21

Introduction to Metabolic and

Biochemical Genetic Diseases
STEPHEN CEDERBAUM

KEY POINTS
• Inborn errors may present in a variety of ways.
• Inborn errors should be systematically considered when one is
evaluating an ill newborn.
• Inborn errors often present with unique or characteristic physical
findings and also laboratory findings that help in developing a
differential diagnosis.
• Newborn screening can be integrated into the evaluation of inborn
errors.
• DNA sequencing can be used in the evaluation of sick infants.

I
nborn errors of metabolism or biochemical genetic
disorders are one type of genetic disease that may be
encountered in the neonatal period as an acute or more
indolent illness. In these disorders, a mutation in a
gene leads to an absent or defective gene product or
enzyme and results in the accumulation of the
precursor of the enzyme or a byproduct of it, a
shortage of the product of the enzymatic reaction, or a
combination of both. In reality the effects of many
inborn errors on normal physiology are much more
profound, causing many changes in gene expression
and normal biochemical function. One example is a
case of propionic acidemia in which interference with
the mitochondrial respiratory apparatus is rarely
measured except by the ascertainment of an elevated
blood lactate level, but that may be much more
frequent and represent only the most obvious and
easily measured alteration.
Inborn errors of metabolism may be inherited by
any genetic mechanism—autosomal dominant,
autosomal recessive, sex-linked recessive—or
through a mutation in the independently inherited
mitochondrial genome (mitochondrial DNA),
which leads to a circumstance in which the mother
alone passes the abnormal DNA to all of her
children, but the affected or carrier father passes
to none of his offspring.
Most inborn errors are inherited as autosomal
recessive conditions, with the carrier parents
rarely expressing any obvious metabolic
phenotype. A small minority are inherited in a
sex-linked recessive or codominant manner, and
they will be discussed in the context of their
particular disease. Examples include ornithine
transcarbamylase deficiency (a urea cycle
disorder) and Fabry disease (a lysosomal storage
disorder), the latter not appearing in the neonatal
period.
When viewed from the perspective of disease
mechanism, most genetic disorders, whether
single-gene disorders or disorders involving
imbalance of chromosomal materials, could be
considered to be inborn errors of metabolism. One
or more changes in the DNA result in either
altered gene expression or expression of a mutated
gene, which then leads secondarily to an altered
product of the reaction or reactions. We will not
use this expansive and grandiose interpretation of
inborn errors but will rather confine ourselves to
the more traditional definition described in the
first paragraph. Thus disorders such as cystic
fibrosis and spinal muscle atrophy, considered
inborn errors that require broader interpretation,
will not be considered.
The advent of newborn screening in the early part
of the 1960s for phenylketonuria (PKU)
established a new paradigm for approaching
inborn errors of metabolism and making the
diagnosis and treatment before the symptomatic
presentation and hence preventing rather than
treating the condition. This approach has proved
to be remarkably successful for PKU and
congenital hypothyroidism, with few patients
becoming intellectually disabled. In subsequent
years the menu of tests expanded gradually, but it
has greatly expanded in the last decade with the
implementation of expanded newborn screening
using tandem mass spectrometry technology,
which allows ascertainment of a constellation of
disorders. This expanded testing should alter the
probability of, and the diagnostic testing for,
inborn errors when incorporated into the
diagnostic algorithms of the ill newborn.
Moreover, the advancing technology permits
some of the newborn dried blood spot to be used
for a wider palette of tests, some of which may
already be available. The consequences of this
expansion have a downside for the neonatologist
and the neonatal intensive care unit staff
members. For a variety of reasons the sick and
premature newborn, usually receiving intravenous
alimentation and having immature or damaged
organs, is far more likely to have a false positive
newborn screening test result and require follow-
up testing. It is important to recognize that a
number of traditionally tested diseases are outside
this class of disorders, such as hypothyroidism,
congenital adrenal hyperplasia, cystic fibrosis, and
hemoglobinopathies.
