Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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been identified, which underscores the complexity of

nutrient–gene regulation.

0021 In contrast, an indirect effect may be exerted by

some nutrient metabolites through secondary metab-

olism. The effect of dietary fiber is a well-studied

example of indirect gene modulation. Intestinal bac-

teria metabolize undigested fiber and release butyric

acid. Although the protective action of butyric acid

on colonocytes has not been fully elucidated, in vitro

studies suggest that butyric acid may modulate gene

expression by direct and indirect means. It may acet-

ylate or phosphorylate histones in the nucleus, which

would affect the binding of transcription factors to

regulatory elements of genes. In particular, elevated

butyrate has been shown to inhibit histone deacety-

lase, which results in the upregulation and secretion

of IL-8, a potent chemotactic factor for neutrophils.

In addition, butyrate could also act as an oxidative

substrate, which would modulate cellular signaling

networks via G-proteins. Investigation of these mech-

anisms may uncover new dietary treatments and

better understanding of the progression of colorectal

cancer. Moreover, butyrate-producing bacteria in the

intestine can vary depending on the diet. Infants fed a

casein-based formula predominantly excrete butyric

acid and propionic acid, in contrast to breast-fed

infants whose stool contains mostly acetic acid.

Thus, the presence of butyrate can relay signals to

the mucosal immune system, providing vital informa-

tion about luminal contents and events.

0022 Expression of genes for proteins involved in anti-

gen presentation, namely major histocompatibility

complex (MHC) class II molecules and the invariant

chain Ii on enterocytes, are also regulated by diet. In

mice, prolonged exposure to dams’ milk delayed the

expression of MHC class II and Ii molecules, suggest-

ing that early oral dosing of antigens could modify the

level of antigen presentation. Furthermore, the ap-

pearance of MHC class II and Ii molecules was

delayed in mice fed an elemental diet composed of

synthetic amino acids and fats as compared to litter-

mates fed standard cereal-based rodent diets. Thus,

gene expression in intestinal epithelial cells can be

manipulated via the presence of specific dietary

proteins in the gut lumen.

0023 The complexity of nutrient–gene interactions in-

volves not only interaction with the genome and

gene transcription but also affects posttranscriptional

events. The regulatory factors involved in posttran-

scriptional control may be the dietary components

themselves, metabolites, or changes in hormones,

making it difficult to distinguish the regulatory path-

way. There are some examples of nutritional modifi-

cations where the regulatory sequences that are

targeted are from 3

and 5

untranslated regions

(UTR) of mRNA that bind specific proteins, a process

that in turn regulates polyadenylation, translation,

localization, and stability of mRNA. It may be pos-

sible in the future to define nutrient–gene interactions

in order to tailor dietary requirements to individuals

with different disease risk profiles.

Immunonutrition

0024Lessons learned from studying the immunomodula-

tory potential of individual nutrients in patients

undergoing surgery or recovering from various tissue

damage have led to the development of a therapeutic

approach called immunonutrition. These special ent-

eral diets are formulated with components that have

been shown to enhance or preserve host immune

reactions, or suppress exaggerated inflammatory re-

sponses, with the aim of decreasing the morbidity and

mortality of critically ill patients. Immune-enhancing

enteral diets have been assessed in 12 prospective,

randomized clinical trials. Although these studies

show a strong and statistically significant benefit to

most patients, the ideal composition of such a diet

still needs to be established. Furthermore, a better

definition of the type of patient who would benefit

most from immunonutrition is needed before this

therapy is widely adopted.

