Review Article

An Overview of Newborn Screening

Paul A. Levy, MD

ABSTRACT: This review of newborn screening examines the beginning of screening with the story of phenylk-
etonuria and explores the principles of screening and the criteria with which disorders were added to newborn
screening panels. The explosion of tests that are screened for followed the adoption of tandem mass spec-
trometry (MS-MS) technology. The inequity of state newborn screening panels was brought to the forefront
with an American Academy of Pediatrics task force report in 2000 that called for a national panel. The
American College of Medical Genetics convened an expert panel to produce such a panel. In 2006, they
published their panel of disorders, recommending a panel of 29 core disorders and 25 additional secondary
targets. Ethical arguments about newborn screening have resurfaced with the recent expansion of testing that
include arguments about consent, mandatory participation, benefits to those screened, and cost both to the
individual and society. Finally, the future direction of screening is discussed. Newborn screening is undergoing
rapid expansion. The addition of tests involves ethical, financial, and social pressures.
(J Dev Behav Pediatr 31:622631, 2010) Index terms: newborn screening, tandem mass spectrometry, core panel, inherited metabolic disorders.

T he story of newborn screening begins with the story

of phenylketonuria (PKU). There is a wonderful review
of PKU by Centerwall and Centerwall.1 They tell about a
child born to American parents living in China in 1920.
It was soon apparent that the child was having develop-
mental delay. When the mother was not getting answers
from the doctors in China, she brought her daughter
back to the United States. The child was examined by
many experts, and none of them could tell the mother
what was wrong with her daughter. The mother was
Pearl S. Buck, a Pulitzer Prize winning author and Nobel
Laureate. In her book, The Child Who Never Grew,
she provides an excellent description of classical PKU,
writing about her daughter who was not diagnosed for
PKU until 1960.
Another determined mother living in Norway in the
1930s enlisted the help of a physician-researcher, named
Asbjorn Folling, to help find an explanation for the
developmental delay and mental retardation of her 2
children. She told Dr. Folling of a strange musty odor to
the childrens urine. He started his investigation with a
sample of the daughters urine. On analyzing the urine
sample, he found a positive reaction for ketones. With
further analysis, he was able to determine that the com-
pound was phenylpyruvic acid. Dr. Folling went on to
discover phenylpyruvic acid in the urine of 1% to 2% of
children institutionalized for mental retardation. By
studying families with multiple children with PKU, he
From the Division of Genetics, Department of Pediatrics, Albert Einstein College
of Medicine, Childrens Hospital at Montefiore, Bronx, NY.
Address for reprints: Paul A. Levy, MD, Pediatric Genetics, Childrens Hospital
at Montefiore, 3415 Bainbridge Avenue, Bronx, NY 10467; e-mail:
plevy@montefiore.org.
Copyright 2010 Lippincott Williams & Wilkins
proved that it was recessively inherited. For many
years, PKU was a known but untreatable cause of
mental retardation.
The enzyme responsible for PKU was later discovered
to be primarily an enzyme found in liver that converted
phenylalanine to tyrosine. Patients with PKU have in-
creased levels of phenylalanine in their blood. The de-
velopment of a treatment occurred in the 1950s, when a
formula low in phenylalanine was produced and used to
treat infants. This advance was encouraging, but to be
effective, the treatment needed to be started as early as
possible after birth.
The question was how to accomplish this goal. Dr.
Follings ferric chloride test was effective only on urine
collected at a few weeks of age. Early attempts at screen-
ing were done on diapers collected at a few weeks of
age. Tracking infants in a screening program, where the
screening would occur after hospital discharge, was a
daunting task.
In 1963, Guthrie and Susi2 published a method of
testing for PKU with only a few drops of blood. This
simple and efficient bacterial inhibition assay enabled
screening for PKU on a wide scale. Blood from new-
borns could be collected on filter paper cards, dried, and
shipped to a central laboratory. Guthrie had discovered
that the growth of bacteria was inhibited by B-2-thieny-
lalanine added to the agar. This was reversed when a
filter paper spot containing the blood of a patient with
PKU was placed on the agar. Phenylalanine present in
the blood permitted the growth of bacteria around the
filter paper spot. The amount of growth is proportional
to the level of phenylalanine in the filter paper blood
spot.
Having a method that enabled easy collection of spec-
imens on a largescale, which was inexpensive, and that

