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Newborn Screening

for Genetic Disorders
Newborn Screening
for Genetic Disorders
Experiments on Plant
Hybridization

Todd T. Eckdahl
Newborn Screening for Genetic Disorders: Experiments on Plant Hybridization
Copyright © Momentum Press®, LLC, 2019.

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Abstract
This book describes newborn screening as a public health program for the
early detection of genetic disorders. It presents the recommended uni-
form screening panel (RUSP), a list of genetic disorders recommended
by the U.S. government for states to include in newborn screening pro-
grams. The author describes the categorization of RUSP genetic disorders,
discusses the symptoms and health complications of examples from each
category, and explains clinical laboratory tests used for newborn screen-
ing. The book explores the underlying molecular genetic causes of gen-
etic disorders and how this information is used for genetic testing during
newborn screening and diagnosis. It presents the patterns of inheritance
of monogenic genetic disorders and uses hypothetical family scenarios to
illustrate them. Treatments and therapies for selected RUSP genetic disor-
ders are described that illustrate the benefits of early diagnosis. The book
explores future prospects for the prevention, diagnosis, and treatment of
genetic disorders detected by newborn screening, including experimental
drug treatments, the possibility of newborn genome sequencing, and
gene therapy.

Keywords
amino acid metabolism disorders; autosomal dominant; autosomal reces-
sive; endocrine disorders; fatty acid oxidation disorders; genetic disease;
hemoglobin disorders; incomplete dominance; newborn screening; or-
ganic acid disorders; recommended universal screening panel; sex-linked
inheritance
Contents
Acknowledgments....................................................................................ix
Introduction...........................................................................................xi
Chapter 1 Symptoms and Diagnosis...................................................1
Chapter 2 Causes and Contributing Factors.....................................15
Chapter 3 Treatment and Therapy....................................................33
Chapter 4 Future Prospects...............................................................43
Conclusion............................................................................................49
Glossary................................................................................................51
Bibliography..........................................................................................61
About the Author...................................................................................67
Index....................................................................................................69
Acknowledgments
I am grateful to my friend Malcolm Campbell for encouraging me to
take a leap of faith on this project and several others who have shaped my
career as a science educator. I value Malcolm as a teaching and research
collaborator, and I am proud of the positive impact that we have made
together on science education and the improvement of science literacy. I
am also grateful for the cheerful and professional support I received from
the publishing team at Momentum Press.
This book would not have been possible without the support of my
wife Patty Eckdahl. She understands my passion for science and science
education and helps me to channel it in ways that benefit students and
others around me. I also appreciate the support and encouragement that
my parents, Tom and Bonnie Eckdahl, gave me in the pursuit of an edu-
cation that would give me the privilege of sharing my love of DNA and
genetics with undergraduate students and everyone else I meet.
I am grateful to my undergraduate genetics professor at the University
of Minnesota, Duluth, Stephen Hedman, for helping me to understand
that I could pursue my love for genetics in graduate school. Thanks to
John Anderson at Purdue University, who taught me to conduct molecu-
lar genetics research and to value undergraduate education. I appreciate
the supportive environment that Missouri Western State University has
provided me, and I am grateful to my mentors in the Missouri Western
Biology Department, Rich Crumley, Bill Andresen, John Rushin, and
Dave Ashley, who helped me to learn how to engage students in the class-
room and the research lab. I appreciate the many students whom I have
worked with in class and collaborated with on research projects outside
of class. I take pride in the contributions that my former students have
already made, and will continue to make, to society.
Introduction
We live in a remarkable era of rapidly advancing genetic technology
that has benefitted basic biology research and found widespread applica-
tions in diverse areas such as energy, the environment, and agriculture.
In medicine, genetic technology is playing an ever-increasing role in the
detection, treatment, and, sometimes, curing of genetic diseases. Like all
technologies, genetic technology comes from a basic understanding of the
natural world that is enabled by scientific inquiry, during which observa-
tions are organized into hypotheses that can be tested by experimenta-
tion. Hypotheses that are rejected by experimental results are a vital part
of scientific progress because they lead to improved hypotheses, and those
that are supported by experimentation must be continuously reassessed
and refined in light of new discoveries. The history of genetics is rich with
hypotheses—some of which did not survive the scrutiny of experimenta-
tion and others of which expressed ideas that were confirmed by experi-
ments and still guide basic and applied genetic research. The maturation
of genetics as a science with hypotheses that make reliable predictions
and form a coherent explanation of the basic mechanisms of heredity
took an important step forward in 1866 with the publication of Experi-
ments on Plant Hybridization by Gregor Mendel. In contrast to blend-
ing inheritance, a widely held hypothesis that incorrectly stated that
genetic information mixed during reproduction cannot be unmixed in
future generations, Mendel developed the hypothesis of particulate in-
heritance and supported it with a large amount of data from experiments
using pea plants. Although he did not coin the term gene, he postulated
the concept of genes as fundamental units of heredity. He hypothesized
that genes have alternative forms that segregate during reproduction into
sex cells and reunite during fertilization. Mendel correctly deduced that
some genes segregate independently of others, and that gene forms can
be either dominant or recessive in hybrid offspring. Mendel did not live
to see the widespread acceptance of his hypotheses. At the dawn of the
xii INTRODUCTION