Autoimmunity

0025Nutrition-based therapies of autoimmune disease are

a novel approach that exploits the immunomodula-

tory nature of certain foods. For example, vitamins

have been reported to act as immune regulators in

multiple sclerosis. 1,25-Dihydroxy vitamin D

sup-

plementation of mice with experimental autoimmune

encephalomyelitis (EAE), a murine model of multiple

sclerosis, prevented the progression of the disease,

while withdrawal caused regression to multiple scler-

osis-like symptoms. Nutrition-based therapy using

gamma-linolenic acid (18:3n-6) supplementation has

also reduced the signs and symptoms of disease activ-

ity in rheumatoid arthritis. Similarly, dietary modifi-

cation has been shown significantly to inhibit the

development of diabetes in both rodent models of

spontaneous autoimmune diabetes, BioBreeding rats

and nonobese diabetic (NOD) mice. It was shown that

hydrolyzed casein diets had less diabetes-inducing

potential than cereal-based diets. Of particular inter-

est, it was also observed that early oral exposure to

antigens from known diabetes-promoting diets

delayed and inhibited development of diabetes in

about one-third of neonates. The identity of the

immunomodulatory agent(s) in the diet is currently

being investigated.

3260 IMMUNOLOGY OF FOOD

0026 In other inflammatory disorders of the human

intestine, such as celiac disease, ulcerative colitis,

and Crohn’s disease, a cytokine imbalance may

trigger and potentiate the destructive process. In the

case of celiac disease, the gut immune system is

sensitized to certain wheat peptides. Upon ingestion

of wheat, individuals with certain disease-risk haplo-

types, particularly the antigen-presenting molecules

human leukocyte antigen (HLA)-DQ2 and HLA-

DQ8, may display gliadin proteins in a conformation

that is recognized by lamina propria T cells. Once

activated, these T cells could initiate a destructive

inflammatory process that releases the endomysial

autoantigen, tissue transglutaminase, and thus po-

tentiates the immune attack and atrophy of intestinal

villi. When wheat proteins are eliminated from the

diet, the immune attack stops and the symptoms dis-

appear. Of note, is the observation that celiac disease

predisposes individuals to other autoimmune dis-

orders such as type 1 diabetes, dermatitis herpeti-

formis, autoimmune thyroiditis, collagen diseases,

autoimmune alopecia, and autoimmune hepatitis.

This correlation is stronger in cases of long-term

undiagnosed and untreated celiac disease, further

suggesting that the GALT is an important site for

immune regulation and potential stimulation of auto-

reactive cells.

New Technologies

0027 New approaches are being explored to assess the

immunomodulatory nature of food components. For

instance, genomic analysis using microarray chip

technology can detect differences in the level of

transcription of genes. Alternatively, protein mixtures

can be characterized using two-dimensional electro-

phoresis and mass spectrometry to obtain amino acid

sequences of proteins that can be matched with those

in existing databases. This approach can be combined

with immunoblotting using sera from susceptible

individuals or specific monoclonal antibodies. Such

proteomic analysis has been used to characterize

wheat allergens in baker’s asthma. Since there is

debate over the risks of toxins, allergens, and other

chemical hazards stemming from new food produc-

tion and processing technologies, these modern tools

may be invaluable in food safety assessment. These

may also serve as predictive tools for predicting risk

of food immunogenicity and allergenicity.

0028 Transgenic plants are being examined as vehicles

for vaccine delivery. A case in point is transgenic

lettuce plants expressing hepatitis B virus surface

antigens that were ingested by human volunteers

and resulted in a specific serum-IgG response to

the plant-produced viral proteins. Other examples

include genetically modified potatoes expressing

Norwalk virus capsid protein or autoantigen for

autoimmune therapy. Transgenic plants may serve as

an inexpensive alternative to fermentation systems

for production of antigens. They may also avoid

costly purification processes because the subject

ingests directly the modified plant. Oral vaccination

with bioengineered plants is currently being evalu-

ated for long-term safety, effectiveness, and cost-

effectiveness. Transgenic tobacco plants containing

the autoantigen GAD-65 (glutamic acid decarboxy-

lase-65) were fed to diabetes-prone NOD mice and

this treatment prevented animals from developing

diabetes. These data open the possibility of using

bioengineered plants as vehicles for the delivery of

molecules that may be tolerogenic.