622 | www.jdbp.org Journal of Developmental & Behavioral Pediatrics

could be accomplished by people with limited training
was not enough to launch newborn screening on a
population-wide basis. Although Dr. Guthrie was a tire-
less crusader, his success was also a product of the
times. A belief that the medicine could identify and
possibly treat or prevent many of the causes of mental
retardation was gaining momentum in the 1950s and
early 1960s. President Kennedy, who had a sister with
mental retardation, committed the country in 1961 to
double the National Institutes of Health funding for the
study of mental retardation and formed a Presidential
Advisory Council on Mental Retardation.3 In 19621963,
Massachusetts became the first state to screen all new-
borns for PKU.4 The screening was hailed as a great
success. If unidentified and untreated, PKU patients will
be severely retarded, with eczema, reduced pigmenta-
tion of skin, hair and iris, poor growth, microcephaly,
and other neurologic abnormalities (seizures, tremor,
and spasticity). If the treatment is started early, patients
have minimal intellectual impairment when compared
with their unaffected siblings.5
With the success of screening for PKU, the question
of which disorders should be added to Newborn Screen-
ing Programs began to be addressed. Dr. Guthrie went
on to develop assays for galactosemia and maple syrup
urine disease (MSUD), which made the addition of these
disorders possible. Many states also added congenital
hypothyroidism and sickle cell disease to their screening
programs. Criteria were developed to help with the
decisions as to which disorders were to be added to
newborn screening panels.
Criteria for Screening
Wilson and Jungner6 were commissioned in 1968 by
the World Health Organization to examine the screening
for chronic disease in developed countries. Most of the
principles developed were applied to newborn screen-
ing, which are as follows:
1. The disease should be prevalent in the population.
2. There should be an effective treatment or interven-
tion for the disease screened.
3. Testing to confirm the screening test should be
available and have good specificity and sensitivity.
4. The natural history of the disease should be well
understood.
5. The cost of screening should be low and balanced
against the possible expenditure of medical care.
With these principles of screening as a guide, states
added these conditions to their screening panels. By
1998, 21 states screened for 6 or more disorders,
whereas 29 states did 5 or less. Seven years later, in
2005, half the states were screening for 22 disorders.
This explosion of new tests followed the adoption of
tandem mass spectrometry (MS-MS) technology to new-
born screening.
Vol. 31, No. 7, September 2010
Tandem Mass Spectrometry
Tandem mass spectrometry or MS-MS uses 2 mass
spectrometers linked together by a collision chamber. A
sample is ionized and a mass/charge is selected, which
moves the selected ionized molecule to the collision
chamber. In the collision chamber, an inert gas is used to
collide with these molecules to fragment them. The
second MS is then used as a detector to analyze these
fragments. This technology enables rapid screening for
many disorders at a low cost. Adding a test is almost as
simple as telling the computer to look for the ions
known to be produced by the MS-MS. Tandem mass
spectrometry has permitted the addition of fatty acid
oxidation and carnitine transport disorders (CPTI, CPT
II, and CACT), and many organic acidurias, disorders of
amino acid metabolism, and urea cycle disorders to new-
born screening panels.
Development of a Uniform Panel of Tests
The Health Resources and Services Administration
(HRSA) and Maternal and Child Health Bureau asked the
American Academy of Pediatrics to convene a national
task force on newborn screening. In 1999, this task force
issued a report that acknowledged the inequity of testing
among the state newborn screening programs and called
for the establishment of a panel of tests that would be
uniform across the country.7 HRSA and Maternal and
Child Health Bureau then contracted with the American
College of Medical Genetics (ACMG) to pursue just such
a panel of tests using the best scientific evidence for
screening. A Newborn Screening Expert Group that in-
cluded physicians and experts in health policy, public
health, ethics, and consumers was convened. This group
polled experts and other interested parties. The results
of these surveys were used to quantify the response into
a score for each disorder reviewed. Eighty-four condi-
tions were selected for the review process. These in-
cluded disorders that were already part of newborn
screening programs, disorders that were possible to
screen for using newer technologies (MS-MS), disorders
that the Expert Group felt worthy of consideration, dis-
orders identified by various advocacy groups, and some
disorders that were part of the differential diagnosis for
another condition. This expert panel recommended a
core panel of 29 disorders.8 This included 9 disorders of
organic acids, 5 fatty acid oxidation defects, 6 amino acid
disorders, 3 forms of hemoglobinopathies, and 6 other
disorders. Twenty-five more disorders were considered
to be secondary targets. Many of these disorders are part
of the differential diagnosis for disorders in the core
panel and are often identified by MS-MS or hemoglobin
electrophoresis testing. Many states either had moved to
using MS-MS technology to do their screening or were in
the process of adopting it. This paved the way for the
adoption of both the core and secondary targets to
newborn screening programs across the United States.
2010 Lippincott Williams & Wilkins 623
Overview of 29 Disorders in the Recommended Panel
Organic Acid Disorders (9)
The presenting features of organic acid disorders
include acidosis, hypoglycemia, lactic acidosis, and
ketosis. These signs may be present either separately
or in combination. Most of these disorders result from
disruptions in the degradation pathways of amino ac-
ids (Table 1).
Deficiencies of enzymes that help degrade isoleucine,
leucine, and valine (branched chain amino acids) result
in isovaleric acidemia (IVA), 3-hydroxy-3-methylglutaryl-
Co-A lyase (HMG Co-A lyase) deficiency, 3-methylcroto-
nyl-Co-A carboxylase (3-MCC) deficiency, methylmalonic
aciduria (MMA), and propionic aciduria. MSUD is the
result of a shared enzyme in branched chain amino acid
degradation pathway. It is included below with disor-
ders of amino acid because it leads to increased levels of
the branched chain amino acids.
IVA is a defect of leucine metabolism. It presents
either in the neonatal period with severe acidosis, keto-
sis, vomiting, and dehydration that generally leads to
coma and death without intervention, or as a later onset
disease with episodes of acidosis, ketosis, neutropenia,
and hyperammonemia. The urine of patients with IVA
often has an odor of sweaty feet. Treatment for the
acute episodes is with a glucose infusion. Carnitine sup-
plementation and oral glycine with a low-protein diet is
often considered to be an effective treatment.
In about a third of patients, HMG-CoA lyase deficiency
presents in the neonatal period after a few symptom-free
days with lactic acidosis, hypoglycemia, vomiting, leth-
argy, hyperammonemia, and liver dysfunction. Those
without the neonatal presentation show similar symp-
toms later in the first year of life during an acute illness.
Patients have hypoglycemia but because of its role in
ketone body formation, they have very low to absent
ketones. HMG-CoA lyase deficiency needs to be distin-
guished from disorders of fatty acid oxidation (which do
not have acidosis). Patients often have neurologic com-
plications from their disease. Treatment is directed to-
ward the prevention of fasting, supplementation with
sugar orally, or if more severe, by intravenous infusion of
glucose. Restriction of dietary protein intake is often
required.
The 3-MCC deficiency is controversial. Most patients
detected by newborn screening have been asymptom-
atic. There are reports of patients with developmental
delay, acidosis, hypoglycemia, hypotonia, and seizures.
Treatment is with supplementation of L-carnitine, pro-
tein restriction with decreased lysine intake may be
necessary, and supplementation with glycine. Acute ep-
isodes need supplementation with oral carbohydrate or
intravenous glucose.
MMA is due to a deficiency (or decreased activity) of
methylmalonyl-CoA mutase. Patients with absent en-
zyme protein are termed mut0, whereas in those whose
enzyme has decreased activity it is referred to as mut.
624 Overview of Newborn Screening
Lactic acidosis, ketosis, hypoglycemia, hyperammone-
mia, hyperglycinemia with vomiting, and dehydration
and lethargy that often progresses to coma are the com-
mon presentations of MMA. Early presentation can occur
in the first few weeks of life, whereas other patients may
later have recurrent episodes of vomiting and dehydra-
tion. Failure to thrive and hypotonia are often accompa-
nying symptoms. Treatment is with dietary protein re-
striction, supplementation with cobalamin (vitamin B12)
given intramuscularly as hydroxocobalamin, and supple-
mentation with L-carnitine orally.
Propionic aciduria (PA) was initially termed ketotic
hyperglycinemia. Patients in most cases present in the
first few days of life with dehydration and coma. Keto-
acidosis with hyperglycinemia and hyperammonemia is
often associated with increased lactic acid, and hypocal-
cemia is the most common presentation. Those patients
who do not present in the newborn period present later in
life with recurrent episodes of ketoacidosis. Neurologic
sequelae are common. Neonates may require hemodialysis
for removal of ammonia and other metabolites. Dietary
protein restriction, with carnitine supplementation, is the
mainstay of therapy. Ammonia-scavenging drugs (so-
dium benzoate) may be necessary to treat persistent
hyperammonemia, and metronidazole may be used to
reduce the production of propionic acid by intestinal
bacteria.
A defect in the lysine pathway results in glutaric
acidemia Type 1 (GA-1). This disorder is characterized
by macrocephaly, hypotonia, and developmental delay.
Patients have a relatively symptom-free period followed
by an acute brain injury often associated with an infec-
tion on average by 9 months of age, with almost 90%
having an encephalopathic episode by 2 years of age.
Treatment is to supplement with carnitine and riboflavin
and to restrict dietary protein, especially the restriction
of lysine intake. Fever management is very important, as
patients decompensate with hyperpyrexia. Emergency
treatment is with oral high-carbohydrate drinks and, if
necessary, with intravenous glucose and carnitine.
Several other metabolic pathways are disrupted not
from enzyme deficiencies of the pathway but from prob-
lems with the processing of a cofactor. For multiple
carboxylase deficiency (MCD), holocarboxylase syn-
thetase activates 4 carboxylases that are important in
gluconeogenesis, fatty acid synthesis, and amino acid
degradation by attaching the vitamin biotin to their in-
active forms. Patients with MCD deficiency present with
disruptions of these 4 pathways that leads to neonatal
onset of respiratory distress, severe metabolic acidosis
with ketosis, and mild hyperammonemia. A later onset
form can develop symptoms similar to biotinidase defi-
ciency with neurologic symptoms, alopecia, and rash.
Treatment is with biotin supplementation. Biotinidase
deficiency is described below.
In MMA, the enzyme methylmalonyl-CoA mutase re-
quires a cobalamin (vitamin B12) cofactor. The cofactor
for the mutase is adenosylcobalamin, which is processed
Journal of Developmental & Behavioral Pediatrics
 Table 1. Recommended Panel of 29 Core Disorders
Disorder Age of Dx Symptoms Available Treatment Neurologic
Symptoms
Organic acid disorders (9)
Isovaleric acidemia Neonatal later Severe acidosis, ketosis, vomiting, and dehydration Glucose infusion, correction of Yes (often)
onset acidosis. Low protein diet, with
glycine and carnitine
supplementation

