Clinic al Appro ach

to the Diagnos es
of I nborn Error s
of Met ab olism
Manmohan Kamboj, MD

KEYWORDS
 Inborn errors of metabolism  Developmental delay
 Replacement therapy  Newborn screening  Phenylketonuria
 Fatty acid oxidation disorders

Inborn errors of metabolism (IEMs) are a set of relatively uncommon complicated

medical conditions involving abnormalities in the complex biochemical and metabolic
pathways of the human body system. They involve great complexity of the underlying
pathophysiology, biochemical workup, and analysis, and have complicated therapeu-
tic options for management. These children are often sick with significant complica-
tions and high rates of morbidity and mortality. The understanding of these complex
disorders requires special in-depth training and experience. Most primary care physi-
cians are less familiar with these disease conditions, and therefore less willing to deal
with them because of the complexity involved. There are metabolic specialists avail-
able, mostly in large medical centers, with expertise to deal with these intricate com-
plicated issues. Primary care physicians and pediatricians usually are the first point of
contact for most of these newborns, children, or adolescents, however. Therefore, it is
important that primary care physicians become comfortable in being able to recognize
early signs and symptoms, be able to initiate appropriate diagnostic and therapeutic
interventions, and be able to make appropriate referrals.
The following article summarizes the key issues basic to understanding IEMs. The
main points of discussion address the following questions:
What are IEMs?
What are the different types of IEMs?
What is the relative frequency of these IEMs?
What is the inheritance pattern of these IEMs?
How can these IEMs be diagnosed in a timely manner?
What is the role of newborn screening (NS) programs in early diagnosis and preven-
tion of morbidity and mortality?

Pediatric Endocrinology, Michigan State University, Kalamazoo Center for Medical Studies,
1000 Oakland Drive, Kalamazoo, MI 49008, USA
E-mail address: kamboj@kcms.msu.edu

Pediatr Clin N Am 55 (2008) 11131127

doi:10.1016/j.pcl.2008.07.004 pediatric.theclinics.com
0031-3955/08/$ see front matter 2008 Elsevier Inc. All rights reserved.
1114 Kamboj

What are the treatment and management options for these IEMs?
What is the long-term prognosis for patients who have IEMs?

WHAT ARE INBORN ERRORS OF METABOLISM?

The term metabolism encompasses the net result of a multitude of complex biochemical
processes that occur in living organisms to maintain cellular activities. These processes
are organized into specific metabolic pathways with the primary function to maintain daily
life activities. Each pathway depends on certain substrates and specific enzymes to en-
sure smooth functioning. IEMs are a group of heritable genetic disorders interfering with
these metabolic pathways in different ways, leading to inadequate functioning of a partic-
ular pathway. This interference in the normal enzymatic or metabolic pathway has varying
consequences, including deficiency of a particular end product or excessive accumula-
tion of a substrate that may be toxic. Either of these two scenarios leads to significant mor-
bidity and mortality by hampering normal functioning of a particular metabolic pathway.
IEMs have been known for the approximately the past 100 years, with the term being
first used by Sir Archibald Garrod in 1902.1 The initial disorders described were alka-
ptonuria, benign pentosuria, albinism, and cystinuria at that time, to be followed by
description of one of the major IEMs, namely, phenylketonuria (PKU), by Folling in
1934. Since that time, advances in medicine have uncovered more than 500 IEMs.2

WHAT ARE THE DIFFERENT TYPES OF INBORN ERRORS OF METABOLISM?

Some of the common metabolic disorders are listed in Box 1.3,4

WHAT IS THE RELATIVE FREQUENCY OF OCCURRENCE OF INBORN ERRORS OF METABOLISM?

The incidence of IEMs is highly variable among the many specific clinical entities,
ranging from 1 in 400 US African Americans for hemoglobinopathies, 1 in 4500 for con-
genital hypothyroidism, 1 in 15,000 for PKU, to 1 in 100,000 for most of the fatty acid
disorders (except MCAD) and organic acidemias. Incidences of some common inborn
errors are listed in Table 1.3

WHAT IS THE INHERITANCE PATTERN OF INBORN ERRORS OF METABOLISM?