Summary

0029The nutrition recommendations that are currently

suggested by government agencies and health profes-

sionals are based on epidemiological studies of dis-

crete populations. The weakness of these studies is

that they do not take into account our inherent bio-

chemical and genetic individuality, as was already

recognized in 1956 by Williams. The food we eat

brings us into direct contact with a complex mixture

of nutrients, nonnutrients, toxins, microbes, and

molecules that are similar to those that make up our

own bodies. Many of these have biological activity

that can modify host immune system reactivity. This

multitude of food components can alter the nutri-

tional milieu, provide antigens that must be dealt

with, act as modifiers of lymphoid cell membranes,

alter the balance of immune regulatory (or other)

cell compounds such as growth factors, hormones,

metabolites, cytokines, chemokines, inflammatory

mediators, or interact directly with the genes that

are important controllers of the immune response.

We are at a stage when new tools for high-throughput

screening and analysis of gene and protein expression

are providing opportunities for understanding com-

plex interactions among food, genes, and proteins.

These technologies and our increasing ability to

categorize and comprehend the large amounts of

information they generate will permit new insights

into the mechanisms by which our exposure to hun-

dreds of chemicals from foods affects our immune

systems. This will eventually permit us to under-

stand the range of immune system reactivity and

how it is influenced by foods we eat as well as other

environmental factors. The advent of genome

and proteome exploration may yield information

that will permit nutrition-based therapies designed

for individuals.

IMMUNOLOGY OF FOOD 3261

Acknowledgements

0030 The authors thank the following agencies for sup-

porting the research program in Dr. Scott’s labora-

tory: 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: Breast-

and 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 expres-

sion. 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: immedi-

ate and long-term effects. Acta Paediatrica 88(430)

(Suppl.): 42–46.

Hesketh JE, Vasconcelos MH and Bermano G (1998) Regu-

latory signals in messenger RNA: determinants of

nutrient–gene interaction and metabolic compartmenta-

tion. British Journal of Nutrition 80: 307–321.

Heyman M (1999) Evaluation of the impact of food tech-

nology on the allergenicity of cow’s milk proteins. Pro-

ceedings of Nutritional Society 58: 587–592.

Koletzko B, Aggett PJ, Bindels JG et al. (1998) Growth,

development and differentiation: a functional food sci-

ence approach. British Journal of Nutrition 80(suppl. 1):

S5–S45.

Lamm DL and Riggs DR (2001) Enhanced immunocompe-

tence by garlic: role in bladder cancer and other malig-

nancies. 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) Micro-

array profiling of gene expression in aging and its alter-

ation 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: Gersh-

win 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

Scope

0001 In clinical medicine and food science, metabolic dis-

orders form a small but important field. Removal of

nutrients which can have a critical effect on develop-

ment of toxic crises or irreversible detrimental effect

on organ function is a potentially simple and some-

times 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, immunolo-

gists, hepatologists, dermatologists, and gynecolo-

gists. 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.

0002Much expert and scientific information on individ-

ual genetic variation in relation to human disease

is available online (Table 1). This article offers a

3262 INBORN ERRORS OF METABOLISM/Overview

conceptual approach to the field, and describes a

selection of diseases in which nutritional intervention

is possible.

Genetics and Inborn Errors of Metabolism

0003 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 derange-

ments during body and tissue formation, and can

also be present as abnormal structural proteins and

diminished enzyme activity in a wide range of pro-

cesses. 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.

000 4 Mutations in the estimated 30000 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 pre-

sentation. 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 labora-

tory investigations are needed to identify the inborn

error of metabolism in an individual patient.

0005From 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 metabol-

ism in which nutritional modulation is an important,

and in some cases the only, is of treatment. They are

summarized in Table 2.

0006Not all inborn errors of metabolism with nutri-

tional 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 glucose-

6-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.

Pathophysiology

0007Metabolic disorders can be divided into groups,

according to the pathophysiological mechanism that

is involved.

tbl0001 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

fromwww.ncbi.nlm.nih.govintheOnlineMendelianInheritanceinMan(OMIM)library.Itcombinesthehumangenemapwitha

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

INBORN ERRORS OF METABOLISM/Overview 3263

0008 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, a

-antitrypsin deficiency, and

congenital disorders of glycosylation are in this

group. With some notable exceptions, nutritional

therapy is not effective in these disorders.