twentieth century, Mendel’s work was fully appreciated in the context of


the chromosomal theory of inheritance, which describes chromosomes
as storehouses of genetic information in all cells.
Over a century and a half after the publication of Experiments on
Plant Hybridization, the hypotheses put forth by Mendel have come to
be known as Mendel’s laws because of their predictive power to explain
patterns of inheritance in organisms throughout the world. Mendel’s laws
help us to understand the relationship between genotype, the collection
of alternative forms of genes known as alleles, and phenotype, the physi-
cal manifestation of genetic information. The law of segregation states
that two alleles for each gene separate during the formation of sex cells,
which carry one allele each. The law of independent assortment states
that genes segregate independently of each other. The law of dominance
asserts that some alleles are dominant over others and are expressed as
dominant phenotypes. There are many patterns of inheritance that can-
not be explained by Mendel’s laws, such as incomplete dominance, co-
dominance, sex-linked inheritance, polygenic inheritance, genetic
linkage, and the interplay between genetics and environmental factors,
but examples of so-called Mendelian inheritance are common in diverse
living things. In humans, Mendelian inheritance is responsible for about
8,000 phenotypes, according to Online Mendelian Inheritance in Man
(OMIM), a database supported by the U.S. National Human Genome
Research Institute. Mendelian phenotypes that contribute to a congenital
genetic disease or syndrome are called Mendelian disorders. Any given
Mendelian disorder is rare in the population, but collectively, Mendelian
disorders affect the quality of life for many individuals. About 8 million
infants worldwide are born each year with a serious Mendelian disor-
der that is life-threatening or is likely to result in physical or intellectual
disability. Of the approximately 20,000 protein-encoding genes in the
human genome, about 4,400 have been connected to a Mendelian phe-
notype, and many of these genes have been tied to Mendelian disorders.
Knowledge of Mendelian disorders and other monogenic genetic dis-
orders that follow non-Mendelian patterns of inheritance supports the
practice of newborn screening for genetic disorders. Newborn screening
began in the 1960s, when Robert Guthrie developed a reliable and afford-
able blood test for the Mendelian disorder phenylketonuria (PKU). It has
INTRODUCTION
xiii

since expanded to include a variety of genetic diseases associated with


life-threatening or potentially disabling health complications that can be
avoided or effectively mitigated by medical treatment.
This book presents newborn screening as a public health program for
the early detection of genetic disorders. Chapter 1 presents the recom-
mended uniform screening panel (RUSP), a list of genetic disorders
recommended by the U.S. government for all states and territories to in-
clude in newborn screening programs. The chapter describes the catego-
rization of RUSP genetic disorders, discusses the symptoms and health
complications of examples of each category, and explains medical tests
used for newborn screening. Chapter 2 describes the underlying molecu-
lar genetic causes of genetic disorders and explains how this information
is used for genetic testing during newborn screening and diagnosis. The
chapter presents patterns of inheritance for monogenic genetic disorders
and uses hypothetical family scenarios to illustrate them. Treatments and
therapies for selected RUSP genetic disorders are described in Chapter 3
that illustrate the benefits of early diagnosis. Chapter 4 explores future
prospects for the prevention, diagnosis, and treatment of genetic disor-
ders detected by newborn screening, including experimental drug treat-
ments, the possibility of newborn genome sequencing, and gene therapy.
CHAPTER 1

Symptoms and Diagnosis

The recommended uniform screening panel (RUSP) is a list of genetic dis-


orders that the Secretary of the U.S. Department of Health and Human
Services (HHS) recommends for use in the establishment of newborn
screening programs. Each state and territory is responsible for passing
laws that establish its own panel of genetic disorders to be included in
a newborn screening program. Variations in panels among states occur
because of differences in the prevalence of various genetic disorders, the
costs of screening, the amount of public funding for screening, and the
availability of treatments for genetic disorders. Many states provide fund-
ing for the diagnosis, treatment, and ongoing evaluation of infants who
test positive for a genetic disorder. The RUSP is currently composed of
35 genetic disorders referred to as core conditions and 26 secondary
­conditions that also can be detected during screening for RUSP core con-
ditions. The HHS Secretary regularly updates the RUSP by collaborating
with the Advisory Committee on Heritable Disorders in Newborns
and Children (ACHDNC) to consider proposals from researchers, or-
ganizations, and parents of children affected by genetic disorders. The
following are the criteria for inclusion of a genetic disorder on the RUSP:
(1) that there should be a specific and sensitive genetic test available to
detect the disorder; (2) that the course of symptoms and health complica-
tions should be well understood; (3) that an effective treatment should be
available; and (4) that information about whether the occurrence of the
disorder would affect future reproductive decisions of the affected family
should be available.
RUSP core conditions are organized into categories according to their
underlying causes and the body systems affected. Twenty of the disorders
are categorized as metabolic disorders, which means that they disrupt
­metabolism. Metabolism can be subdivided into catabolism, the processes
2 NEWBORN SCREENING FOR GENETIC DISORDERS

