be causally related to more than one disease. Within one disease the same genotype can be associated with more than one phenotypical presentation. Given the magnitude of the human genome, and the multitude of possible mutations and phenotypic disease states, it is not possible to
recognize all inborn errors of metabolism by neonatal screening. Apart from dedicated neonatal screening for the more frequent and treatable disorders, simple methods using clinical diagnosis and targeted laboratory investigations are needed to identify the inborn error of metabolism in an individual patient. From a pathophysiological point of view, the metabolic disorders can be divided into a number of groups that can be used to facilitate diagnostic decision making, including the initial differential diagnosis by the general practitioner and specialist. Specialists in pediatrics, internal medicine, neurology, clinical chemistry, and genetics collaborate in the clinical field of metabolic diseases for establishing the diagnosis on the level of the protein or gene, and to provide treatment and genetic counseling. The focus of this chapter is on inborn errors of metabolism in which nutritional modulation is an important, and in some cases the only, is of treatment. They are summarized in Table 2. Not all inborn errors of metabolism with nutritional consequences are covered in this article. Familial hyperlipidemias are, also in terms of numbers of patients, a very important group of inborn errors of metabolism, and are dealt with elsewhere in this encyclopedia. Some inborn errors of metabolism in which food components play a role, notably glucose6-phosphate dehydrogenase deficiency, in which fava beans can trigger symptoms, and porphyrias in which low carbohydrate intake can aggravate symptoms, are not further explored here.
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Pathophysiology Metabolic disorders can be divided into groups, according to the pathophysiological mechanism that is involved.
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Table 2 Selected metabolic disorders for which nutritional therapy is used Amino acid disorders Phenylketonuria Tyrosinemia type I and II Maple syrup urine disease Urea cycle defects Homocysteinuria (CBS-deficiency) Isovaleric acidemia Serine synthesis defect (3-PGDHD) Hartnup disease
Protein restriction, tyrosine and docosa-hexanoic acid supplementation Protein restriction, NTBC in type I Valine, leucine, isoleucine restriction, and thiamin supplementation Protein restriction, arginine and sodium benzoate and phenylacetate supplementation Methionine restriction, vitamin B6, and betaine supplementation Leucine restriction, glycine and carnitine supplementation Serine and glycine supplementation High-protein, nicotinamide supplementation
Carbohydrate disorders GSD type I and III Galactosemia Hereditary fructose intolerance Glucose-galactose malabsorption Congenital disorder of glycosylation Ib
High carbohydrate/low fat and cholesterol Galactose (and lactose) restriction Fructose restriction High fructose/low glucose-galactose Mannose supplementation
Organic acidemias and acidurias Propionic acidemia Methyl malonic acidemia Multiple acyl coenzyme A dehydrogenase deficiency Glutaric aciduria type I
Protein restriction, avoidance of dehydration, Inhibition of colonic flora with metronidazole Protein restriction, vitamin B12 supplementation Fat restriction, riboflavin and carnitine supplementation Lysine restriction, riboflavin supplementation
Fatty acid oxidation and ketolysis defects b-Ketothiolase deficiency MCAD, LCAD, LCHAD deficiency
Low protein, avoid fasting Low fat, avoid fasting, + carnitine
Mitochondrial disorders Respiratory-chain disorders Pyruvate dehydrogenase deficiency
Increased energy need in early life High fat/low carbohydrate and thiamin
Micronutrient disorders Biotinidase deficiency Vitamin B6-dependent epilepsy Transcobalamin II deficiency Immerslund-Grsbeck disease Hereditary folate malabsorption Methylene tetrahydrofolate reductase deficiency Acrodermatitis enterohepatica Wilson disease
Biotin supplementation Vitamin B6 supplementation Vitamin B12 supplementation Vitamin B12 supplementation Folate supplementation Folate supplementation Zinc supplementation Zinc supplementation
NTBC, nitro-trifluoro-methylbenzoyl-cyclohexanedione; CBS, cystathionine b-synthase: homozygous patients cannot metabolize homocysteine which is formed after transmethylation of methionine; 3-PGDHD, 3-phosphoglycerate dehydrogenase deficiency: the enzyme block prevents the biosynthesis of serine; GSD, glycogen storage disease; MCAD, medium-chain acyl coenzyme A dehydrogenase; LCAD, long-chain acyl coenzyme A dehydrogenase; LCHAD, long-chain hydroxy acyl coenzyme A dehydrogenase: these mitochondrial enzymes form part of the oxidation of fatty acids.
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Group 1 is comprised of disorders characterized by the disturbed synthesis or catabolism of complex molecules. Symptoms are not related to food intake, and are permanent, progressive, and independent of intercurrent infections. Lysosomal storage disease, peroxisomal disorders, a1-antitrypsin deficiency, and congenital disorders of glycosylation are in this group. With some notable exceptions, nutritional therapy is not effective in these disorders. Group 2 includes all disorders of intermediate metabolism. Because multiple enzymes are involved in the metabolism between macronutrients and end products, these disorders lead to accumulation of toxic compounds proximal to the metabolic block. There can be progressive or acute intoxication due to
these compounds, and intercurrent infections or excessive intake of foods can lead to a metabolic crisis. A symptom-free interval is characteristic. Late onset or an intermittent clinical presentation is typical. Aminoacidemias, most organic acidurias, urea cycle defects, and sugar intolerances belong to this group. Group 3 consists of inborn errors involved in intermediate metabolism which is directly related with cellular energy transfer. Enzyme defects can affect the supply with macromolecules involved in energy production as well as the transfer of energy by molecules in the matrix and in the inner membrane respiratory chain system within the mitochondria. Glycogen storage diseases, gluconeogenesis defects, defects in pyruvate carboxylase and dehydrogenase,
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fatty acid oxidation defects, and mitochondrial respiratory chain disorders are present in this group. Group 4 is comprised of diseases in which disturbances are present in: (1) membrane transport; (2) intracellular signaling; or (3) critical developmental periods. Defects of transmembrane transporters for carbohydrates, amino acids, and lipids in the intestine are suspected by clinical observation (diarrhea, failure to thrive) and absorption studies. Similarly, defects can be present in tubular reabsorption in the kidney. Other clinical entities are related to disturbed transport of metals (e.g., of copper, such as Menkes and Wilson disease). New insights have been developed that complex compounds, produced in specialized metabolic tissues and necessary for specialized functions in the brain, must undergo a critical step in transport over the cell membrane for proper function. Similarly, with respect to intracellular signaling functions, the assembly or metabolism of complex compounds in the central nervous system and other organs can be deranged. Defects of intracellular membrane transport comprise another group of newly recognized disorders. The transport defects generally result in the dysfunction of one or more affected organs (e.g., diarrhea in carbohydrate malabsorption, liver failure and brain dysfunction by copper storage in Wilson disease, brain dysfunction in creatine transporter deficiency, X-linked nonspecific mental retardation, and abnormal neurotransmitter synthesis) or deficiency syndromes (due to malabsorption). Recently, insights in developmental biology led to the discovery that certain compounds (e.g., cholesterol) with known functions during extrauterine life are critical for developmental gene description in the embryo (e.g., absence of 7-dehydrocholsterol biosynthesis causes Smith–Lemli–Opitz syndrome, characterized by dysmorphic features and severe mental retardation). Developments in molecular biology and the genome project, human genetics, and clinical chemistry enable discovery of the etiology and pathophysiology of newly recognized disorders with a range of clinical presentations.