When one is considering inborn errors of
metabolism, it is important to consider the
molecular basis of mutation. Large deletions of a
gene are certain to eliminate enzymatic function
and any residual gene product. Smaller deletions,
especially if they remove one or more of the in-
phase coding triplets, may permit a stable protein
to be made and to function to some extent. Most
small deletions, however, cause the synthesis of
unstable and outof-phase proteins that do not
function and that have a short half-life within the
cell. Some single-base-change mutations can
introduce a stop codon, causing the synthesis of
the polypeptide to halt abruptly and leave a
nonfunctional enzyme. Single-base changes
introducing a new amino acid differ in their
effects from complete loss of activity to a lesser
impact and finally to having no effect whatsoever.
When one considers that test is then all modulated
through the unique genetic background of the
individual, there is no single final phenotype,
severity, or time of onset for any genetic disorder.
This variation must be considered when any
diagnosis, genetic or not genetic, is considered.
In the period since the publication of the previous
edition of this book, DNA sequencing has become
a much more accessible and affordable diagnostic
modality, and it is likely to increase in relevance
and use in the near-term future. When the
diagnosis is established by biochemical criteria,
mutation analysis, done electively, is likely to
enhance our understanding of the disorder in an
individual patient and help to guide therapy.
When one is confronted with a more challenging
and ambiguous patient, DNA testing in the form
of whole exome or whole genome sequencing is
likely to become the genetic diagnostic modality
of choice.
Classification of Inborn Errors of
Metabolism
Each professional uses classification systems to
permit effective reasoning as to possible causes of
a symptom complex. A system for understanding
inborn errors of metabolism is shown in Box 21.1.
Each group has common characteristics, modes of
presentation, types of molecules involved, and
tests that would be applied. Because the
demarcation between the groups is not sharp,
other systems can see them differently. This
discussion is restricted to those disorders that may
be symptomatic in the newborn period or in early
infancy, whereas many severe disorders would be
unlikely to be associated with neonatal disease
and will be given less emphasis.
The disorders more commonly seen in the
neonatal period are listed in Box 21.2.
The first group consists of newborns with
• BOX Classification of Inborn Errors
of
Metabolism, 2007
Small-molecule disorders
• Amino acids
• Organic acids
• Sugars
Lysosomal storage disorders
• Mucopolysaccharides
• Sphingolipids
• Glycolipids
Energy metabolism disorders
• Oxidation disorders
• Fatty acid mobilization and metabolism disorders
• Glycogen storage diseases
Peroxisomal and membrane biogenesis disorders
Carbohydrate-deficient glycoprotein disorders
Cholesterol biosynthetic disorders
Disorders of biogenic amines, folate, and pyridoxine
Transport disorders
Purine and pyrimidine metabolism disorders
Receptor disorders
progressive lethargy, poor suck, neurologic
deterioration, and often death. They have inborn
errors of amino acids, the urea cycle, organic
acids, or sugar metabolism. This group of patients
is the product of normal pregnancies and
deliveries and becomes ill after 36 hours of life,
when the maternal circulation no longer cleanses
the accumulating small molecules from the fetal
or newborn blood, and the offending metabolites
accumulate in intoxicating amounts (Box 21.3).
Examples include maple syrup urine disease,
methylmalonic and propionic acidemias,
galactosemia, and ornithine transcarbamylase
deficiency. The general characteristics are given
in Box 21.4; they are the disorders for which
expanded newborn screening may lead to earlier
detection and a more rapid diagnosis. These
patients’ condition is most likely to resemble
sepsis, and they should be treated with antibiotics.