Vol. 31, No. 7, September 2010

HMG-CoA lyase (3-OH- Neonatal later Lactic acidosis, hypoglycemia, vomiting, lethargy, Treatment to prevent fasting. Oral Possibly
3-methylglutaryl-CoA onset hyperammonemia, and liver dysfunction. Patients lack supplementation of carbohydrates. IV
lyase) ketosis glucose if necessary
3-MCC (3- Later onset Developmental delay, hypoglycemia, seizures as well as Carnitine supplementation and Yes (generally
methylcrotonyl-CoA hypotonia have been reported. Most patients are supplementation with glycine has asymptomatic)
carboxylase) asymptomatic helped with symptomatic children.
An acute episode may need IV
glucose
Methylmalonic aciduria Neonatal later Lactic acidosis, ketosis, hypoglycemia, hyperammonemia, IM vitamin B12. Dietary treatment is Yes
onset vomiting, dehydration, failure to thrive, hypotonia with protein restriction and
supplementation with carnitine
Methylmalonic aciduria Neonatal later Same as methylmalonic aciduria above Hydroxocoblamin supplementation Yes
(CblA and CblB) onset
Propionic aciduria Neonatal later Ketoacidosis, hyperglycinemia, hyperammonemia, elevated Low protein diet and carnitine Yes
onset lactic acid and hypocalcemia supplementation
Glutaric aciduria, Type 1 Late infantile Macrocephaly, hypotonia, developmental delay Supplementation with carnitine and Yes
riboflavin. Dietary restriction of
protein intake, especially lysine.
Acute episodes require high
carbohydrate drinks or IV glucose
Multiple carboxylase Neonatal later Respiratory distress, severe metabolic acidosis with ketosis Biotin supplementation Yes
def onset and hyperammonemia
Amino acid disorders (6)
Phenylketonuria Newborn screen Initially no symptoms. Slow intellectual disability ending in Dietary management with a low Yes
later onset severe mental retardation. Eczema, poor growth phenylalanine diet
microcephaly, seizures, tremor and spasticity
Homocystinuria Later onset Patients develop problems with their eyes (dislocated About 10% respond to pyridoxine, if Yes
lenses), skeleton (elongation of the long bones), CNS not, then a diet low in methionine
(mental retardation in 60%) and thromboembolic and high in cystine. Betaine may be
abnormalities useful
Tyrosinemia Type 1 Infantile later onset Liver failure, failure to thrive, peripheral neuropathy, NTBC orally. Low tyrosine and Yes
Fanconi-like kidney disease phenylalanine diet
Maple syrup urine Neonatal later Poor feeding, coma. Later onset forms may have Low protein diet with restriction of the Yes