Clinical and Laboratory Expertise in Diagnosis 0013
Children with inborn errors of metabolism may present with one or more of a large variety of symptoms and signs. Although most Mendelian phenotypes are expressed early in life, adult presentations are recognized in increasing numbers. The patient history, clinical assessment (for color, odor, hepatomegaly, neurological abnormalities, including hypotonia, and dysmorphic features), and immediate laboratory
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investigations are necessary for initial judgment in terms of the pathophysiology group and index of suspicion for an inborn error of metabolism. A full medical and genetic family history is important and should include the circumstances of any stillbirth, sudden infant death, unusual death in childhood or early adulthood, and information on consanguinity between the parents. Blood investigations should include routine hematology and electrolytes (search for anion gap), glucose, creatinine, liver enzymes, bilirubin, ammonia, calcium, phosphate, lactate, pyruvate, ketone bodies (3-hydroxy- and ketobutyrate), fatty acids, uric acid, blood-gas analysis, and prothrombin time. Urinalysis should include acetone, reducing substances, pH, sulfite, electrolytes, and uric acid. Further investigation may comprise lumbar puncture, chest X-ray, and cardiac and central nervous system function studies. Further laboratory and other investigations are guided by the pathophysiological group, abnormalities in the routine investigations, and suspicion of an individual disorder. The metabolic laboratory is specialized in the investigation of body fluids in the search of abnormal metabolites which are present in many inborn errors of metabolism. Apart from the routine investigations mentioned above, liquid, gas, and thin-layer chromatography are performed on plasma, urine and cerebrospinal fluid, and mass spectrometry, electrophoresis and spectrometric analysis techniques are other methods available for investigation. The use and distribution of these techniques in the investigation of patients suspected of an inborn error of metabolism are depicted in Figure 1. A systematic description of the metabolites and abnormalities frequently observed in inborn errors of metabolism is beyond the scope of this overview. In practice, the inborn errors in which laboratory abnormalities are found are grouped using three different conceptual approaches. Grouping takes place by: (1) the main laboratory abnormality in a body fluid (e.g., aminoacidemia or organic aciduria) as a result of the enzyme defect; (2) the cell organelle where the abnormality is located (e.g., lysosomal storage disease, perixisomal disorder); and (3) the abnormal structural molecule (e.g., defect of purine metabolism, mucopolysacharidosis, or congenital disorder of glycosylation). Figure 2 shows the distribution of diagnosis of inborn error of metabolism based on records in one laboratory of metabolic diseases where both regional and international patient investigations take place. The diagnosis system of an inborn error of metabolism is eventually based on the enzyme nomenclature, the MIM number (Mendelian inheritance in
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3266 INBORN ERRORS OF METABOLISM/Overview 32%
37% Liquid chromatography Thin-layer chromatography Gas chromatography Mass spectometry Spectrometric analysis Electrophoresis Routine analyses
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8%
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Figure 1 (see color plate 99) Laboratory analyses performed in body fluids of 2150 patients investigated over a period of 5 years in the laboratory for metabolic diseases of the Vrije Universiteit Medical Center in Amsterdam. Investigations were performed in whole blood, plasma, urine, amniotic fluid, and cerebrospinal fluid.
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16% 7%
Aminoacidemias Organic acidurias Carbohydrate disorders Lysosomal disorders Peroxisomal disorders Mitochondrial disorders Rest
18% 41% 5% fig0002
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Figure 2 (see color plate 100) Frequency distribution according to diagnostic group in 263 patients newly identified with an inborn error of metabolism over a period of 5 years in the Laboratory for Metabolic Diseases of the Vrije Universiteit Medical Center in Amsterdam. Fatty acid oxidation defects included in organic acidurias.
man, formerly the McKusick number) for each disease entity, and the mutations linked with the clinical entities in the OMIM database (Online Mendelian inheritance in man: Table 1). Enzyme diagnosis, using leukocytes, cultured fibroblasts, or biopsies from chorionic villi or other affected tissue, is increasingly used to confirm the diagnosis. DNA diagnosis is also developed for an increasing number of inborn errors. In the following paragraphs, some important disorders and clinical problems are presented, to illustrate the interactions between nutrition and inborn errors of metabolism.
Amino Acid Disorders (Group 2 Pathophysiology) 0019
Amino acids are the building blocks of body protein and are mainly derived from the diet. Ingested protein is absorbed almost completely. Amino acids which become available in the body, in excess of the needs for protein synthesis and growth, are eventually oxidized through several pathways. For the nonessential amino acids there are also pathways of
biosynthesis. Some of these pathways are shared between two or more amino acids, and others are unique to one amino acid. Inborn errors of metabolism are known for each amino acid. Here we discuss two of the most frequently encountered aminoacidemias. Hyperphenylalaninemia
Phenylalanine is an essential amino acid. It is normally degraded via the tyrosine pathway. To enter the tyrosine pathway, phenylalanine is converted into tyrosine by the enzyme phenylalanine hydroxylase, which has tetrahydrobiopterin as a cofactor. Deficiency of the enzyme or of its cofactor causes accumulation of phenylalanine in the body fluids and tissues. Hyperphenylalaninemia is present, and detection in plasma is a reliable way of establishing the suspected diagnosis. Classic phenylketonuria (PKU) is caused by the deficiency of the enzyme phenylalanine hydroxylase. In the first weeks after birth patients have no symptoms, although in the neonatal period vomiting can be an early symptom. Mental retardation is the major abnormality in untreated patients, with an estimated loss of about 50 IQ points by the end of the first year
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of life. Untreated patients develop behavioral and neurological abnormalities, including hypertonicity and athetosis, and 25% of patients develop epilepsy. On clinical examination they have an unpleasant smell, probably due to the accumulation of abnormal metabolites of phenylalanine such as phenylacetic acid (which has a musky odor). Microcephaly and growth retardation are common. If protein and phenylalanine restriction is instituted early after birth, the patients remain free of these symptom. Special PKU infant formulas are available, but careful follow-up of the patient’s physical growth and development is needed and regular measurement of phenylalanine plasma levels are mandatory in order to prevent under- and overtreatment. Metabolic derangement can take place under catabolic conditions, e.g., during infections. Proper treatment requires early detection. Mass newborn screening for PKU became effective when Guthrie developed a bacterial inhibition assay which could be done on dried blood collected on paper obtained after a heel puncture during the second half of the first week of life. About one in 50 patients with hyperphenylalaninemia have a defect in one of the enzymes necessary for the synthesis or recycling of the cofactor tetrahydrobiopterin. If undetected and treated as PKU, these patients show normalized phenylalanine plasma levels but develop severe neurological symptoms. The reason is that tetrahydrobiopterin is a cofactor for other hydroxylases, involved not only in hydroxylation of phenylalanine but also of tyrosine and tryptophan. The latter two are involved in the biosynthesis of the neurotransmitters dopamine and serotinin. For this reason all neonates with hyperphenylalaninemia are required to undergo tests for deficiency of the cofactor. Treatment of these patients requires protein restriction and supplementation with tetrahydrobiopterin (because they also have nonclassical PKU), and supplementation of l-dopa and 5-hydroxytryptophan (because the supplemented cofactor does not cross the blood–brain barrier). Research has demonstrated that in vivo hydroxylation in children with PKU can be so low that patients may suffer from the effects of a diminished availability of the metabolic product of phenylalanine hydroxylase, tyrosine. Tyrosine is an essential amino acid required for physical growth but also a precursor for dopamine biosynthesis. Tyrosine supplementation thus is required in some patients with PKU. PKU is one of the more common inborn errors of metabolism and this autosomal recessive disease is a major cause of preventable hereditary mental retardation and neurological debilitation in the population. Neonatal screening programs have saved thousands
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of patients who would otherwise have spent their life in asylums. Nowadays, many adult patients cease the diet and report no psychological or neurological problems. None the less, new problems have emerged in the management of these patients. Pregnancies in mothers with PKU who no longer use the lowphenylalanine diet are complicated by spontaneous abortions, and their living offspring are often mentally retarded and show microcephaly or congenital heart disease. It has become clear that women with PKU who are of child-bearing age should start a lowphenylalanine diet before conception and should be closely monitored for their phenylalanine blood levels before and during pregnancy. Also, deficiency of n-6 polyunsaturated fatty acids has been described in patients with PKU (and supplementation has been advocated). The complications during pregnancy and of polyunsaturated fatty acid synthesis demonstrate one of the concepts of group 2 pathophysiology, i.e., that metabolites accumulating proximal to the metabolic block can cause derangements in distant organs and metabolic pathways. Tyrosinemia Type 1
Tyrosine is likewise an essential amino acid derived from ingested protein. Excess tyrosine is oxidized. Several inborn errors of metabolism in the degradative pathway are known. Deficiency of fumarylacetoacetate hydroxylase causes type 1 tyrosinemia, and has an acute or chronic clinical manifestation. The acute form presents in infancy, and comprises most reported cases. Some symptoms resemble that of PKU with failure to thrive, developmental delay, and vomiting, but hepatic manifestations with organ enlargement, jaundice, and bleeding tendency are common findings as well. Apart from elevated tyrosine, elevated methionine is also found in many patients. Hypoproteinema and low prothrombin are often present. Many patients develop end-stage hepatic failure in childhood and die unless appropriate therapy is started. Patients with the chronic form also present with failure to thrive and development delay, but generally not during the first year of life. Cirrhosis (which can be associated with acute liver failure during catabolic episodes), renal tubular dysfunction, and vitamin D-resistant rickets are often found. Acute episodes of polyneuropathy may complicate the disease. In the long term, a substantial proportion of patients with type 1 tyrosinemia develop hepatic adenoma, and over time hepatocellular carcinoma can develop in these lesions. The wide spectrum of organ pathology, including malignant disease in tyrosinemia, demonstrates the effect of toxic substances that accumulate due to the inability to catabolize tyrosine. Although dietary restriction of tyrosine and
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methionine has been advocated over the years, many patients have shown progression of hepatorenal and hematological symptoms and developed malignant liver disease under this treatment regimen. Liver transplantation is a cure for patients with liver cirrhosis or (solitary) tumors, as the donor liver provides the patients with a normally functioning liver, including normal activity of the deficient enzyme. Liver transplantation has a high risk of acute and chronic complications and thus is only an option for patients with severe liver disease. Since 1994 a promising new pharmacological therapy has been successful in reducing morbidity and liver complications: nitrotrifluoro-methylbenzoyl-cyclohexanedione (NTBC), an inhibitor of p-hydroxyphenylpyruvate dioxygenase, prevents the formation of (cytotoxic and carcinogenic) metabolites distal of this enzyme and proximal of the inborn error. Although the elevated tyrosine levels do not disappear during NTBC therapy, and tyrosine and methionine restriction remain necessary, this treatment appears remarkably effective. Patient follow-up of this treatment has been less than 10 years at present. There is hope that the long-term life-threatening complications such as liver failure, bleeding disorders and tumor induction are preventable with NTBC.