Most disorders manifesting themselves acutely in
the newborn period will be detected by the
newborn screen, with only some urea cycle
disorders and lactic acidosis likely to be missed by
this screening panel. When diagnosed, these
conditions are treated with dialysis, limitation of
protein intake
(except for galactosemia), fluid, and caloric
support and some specific interventions. The
association of identifying physical and laboratory
characteristics and various disorders is listed in
Tables 21.1–21.2. The individual disorders are
discussed in Chapters 22 and 23. When a
diagnosis of a metabolic disorder appears
• BOX Common Types of Inborn Errors of
Metabolism With Newborn
Presentation
• Amino acid disorders
• Organic acid disorders
• Disorders of ammonia metabolism
• Disorders of carbohydrate metabolism
• Disorders of gluconeogenesis or hypoglycemia
• Disorders of fatty acid oxidation
• Primary lactic acidoses (respiratory chain defects)
• Disorders of vitamin or metal metabolism
• Storage diseases (infrequently)
• Peroxisomal disorders
• Disorders of sterol metabolism
• Congenital defects in glycosylation
Metabolic Diseases With Newborn
• BOX
Coma Secondary to Toxic Metabolite
Accumulation or Mitochondrial Failure
• Galactosemia
• Inborn errors of ammonia metabolism
• Maple syrup urine disease
• Nonketotic hyperglycinemia
• Methylmalonic acidemia with or without homocystinuria
• Propionic acidemia
• Isovaleric acidemia
• Multiple carboxylase deficiency
• Glutaric aciduria type 2
• Fatty acid oxidation defects
• Primary lactic acidosis
• Pyruvate dehydrogenase deficiency
• Pyruvate carboxylase deficiency
• Mitochondrial respiratory chain or electron transport chain defects
• BOX Characteristics of Small-Molecule
Disorders
• High levels of metabolites in body fluids
• Normal physical phenotype
• Neonatal presentation
• Periods of stability and instability
• Considered to be intoxication disorders
• Can often be treated by external manipulation
Lysosomal storage disorders
• Usually born normally
• Course is progressive, relentless, and indolent
• Deposition of material seen clinically and microscopically
• May be deforming
• Cannot be addressed exogenously by dietary means
Disorders of energy metabolism
• Mixed presentation between the first two categories
• Can be catastrophic at presentation
• May be present at birth or develop later
• Usually progressive
• May cause malformations
• May have episodes of deterioration
• Usually not treatable by dietary means
• May be tissue specific or preferential• Mitochondrial respiratory chain • Neonatal catastrophe (life threatening)
or electron transport chain defects
likely, tests for plasma amino acids, urine organic
acids, plasma acylcarnitine, and plasma carnitine
should be repeated, and ammonia and lactate
levels should be determined. The second major
category of inborn errors is the lysosomal storage
diseases. This group of disorders results from
defective function of a catabolic hydrolase located
in the lysosome that is generally responsible for
breaking down complex glycosaminoglycans and
sphingolipids that are products of normal cellular
turnover (see Box 21.4). Unlike the small-
molecule disorders in which the metabolites are
found freely circulating in the body fluid
compartments, these compounds accumulate
intracellularly, are not removed by the maternal
circulation, and are present in limited amounts in
the body fluids. They most often cause no
apparent symptoms in the newborn period or early
infancy, because the pathologic metabolites
accumulate slowly with time. Exceptions to this
finding are the severe form of α-glucosidase
deficiency or Pompe disease, the neonatal form of
α-galactosidase deficiency, or Krabbe disease and
galactosialidosis. These findings are discussed in
Chapter 23, and some are listed in Table 21.1. The
disorders of mucopolysaccharides and glycolipids
lead to the characteristic features pejoratively and
inappropriately referred to as gargoylism, which
consist of an exaggerated eyebrow, coarse-
appearing facies, thick skin, hirsutism, and
multiple abnormalities of the bones and joints
seen on a radiograph. Attention to the disorder is
often drawn by the hepatosplenomegaly. The
metabolites are synthesized in the body and are
not influenced by dietary intake.
The third important category of metabolic
disorders is insufficient generation of energy by
the mitochondrial machinery. These disorders can
be caused by the inability to provide substrates
such as glucose in glycogenoses; the inability to
deliver substrate to the site of oxidation, such as
the fatty acid and carnitine transport disorders; the
inability to break down fatty acids in a stepwise
fashion to provide reduced flavin adenine
dinucleotide to be oxidized; or the deficient
function of the mitochondrial respiratory pathway
and energy-generating system itself. These
disorders have characteristics in between those of
the acute, small-molecule disorders and the
storage disorders (see Box 21.4). They differ
• BOX 21.5 Signs and Symptoms of Inborn
Errors in the Newborn
• Poor suck and feeding
• Gastrointestinal problems, vomiting
• Respiratory distress
• Cardiac failure
• Neurologic abnormalities: alertness, tone, seizures
• Organomegaly
• Ocular abnormalities
• Cutaneous changes
• BOX 21.6 Metabolic Diseases With Congenital
Malformations or Dysmorphic
Features
• Cholesterol biosynthetic disorders
• Peroxisomal disorders
• Glutaric aciduria type 2
• Primary lactic acidoses
• Congenital defects in glycosylation
• Lysosomal storage disorders
• Menkes disease
from the small-molecule disorders in the possible
onset immediately at birth or before and from
storage disorders in the generally normal physical
features with hepatomegaly alone, a regular
feature of glycogen storage disorders. The small-
molecule and energy generating disorders are
discussed in Chapter 22, and the lysosomal
storage disorders are discussed in Chapter 23.