Several patterns of inheritance are possible for the different IEMs. It is important to detail
a three- to four-generation pedigree to evaluate the mode of inheritance accurately.
Autosomal recessive (AR) inheritance is the most common mode of inheritance for
metabolic disorders. In this case, both the parents are heterozygous for the mutant
gene; hence, they do not express the disorder, but the offspring are homozygous
for that particular gene defect; hence, they express the defect and present clinically
with the disorder. The family history is generally negative in the parents, but there
may be a history of early neonatal deaths or a clinical disorder expressed as a concern.
Consanguinity has an increased chance of expression of an AR disorder. Rarely, these
mutations may occur de novo.5
X-linked recessive inheritance may also be seen in some IEMs, in which one copy of
the mutated gene on the X-chromosome is sufficient for causing the disorder. There-
fore, in this mode of inheritance, the disorder is transmitted from a carrier mother to
her male offspring. Also, de novo mutations are observed with a much higher inci-
dence in this pattern of inheritance.5
Autosomal dominant (AD) inheritance is a less common mode of inheritance for
IEMs. The incidence of de novo mutations causing AD disorders is much higher
than in other patterns of inheritance. AD transmission generally means that one of
 Diagnoses of Inborn Errors of Metabolism 1115

Box 1
Some common disorders of inborn errors of metabolism

Disorders of carbohydrate metabolism

 Glycogen storage diseases
 Galactosemia
Disorders of amino acid metabolism (aminoacidurias)
 PKU
 Maple syrup urine disease
 Homocystinuria
 Tyrosinemia
 Nonketotic hyperglycemia
Disorders of organic acids metabolism (organic acidemias)
 Methylmalonic acidemia
 Propionic acidemia
Disorders of fatty acid oxidation
 Short-chain acyl coenzyme A (CoA) dehydrogenase (SCAD)
 Medium-chain acyl CoA dehydrogenase (MCAD)
 Long-chain acyl CoA dehydrogenase (LCAD)
 Very long-chain acyl CoA dehydrogenase (VLCAD)
Disorders of mitochondrial metabolism
 Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)
 Glutaric aciduria
 Pyruvate dehydrogenase deficiency
Disorders of urea cycle
 Carbamyl phosphate synthetase deficiency
 Ornithine transcarbamylase deficiency
 Arginosuccinate deficiency
Peroxisomal disorders
 Adrenoleukodystrophy
 Zellweger syndrome
 Chondrodysplasia punctata
 Adult Refsum disease
Disorders of the steroid pathway
 Congenital adrenal hyperplasia
 Smith Lemli Opitz syndrome
Disorders of lipid storage
 Tay-Sachs disease
 Gauchers disease
 Metachromatic leukodystrophy
Disorders of purine metabolism
 Lesch-Nyhan syndrome
(continued on next page)
1116 Kamboj

Box 1
(continued)

Transport disorders
 Cystinosis
 Hypercholesterolemia
Lysosomal disorders
 Mucopolysaccharidoses (MPS)
 MPS I (Hurler and Scheie disease)
 MPS II (Hunter disease)
 MPS III (Sanfilippo disease)
 MPS IV (Morquio disease)
 MPS VI
 MPS VII
 Glycoproteinosis
 Sphingolipidosis
 Combined defects
 I-cell disease
Disorders of metal metabolism
 Wilson disease
 Hemochromatosis
 Menkes disease
Others
 Hypothyroidism
 Hemoglobinopathies
 MELAS

the parents has the disease; 50% of the progeny have the disorder, and there is an
equal gender distribution.5
A mitochondrial mode of inheritance is also seen in some IEMs. It is interesting to
note that the mitochondrial DNA is always natural in origin; therefore, a mutation in
Table 1
Incidence of some inborn errors of metabolism

Congenital hypothyroidism 1:4500

Congenital adrenal hyperplasia 1:10,000
PKU 1:15,000
Galactosemia 1:30,000
Other aminoacidurias 1:100,000
Homocystinuria
MSUD
Organic acidemias 1:100,000
Fatty acid oxidation disorders 1:100,000
MCAD 1:15,000

Abbreviation: MSUD, maple syrup urine disease.

 Diagnoses of Inborn Errors of Metabolism 1117

the mitochondrial DNA is inherited only from the mother. Mitochondrial DNA is prone
to de novo mutations; hence, diseases transmitted in this manner may be found to be
sporadic in occurrence.5
Box 2 lists the modes of inheritance of some common IEMs.5

HOW CAN YOU DIAGNOSE INBORN ERRORS OF METABOLISM IN A TIMELY MANNER?