Table 3 Metabolic causes of hypoglycemia in childhood Decreased production of glucose Decreased release of glucose from the liver Glycogen synthase deficiency Glucose-6-phosphate deficiency (GSD type Ia or Ib) Amylo-1,6-glucosidase deficiency (GSD type III) Galactose-1-phosphate deficiency (galactosemia) Fructose-1-phosphate aldolase deficiency (hereditary fructose intolerance) Decreased rate of gluconeogenesis Pyruvate carboxylase deficiency Phosphoenolpyruvate carboxylase deficiency Fructose-1,6-diphosphatase deficiency Glycerokinase deficiency Decreased availability of alternative fuels, resulting in increased use or decreased conservation of glucose Impaired oxidation of fatty acids Medium-chain acyl-coenzyme A dehydrogenase deficiency Long-chain acyl-coenzyme A dehydrogenase deficiency Carnitine acyltransferase I deficiency Multiple acyl coenzyme A dehydrogenase deficiency Impaired synthesis or use of ketones b-Ketothiolase deficiency Hydroxymethylglutaryl coenzyme A lyase deficiency Decreased fat stores Prematurity Malnutrition GSD, glycogen storage disease. Other metabolic disturbances resulting in hypoglycemia are toxic (exposure to ethanol or salicylate), endocrine (hyperinsulinemia, growth hormone deficiency, cortisol deficiency), hyperleucinemia, and a selflimiting ketotic hypoglycemia.
Energy Disturbance (Group 3 Pathophysiology) Hypoglycemia 0027
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A low blood sugar level is potentially dangerous (for central nervous system function) and can be lifethreatening. Some organs (the heart, the brain) have a high energy expenditure while using only a limited selection of metabolic fuels. For the brain the balance between energy supply and expenditure is the most critical because glucose and ketone bodies (and, under certain conditions, lactate) are its only energy substrates and the specific energy demand is high. Energy stores in the neural cells are very low and rapidly consumed. Although hypoglycemia can be caused by nonmetabolic disorders it is a hallmark symptom for a large number of inborn errors of metabolism, particularly those of intermediate carbohydrate and triacylglycerol metabolism (Table 3). Symptoms can be present within hours after birth (and, in the case of low liver stores, even within minutes). The time of presentation after the last meal is indicative of the relevant group of disorders, with glycogen storage disease, gluconeogenesis defects, and fatty acid oxidation defects and impaired availability of ketones successively being the most probable cause when a wider gap is reported between
the time of the last meal and the presentation of the hypoglycemia. For the diagnosis of the inborn error, and for the differential diagnosis, including endocrine disorders, blood and urine sampling at the time of the hypoglycemic crisis is essential. In life-threatening situations such as coma, treatment prevails over the complete collection of samples for the diagnostic work-up. Some abnormalities may still be present in blood and urine even hours after intravenous administration of glucose and restoration of the blood glucose level to the normal range. In some disorders symptoms can develop only months or even years after birth. The clinical spectrum is wide, with liver enlargement present in some (e.g., glycogen storage type I and III, hereditary fructose intolerance) but not all disorders and toxic crises present in some (e.g., coma and severe liver function abnormalities in medium-chain acyl-coenzyme A dehydrogenase deficiency) but not all disorders. Hyperlipidemia, granulocyte dysfunction, hyperuricacidemia and gout, hyperlactatemia and osteoporosis, liver adenomas, and pancreatitis are complications in just one of these disorders (glycogen storage disease type I). Cataracts with or without liver dysfunction are seen in galactosemia. This illustrates that virtually any organ
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system can be affected in the wide spectrum of disorders encountered as the cause of a decreased blood level of just one metabolite, glucose. A systematic overview of the spectrum of disease and complications of inborn errors of metabolism causing hypoglycemia cannot be further pursued here. Treatment depends on the cause, and ranges from strict avoidance of certain foods (e.g., galactose and lactose in galactosemia) to continuous dripfeeding (e.g., in glycogen storage disease type I). Avoidance of prolonged fasting is important in a large proportion of disorders. Early diagnosis is essential to prevent brain damage and other irreversible organ failure. Thus recurrent or severe hypoglycemia should bear a high degree of suspicion of a metabolic cause. Elevated Resting Energy Expenditure
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Mitochondrial respiratory chain enzyme defects are associated with myopathy and failure to thrive in early life in mildly affected patients and severe multiorgan involvement, including brain damage and early death in other patients. The failure to thrive in infants with the disease can result from neurological impairment (vomiting, difficulty with swallowing) but also elevated energy expenditure is often found. The pathophysiology of the increased resting energy expenditure is of conceptual interest for this overview on human inborn errors and nutrition. The mitochondrial respiratory chain is comprised of five enzyme complexes which together drive the process of oxidative phosphorylation and maintain the proton gradient through which adenosine triphosphate (ATP) production is maintained. Complex I, III, and IV have proton-pumping capacity, and the efficiency of the protons (with eventually energy transfer to ATP, P) pumped and coupled electron flow through the respiratory chain to oxygen (O) can be expressed as the P/O ratio. In normal mitochondria the ratio is about 1.75 for reduced nicotinamide adenine dinucleotide (NADH)-linked substrates and 2.75 for reduced flavin adenine dinucleolide (FADH)-linked substrates. However, in patients with deficiency of complex I, II, or III, the respiratory chain is substantially less efficient as one proton (ATP) less is produced by the electron’s energy transfer between complex I and V. Adaptive changes, including a higher adenosine diphosphate (ADP) concentration (a known stimulus of oxidative phosphorylation activity) and higher resting oxygen consumption are present in many patients. To find out whether, and to what extent, this pathophysiological mechanism is present in an individual patient diagnosed with a respiratory chain defect indirect calorimetry can be useful. Therapy exists in high-energy feedings, and
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growth monitoring is important. This is particularly important during infancy when energy demands and growth rates are already high and patients depend on food offered by the mother. In later life many patients expend less energy due to muscle fatigue and lower physical activity levels, and the balance between total daily energy expenditure and energy intake is more easily maintained.
Lipids and Essential Fatty Acid Deficiency In the affluent world and in poor parts of the world, nonhereditary causes of insufficient essential fatty acid status prevail and are worldwide much more frequent than hereditary causes. Disturbance of n-6 and n-3 polyunsaturated fatty acid status is caused by a number of inborn errors. The most frequent ones are shown in Table 4. Single-enzyme deficiencies in the metabolic pathways of n-6 and n-3 polyunsaturated fatty acid synthesis and oxidation are extremely rare, probably because essential fatty acids from food and the interconnections between the n-6 and n-3 desaturase pathways provide alternative provisions and overflow routes for affected metabolites. These rare patients are not reviewed here or included in Table 4.