Of the remaining groups that are encountered less
frequently, the peroxisomal biogenesis disorders,
carbohydrate-deficient glycoprotein disorders, and
Smith–Lemli–Opitz syndrome (a cholesterol
biosynthetic disorder) are discussed in Chapter 23.
Other disorders are too infrequent to be
considered in a general neonatology textbook.
Disorders of biogenic amines are discussed in
Chapter 22 and in greater depth in Chapter 65 on
neonatal seizures, along with consideration of
pyridoxine and folate disorders.
Signs and Symptoms of Inborn Errors
The limited symptomatic repertoire of the sick
newborn is well established, but it is worth
repeating. For this reason, the first thought when
one is confronting a newborn in a deteriorating
condition, with lethargy, poor suck, temperature
instability, and neurologic abnormalities, is sepsis
(Box 21.5). Most metabolic specialists have never
confronted a sick newborn who has not had a
“septic work up” and who is not receiving
standard antibiotics. The issue then becomes when
to perform a metabolic work-up. The standard
answer is that it should be performed when the
neonatologist is concerned that the newborn in
extremis does not fit the pattern that is expected
from a child with sepsis or hypoxia. That Although dysmorphic features are not
threshold will differ by individual. Negative characteristic of inborn errors, there are some that
results of tests for infectious agents, a may have subtle or occasionally pronounced
nonconfirmatory white blood cell count, abnormality on a physical examination; they are
hypoglycemia, unexpectedly severe acidosis, or listed in Box 21.6 and Table 21.2.
hyperammonemia could be important triggers.
TABLE
21.1
Unique or Characteristic Physical Findings in Inborn Errors (Major Examples)
Finding Error Finding Error
Hepatomegaly Galactosemia Retinitis Mitochondrial respiratory or electron transport
Glycogen storage diseases pigmentosa chain defects
Gluconeogenic defects Sjögren–Larsson syndrome
Disorders of fatty acid oxidation and transport Peroxisomal disorders
Mitochondrial respiratory or electron transport Abetalipoproteinemia
chain defects Optic atrophy or Pyruvate dehydrogenase complex deficiency
Hereditary tyrosinemia type 1 Hypoplasia Mitochondrial disorders
Urea cycle defects Leigh disease
Peroxisomal defects Peroxisomal disorders
Niemann–Pick disease type C
Corneal clouding Mucolipidoses
Congenital defects in glycosylation
or opacities Mucopolysaccharidoses
Hepatosplenomegaly Gangliosidoses Steroid sulfatase deficiency
Niemann–Pick disease type C
Mucopolysaccharidoses Cataracts Galactosemia
Wolman disease Lowe syndrome
Ceramidase deficiency Mitochondrial respiratory or electron transport
chain defects
Macrocephaly Glutaric acidemia type 1
Peroxisomal disorders
Canavan disease
Congenital defects in glycosylation
Microcephaly Mitochondrial respiratory or electron transport
chain defects Dislocated lens Methionine synthetase deficiency
Leigh disease Sulfite oxidase deficiency
Methylmalonic acidemia with homocystinuria
Bone or limb Storage, peroxisomal, or connective tissue
Coarse facial features Gangliosidosis deformities disorders
Mucolipidoses or contractures Inborn errors of cholesterol biosynthesis
Mucopolysaccharidosis type VII Thick skin Mucolipidoses
Sialidosis Gangliosidoses
Galactosialidosis Mucopolysaccharidoses
Macroglossia Pompe disease Desquamating, Acrodermatitis enteropathica
Gangliosidoses eczematous, or Organic acidemias
Mucopolysaccharidoses vesiculobullous Early-onset forms of porphyria
Mucolipidoses skin lesions
Dystonia or Gaucher disease type 2 Ichthyosis Gaucher disease type 2
extrapyramidal signs Glutaric acidemia type 1 Steroid sulfatase deficiency
Krabbe disease
Crigler–Najjar syndrome Alopecia Multiple carboxylase deficiency
Biopterin defects Steely or kinky Menkes disease
Macular “cherry-red GM1 gangliosidosis hair
spot” Galactosialidosis Persistent diarrhea Persistent diarrhea Glucose galactose malabsorption
Niemann–Pick disease type A Congenital lactase deficiency
Tay–Sachs disease (GM2 gangliosidosis) Congenital chloride diarrhea
Sucrase isomaltase deficiency
Acrodermatitis enteropathica
Congenital folate malabsorption
Wolman disease
Galactosemia

For discussion of specific disorders, see Chapters 22 and 23.