2010 Lippincott Williams & Wilkins

disease onset developmental delay branched chain amino acids (leucine,
isoleucine, and valine)

625
(Table Continues)
 Table 1. Continued

626
Neurologic
Disorder Age of Dx Symptoms Available Treatment Symptoms

Citrullinemia Neonatal Elevated ammonia. Poor feeding, lethargy then coma Protein restricted diet. Ammonia Yes
argininosuccinic scavenging drugs (buphenyl orally)
aciduria
Fatty acid oxidation
disorders (5)
Medium chain Acyl-CoA Infantile childhood Hypoglycemia without ketosis. Lethargy progressing to Prevention of fasting. IV glucose if not Yes, in some
dehydrogenase coma taking PO patients

Overview of Newborn Screening

(MCAD)
VLCAD Neonatal childhood Coma, dilated or hypertrophic cardiomyopathy, multiorgan Energy provided as glucose. Neonatal Yes
later onset failure (neonatal). Hypoglycemia and hypoketosis in the form benefits from low fat diet and
childhood form. Myopathy, rhabdomyolysis, muscle pain formula high in MCT oil
and exercise intolerance
LCHAD/MTP (long Infantile later onset Hypoketotic hypoglycemia. More chronic presentation Diet high in carbohydrates and low in Yes
chain 3-OH-acyl-CoA with hypotonia, cholestasis, failure to thrive and feeding fat
dehydrogenase/ difficulties. MTP is more severe with lactic acidosis,
mitochondrial hypoglycemia, hypotonia, and lethargy. Both forms
trifunctional protein) develop a peripheral neuropathy and pigmentary
retinopathy
Carnitine uptake disorder Later onset Muscle weakness, severe cardiomyopathy Supplementation with carnitine No
Hemoglobinopathies and
other disorders (9)
Sickle cell disease Infantile childhood Anemia, pain, multiorgan involvement, stroke, lung, and Penicillin prohylaxis, hydroxyurea, Yes
kidney disease. Developmental delay and learning transfusion therapy
problems are not uncommon
Sickle-B thalessemia Infantile childhood Milder form of sickle cell disease Maybe
Sickle-hemoglobin C Infantile childhood Mild anemia, splenomegaly. Milder than Sickle cell disease Similar to sickle cell disease if Maybe
but may have many of the complications of sickle cell symptoms severe
disease
Biotinidase deficiency Infantile childhood Rash, alopecia, seizures, ataxia, hypotonia, and lethargy, Biotin supplementation Yes
hearing loss. Developmental delay without treatment
Galactosemia Neonatal infantile Jaundice, liver dysfunction, vomiting, and poor feeding. Dietary restriction of galactose Yes
Many patients with developmental delay or learning
problems
Congenital Infantile Developmental delay, poor growth, lethargy, constipation Thyroid hormone supplementation Yes
hypothyroidism
Congenital adrenal Neonatal infantile Female infants with ambiguous genitalia or completely Supplementation with glucocorticoids No
hyperplasia masculinized. Salt losing form of disease is critical in the
first few weeks of life
(Table Continues)

Journal of Developmental & Behavioral Pediatrics

 from absorbed vitamin B12 (cobalamin) by a number of

Neurologic
Symptoms
enzymes. Deficiencies of these enzymes will lead to the
CblA and CblB forms of MMA. Treatment is with supple-
mentation with hydroxocobalamin given intramuscu-
larly and protein restriction.

Yes
No
Amino Acid Disorders (6)
PKU is diagnosed by a significant elevation of phenyl-
alanine (usually 240 mol/L). PKU is a slow insidious

aggressive chest physiotherapy and

Pancreatic enzyme supplementation, disease. If untreated, PKU will lead to significant intel-

antibiotics, inhalation therapies

Hearing aids, cochlear implant if
lectual disability. Treatment involves a diet low in phe-
Available Treatment

nylalanine. Patients treated soon after birth have IQ

scores similar to their unaffected siblings.
The most common form of homocystinuria, due to a
deficiency of cystathionine -synthase, has increased me-
thionine on newborn screen. Homocystine will be found
significantly increased in urine. These patients are nor-
indicated

mal at birth but then develop problems with the eye

(ectopia lentisdislocation), skeleton (osteoporosis, scoli-
osis, and elongation of long bones [dolichostenomelia]),
central nervous system (mental retardation in 60%), and
vascular (thromboembolic abnormalities). Treatment for
Respiratory infections, malabsorption, diarrhea, and failure