Clinical Signs and Symptoms
IEMs may present early in the newborn period, later on in early or late childhood, or
much later in adulthood. A high index of suspicion needs to be maintained for IEMs,
because the symptomatology of these disorders is often nonspecific, and hence
may lead to a workup for other medical conditions. The clinical presentation attribut-
able to IEMs may be subclassified into a few broad categories.

Early-onset disorders
These present in the newborn period and can be further subgrouped into the following
categories.

Silent disorders IEMs in this category do not cause life-threatening signs and symp-
toms in infancy but present later on in the early childhood period with mental retarda-
tion and developmental delay. This group includes PKU and congenital
hypothyroidism.6
Disorders presenting with acute metabolic encephalopathy This group includes urea cycle
disorders, organic acidemias, and aminoacidurias. These conditions may present with

Box 2
Modes of inheritance in some common inborn errors of metabolism

AR inheritance
 PKU
 Maple syrup urine disease
 Glycogen storage disease
 Galactosemia
 Organic acidurias
 MCAD
 Zellweger syndrome
X-linked recessive (XLR) inheritance
 Ornithine carbamylase deficiency
 Fabry disease
 Pyruvate dehydrogenase deficiency
AD inheritance
 Marfan syndrome
 Acute intermittent porphyria
 Familial hypercholesterolemia
Mitochondrial inheritance
 Kearns-Sayre syndrome
 Leigh syndrome
1118 Kamboj

metabolic disturbances caused by accumulations of precursors or metabolites, which

are reflected early in the newborn period with poor feeding, lethargy, persistent vomiting,
seizures, hypotonia, apnea, respiratory distress, tachypnea, and tachycardia. These
newborns usually end up getting a workup for sepsis with this type of presentation.6
These features are attributed to the toxic effect of metabolites on the central ner-
vous system, causing a picture of a metabolic encephalopathy. The biochemical fea-
tures are significant for metabolic acidosis, hyperammonemia, or other metabolic
abnormalities.

Disorders presenting with metabolic acidosis This group generally includes organic acid-
emias. These neonates exhibit severe metabolic acidosis with an increased anion gap
along with elevated organic acid intermediates specific for the defect or lactate. Lactic
acidosis is present in disorders of pyruvate metabolism including pyruvate dehydroge-
nase deficiency, defects in gluconeogenesis, pyruvate carboxylase deficiency, and
mitochondrial disorders.7

Disorders presenting with hyperammonemia Many newborns with defects in the urea cy-
cle, organic acidemias, and transient hyperammonemia of the newborn (THAN) pres-
ent with metabolic encephalopathy and hyperammonemia.

Disorders presenting later on in childhood

This group of IEMs includes lysosomal storage disorders, Tay-Sachs disease,
Gauchers disease, and metachromatic leukodystrophy. These disorders generally
present with progressive neurologic deterioration.8
Other clinical signs and symptoms, including generalized nonspecific manifesta-
tions; neurologic signs and symptoms; developmental disorders; dysmorphic pheno-
types; and disorders in the gastrointestinal, hematologic, and dermatologic systems,
are summarized in Box 3.6,7,9
One of the most unique and intriguing features of IEMs is the presence of specific
odors in some of these metabolic disorders. Some of these are listed in Table 2.7,911

HOW TO MAKE A TIMELY DIAGNOSIS

Clinical presentation should raise suspicion of an IEM. Details of history, including

a family history of consanguinity, similar disorders in close and extended family,
and any neonatal deaths, should be sought. Details of relation of symptoms to eating
in terms of timing and in relation to specific type of food consumption, cyclic pattern of
vomiting, lethargy, and behavioral changes should be inquired about. Signs mani-
fested on clinical examination, including hepatosplenomegaly, skin lesions, and neu-
rologic deficits, should guide one toward an initial laboratory workup. In children who
may be critically ill, it is important to consider and then rule out options in the differen-
tial diagnosis of the specific clinical scenario. General laboratory investigations indi-
cated are listed in Box 4.6,12 Additional specific biochemical workup should be
decided on based on details of the history, clinical presentation, results of preliminary
laboratory investigations, and suspicion of a specific IEM. It is preferred that extra
blood and urine samples be drawn and saved for later investigations. A second tier
of laboratory workup that may be indicated is listed in Box 5. Special precautions
may be needed in the drawing and processing of some of these samples. The samples
for plasma ammonia, lactate, and pyruvate should be obtained without the use of
a tourniquet and need to be transported on ice for immediate analysis in the labora-
tory; pyruvate samples should be collected in perchlorate to prevent degradation.12
 Diagnoses of Inborn Errors of Metabolism 1119