Modern neonatology has one tool that was
previously unavailable: the expanded newborn
screen. This screening will diminish the
probability of many disorders, and the newborn
screening follow-up hotline should be on the
speed dial of every neonatal intensive care unit.
The only acutely presenting disorders not
ascertained by these studies are most
hyperammonemias and lactic acidoses. These test
results are available immediately in any tertiary or
secondary care hospital. With a high level of
concern and near normal levels of lactate and
ammonia, the standard battery of metabolic include plasma amino acid levels, plasma
studies should be performed only when the index acylcarnitine levels, and urinary organic acid
of suspicion for a metabolic disorder is levels. The abnormalities associated with
particularly high and no alternative explanation individual disorders are discussed in Chapter 22.
for the poor condition of the patient is likely.
When deemed necessary, these studies should
TABLE
Characteristic or Unique Laboratory or Diagnostic Testing Outcomes in Inborn Errors (Major Examples)
21.2
Outcome Error Outcome Error
Metabolic acidosis Organic acidemias Thrombocytopenia Organic acidemias
with or without Maple syrup urine disease Pearson syndrome
increasedanion gap Fatty acid oxidation defects Anemia Organic acid disorders
β-Ketothiolase deficiency Wolman disease
Ketogenesis defects Pearson syndrome
Disorders of pyruvate metabolism Severe liver failure
Mitochondrial respiratory chain Galactosemia
or electron transport chain Vacuolated Lysosomal storage disorders
defects, including Leigh disease lymphocytes
Galactosemia or neutrophils
Glycogen storage disease type 1 Cardiomegaly Pompe disease
Gluconeogenesis defects Barth syndrome
Fatty acid oxidation defects
Mitochondrial respiratory or electron
Respiratory alkalosis Urea cycle disorders transport
chain defects
Hyperammonemia Urea cycle disorders Carbohydrate-deficient glycoprotein
Methylmalonic acidemia syndrome
Organic acidemias
Electrocardiographic Pompe disease (short PR interval, large
Fatty acid oxidation disorders
abnormalities QRS
Ketosis Organic acidemias interval)
Maple syrup urine disease Fatty acid oxidation disorders
Glutaric acidemia type 2 Mitochondrial respiratory or electron
Ketogenesis defects transport
Glycogen storage disease type 1 chain defects
Gluconeogenesis disorders Ventricular Pompe disease
hypertrophy Organic acidemias
Lactic acidosis Mitochondrial respiratory or electron Glutaric acidemia type 2
transport chain defects, including Leigh Fatty acid oxidation defects
disease Mitochondrial respiratory or electron
Pyruvate dehydrogenase complex transport
deficiency chain defects, including Leigh disease
Pyruvate carboxylase deficiency
Organic acidemias Dysostosis multiplex Gangliosidoses
Glutaric acidemia type 2 Mucopolysaccharidoses
Fatty acid oxidation defects Mucolipidoses
Ketogenesis defects Sialidosis
Glycogen storage disease type 1
Gluconeogenesis disorders Stippled calcifications Peroxisomal disorders
of Cholesterol biosynthetic defects
Hypoglycemia Hyperinsulinism patellae
Glycogen storage disease type 1
Gluconeogenesis disorders
Maple syrup urine disease Adrenal calcifications Wolman disease
Glutaric acidemias
Fatty acid oxidation defects
Ketogenesis defects Rhizomelica Rhizomelic chondrodysplasia punctata
Galactosemia
Severe liver failure Hair abnormalities Menkes disease
Mitochondrial respiratory or electron Argininosuccinicaciduria
transport chain defects Basal ganglia lesions Organic acidemias (later in life)
on Pyruvate dehydrogenase complex
Lipemia Glycogen storage disease type 1 MRI deficiency
Lipoprotein lipase deficiency Mitochondrial respiratory or electron
transport
Positive urinary-reducing Galactosemia chain defects, including Leigh disease
substances Hereditary fructose intolerance
Lowe síndrome
Discolored urine Alkaptonuria
Tryptophan malabsorption
Leukopenia Organic acidemias
Glycogen storage disease type 1B
Barth syndrome
Pearson syndrome

MRI, Magnetic resonance imaging.