Table 4 Causes of essential fatty acid deficiency Mechanism and disease state Hereditary causes Intestinal malabsorption Abetalipoproteinemia Hypobetalipoproteinemia Anderson disease Exocrine pancreas insufficiency Cystic fibrosis Shwachman syndrome Pearson syndrome Deranged metabolism of polyunsaturated fatty acids Decreased synthesis of docosahexanoic acid Phenylketonuria Zellweger syndrome Decreased inhibition of leukotriene B4 Sjo¨gren–Larsson syndrome Nonhereditary causes Malnutrition Fat-free diet Parenteral nutrition without essential fatty acid supplementation
Affected gene(s)
MTTP Apolipoprotein B ? CFTR Mapped to 7p11-q11 Mitochondrial DNA deletions
PAH PEX
FALDH None
MTTP, microsomal triglyceride transfer protein; CFTR, cystic fibrosis transmembrane conductance regulator; PAH, phenylalanine hydroxylase; PEX, peroxin, involved in peroxisome biogenesis; FALDH, microsomal fatty aldehyde dehydrogenase.
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In patients with disorders in which the assembly of peroxisomes is deficient (mutations in PEX protein complementation groups, e.g., Zellweger syndrome), deficiency of some essential fatty acids has been documented. Enzymes required for the oxidation of verylong-chain fatty acids (including arachidonic acid) and in the synthesis of some polyunsaturated compounds are located in the peroxisome and these are absent or have a very low activity in these patients. PKU is a single-enzyme disease in phenylalanine hydroxylation in which low essential fatty acid status has been found. It is associated with neuropathy in some patients. Circulating abnormal metabolites affect the synthesis of n-6 (arachidonic acid) and n-3 (docosahexanoic acid) fatty acids. Secondary deficiency of essential fatty acids has been found in relatively rare disorders causing lipid malabsorption (transport defects, group 4 pathophysiology) and hereditary exocrine pancreas insufficiency. In the latter group, cystic fibrosis is the most frequently encountered disorder. Sjo¨ gren–Larsson syndrome (in which microsomal conversion of medium- and long-chain fatty aldehydes to their carboxylic acids is defective) causes a unique inactivation in leukotriene B4 inhibition. Patients have elevated leukotriene levels and inflammatory skin changes. Symptoms of essential fatty acid deficiency in other patients are nonspecific and range from dermatitis to
severe failure to thrive. Diagnosis is often delayed. Treatment of exocrine pancreas insufficiency by pancreas enzyme supplementation often corrects the essential fatty acid profile. In other disorders skin ointments (on the basis of vegetable oil rich in polyunsaturated fatty acids) are a treatment option. The course of several severe and fatal disorders, such as abetaliproteinema or Zellweger syndrome (in which oral supplementation is given), is not clearly altered by such treatment however. See also: Amino Acids: Properties and Occurrence; Determination; Metabolism; Diabetes Mellitus: Problems in Treatment; Fatty Acids: Trans-fatty Acids: Health Effects; Hyperlipidemia (Hyperlipidaemia); Nucleic Acids: Properties and Determination; Physiology
Further Reading Blau N, Duran M, Blaskovics ME and Gibson KM (eds) (2003) Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases. London: Springer. Fernandes J, Saudubray JM and van den Berghe G (eds) (2000) Inborn Metabolic Diseases. Berlin: Springer. Leonard JV and Morris AAM (2000) Inborn errors of metabolism around time of birth. Lancet 356: 583–587. Scriver CR, Beaudet AL, Sly WS et al. (eds) (2001) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill.
INFANT FOODS Contents Milk Formulas Weaning Foods
Milk Formulas D Hileti-Telfer, The Hospitals for Sick Children, London, UK Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Background 0001
Until the early 1900s, there was no alternative to human breast milk for feeding newborn infants. Consequently, over 80% of infants were breast-fed. If a mother was unable to breast-feed her baby, a wet nurse had to be found, or diluted cow’s milk had to be given. The 1940s marked a major turning point
in the history of infant feeding in the UK, with an increasing proportion of babies being bottle-fed. A number of social, economic, and practical factors contributed to this radical change in infant feeding practices. The major influence was the introduction of the Welfare Food Scheme during World War II. This allowed mothers and children to have free or subsidized National Dried Milk (NDM) at a time when cows’ milk was rationed. Inevitably, the use of NDM spread to infants and escalated as social attitudes gradually changed towards women working outside the home. Unfortunately, NDM and most commercial infant formulas available over the succeeding years were not
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Acknowledgements 0030
The authors thank the following agencies for supporting the research program in Dr. Scott’s laboratory: Juvenile Diabetes Research Foundation (JDF), Canadian Inistitutes of Health Research (CIHR), Ontario Research and Development Challenge Fund, Canada Founation for Innovation, Health Canada. Karolina Burghardt was the recipient of a scholarship from the Diabetic Childrens Foundation and the CIHR. See also: Anemia (Anaemia): Iron-deficiency Anemia; Copper: Properties and Determination; Physiology; Essential Fatty Acids; Fats: Classification; Food Intolerance: Types; Food Allergies; Milk Allergy; Lactose Intolerance; Elimination Diets; Garlic; Infants: Breastand Bottle-feeding; Nutrition Education; Selenium: Properties and Determination; Zinc: Deficiency
Further Reading Brandtzaeg P (1998) Development and basic mechanisms of human gut immunity. Nutrition Reviews 56: S5–S18. Cousins RJ (1999) Nutritional regulation of gene expression. American Journal of Medicine 106(1A): 20S–23S. Cunningham-Rundles S (2001) Nutrition and the mucosal immune system. Current Opinion in Gastroenterology 17: 171–176. Hanson LA (1999) Human milk and host defense: immediate and long-term effects. Acta Paediatrica 88(430) (Suppl.): 42–46. Hesketh JE, Vasconcelos MH and Bermano G (1998) Regulatory signals in messenger RNA: determinants of
nutrient–gene interaction and metabolic compartmentation. British Journal of Nutrition 80: 307–321. Heyman M (1999) Evaluation of the impact of food technology on the allergenicity of cow’s milk proteins. Proceedings of Nutritional Society 58: 587–592. Koletzko B, Aggett PJ, Bindels JG et al. (1998) Growth, development and differentiation: a functional food science approach. British Journal of Nutrition 80(suppl. 1): S5–S45. Lamm DL and Riggs DR (2001) Enhanced immunocompetence by garlic: role in bladder cancer and other malignancies. Journal of Nutrition 131: 1067S–1070S. Scott FW (1996) Food induced Type 1 diabetes in the BB rat. Diabetes Metabolism Reviews 12: 341–359. Smith KM, Eaton AD, Finlayson LM and Garside P (2000) Oral tolerance. American Journal of Respiratory Critical Care Medicine 162: S175–S178. Strobel S and Mowat AM (1998) Immune responses to dietary antigens: oral tolerance. Immunology Today 19: 173–181. Voelker R (2000) The hygiene hypothesis. Journal of the American Medical Association 283: 1282. Weindruch R, Kayo T, Lee CK and Prolla TA (2001) Microarray profiling of gene expression in aging and its alteration by caloric restriction in mice. Journal of Nutrition 131: 918S–923S. Williams RJ (1956) Biochemical variations; its significance in biology and medicine. In: Biochemical Individuality, pp. 1–7. New York: Wiley. Ziboh VA (2000) Nutritional modulation of inflammation by polyunsaturated fatty acids/eicosanoids. In: Gershwin ME, German JB and Keen CL (eds) Nutrition and Immunology: Principles and Practice, pp. 157–167. Totowa, NJ: Humana Press.