Box 3
Important clinical signs and symptoms of inborn errors of metabolism

Dysmorphism
 Peroxisomal disorders
 Zellweger syndrome
 Lysosomal storage disorders
 Mucopolysaccharidosis
 Mucolipidosis
 Gangliosidosis
 Homocystinuria
 Smith-Lemli-Opitz syndrome
Neurologic manifestations
 Seizures: seen in any IEM because of toxic metabolites
 Pyridoxine dependent
 Folinic acid dependent
 Secondary to hypoglycemia
 Peripheral neuropathy
 Mitochondrial disorders
 Lysosomal storage disorders
 Hypotonia
 Fatty acid oxidation disorders
 Peroxisomal disorders
 Urea cycle disorders
 Mitochondrial disorders
 Pompes disease
 Glycogen storage disorders
 Myopathy
 Glycogen storage diseases
 Fatty acid oxidation disorders
 Mitochondrial disorders
 Ataxia
 Peroxisomal disorders
 Mitochondrial disorders
 Lysosomal storage disorders
 Lethargy or coma
 Aminoacidurias
 Organic acidemias
 Urea cycle disorders
 Fatty acid oxidation defects
 Mitochondrial disorders
(continued on next page)
1120 Kamboj

Box 3
(continued)

Developmental delay
 May occur in all IEMs: rare
Gastrointestinal manifestations
 Hepatomegaly or splenomegaly
 Lysosomal storage disorders
 Glycogen storage diseases
 Jaundice or liver dysfunction
 Galactosemia
 Fatty acid oxidation disorders
 Tyrosinemia
 Peroxisomal disorders
 a1-Antitrypsin deficiency
 Niemann-Pick disease
Cardiac manifestations
 Hypertrophic cardiomyopathy
 Glycogen storage disease: type 2
 Pompes disease
 Mucopolysaccharidosis
 Dilated cardiomyopathy
 Fatty acid oxidation disorders
 Organic acidemias
 Mitochondrial disorders
Ophthalmologic manifestations
 Lenticular cataracts
 Galactosemia
 Mitochondrial disorders
 Corneal opacities
 Fabry disease
 Mucopolysaccharidosis
 Cystinosis
 Cherry red macular spots
 Tay Sachs disease
 Galactosialidosis
 Niemann-Pick disease
 GM1 gangliosidosis
 Dislocated lens
 Homocystinuria
 Marfan syndrome
 Molybdenum cofactor deficiency
 Diagnoses of Inborn Errors of Metabolism 1121

 Sulfite oxidase deficiency

 Retinitis pigmentosa
 Abetelipoprotemia
 Peroxisomal disorders
 Mitochondrial disorders
Hydrops fetalis: nonimmune
 Lysosomal storage disorders
 Mitochondrial disorders
 Neonatal hemochromatosis
 Glycogen storage disease type IV
Dermatologic manifestations
 Skin rash
 Acrodermatitis enteropathica
 Ichthyosis
 X-linked ichthyosis
 Sjogren-Larsson syndrome
 Angiokeratomas
 Fabry disease
 Lysosomal storage disorders

Table 3 lists correlations with some alterations in laboratory evaluations with possible
IEMs.12
WHAT IS THE ROLE OF NEWBORN SCREENING PROGRAMS IN EARLY DIAGNOSIS AND
PREVENTION OF MORBIDITY AND MORTALITY?

NS for genetic disorders for all newborns endeavors to make early and timely diag-
nosis of otherwise potentially life-threatening or debilitating inherited disorders. For
a genetic disorder to be considered for NS, several criteria should be justified. These
include the following: the particular genetic disorder should result in significant mor-
bidity or mortality; should have a known mechanism of pathogenesis; should offer
Table 2
Odors characteristic of some inborn errors of metabolism

Odor Metabolic Disorder

Fruity odor Methylmalonic acidemia
Propionic acidemia
Burnt sugar/maple syrup-like Maple syrup urine disease
Mousy/musty Phenylketonuria
Sweaty socks, cheese-like Isovaleric acidemia
Malt-like Methionine malabsorption
Cat urine 3-Methylcrotonic acidemia
3-Hydroxy, 3-methyl glutaric aciduria
Fish-like Trimethylaminuria
Carnitine excess
Cabbage-like Tyrosinemia
1122 Kamboj