10% of patients is with pyridoxine alone. For those

who are unresponsive to this vitamin, a diet low in
methionine and high in cystine is the mainstay of treat-
Many children with late diagnosis (before newborn

ment. Betaine, a methyl donor, is used to lower homo-

screen), which lead to speech and language

cysteine levels.
Patients with tyrosinemia Type I (hepatorenal
tyrosinemia) are also normal at birth. The different forms
of this disorder are classified by their different ages of
Symptoms

presentation. All present with liver and renal disease or

failure. The acute form presents with liver failure before
6 months of age, a subacute form presents from 6
months to a year of age, and a chronic form presents
after the first year of life. A secondary marker, succiny-
lacetone is found to be increased in these tyrosinemia
development

patients. Treatment until the early 1990s relied on liver

transplantation, but the introduction of 2-(2-nitro-4-flu-
to thrive

oromethylbenzoyl)-1,3-cyclohexanedione (NTBC) revo-

lutionized the treatment. NTBC inhibits degradation of
tyrosine, which prevents the production of toxic metab-
olites. Patients must also be on a diet that restricts ty-
rosine and phenylalanine (which phenylalanine hydrox-
ylase converts to tyrosine).
Age of Dx

As with many inherited metabolic disorders, there are

Childhood

Childhood

multiple forms of MSUD. The severe neonatal form pre-

sents with poor feeding and sleepiness followed by en-
cephalopathic coma. There are really no significant lab-
oratory abnormalities, except that ketones may be
present in the urine. This makes diagnosis extremely
difficult. The branched chained amino acids (leucine,
isoleucine, and valine) share a dehydrogenase (branched
chain-2-keto acid dehydrogenase). Deficiency of this en-
Table 1. Continued

Cystic fibrosis

Hearing loss

zyme complex results in MSUD. Treatment of neonates

with a diet that limits the branched chain amino acids
Disorder

(specifically leucine) is effective.

Citrullinemia and argininosuccinic aciduria are 2 dis-
orders of the urea cycle and both have increased citrul-