INBORN ERRORS OF METABOLISM Overview K de Meer, Vrije Universiteit Medical Center, Amsterdam, The Netherlands Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Scope 0001
In clinical medicine and food science, metabolic disorders form a small but important field. Removal of nutrients which can have a critical effect on development of toxic crises or irreversible detrimental effect on organ function is a potentially simple and sometimes life-saving treatment. Simple measures, such as avoidance of prolonged fasting, can be very effective in selected cases. Special diets and costly supplements
are necessary in others. Although inborn errors of metabolism are collectively numerous, most disorders are individually rare. Clinical presentation can vary substantially over the spectrum of inborn errors of metabolism and patients can be seen at any age by pediatricians, neurologists, cardiologists, immunologists, hepatologists, dermatologists, and gynecologists. There is no common single test to screen for the whole group of diseases. Collaboration between specialized clinicians and biochemists, metabolic laboratories, and the food industry is required for adequate procedures in the diagnostic work-up and for proper treatment. Much expert and scientific information on individual genetic variation in relation to human disease is available online (Table 1). This article offers a
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Table 1 Inborn errors of metabolism: online information sources OMIM (Johns Hopkins University, Baltimore) Extensive information on clinical and molecular topics of inborn errors of metabolism and other inherited diseases is available from www.ncbi.nlm.nih.gov in the Online Mendelian Inheritance in Man (OMIM) library. It combines the human gene map with a morbidity map. The OMIM database assigns a code (MIM) number, gives the locus symbol, and provides a complete list of clinical phenotypes for each disease entity. Experts also describe the clinical picture. OMIM provides a morbidity search machine for differential diagnosis on the basis of clinical symptoms and signs. At present, the number of gene loci with an associated clinical disease entity exceed 1700, and more than 2250 human phenotypes have been mapped on the genome. In more than 70% of these disease phenotypes, the molecular basis has been defined. The National Center of Biomedical Information (NCBI) website of the National Library of Medicine at the National Institute of Health also hosts the medical scientific literature (PubMed) and human genome (GenBank) library databases. Together these resources provide an intertwined and up-to-date online source for practitioners and scientists HUGO Mutation Database Initiative (University of Melbourne) The website ariel.ucs.unimelb.edu.au/*cotton/mdi.htm provides a list of locus-specific databases according to gene designation, available from university and research institute sources around the world. Connected by the MIM number of each locus, the information from OMIM is only one click away. The drawback is that the visitor should already know the locus lettercode prior to starting up the link. HUGO also lists patient information sites. Information on nonhuman genetic variation is also available
conceptual approach to the field, and describes a selection of diseases in which nutritional intervention is possible.
Genetics and Inborn Errors of Metabolism 0003
0004
Inherited metabolic diseases cause structural changes or metabolic derangements in the body. The term ‘inborn error of metabolism’ was presented by John Garrow in 1906 in a lecture about alcaptonuria, in which he also hypothesized the theory of one gene, one protein as its cause. Although the concept of inborn error of metabolism implies that a deficiency of a single enzyme is present, the term has also come into use to describe inherited disorders in proteins not involved in metabolism. Mutated genes and their translation products, proteins, can cause derangements during body and tissue formation, and can also be present as abnormal structural proteins and diminished enzyme activity in a wide range of processes. Autosomal recessive inheritance is the most common form of inheritance encountered in inborn errors of metabolism, but not all affected individuals necessarily have symptoms and other inheritance patterns are all but rare. Mutations in the estimated 30 000 human genes can in principle cause a very large number of diseases. More than 2200 disease loci are now known. In the human genome, mutations in a number of genes are not compatible with survival at the time the embryo develops. In some cases the same mutation in an allele is known to be causally related to more than one disease. Within one disease the same genotype can be associated with more than one phenotypical presentation. Given the magnitude of the human genome, and the multitude of possible mutations and phenotypic disease states, it is not possible to
recognize all inborn errors of metabolism by neonatal screening. Apart from dedicated neonatal screening for the more frequent and treatable disorders, simple methods using clinical diagnosis and targeted laboratory investigations are needed to identify the inborn error of metabolism in an individual patient. From a pathophysiological point of view, the metabolic disorders can be divided into a number of groups that can be used to facilitate diagnostic decision making, including the initial differential diagnosis by the general practitioner and specialist. Specialists in pediatrics, internal medicine, neurology, clinical chemistry, and genetics collaborate in the clinical field of metabolic diseases for establishing the diagnosis on the level of the protein or gene, and to provide treatment and genetic counseling. The focus of this chapter is on inborn errors of metabolism in which nutritional modulation is an important, and in some cases the only, is of treatment. They are summarized in Table 2. Not all inborn errors of metabolism with nutritional consequences are covered in this article. Familial hyperlipidemias are, also in terms of numbers of patients, a very important group of inborn errors of metabolism, and are dealt with elsewhere in this encyclopedia. Some inborn errors of metabolism in which food components play a role, notably glucose6-phosphate dehydrogenase deficiency, in which fava beans can trigger symptoms, and porphyrias in which low carbohydrate intake can aggravate symptoms, are not further explored here.
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Pathophysiology Metabolic disorders can be divided into groups, according to the pathophysiological mechanism that is involved.
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3264 INBORN ERRORS OF METABOLISM/Overview tbl0002
Table 2 Selected metabolic disorders for which nutritional therapy is used Amino acid disorders Phenylketonuria Tyrosinemia type I and II Maple syrup urine disease Urea cycle defects Homocysteinuria (CBS-deficiency) Isovaleric acidemia Serine synthesis defect (3-PGDHD) Hartnup disease
Protein restriction, tyrosine and docosa-hexanoic acid supplementation Protein restriction, NTBC in type I Valine, leucine, isoleucine restriction, and thiamin supplementation Protein restriction, arginine and sodium benzoate and phenylacetate supplementation Methionine restriction, vitamin B6, and betaine supplementation Leucine restriction, glycine and carnitine supplementation Serine and glycine supplementation High-protein, nicotinamide supplementation
Carbohydrate disorders GSD type I and III Galactosemia Hereditary fructose intolerance Glucose-galactose malabsorption Congenital disorder of glycosylation Ib
High carbohydrate/low fat and cholesterol Galactose (and lactose) restriction Fructose restriction High fructose/low glucose-galactose Mannose supplementation
Organic acidemias and acidurias Propionic acidemia Methyl malonic acidemia Multiple acyl coenzyme A dehydrogenase deficiency Glutaric aciduria type I
Protein restriction, avoidance of dehydration, Inhibition of colonic flora with metronidazole Protein restriction, vitamin B12 supplementation Fat restriction, riboflavin and carnitine supplementation Lysine restriction, riboflavin supplementation
Fatty acid oxidation and ketolysis defects b-Ketothiolase deficiency MCAD, LCAD, LCHAD deficiency
Low protein, avoid fasting Low fat, avoid fasting, + carnitine
Mitochondrial disorders Respiratory-chain disorders Pyruvate dehydrogenase deficiency
Increased energy need in early life High fat/low carbohydrate and thiamin
Micronutrient disorders Biotinidase deficiency Vitamin B6-dependent epilepsy Transcobalamin II deficiency Immerslund-Grsbeck disease Hereditary folate malabsorption Methylene tetrahydrofolate reductase deficiency Acrodermatitis enterohepatica Wilson disease
Biotin supplementation Vitamin B6 supplementation Vitamin B12 supplementation Vitamin B12 supplementation Folate supplementation Folate supplementation Zinc supplementation Zinc supplementation
NTBC, nitro-trifluoro-methylbenzoyl-cyclohexanedione; CBS, cystathionine b-synthase: homozygous patients cannot metabolize homocysteine which is formed after transmethylation of methionine; 3-PGDHD, 3-phosphoglycerate dehydrogenase deficiency: the enzyme block prevents the biosynthesis of serine; GSD, glycogen storage disease; MCAD, medium-chain acyl coenzyme A dehydrogenase; LCAD, long-chain acyl coenzyme A dehydrogenase; LCHAD, long-chain hydroxy acyl coenzyme A dehydrogenase: these mitochondrial enzymes form part of the oxidation of fatty acids.