Box 4
Initial laboratory investigations for inborn errors of metabolism

Blood
 Complete blood cell count
 Comprehensive metabolic panel, including
 Liver and kidney function
 Electrolytes
 Uric acid
 Serum ammonia
 Arterial blood gas

Urine
 Urinalysis
 pH
 Color
 Odor
 Specific gravity
 Ketones
 Urine-reducing substances

Box 5
Additional laboratory investigations for inborn errors of metabolism

Blood or plasma
 Quantitative amino acids
 Lactate
 Aldolase, creatine kinase
 Acyl carnitine profile
 Lipid profile
Urine
 Quantitative amino acids
 Organic acids
 Myoglobin
Imaging
 MRI: brain
 Echocardiogram
Biopsy
 Muscle biopsy
 Skin biopsy
Genetic studies
 As specifically indicated
 Diagnoses of Inborn Errors of Metabolism 1123

Table 3
Laboratory findings in inborn errors of metabolism

Metabolic Acidosis with Increased Anion Gap Organic Acidemias

Respiratory alkalosis Urea cycle disorders
Hyperammonemia Urea cycle disorders
Organic acidemias
Lactic acidosis Mitochondrial disorders
Glycogen storage diseases
Disorders of
Glyconeogenesis
Pyruvate metabolism
Organic acidemias
Fatty acid oxidation disorders
Aminoacidurias
High lactate/pyruvate ratio (normal: 10:1 Mitochondrial disorders
to 20:1) Pyruvate carboxylase deficiency
Acylcarnitine profile abnormalities Fatty acid oxidation disorders
Organic acidemias
Hypoglycemia Glycogen storage disease
With ketosis Organic acidemias
Without ketosis Maple syrup urine disease
Fatty acid oxidation disorders
Disorders of ketogenesis
Quantitative amino acid profiles Specific defects in amino acid metabolism
have specific patterns
Urine organic acids Specific defects in amino acid metabolism
have specific patterns

the potential of prevention or adequate treatment; should have an easy, inexpensive,

and rapid test available for screening; should have reliable follow-up confirmatory
testing available; and the cost-to-benefit ratio of incorporating the testing in the
NS should be less than cost of diagnosing, testing, and managing the condition
otherwise.3,13
NS was initially stated for PKU in 1959 by Guthrie; since then, it has expanded to
include an extended list of predominantly IEMs and some hematologic and endocrine
disorders.8 Advances in biochemical testing with tandem mass spectrometry have fa-
cilitated the incorporation of many genetic disorders in the NS. Common disorders
screened for are listed in Box 6.3,14,15 Most NS programs in the United States are state
controlled and state specific, and different states include different disorders in their
specific NS programs. Many other countries worldwide offer variable genetic NS pro-
grams as well. It is therefore important to remember to look into the specific screening
program that a particular newborn underwent. Moreover, it is imperative to realize that
a normal newborn screen does not rule out all inborn or inherited disorders. The aim of
the NS is to make an early diagnosis for the conditions being screened for. There may
be false-positive and false-negative results. Once positive NS is obtained for an IEM,
the primary care physician or pediatrician should perform a clinical examination and
make an assessment and then seek consultation with the metabolic or genetic spe-
cialist who has expertise in the field for initiating further diagnostic testing and imple-
menting the required therapeutic measures. These patients should be closely
followed, preferably by the metabolic specialists. Early therapeutic intervention can
lower morbidity and mortality significantly.
1124 Kamboj

Box 6
Genetic disorders available for screening on the newborn screening programs

Amino acid disorders

 PKU
 Homocystinuria
 Tyrosinemia
 Maple syrup urine disease
 Nonketotic hyperglycinemia
 Citrullinemia
 Arginosuccinate deficiency
 Hyperornithinemia
Carbohydrate disorders
 Galactosemia
Fatty acid oxidation disorders
 SCAD
 MCAD
 LCAD
 VLCAD
 Carnitine palmityl transferase (CPT) deficiency
Organic acidemias
 Methyl malonic acidemia
 Propionic acidemia
 Isovaleric acidemia
 Glutaric acidemia
 b-methyl crotonyl CoA carboxylase (MCC) deficiency
Other IEMs
 Biotinidase deficiency
Endocrine disorders
 Hypothyroidism
 Congenital adrenal hyperplasia
Hematologic disorders
 Various hemoglobinopathies