0009 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 ex-

cessive 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.

0010Group 3 consists of inborn errors involved in inter-

mediate 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 mol-

ecules 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,

tbl0002 Table 2 Selected metabolic disorders for which nutritional therapy is used

Amino acid disorders

Phenylketonuria Protein restriction, tyrosine and docosa-hexanoic acid supplementation

Tyrosinemia type I and II Protein restriction, NTBC in type I

Maple syrup urine disease Valine, leucine, isoleucine restriction, and thiamin supplementation

Urea cycle defects Protein restriction, arginine and sodium benzoate and phenylacetate

supplementation

Homocysteinuria (CBS-deficiency) Methionine restriction, vitamin B

, and betaine supplementation

Isovaleric acidemia Leucine restriction, glycine and carnitine supplementation

Serine synthesis defect (3-PGDHD) Serine and glycine supplementation

Hartnup disease High-protein, nicotinamide supplementation

Carbohydrate disorders

GSD type I and III High carbohydrate/low fat and cholesterol

Galactosemia Galactose (and lactose) restriction

Hereditary fructose intolerance Fructose restriction

Glucose-galactose malabsorption High fructose/low glucose-galactose

Congenital disorder of glycosylation Ib Mannose supplementation

Organic acidemias and acidurias

Propionic acidemia Protein restriction, avoidance of dehydration, Inhibition of colonic flora with

metronidazole

Methyl malonic acidemia Protein restriction, vitamin B

supplementation

Multiple acyl coenzyme A dehydrogenase deficiency Fat restriction, riboflavin and carnitine supplementation

Glutaric aciduria type I Lysine restriction, riboflavin supplementation

Fatty acid oxidation and ketolysis defects

b-Ketothiolase deficiency Low protein, avoid fasting

MCAD, LCAD, LCHAD deficiency Low fat, avoid fasting, + carnitine

Mitochondrial disorders

Respiratory-chain disorders Increased energy need in early life

Pyruvate dehydrogenase deficiency High fat/low carbohydrate and thiamin

Micronutrient disorders

Biotinidase deficiency Biotin supplementation

Vitamin B

-dependent epilepsy Vitamin B

supplementation

Transcobalamin II deficiency Vitamin B

supplementation

Immerslund-Grsbeck disease Vitamin B

supplementation

Hereditary folate malabsorption Folate supplementation

Methylene tetrahydrofolate reductase deficiency Folate supplementation

Acrodermatitis enterohepatica Zinc supplementation

Wilson disease 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.

3264 INBORN ERRORS OF METABOLISM/Overview

fatty acid oxidation defects, and mitochondrial

respiratory chain disorders are present in this group.

0011 Group 4 is comprised of diseases in which disturb-

ances 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, fail-

ure 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 de-

veloped 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 intracellu-

lar signaling functions, the assembly or metabolism of

complex compounds in the central nervous system

and other organs can be deranged. Defects of intra-

cellular 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 mal-

absorption, liver failure and brain dysfunction by

copper storage in Wilson disease, brain dysfunction

in creatine transporter deficiency, X-linked non-

specific mental retardation, and abnormal neuro-

transmitter synthesis) or deficiency syndromes (due

to malabsorption).

0012 Recently, insights in developmental biology led to

the discovery that certain compounds (e.g., choles-

terol) with known functions during extrauterine life

are critical for developmental gene description in the

embryo (e.g., absence of 7-dehydrocholsterol biosyn-

thesis causes Smith–Lemli–Opitz syndrome, charac-

terized 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 patho-

physiology of newly recognized disorders with a

range of clinical presentations.

Clinical and Laboratory Expertise in

Diagnosis

0013 Children with inborn errors of metabolism may pre-

sent with one or more of a large variety of symptoms

and signs. Although most Mendelian phenotypes are

expressed early in life, adult presentations are recog-

nized in increasing numbers. The patient history,

clinical assessment (for color, odor, hepatomegaly,

neurological abnormalities, including hypotonia, and

dysmorphic features), and immediate laboratory

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.