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Group 1 is comprised of disorders characterized by the disturbed synthesis or catabolism of complex molecules. Symptoms are not related to food intake, and are permanent, progressive, and independent of intercurrent infections. Lysosomal storage disease, peroxisomal disorders, a1-antitrypsin deficiency, and congenital disorders of glycosylation are in this group. With some notable exceptions, nutritional therapy is not effective in these disorders. Group 2 includes all disorders of intermediate metabolism. Because multiple enzymes are involved in the metabolism between macronutrients and end products, these disorders lead to accumulation of toxic compounds proximal to the metabolic block. There can be progressive or acute intoxication due to
these compounds, and intercurrent infections or excessive intake of foods can lead to a metabolic crisis. A symptom-free interval is characteristic. Late onset or an intermittent clinical presentation is typical. Aminoacidemias, most organic acidurias, urea cycle defects, and sugar intolerances belong to this group. Group 3 consists of inborn errors involved in intermediate metabolism which is directly related with cellular energy transfer. Enzyme defects can affect the supply with macromolecules involved in energy production as well as the transfer of energy by molecules in the matrix and in the inner membrane respiratory chain system within the mitochondria. Glycogen storage diseases, gluconeogenesis defects, defects in pyruvate carboxylase and dehydrogenase,
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INBORN ERRORS OF METABOLISM/Overview
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fatty acid oxidation defects, and mitochondrial respiratory chain disorders are present in this group. Group 4 is comprised of diseases in which disturbances are present in: (1) membrane transport; (2) intracellular signaling; or (3) critical developmental periods. Defects of transmembrane transporters for carbohydrates, amino acids, and lipids in the intestine are suspected by clinical observation (diarrhea, failure to thrive) and absorption studies. Similarly, defects can be present in tubular reabsorption in the kidney. Other clinical entities are related to disturbed transport of metals (e.g., of copper, such as Menkes and Wilson disease). New insights have been developed that complex compounds, produced in specialized metabolic tissues and necessary for specialized functions in the brain, must undergo a critical step in transport over the cell membrane for proper function. Similarly, with respect to intracellular signaling functions, the assembly or metabolism of complex compounds in the central nervous system and other organs can be deranged. Defects of intracellular membrane transport comprise another group of newly recognized disorders. The transport defects generally result in the dysfunction of one or more affected organs (e.g., diarrhea in carbohydrate malabsorption, liver failure and brain dysfunction by copper storage in Wilson disease, brain dysfunction in creatine transporter deficiency, X-linked nonspecific mental retardation, and abnormal neurotransmitter synthesis) or deficiency syndromes (due to malabsorption). Recently, insights in developmental biology led to the discovery that certain compounds (e.g., cholesterol) with known functions during extrauterine life are critical for developmental gene description in the embryo (e.g., absence of 7-dehydrocholsterol biosynthesis causes Smith–Lemli–Opitz syndrome, characterized by dysmorphic features and severe mental retardation). Developments in molecular biology and the genome project, human genetics, and clinical chemistry enable discovery of the etiology and pathophysiology of newly recognized disorders with a range of clinical presentations.
Clinical and Laboratory Expertise in Diagnosis 0013
Children with inborn errors of metabolism may present with one or more of a large variety of symptoms and signs. Although most Mendelian phenotypes are expressed early in life, adult presentations are recognized in increasing numbers. The patient history, clinical assessment (for color, odor, hepatomegaly, neurological abnormalities, including hypotonia, and dysmorphic features), and immediate laboratory
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investigations are necessary for initial judgment in terms of the pathophysiology group and index of suspicion for an inborn error of metabolism. A full medical and genetic family history is important and should include the circumstances of any stillbirth, sudden infant death, unusual death in childhood or early adulthood, and information on consanguinity between the parents. Blood investigations should include routine hematology and electrolytes (search for anion gap), glucose, creatinine, liver enzymes, bilirubin, ammonia, calcium, phosphate, lactate, pyruvate, ketone bodies (3-hydroxy- and ketobutyrate), fatty acids, uric acid, blood-gas analysis, and prothrombin time. Urinalysis should include acetone, reducing substances, pH, sulfite, electrolytes, and uric acid. Further investigation may comprise lumbar puncture, chest X-ray, and cardiac and central nervous system function studies. Further laboratory and other investigations are guided by the pathophysiological group, abnormalities in the routine investigations, and suspicion of an individual disorder. The metabolic laboratory is specialized in the investigation of body fluids in the search of abnormal metabolites which are present in many inborn errors of metabolism. Apart from the routine investigations mentioned above, liquid, gas, and thin-layer chromatography are performed on plasma, urine and cerebrospinal fluid, and mass spectrometry, electrophoresis and spectrometric analysis techniques are other methods available for investigation. The use and distribution of these techniques in the investigation of patients suspected of an inborn error of metabolism are depicted in Figure 1. A systematic description of the metabolites and abnormalities frequently observed in inborn errors of metabolism is beyond the scope of this overview. In practice, the inborn errors in which laboratory abnormalities are found are grouped using three different conceptual approaches. Grouping takes place by: (1) the main laboratory abnormality in a body fluid (e.g., aminoacidemia or organic aciduria) as a result of the enzyme defect; (2) the cell organelle where the abnormality is located (e.g., lysosomal storage disease, perixisomal disorder); and (3) the abnormal structural molecule (e.g., defect of purine metabolism, mucopolysacharidosis, or congenital disorder of glycosylation). Figure 2 shows the distribution of diagnosis of inborn error of metabolism based on records in one laboratory of metabolic diseases where both regional and international patient investigations take place. The diagnosis system of an inborn error of metabolism is eventually based on the enzyme nomenclature, the MIM number (Mendelian inheritance in
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3266 INBORN ERRORS OF METABOLISM/Overview 32%
37% Liquid chromatography Thin-layer chromatography Gas chromatography Mass spectometry Spectrometric analysis Electrophoresis Routine analyses
1% 14% fig0001
8%
6%
2%
Figure 1 (see color plate 99) Laboratory analyses performed in body fluids of 2150 patients investigated over a period of 5 years in the laboratory for metabolic diseases of the Vrije Universiteit Medical Center in Amsterdam. Investigations were performed in whole blood, plasma, urine, amniotic fluid, and cerebrospinal fluid.
9%
16% 7%
Aminoacidemias Organic acidurias Carbohydrate disorders Lysosomal disorders Peroxisomal disorders Mitochondrial disorders Rest
18% 41% 5% fig0002
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4%
Figure 2 (see color plate 100) Frequency distribution according to diagnostic group in 263 patients newly identified with an inborn error of metabolism over a period of 5 years in the Laboratory for Metabolic Diseases of the Vrije Universiteit Medical Center in Amsterdam. Fatty acid oxidation defects included in organic acidurias.
man, formerly the McKusick number) for each disease entity, and the mutations linked with the clinical entities in the OMIM database (Online Mendelian inheritance in man: Table 1). Enzyme diagnosis, using leukocytes, cultured fibroblasts, or biopsies from chorionic villi or other affected tissue, is increasingly used to confirm the diagnosis. DNA diagnosis is also developed for an increasing number of inborn errors. In the following paragraphs, some important disorders and clinical problems are presented, to illustrate the interactions between nutrition and inborn errors of metabolism.