Vol. 31, No. 7, September 2010 2010 Lippincott Williams & Wilkins 627
line and increased ammonia. As with MSUD, the urea
cycle disorders are difficult to diagnose, because routine
tests are usually without significant abnormality. It is
only with clinical suspicion that an ammonia level might
be obtained. Treatment is with a protein-restricted diet
and ammonia-scavenging drugs (sodium benzoate and
sodium phenylacetate by intravenous infusion or sodium
phenylbutyrate orally). Liver transplantation is a curative
option.
Fatty Acid Oxidation Disorders (5)
Mitochondrial fatty acid -oxidation involves a num-
ber of enzymes that are specific for different length fatty
acids. Most mitochondrial fatty acid -oxidation begins
with fatty acids that are 18 or fewer carbons in length.
Medium chain acyl-CoA dehydrogenase (MCAD) is spe-
cific for fatty acids with chain lengths of 12 carbons
down to 6 carbons. Patients with MCAD deficiency are
asymptomatic until provoked by a period of fasting.
Their first episode usually occurs between 3 and 24
months of age, after a period of prolonged fasting, be-
cause either feeding was delayed or an intercurrent ill-
ness prevented feeding. Hypoglycemia develops but
there is an inappropriately low level of ketones. Initial
lethargy with nausea and vomiting can progress to coma
if there is no intervention. Patients should be treated
with infusions of glucose during an intercurrent illness if
there is loss of appetite. It is reported that up to 25% of
undiagnosed patients with MCAD die with their first
attack, whereas others may never become symptomatic.
Patients become more tolerant to fasting with increasing
body mass.
Very long-chain acyl-CoA dehydrogenase (VLCAD) de-
ficiency has 3 presentations. The first presentation is a
severe neonatal form with coma, dilated or hypertrophic
cardiomyopathy, and multiorgan failure. The cardiomy-
opathy and associated arrhythmias are often fatal. A
second form presents in early childhood, with episodes
of hypoglycemia and hypoketosis but without cardiac
involvement. The third form presents still later and is a
myopathic form, with episodes of rhabdomyolysis, mus-
cle pain, and exercise intolerance. The mainstay of treat-
ment is to provide energy in the form of glucose. The
severe, early onset form benefits from a low-fat diet and
a formula high in medium chain triglycerides oil. The
later onset form with rhabdomyolysis requires hydration
until the myoglobinuria resolves.
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)
deficiency and mitochondrial trifunctional protein (MTP) de-
ficiency share a multienzyme complex in common. MTP
is composed of and subunits. Four and 4 tion, and there is excellent clinical outcome.
subunits combine into a mitochondrial membrane-
bound protein complex. This enzyme complex has
LCHAD activity, long-chain enoyl-CoA hydratase activity,
and long-chain 3-ketothiolase activity. Patients with iso-
lated LCHAD deficiency have been reported and may
present within the first 6 months of life with an acute
episode of hypoketotic hypoglycemia. There is increas-
628 Overview of Newborn Screening
ing evidence that, these patients have subtle, more
chronic symptoms that are nonspecific and so are easily
missed. A more chronic presentation is likely the most
common form. Patients may have cholestasis, failure to
thrive with feeding difficulties, hypotonia, cardiomyop-
athy, and episodes of rhabdomyolysis. Patients with MTP
abnormalities that result in the loss of all 3 enzyme
functions would be expected to have more severe symp-
toms, and they do. Most have a rapidly progressive
course with lactic acidosis, hypoglycemia, hypotonia,
and lethargy. A progressive peripheral neuropathy and a
pigmentary retinopathy are symptoms unique to isolated
LCHAD and MTP deficiencies among the fatty acid oxi-
dation defects.
A mother of a fetus with LCHAD can develop hemo-
lysis, elevated liver enzymes, low platelets (HELLP) syn-
drome or acute fatty liver of pregnancy.
Treatment of the isolated LCHAD deficiency is with a
diet high in carbohydrates and low in fat. Mortality is
quite high, despite the dietary treatment. Treatment
with L-carnitine is controversial because of the potential
for toxic metabolites of long-chain fatty acids that might
accumulate within mitochondria.
Carnitine uptake disorder is a deficiency of an or-
ganic cation transporter that is responsible for the
transport of carnitine into cells. Patients present with
severe cardiomyopathy and muscle weakness. The car-
diomyopathy shows poor contractility and thickened
ventricular walls. Treatment with carnitine is gener-
ally quite effective.
Hemoglobinopathies (3)
All states screen for sickle cell disease. Sickle cell
disease presents with anemia, pain, and multiorgan in-
volvement. Patients are prone to infection and stroke.
Treatment is with antibiotic prophylaxis, transfusion
therapy, and oral hydroxyurea in some patients. Many
states report out other associated hemoglobinopathies,
including sickle- thalassemia and sickle hemoglobin C.
Other Disorders (6)
Biotinidase is an enzyme that releases the vitamin
biotin from its normal protein-bound state. In this way,
biotinidase permits both recycling of biotin and the use
of biotin from the foods that we eat. Biotin is a coenzyme
for 4 carboxylases that are important in fatty acid syn-
thesis, gluconeogenesis, and amino acid degradation.
Deficiency of biotinidase leads to a clinical picture sim-
ilar to MCD, but onset is later and more gradual with
development of rash, alopecia, seizures, ataxia, hypoto-
nia, and lethargy. Treatment is with biotin supplementa-
Classic galactosemia is because of deficiency of the
enzyme galactose-1-phosphate uridyl transferase (GALT).
Undiagnosed patients may present as newborns with
jaundice, liver dysfunction, vomiting, and poor feeding.
There is a predisposition to Escherichia coli infections,
and some neonates may present with sepsis. Early cata-
racts develop, usually within a few days to weeks of
Journal of Developmental & Behavioral Pediatrics
birth. If patients survive the initial newborn period, they
progress to hepatomegaly and then to cirrhosis. Treat-
ment is the dietary restriction of galactose.
Congenital hyperthyroidism is usually asymptomatic
in the newborn period. If undiagnosed, patients are
developmentally delayed (later with mental retardation),
poor growth, delayed closure of the anterior fontanelle,
and lethargy. Treatment with thyroid hormone supple-
mentation has excellent results if started early.
Congenital adrenal hyperplasia (CAH) is most often
because of deficiency of 21-hydroxylase. Female in-
fants may have ambiguous genitalia or be completely
masculinized. Male genitalia are unaffected, so boys
with CAH are more susceptible to the salt-losing form
of the disease because they do not come to medical
attention in the nursery. Treatment is with replace-
ment of glucocorticoids.
Cystic fibrosis is a disorder of an epithelial cell trans-
membrane regulator, which interferes with chloride
transport. This leads to increased salt concentrations in
secretions, thickened mucus, which is not cleared well,
and results in respiratory infections and exocrine pan-
creatic failure with resulting malabsorption and failure to
thrive. Treatment is focused on the pulmonary tract with
inhalation therapy, chest physiotherapy, antibiotics, and
supplementation of pancreatic enzymes.
Hearing loss affects 1 to 3 of 1000 newborns. Con-
sequences of late diagnosis include delayed speech and
language development. Early diagnosis permits interven-
tion to assist hearing and language development.
Secondary Targets (25)
The secondary targets generally are disorders that are
part of the differential diagnosis for a primary target.
Most of these are easily detected by MS-MS technology
during the initial run. For example, 6 additional amino
acid disorders are included. PKU, which is part of the
core panel, is a severe form of hyperphenylalaninemia.
There are other disorders that do not have such severe
increase of phenylalanine. Phenylalanine hydroxylase,
the enzyme deficient in PKU, has a cofactor (tetrahydro-
biopterin). If there are defects in the synthesis of this
cofactor, it could lead to hyperphenylalaninemia. De-
fects in tetrahydrobiopterin metabolism are usually ruled
out in patients with hyperphenylalaninemia. On the sec-
ondary panel, there are 2 defects of tetrahydrobiopterin
synthesis and hyperphenylalaninemia that is increased
but at a lower level than reported for classic PKU. Two
other disorders of tyrosine metabolism are on this sec-
ondary list and arginine for arginase deficiency and a
disorder with increased citrulline that needs to be in-
cluded when considering a case of citrullinemia. There
are 6 more organic acid disorders including 2 additional
forms of MMA and several other rare disorders of the
branched chain amino acids (2-methyl-3-hydroxybu-
tyric aciduria, 2-methylbutyryl-CoA dehydrogenase defi-
ciency, and 3-methylglutaconic aciduria). In addition, 8
more fatty acid oxidation defects including the 3 carni-
Vol. 31, No. 7, September 2010
tine transport disorders (CPTI, CPT II, and CACT) are on
the list. Finally, other forms of galactosemia (GALK,
GALE) and some variants of hemoglobin round out the
secondary list.
How Conditions are Added?
Initially, there was much criticism of the ACMG panel
recommendation for the 29 core disorders and the 25
secondary targets. Much of the criticism involved the
process, which was not felt to be as evidenced-based as
it could have been, that it seemed to be influenced by
parents and advocacy groups, and that it moved away
from the core principles that had guided newborn
screening previously.9,10 Despite these criticisms, most
states have now adopted the core panel and many of the