Emergency Treatment per day and increasing gradually to maintenance

An acutely ill child with an inborn error of
metabolism is an emergency, and rapid rescue
treatment is mandatory. When one is considering
a differential diagnosis, special emphasis should
be placed on disorders for which there is
treatment, as opposed to those for which there is
no treatment. As with all acutely ill patients,
supportive care, including cardiorespiratory,
hemodynamic status, fluids, and electrolytes, are
the mainstays of treatment. Transfer from
institution to institution should not be performed
unless the patient’s condition is stable and there is
adequate vascular access for emergency treatment.
Transfer to a tertiary care center with experience
in caring for these children is desirable and should
be performed as quickly as possible.
Virtually all disorders require a maximum source
of calories (150 cal/kg is desirable, but 120 cal/kg
is a minimum target) to prevent or diminish
catabolism, and glucose is the most important part
of this, especially in the absence of primary lactic
acidemia or acidosis. As much lipid as is safe
should be added to compensate for the caloric
deficit.
Hemodialysis will remove most metabolites
rapidly, but this is an extreme intervention in a
newborn. It should be performed routinely in
extreme and symptomatic hyperammonemia
(ammonia levels of 400 mol/L or more), and many
would consider dialysis in severe acidosis caused
by acids other than lactate or ketones. Once a
diagnosis has been established, specific therapy
can be initiated. It is important to emphasize that
during this period of generic therapy, prolonged
deprivation of exogenous protein or amino acids
will cause endogenous protein breakdown and
exacerbate the metabolic process. As a result,
protein is added to the intravenous support fluids
after 36–48 hours, beginning with 0.25–0.5 g/kg
levels of 1.2–1.5 g/kg per day, pending a
definitive diagnosis and assuming that it is
tolerated.
Suggested Readings
Online Mendelian Inheritance in Man, OMIM.
McKusick-Nathans Institute of Genetic Medicine, Johns
Hopkins University (Baltimore, Md.) and National
Center for Biotechnology Information, National Library
of Medicine (Bethesda, Md.), Available at
http://www.omim.org.
Saudubray J-M. Classification of inborn errors of
metabolism. In: Saudubray J-M, van den Berghe G,
Walter JH, eds. Inborn Metabolic Diseases: Diagnosis
and Treatment. 5th ed. Heidelberg: Springer-Verlag;
2012:1-52.
Saudubray JM, Charpentier C. Clinical phenotypes:
diagnosis/algorithms. In: Valle D, Beaudet AL,
Vogelstein B, et al., eds. The Online Metabolic and
Molecular Bases of Inherited Disease. Available online
at: http://www.ommbid.com. see Chapter 66, Springer-
Verlage; updated 2014.
Saudubray J-M, van den Berghe G, Walter JH. Inborn
Metabolic Diseases: Diagnosis and Treatment. 5th ed.
Heidelberg: Springer-Verlag; 2012. Valle D, Beaudet
AL, Vogelstein B, et al., eds. The Metabolic and
Molecular Bases of Inherited Disease. Available online
at: http://www.ommbid.com; McGraw-Hill.