Amino Acid Disorders (Group 2 Pathophysiology) 0019
Amino acids are the building blocks of body protein and are mainly derived from the diet. Ingested protein is absorbed almost completely. Amino acids which become available in the body, in excess of the needs for protein synthesis and growth, are eventually oxidized through several pathways. For the nonessential amino acids there are also pathways of
biosynthesis. Some of these pathways are shared between two or more amino acids, and others are unique to one amino acid. Inborn errors of metabolism are known for each amino acid. Here we discuss two of the most frequently encountered aminoacidemias. Hyperphenylalaninemia
Phenylalanine is an essential amino acid. It is normally degraded via the tyrosine pathway. To enter the tyrosine pathway, phenylalanine is converted into tyrosine by the enzyme phenylalanine hydroxylase, which has tetrahydrobiopterin as a cofactor. Deficiency of the enzyme or of its cofactor causes accumulation of phenylalanine in the body fluids and tissues. Hyperphenylalaninemia is present, and detection in plasma is a reliable way of establishing the suspected diagnosis. Classic phenylketonuria (PKU) is caused by the deficiency of the enzyme phenylalanine hydroxylase. In the first weeks after birth patients have no symptoms, although in the neonatal period vomiting can be an early symptom. Mental retardation is the major abnormality in untreated patients, with an estimated loss of about 50 IQ points by the end of the first year
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INBORN ERRORS OF METABOLISM/Overview
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of life. Untreated patients develop behavioral and neurological abnormalities, including hypertonicity and athetosis, and 25% of patients develop epilepsy. On clinical examination they have an unpleasant smell, probably due to the accumulation of abnormal metabolites of phenylalanine such as phenylacetic acid (which has a musky odor). Microcephaly and growth retardation are common. If protein and phenylalanine restriction is instituted early after birth, the patients remain free of these symptom. Special PKU infant formulas are available, but careful follow-up of the patient’s physical growth and development is needed and regular measurement of phenylalanine plasma levels are mandatory in order to prevent under- and overtreatment. Metabolic derangement can take place under catabolic conditions, e.g., during infections. Proper treatment requires early detection. Mass newborn screening for PKU became effective when Guthrie developed a bacterial inhibition assay which could be done on dried blood collected on paper obtained after a heel puncture during the second half of the first week of life. About one in 50 patients with hyperphenylalaninemia have a defect in one of the enzymes necessary for the synthesis or recycling of the cofactor tetrahydrobiopterin. If undetected and treated as PKU, these patients show normalized phenylalanine plasma levels but develop severe neurological symptoms. The reason is that tetrahydrobiopterin is a cofactor for other hydroxylases, involved not only in hydroxylation of phenylalanine but also of tyrosine and tryptophan. The latter two are involved in the biosynthesis of the neurotransmitters dopamine and serotinin. For this reason all neonates with hyperphenylalaninemia are required to undergo tests for deficiency of the cofactor. Treatment of these patients requires protein restriction and supplementation with tetrahydrobiopterin (because they also have nonclassical PKU), and supplementation of l-dopa and 5-hydroxytryptophan (because the supplemented cofactor does not cross the blood–brain barrier). Research has demonstrated that in vivo hydroxylation in children with PKU can be so low that patients may suffer from the effects of a diminished availability of the metabolic product of phenylalanine hydroxylase, tyrosine. Tyrosine is an essential amino acid required for physical growth but also a precursor for dopamine biosynthesis. Tyrosine supplementation thus is required in some patients with PKU. PKU is one of the more common inborn errors of metabolism and this autosomal recessive disease is a major cause of preventable hereditary mental retardation and neurological debilitation in the population. Neonatal screening programs have saved thousands
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of patients who would otherwise have spent their life in asylums. Nowadays, many adult patients cease the diet and report no psychological or neurological problems. None the less, new problems have emerged in the management of these patients. Pregnancies in mothers with PKU who no longer use the lowphenylalanine diet are complicated by spontaneous abortions, and their living offspring are often mentally retarded and show microcephaly or congenital heart disease. It has become clear that women with PKU who are of child-bearing age should start a lowphenylalanine diet before conception and should be closely monitored for their phenylalanine blood levels before and during pregnancy. Also, deficiency of n-6 polyunsaturated fatty acids has been described in patients with PKU (and supplementation has been advocated). The complications during pregnancy and of polyunsaturated fatty acid synthesis demonstrate one of the concepts of group 2 pathophysiology, i.e., that metabolites accumulating proximal to the metabolic block can cause derangements in distant organs and metabolic pathways. Tyrosinemia Type 1
Tyrosine is likewise an essential amino acid derived from ingested protein. Excess tyrosine is oxidized. Several inborn errors of metabolism in the degradative pathway are known. Deficiency of fumarylacetoacetate hydroxylase causes type 1 tyrosinemia, and has an acute or chronic clinical manifestation. The acute form presents in infancy, and comprises most reported cases. Some symptoms resemble that of PKU with failure to thrive, developmental delay, and vomiting, but hepatic manifestations with organ enlargement, jaundice, and bleeding tendency are common findings as well. Apart from elevated tyrosine, elevated methionine is also found in many patients. Hypoproteinema and low prothrombin are often present. Many patients develop end-stage hepatic failure in childhood and die unless appropriate therapy is started. Patients with the chronic form also present with failure to thrive and development delay, but generally not during the first year of life. Cirrhosis (which can be associated with acute liver failure during catabolic episodes), renal tubular dysfunction, and vitamin D-resistant rickets are often found. Acute episodes of polyneuropathy may complicate the disease. In the long term, a substantial proportion of patients with type 1 tyrosinemia develop hepatic adenoma, and over time hepatocellular carcinoma can develop in these lesions. The wide spectrum of organ pathology, including malignant disease in tyrosinemia, demonstrates the effect of toxic substances that accumulate due to the inability to catabolize tyrosine. Although dietary restriction of tyrosine and
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3268 INBORN ERRORS OF METABOLISM/Overview
methionine has been advocated over the years, many patients have shown progression of hepatorenal and hematological symptoms and developed malignant liver disease under this treatment regimen. Liver transplantation is a cure for patients with liver cirrhosis or (solitary) tumors, as the donor liver provides the patients with a normally functioning liver, including normal activity of the deficient enzyme. Liver transplantation has a high risk of acute and chronic complications and thus is only an option for patients with severe liver disease. Since 1994 a promising new pharmacological therapy has been successful in reducing morbidity and liver complications: nitrotrifluoro-methylbenzoyl-cyclohexanedione (NTBC), an inhibitor of p-hydroxyphenylpyruvate dioxygenase, prevents the formation of (cytotoxic and carcinogenic) metabolites distal of this enzyme and proximal of the inborn error. Although the elevated tyrosine levels do not disappear during NTBC therapy, and tyrosine and methionine restriction remain necessary, this treatment appears remarkably effective. Patient follow-up of this treatment has been less than 10 years at present. There is hope that the long-term life-threatening complications such as liver failure, bleeding disorders and tumor induction are preventable with NTBC.
Table 3 Metabolic causes of hypoglycemia in childhood Decreased production of glucose Decreased release of glucose from the liver Glycogen synthase deficiency Glucose-6-phosphate deficiency (GSD type Ia or Ib) Amylo-1,6-glucosidase deficiency (GSD type III) Galactose-1-phosphate deficiency (galactosemia) Fructose-1-phosphate aldolase deficiency (hereditary fructose intolerance) Decreased rate of gluconeogenesis Pyruvate carboxylase deficiency Phosphoenolpyruvate carboxylase deficiency Fructose-1,6-diphosphatase deficiency Glycerokinase deficiency Decreased availability of alternative fuels, resulting in increased use or decreased conservation of glucose Impaired oxidation of fatty acids Medium-chain acyl-coenzyme A dehydrogenase deficiency Long-chain acyl-coenzyme A dehydrogenase deficiency Carnitine acyltransferase I deficiency Multiple acyl coenzyme A dehydrogenase deficiency Impaired synthesis or use of ketones b-Ketothiolase deficiency Hydroxymethylglutaryl coenzyme A lyase deficiency Decreased fat stores Prematurity Malnutrition GSD, glycogen storage disease. Other metabolic disturbances resulting in hypoglycemia are toxic (exposure to ethanol or salicylate), endocrine (hyperinsulinemia, growth hormone deficiency, cortisol deficiency), hyperleucinemia, and a selflimiting ketotic hypoglycemia.