secondary targets. The move to add additional tests was
relatively easy, because the technology (MS-MS) had al-
ready been adopted by many states to do their screening.
Although all the core panel disorders do not have treat-
ments available, it was felt that identification of affected
infants would have its own benefits.
For the HRSA in the Department of Health and Human
Services, there is a Secretary Advisory Committee on
Heritable Disorders in Newborns and Children. This
committee is now charged with evaluating disorders
nominated by individuals or groups for addition to the
core panel of disorders. The committee replaces the
ACMG panel. In 2010, the committee published its
guidelines for this process.11 The published process goes
far toward resolving the criticisms of the earlier process.
They have been considering 6 disorders (Fabry, Krabbe,
Niemann-Pick, Pompe, severe combined immunodefi-
ciency, and spinal muscular atrophy) that were nomi-
nated for inclusion into the uniform screening panel. In
January 2010, the committee voted to include severe
combined immunodeficiency but has not voted to add
any of the other nominated disorders.12
Ethical Issues
There are multiple ethical issues involved with
screening asymptomatic newborns.13,14 Medicine today
is moving more and more toward prevention. Screening
asymptomatic individuals for hypertension, diabetes,
lead poisoning, scoliosis, and visual problems is consid-
ered routine. Prenatally, today, women are routinely
screened for sickle cell disease, HIV, group B streptococ-
cus, and cystic fibrosis. The issue of screening an asymp-
tomatic individual is really if the information will lead to
an intervention that could improve the health of the
individual tested.
The second issue is consent. For newborns, the par-
ents need to consent for the baby. It is generally felt that
to override parental consent, the harm to the infant will
be very great. For PKU, the first disorder screened, the
asymptomatic newborn needed to be treated as early as
possible to prevent sequelae. This great societal need to
prevent harm to the infant was felt to be great enough
that parental rights were overruled and participation was
2010 Lippincott Williams & Wilkins 629
made mandatory. For many of the initial disorders, such
as PKU, galactosemia, congenital hypothyroidism, CAH,
this high standard was felt to be met. As newborn screen-
ing has expanded, the standard has been lessened so that
the benefit to the patient is not immediate, and some-
times it is not clear. Disorders have been added for
which there is no treatment. The benefit in these cases
is that diagnosis will prevent a diagnostic odyssey, where
the parents go from doctor to doctor searching for a
diagnosis for their child. It has been argued that for
disorders where there is no clear and immediate benefit
to the infant, the parents should be asked to give con-
sent. Advocates of newborn screening argue that if par-
ticipation in newborn screening programs were volun-
tary and required parental consent, then the societal
benefit and benefit to the infant could be lost. As a
compromise, a proposal was made to do a two-tiered
system, with some testing being mandatory and newer
tests with less clear benefits requiring consent. For many
of the disorders that were added with the expansion of
newborn screening, the natural history was not com-
pletely known. If there was a two-tiered system, the
ability to learn this natural history information could be
lost. An example of this benefit with mandatory screen-
ing is with 3-MCC deficiency. Before the expansion of
newborn screening, 3-MCC deficiency was reported as a
disorder with developmental delay and possible epi-
sodes of acidosis and hypoglycemia. As infants were
identified with 3-MCC through screening, it became ap-
parent that most of the 3-MCC infants identified were
asymptomatic. It is likely that for most individuals 3-MCC
deficiency is a detectable biochemical abnormality,
rather than a true disease.
For other disorders, patients with later onset forms
may be identified together with the patients that have
early onset disease, creating much parental anxiety.
When there is no intervention for the later onset forms,
it has been argued that parental consent for testing
would make the natural history study that follows the
identification of later onset patients more ethical.
Another issue with the expansion of newborn
screening involves the nature of the testing. For each
test, the sensitivity is kept high, in the hope that there
will be no false negatives. The trade-off for this is a
high false positive rate. As the number of tests in-
creases with the expansion of newborn screening, the
number of patient referrals increases. The increased
number of false positives greatly increases parental
anxiety and puts strain on the follow-up systems for
newborn screening.
A final ethical argument involves allocation of re-
sources. Today with MS-MS technology, the cost of each
individual test may be very low, but there are increased
costs for follow-up, counseling, and there is the oppor-
tunity cost for monies that might have been spent on
other potential ways to improve societal health.
630 Overview of Newborn Screening
Future of Newborn Screening
The future of newborn screening is increasingly tech-
nology dependant. It is likely that a modified form of the
original rules that guided the addition of tests to new-
born screening panels will continue to guide further
development. The caveat that testing should be low in
cost will likely exclude expensive technologies such as
array comparative genomic hybridization and sophisti-
cated genome sequencing (NextGen) for the near future.
Screening will likely continue to be done only if there is
a reasonable incidence in the population, and if there is
either treatment available or if intervention will benefit
the patient. As treatments are available for a number of
lysosomal storage disorders (Fabry, Hurler, Hunter,
Maroteaux-Lamy, Pompe) momentum is gaining to add
these to newborn screening panels. Patients with X-
linked adrenoleukodystrophy (ALD) may benefit from
treatment before they become symptomatic, which
seems to delay the onset of symptoms. Testing for ALD
by newborn screening is being developed. There have
been calls to screen for DiGeorge syndrome/velocardio-
facial syndrome (22q11.2 deletion) as well as fragile-X
syndrome, spinal muscular atrophy, and Duchene mus-
cular dystrophy.
The Secretarys Advisory Committee on Heritable Dis-
orders in Newborns and Children is charged with eval-
uating disorders that have been nominated to be added
to the recommended screening panel. Despite their ef-
forts to make this process evidence based and objective,
in some cases, pressure from parental advocacy groups
have had great influence on the process of adding dis-
orders to state panels. Advocacy groups have already
been successful in adding Krabbe to a number of states
newborn screening panels, despite the recent Secre-
tarys Advisory Committee vote against adding Krabbe to
the universal panel.
The adoption of the recommended core panel of tests
has gone far to end the previous inequity of newborn
screening. No longer is the testing for the core panel of
disorders dependant on which state you are born in. If
the process adopted by the Secretarys Advisory panel is
followed for the addition of new disorders to the core
panel, then the system will remain equitable. In some
ways as we struggle with the question of which disor-
ders to add to newborn screening panels, we are coming
closer to the original hopes for newborn screening, that
identification and intervention could prevent mental dis-
ability and ensure health.
REFERENCES
1. Centerwall SA, Centerwall WR. The discovery of
phenylketonuria: the story of a young couple, two retarded
children and a specialist. Pediatrics. 2000;105:89 103.
2. Guthrie R, Susi A. A simple phenylalanine method for detecting
phenylketonuria in large populations of newborn infants.
Pediatrics. 1963;32:338 343.
3. Tarini BA. The current revolution in newborn screening. Arch
Pediatr Adoles Med. 2007;161:767772.
Journal of Developmental & Behavioral Pediatrics
 4. MacCready RA, Hussey MG. Newborn phenylketonuria detection
program in Massachusetts. Am J Public Health Nations Health.
1964;54:20752081.
5. Dobson JC, Kushida E, Williamson M, Friedman EG. Intellectual
performance of 36 phenylketonuria patients and their
nonaffected siblings. Pediatrics. 1976;58:5358.
6. Wilson JMG, Jungner G. Principles and Practice of Screening
for Disease. France: World Health Organization; 1968.
7. Serving the family from birth to the medical home. Newborn
screening: a blueprint for the futurea call for a national
agenda on state newborn screening programs. Pediatrics. 2000;
106:389 422.
8. Watson MS, Lloyd-Puryear MA, Mann MY, Rinaldo P, Howell RR.
Main report. Genet Med. 2006;8(suppl):12S252S.
9. Moyer VA, Calonge N, Teutsch SM, Botkin JR; United States
Preventive Services Task Force. Expanding newborn
screening: process, policy, and priorities. Hastings Cent Rep.
2008;38:2331.
10. Baily MA, Murray TH. Ethics, evidence and cost in newborn
screening. Hastings Cent Rep. 2008;38:2331.
11. Calonge N, Green NS, Rinaldo P, et al. Committee report:
method for evaluating conditions nominated for population-
based screening of newborns and children. Genet Med. 2010;12:
153159.
12. Advisory Committee on Heritable Disorders in Newborns
and Children. Available at: http://www.hrsa.gov/
heritabledisorderscommittee/reports/. Accessed August 6, 2010.
13. Fost N. Ethical implications of screening asymptomatic
individuals. FASEB J. 1992;6:28132817.
14. Orzalesi M, Danhaive O. Ethical problems with
neonatal screening. Ann Ist Super Sanita. 2009;
45:325330.