The aim of the NS is to make an early diagnosis for the previously mentioned con-
ditions. There may be false-positive and false-negative results. Once positive NS is
obtained for an IEM, the primary care physician or pediatrician should initiate dialog
with the metabolic or genetic specialist who has expertise in the field for initiating fur-
ther clinical examination and assessment, diagnostic testing, and implementation of
the required therapeutic measures. These patients should preferably be followed
closely by the metabolic specialist. With this early intervention, morbidity and mortality
can be significantly lowered.
 Diagnoses of Inborn Errors of Metabolism 1125

WHAT ARE THE PRINCIPLES OF TREATMENT FOR INBORN ERRORS OF METABOLISM?

Treatment Options for Inborn Errors of Metabolism Broadly Include Two
Main Options
General principles of treatment
The general measures of treatment are put into place before a definitive diagnosis of
a specific IEM is made. Some of these interventions include withholding of all dietary
oral intake until some specific investigations and guidelines can be established, pref-
erably after consultation with metabolic specialists. In most cases, intravenous dex-
trose fluid with saline may be initiated after adequate hydration with normal saline.
Acidosis may also need correction by replacement with bicarbonate.16

Specific therapeutic measures

The specific therapeutic options are disease specific and are instituted once a partic-
ular IEM is diagnosed. These measures are geared toward addressing the specific
concerns of the particular underlying defect. Fig. 1 represents the underlying ap-
proaches to treatment strategies for various IEMs.8
Table 4 outlines some of the specific therapeutic options available for various met-
abolic disorders.8

WHAT IS THE LONG-TERM PROGNOSIS?

The clinical outcome of children depends on multiple factors. These include severity of
the underlying metabolic defect, ability to make the diagnosis early, availability of spe-
cific adequate treatment options, and appropriate institution of the therapeutic mea-
sures. Depending on all these variables, some IEMs have a relatively better
prognosis than others. Many of these children are living longer but many may be at
high risk for developing progressive neurologic deficits, learning disabilities, and men-
tal retardation. A study done to evaluate response to treatment in IEMs revealed

Fig.1. Approaches to treatment of IEMs. Treatment can be directed at (1) limiting the intake
of a potentially toxic compound, (2) supplementing the deficient product, (3) stimulating an
alternate metabolic pathway, (4) providing a vitamin cofactor to activate residual enzyme
activity, (5) supplying the enzyme itself, (6) transplanting a body organ containing the de-
ficient enzyme, and (7) gene therapy. (From Batshaw ML, Tuchman M. PKU and other inborn
errors of metabolism. In: Batshaw ML, editor. Children with disabilities. 5th edition. Balti-
more: Paul H. Brookes Publishing Co.; 2002. p. 339; with permission.)
1126 Kamboj

Table 4
Examples of treatment approaches for inborn errors of metabolism

Approaches Disorder Specific Treatment

Restrict diet PKU Phenylalanine restriction
Maple syrup urine disease Branch chain amino acid
Galactosemia restriction
Galactose restriction
Supplement deficient Congenital Synthroid
product hypothyroidism Cornstarch
Glycogen storage disease Arginine
Urea cycle disorders
(except argininemia)
Stimulate alternate Urea cycle disorders Sodium phenylbutyrate
pathway Organic acidemias Carnitine
Isovaleric acidemia Glycine
Wilson disease Penicillamine
Supply vitamin cofactor Multiple carboxylase Biotin
deficiency Pyridoxine
Homocystinuria Vitamin B12
Methylmalonic acidemia
Replace enzyme Severe combined PEG-ADA
immunodeficiency
(SCID)
Transplant organ Metachromatic Bone marrow
leukodystrophy Liver
Ornithine Liver
transcarbamylase Liver
deficiency
Tyrosinemia
Glycogen storage disease
Use gene therapy SCID Retrovirus gene transfer
Use other therapies or Inhibit pathway: NTBC
emerging technologies tyrosinemia Recombinant enzyme
Use substrate
deprivation: PKU

From Batshaw ML, Tuchman M. PKU and other inborn errors of metabolism. In: Batshaw ML, editor.
Children with disabilities. 5th edition. Baltimore: Paul H. Brookes Publishing Co.; 2002. p. 340; with
permission.

improvement in clinical parameters in approximately half of the patients who have

metabolic disorders.17

ACKNOWLEDGMENTS

The author thanks Amy Esman for her expert administrative assistance.

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