0014Blood investigations should include routine hema-

tology and electrolytes (search for anion gap), glu-

cose, 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. Urin-

alysis should include acetone, reducing substances,

pH, sulfite, electrolytes, and uric acid. Further investi-

gation 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, abnor-

malities in the routine investigations, and suspicion of

an individual disorder.

0015The metabolic laboratory is specialized in the

investigation of body fluids in the search of abnor-

mal metabolites which are present in many inborn

errors of metabolism. Apart from the routine investi-

gations mentioned above, liquid, gas, and thin-layer

chromatography are performed on plasma, urine and

cerebrospinal fluid, and mass spectrometry, electro-

phoresis and spectrometric analysis techniques are

other methods available for investigation. The use

and distribution of these techniques in the investiga-

tion of patients suspected of an inborn error of

metabolism are depicted in Figure 1.

0016A 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 dif-

ferent 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 distri-

bution 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.

0017The diagnosis system of an inborn error of metab-

olism is eventually based on the enzyme nomenclat-

ure, the MIM number (Mendelian inheritance in

INBORN ERRORS OF METABOLISM/Overview 3265

man, formerly the McKusick number) for each dis-

ease 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 increas-

ingly used to confirm the diagnosis. DNA diagnosis is

also developed for an increasing number of inborn

errors.

0018 In the following paragraphs, some important dis-

orders and clinical problems are presented, to illus-

trate 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 eventu-

ally oxidized through several pathways. For the non-

essential amino acids there are also pathways of

biosynthesis. Some of these pathways are shared be-

tween 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

0020Phenylalanine is an essential amino acid. It is nor-

mally degraded via the tyrosine pathway. To enter

the tyrosine pathway, phenylalanine is converted

into tyrosine by the enzyme phenylalanine hydroxy-

lase, 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.

0021Classic phenylketonuria (PKU) is caused by the

deficiency of the enzyme phenylalanine hydroxylase.

In the first weeks after birth patients have no symp-

toms, 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

37%

14%

32%

Liquid chromatography

Thin-layer chromatography

Gas chromatography

Mass spectometry

Spectrometric analysis

Electrophoresis

Routine analyses

fig0001 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.

18%

Aminoacidemias

Organic acidurias

Carbohydrate disorders

Lysosomal disorders

Peroxisomal disorders

Mitochondrial disorders

Rest

41%

16%

fig0002 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.

3266 INBORN ERRORS OF METABOLISM/Overview

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 devel-

opment is needed and regular measurement of

phenylalanine plasma levels are mandatory in order

to prevent under- and overtreatment. Metabolic de-

rangement can take place under catabolic conditions,

e.g., during infections.

0022 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.

0023 About one in 50 patients with hyperphenylalanine-

mia have a defect in one of the enzymes necessary

for the synthesis or recycling of the cofactor tetrahy-

drobiopterin. 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 hydro-

xylation of phenylalanine but also of tyrosine and

tryptophan. The latter two are involved in the bio-

synthesis of the neurotransmitters dopamine and

serotinin. For this reason all neonates with hyperphe-

nylalaninemia are required to undergo tests for defi-

ciency 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).

0024 Research has demonstrated that in vivo hydroxyla-

tion in children with PKU can be so low that patients

may suffer from the effects of a diminished availabil-

ity of the metabolic product of phenylalanine hydro-

xylase, 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.

0025 PKU is one of the more common inborn errors of

metabolism and this autosomal recessive disease is a

major cause of preventable hereditary mental retard-

ation and neurological debilitation in the population.

Neonatal screening programs have saved thousands

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 emerg-

ed in the management of these patients. Pregnancies

in mothers with PKU who no longer use the low-

phenylalanine diet are complicated by spontaneous

abortions, and their living offspring are often men-

tally 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 low-

phenylalanine 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 demon-

strate one of the concepts of group 2 pathophysiol-

ogy, i.e., that metabolites accumulating proximal to

the metabolic block can cause derangements in dis-

tant organs and metabolic pathways.