Energy Disturbance (Group 3 Pathophysiology) Hypoglycemia 0027
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A low blood sugar level is potentially dangerous (for central nervous system function) and can be lifethreatening. Some organs (the heart, the brain) have a high energy expenditure while using only a limited selection of metabolic fuels. For the brain the balance between energy supply and expenditure is the most critical because glucose and ketone bodies (and, under certain conditions, lactate) are its only energy substrates and the specific energy demand is high. Energy stores in the neural cells are very low and rapidly consumed. Although hypoglycemia can be caused by nonmetabolic disorders it is a hallmark symptom for a large number of inborn errors of metabolism, particularly those of intermediate carbohydrate and triacylglycerol metabolism (Table 3). Symptoms can be present within hours after birth (and, in the case of low liver stores, even within minutes). The time of presentation after the last meal is indicative of the relevant group of disorders, with glycogen storage disease, gluconeogenesis defects, and fatty acid oxidation defects and impaired availability of ketones successively being the most probable cause when a wider gap is reported between
the time of the last meal and the presentation of the hypoglycemia. For the diagnosis of the inborn error, and for the differential diagnosis, including endocrine disorders, blood and urine sampling at the time of the hypoglycemic crisis is essential. In life-threatening situations such as coma, treatment prevails over the complete collection of samples for the diagnostic work-up. Some abnormalities may still be present in blood and urine even hours after intravenous administration of glucose and restoration of the blood glucose level to the normal range. In some disorders symptoms can develop only months or even years after birth. The clinical spectrum is wide, with liver enlargement present in some (e.g., glycogen storage type I and III, hereditary fructose intolerance) but not all disorders and toxic crises present in some (e.g., coma and severe liver function abnormalities in medium-chain acyl-coenzyme A dehydrogenase deficiency) but not all disorders. Hyperlipidemia, granulocyte dysfunction, hyperuricacidemia and gout, hyperlactatemia and osteoporosis, liver adenomas, and pancreatitis are complications in just one of these disorders (glycogen storage disease type I). Cataracts with or without liver dysfunction are seen in galactosemia. This illustrates that virtually any organ
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system can be affected in the wide spectrum of disorders encountered as the cause of a decreased blood level of just one metabolite, glucose. A systematic overview of the spectrum of disease and complications of inborn errors of metabolism causing hypoglycemia cannot be further pursued here. Treatment depends on the cause, and ranges from strict avoidance of certain foods (e.g., galactose and lactose in galactosemia) to continuous dripfeeding (e.g., in glycogen storage disease type I). Avoidance of prolonged fasting is important in a large proportion of disorders. Early diagnosis is essential to prevent brain damage and other irreversible organ failure. Thus recurrent or severe hypoglycemia should bear a high degree of suspicion of a metabolic cause. Elevated Resting Energy Expenditure
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Mitochondrial respiratory chain enzyme defects are associated with myopathy and failure to thrive in early life in mildly affected patients and severe multiorgan involvement, including brain damage and early death in other patients. The failure to thrive in infants with the disease can result from neurological impairment (vomiting, difficulty with swallowing) but also elevated energy expenditure is often found. The pathophysiology of the increased resting energy expenditure is of conceptual interest for this overview on human inborn errors and nutrition. The mitochondrial respiratory chain is comprised of five enzyme complexes which together drive the process of oxidative phosphorylation and maintain the proton gradient through which adenosine triphosphate (ATP) production is maintained. Complex I, III, and IV have proton-pumping capacity, and the efficiency of the protons (with eventually energy transfer to ATP, P) pumped and coupled electron flow through the respiratory chain to oxygen (O) can be expressed as the P/O ratio. In normal mitochondria the ratio is about 1.75 for reduced nicotinamide adenine dinucleotide (NADH)-linked substrates and 2.75 for reduced flavin adenine dinucleolide (FADH)-linked substrates. However, in patients with deficiency of complex I, II, or III, the respiratory chain is substantially less efficient as one proton (ATP) less is produced by the electron’s energy transfer between complex I and V. Adaptive changes, including a higher adenosine diphosphate (ADP) concentration (a known stimulus of oxidative phosphorylation activity) and higher resting oxygen consumption are present in many patients. To find out whether, and to what extent, this pathophysiological mechanism is present in an individual patient diagnosed with a respiratory chain defect indirect calorimetry can be useful. Therapy exists in high-energy feedings, and
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growth monitoring is important. This is particularly important during infancy when energy demands and growth rates are already high and patients depend on food offered by the mother. In later life many patients expend less energy due to muscle fatigue and lower physical activity levels, and the balance between total daily energy expenditure and energy intake is more easily maintained.
Lipids and Essential Fatty Acid Deficiency In the affluent world and in poor parts of the world, nonhereditary causes of insufficient essential fatty acid status prevail and are worldwide much more frequent than hereditary causes. Disturbance of n-6 and n-3 polyunsaturated fatty acid status is caused by a number of inborn errors. The most frequent ones are shown in Table 4. Single-enzyme deficiencies in the metabolic pathways of n-6 and n-3 polyunsaturated fatty acid synthesis and oxidation are extremely rare, probably because essential fatty acids from food and the interconnections between the n-6 and n-3 desaturase pathways provide alternative provisions and overflow routes for affected metabolites. These rare patients are not reviewed here or included in Table 4.
Table 4 Causes of essential fatty acid deficiency Mechanism and disease state Hereditary causes Intestinal malabsorption Abetalipoproteinemia Hypobetalipoproteinemia Anderson disease Exocrine pancreas insufficiency Cystic fibrosis Shwachman syndrome Pearson syndrome Deranged metabolism of polyunsaturated fatty acids Decreased synthesis of docosahexanoic acid Phenylketonuria Zellweger syndrome Decreased inhibition of leukotriene B4 Sjo¨gren–Larsson syndrome Nonhereditary causes Malnutrition Fat-free diet Parenteral nutrition without essential fatty acid supplementation
Affected gene(s)
MTTP Apolipoprotein B ? CFTR Mapped to 7p11-q11 Mitochondrial DNA deletions
PAH PEX
FALDH None
MTTP, microsomal triglyceride transfer protein; CFTR, cystic fibrosis transmembrane conductance regulator; PAH, phenylalanine hydroxylase; PEX, peroxin, involved in peroxisome biogenesis; FALDH, microsomal fatty aldehyde dehydrogenase.
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In patients with disorders in which the assembly of peroxisomes is deficient (mutations in PEX protein complementation groups, e.g., Zellweger syndrome), deficiency of some essential fatty acids has been documented. Enzymes required for the oxidation of verylong-chain fatty acids (including arachidonic acid) and in the synthesis of some polyunsaturated compounds are located in the peroxisome and these are absent or have a very low activity in these patients. PKU is a single-enzyme disease in phenylalanine hydroxylation in which low essential fatty acid status has been found. It is associated with neuropathy in some patients. Circulating abnormal metabolites affect the synthesis of n-6 (arachidonic acid) and n-3 (docosahexanoic acid) fatty acids. Secondary deficiency of essential fatty acids has been found in relatively rare disorders causing lipid malabsorption (transport defects, group 4 pathophysiology) and hereditary exocrine pancreas insufficiency. In the latter group, cystic fibrosis is the most frequently encountered disorder. Sjo¨ gren–Larsson syndrome (in which microsomal conversion of medium- and long-chain fatty aldehydes to their carboxylic acids is defective) causes a unique inactivation in leukotriene B4 inhibition. Patients have elevated leukotriene levels and inflammatory skin changes. Symptoms of essential fatty acid deficiency in other patients are nonspecific and range from dermatitis to
severe failure to thrive. Diagnosis is often delayed. Treatment of exocrine pancreas insufficiency by pancreas enzyme supplementation often corrects the essential fatty acid profile. In other disorders skin ointments (on the basis of vegetable oil rich in polyunsaturated fatty acids) are a treatment option. The course of several severe and fatal disorders, such as abetaliproteinema or Zellweger syndrome (in which oral supplementation is given), is not clearly altered by such treatment however. See also: Amino Acids: Properties and Occurrence; Determination; Metabolism; Diabetes Mellitus: Problems in Treatment; Fatty Acids: Trans-fatty Acids: Health Effects; Hyperlipidemia (Hyperlipidaemia); Nucleic Acids: Properties and Determination; Physiology
Further Reading Blau N, Duran M, Blaskovics ME and Gibson KM (eds) (2003) Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases. London: Springer. Fernandes J, Saudubray JM and van den Berghe G (eds) (2000) Inborn Metabolic Diseases. Berlin: Springer. Leonard JV and Morris AAM (2000) Inborn errors of metabolism around time of birth. Lancet 356: 583–587. Scriver CR, Beaudet AL, Sly WS et al. (eds) (2001) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill.
INFANT FOODS Contents Milk Formulas Weaning Foods
Milk Formulas D Hileti-Telfer, The Hospitals for Sick Children, London, UK Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Background 0001
Until the early 1900s, there was no alternative to human breast milk for feeding newborn infants. Consequently, over 80% of infants were breast-fed. If a mother was unable to breast-feed her baby, a wet nurse had to be found, or diluted cow’s milk had to be given. The 1940s marked a major turning point
in the history of infant feeding in the UK, with an increasing proportion of babies being bottle-fed. A number of social, economic, and practical factors contributed to this radical change in infant feeding practices. The major influence was the introduction of the Welfare Food Scheme during World War II. This allowed mothers and children to have free or subsidized National Dried Milk (NDM) at a time when cows’ milk was rationed. Inevitably, the use of NDM spread to infants and escalated as social attitudes gradually changed towards women working outside the home. Unfortunately, NDM and most commercial infant formulas available over the succeeding years were not
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