Book Review
Cognitive Therapy Techniques for Children and
Adolescents: Tools for Enhancing Practice
by Robert D. Friedberg, Jessica M. McClure, Jolene Hillwig Garcia, New York,
NY, The Guildford Press, 2009, 326 pp, Hardcover, $38.00.

The authors present a comprehensive
series of cognitive behavioral techniques
that address a wide range of psychologi-
cal conditions found in typical, clinical
settings. The theoretical framework and
intervention strategies exemplify the ap-
plication of evidence-based practice for
psychological treatment in children and
adolescents. The intervention strategies
described are drawn from the theoretical
paradigms described, in depth, in their
previous book, Clinical Practice of Cog-
nitive Therapy with Children and Adoles-
cents. Treating clinicians with expertise
in behavioral therapy and child develop-
ment will find the book to be an invalu-
able reference for specific techniques.
The use of both books is appropriate for
individuals developing their theoretical
and practical application of cognitive
therapies. The book is ideal for individu-
als developing or practicing cognitive be-
havioral therapy (CBT) and who are
looking for additional tools and tech-
niques to expand and/or improve their
range of CBT techniques. The creative
and innovative interventions described
were specifically designed for children
and adolescents with a variety of inter-
vention needs.
The authors present a highly useful
framework for individuals in training, de-
veloping both their assessment and case
conceptualization skills for interventions
with children and adolescents. The in-
tervention techniques are presented as
a modular approach to CBT. The book
presents techniques and procedures
that are organized into six modules,
which address six domains. The chap-
ters address, in depth, each of the mod-
ules including psychoeducation, as-
sessment and behavioral interventions,
self-monitoring, cognitive restructur-
ing, rational analysis, and exposure/ex-
periential methods. The modular ap-
proach to CBT is based on the context
of psychoeducational functional assess-
ment, self-monitoring, and evaluation
process. A significant strength of the
book is its comprehensive presentation
of specific techniques and instruments
for assessment and self-monitoring meth-
ods. Emphasis on developmentally ap-
propriate case conceptualization is also
effective because of its focus on not only
developmental history but also cultural
context and a variety of behavioral and
cognitive issues related to the presenting
problems. Their emphasis on the eco-
logical variables that relate to problems
including learned history and cultural
and systemic factors make this a useful
text for both training and expanding
CBT techniques.
The authors extensive use of case
vignettes with specific examples, rating
scales, and many specific age-related
case studies makes this textbook highly
useful for both students and experienced
cognitive behavior therapists. There are
many specific behavioral interventions,
self-instruction, and cognitive restructur-
ing methods as well as rational analysis
techniques and tools. The authors fre-
quent emphasis on both the cultural and
behavioral contexts, involving and en-
gaging the children and their families in
the process, is a substantial strength of
the approach. They also frequently em-
phasize the importance of remaining
flexible with both technique and process
and do not seem to be overly rigid or
linear about the application of CBT tech-
niques. Their emphasis on the impor-
tance of clinicians embracing difficult
moments and mistakes is also a highly
effective and appropriate focus in the
interventions. This very readable and
useful text has been praised by my stu-
dents and has been found to be useful in
my practice.
Gordon L. Ulrey, PhD
Davis, CA

Vol. 31, No. 7, September 2010 2010 Lippincott Williams & Wilkins 631