Tyrosinemia Type 1

0026Tyrosine is likewise an essential amino acid derived

from ingested protein. Excess tyrosine is oxidized.

Several inborn errors of metabolism in the degrada-

tive pathway are known. Deficiency of fumarylace-

toacetate 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 tyro-

sine, elevated methionine is also found in many pa-

tients. Hypoproteinema and low prothrombin are

often present. Many patients develop end-stage hep-

atic 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 dis-

ease. In the long term, a substantial proportion of

patients with type 1 tyrosinemia develop hepatic ad-

enoma, and over time hepatocellular carcinoma can

develop in these lesions. The wide spectrum of organ

pathology, including malignant disease in tyrosine-

mia, demonstrates the effect of toxic substances

that accumulate due to the inability to catabolize

tyrosine. Although dietary restriction of tyrosine and

INBORN ERRORS OF METABOLISM/Overview 3267

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 cirrho-

sis or (solitary) tumors, as the donor liver provides the

patients with a normally functioning liver, including

normal activity of the deficient enzyme. Liver trans-

plantation 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: nitro-

trifluoro-methylbenzoyl-cyclohexanedione (NTBC),

an inhibitor of p-hydroxyphenylpyruvate dioxygen-

ase, prevents the formation of (cytotoxic and carcino-

genic) 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 prevent-

able with NTBC.

Energy Disturbance (Group 3

Pathophysiology)

Hypoglycemia

0027 A low blood sugar level is potentially dangerous (for

central nervous system function) and can be life-

threatening. 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 carbo-

hydrate and triacylglycerol metabolism (Table 3).

0028 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 admin-

istration 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 defi-

ciency) but not all disorders. Hyperlipidemia, gran-

ulocyte dysfunction, hyperuricacidemia and gout,

hyperlactatemia and osteoporosis, liver adenomas,

and pancreatitis are complications in just one of

these disorders (glycogen storage disease type I). Cat-

aracts with or without liver dysfunction are seen in

galactosemia. This illustrates that virtually any organ

tbl0003Table 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 self-

limiting ketotic hypoglycemia.

3268 INBORN ERRORS OF METABOLISM/Overview

system can be affected in the wide spectrum of dis-

orders encountered as the cause of a decreased blood

level of just one metabolite, glucose.

0029 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 drip-

feeding (e.g., in glycogen storage disease type I).

Avoidance of prolonged fasting is important in a

large proportion of disorders. Early diagnosis is es-

sential 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

0030 Mitochondrial respiratory chain enzyme defects are

associated with myopathy and failure to thrive in

early life in mildly affected patients and severe multi-

organ involvement, including brain damage and early

death in other patients. The failure to thrive in infants

with the disease can result from neurological impair-

ment (vomiting, difficulty with swallowing) but also

elevated energy expenditure is often found. The

pathophysiology of the increased resting energy ex-

penditure is of conceptual interest for this overview

on human inborn errors and nutrition. The mitochon-

drial respiratory chain is comprised of five enzyme

complexes which together drive the process of oxida-

tive phosphorylation and maintain the proton gradi-

ent 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 substan-

tially 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

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

0031In 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 polyunsatur-

ated 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.

tbl0004Table 4 Causes of essential fatty acid deficiency

Mechanism and disease state Affected gene(s)

Hereditary causes

Intestinal malabsorption

Abetalipoproteinemia MTTP

Hypobetalipoproteinemia Apolipoprotein B

Anderson disease ?

Exocrine pancreas insufficiency

Cystic fibrosis CFTR

Shwachman syndrome Mapped to 7p11-q11

Pearson syndrome Mitochondrial DNA deletions

Deranged metabolism of

polyunsaturated fatty acids

Decreased synthesis

of docosahexanoic acid

Phenylketonuria PAH

Zellweger syndrome PEX

Decreased inhibition of

leukotriene B

Sjo

gren–Larsson syndrome FALDH

Nonhereditary causes None

Malnutrition

Fat-free diet

Parenteral nutrition without

essential fatty acid

supplementation

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.

INBORN ERRORS OF METABOLISM/Overview 3269