by which enzymes extract energy from food in support of cellular activities


throughout the body, and anabolism, the use of chemical building blocks
derived from the breakdown of food to synthesize proteins, lipids, carbo-
hydrates, and nucleic acids responsible for the structure and function of
cells. Metabolic disorders are subcategorized on the RUSP into those that
affect the metabolism of organic acids, fatty acids, and amino acids. Two
RUSP core conditions are categorized as endocrine disorders and three as
hemoglobin disorders. The remaining 10 RUSP core conditions are cat-
egorized as “other disorders” because they affect a variety of body systems
and have disparate underlying causes. The RUSP also lists secondary con-
ditions, defined as genetic disorders that can be identified when screening
newborns for RUSP core conditions. Although most of the 26 secondary
conditions currently on the RUSP are metabolic disorders, hemoglobin dis-
orders and a genetic disease affecting the immune system are also included.

Symptoms of Genetic Disorders Identified by


Newborn Screening
Organic acid disorders (OADs) are RUSP metabolic disorders that affect
catabolism. OADs occur because of inherited errors in catabolic pathways
for the degradation of amino acids, carbohydrates, and lipids. OADs cause
organic acidemia, an abnormal accumulation of harmful organic acids
in the blood, or organic aciduria, an abnormal accumulation of harmful
organic acids in the urine. The term organic acid refers to a wide variety of
­carbon-containing chemicals that have acidic properties because of chemi-
cal groups that include oxygen, sulfur, or phosphorus. In the context of ge-
netic disorders, organic acids are limited to chemicals that have one of two
types of chemical groups called carboxylic acid or phenolic acid. Table 1.1
lists the nine OADs currently on the RUSP, along with their estimated
rates of occurrence among newborns. Although each OAD is characterized
by the accumulation of a different organic acid, they cause similar symp-
toms and health complications. Most OADs have a severe form that causes
symptoms in newborns. Symptoms include lethargy, drowsiness, poor
feeding, vomiting, diarrhea, rapid heart rate, and low body temperature.
Infants with an OAD often have weak muscle tone, known as hypotonia,
and are prone to muscle spasms. Because the early symptoms can transition
Symptoms and Diagnosis 3

Table 1.1  RUSP organic acid disorders


Disorder Live birth prevalence
Isovaleric acidemia (IVA) 1 in 25,000
Glutaric acidemia type I (GA1) 1 in 35,000
3-Methylcrotonyl-CoA carboxylase (3MCC) deficiency 1 in 35,000
Methylmalonic acidemia (MA), vitamin B12-responsive 1 in 55,000
Methylmalonic acidemia, methylmalonyl-CoA mutase 1 in 75,000
(MUT) deficiency
Holocarboxylase synthetase deficiency (HCSD) 1 in 90,000
Propionic acidemia (PROP) 1 in 100,000
Beta-ketothiolase (BKT) deficiency <1 in 1,000,000
3-Hydroxy-3-methylglutaric aciduria (HMG) <1 in 1,000,000

rapidly to heart problems, seizures, or coma, OADs can constitute a neo-


natal emergency. Some OAD forms present their first symptoms later in
infancy, early childhood, or in teenage years. Although they are associated
with the same types of symptoms as severe forms, these late-onset forms of
OAD have milder symptoms that often come and go with time and can be
triggered by environmental influences such as infectious disease or changes
in diet. Both the severe and mild forms of OADs cause an increased risk of
heart problems and neurological damage, including brain damage, intel-
lectual disability, and vision problems. Children and adults with OADs
are also at greater risk of serious health complications from infectious dis-
eases such as colds and flu because part of the immune response is the
release of biomolecules that are metabolized into harmful organic acids.
A second subtype of metabolic disorders on the RUSP called fatty
acid oxidation disorders (FAODs) results from a diminished catabolic
capacity to extract energy from fats and the subsequent accumulation of
harmful fatty acids. Table 1.2 lists the five FAODs currently on the RUSP
and their estimated rates of occurrence among newborns. The onset of
symptoms varies among FAODs and ranges from infancy to early child-
hood. Because deficiencies in enzymes needed to extract energy from fat
place an extra burden on gaining energy from blood glucose, FAODs
are associated with hypoglycemia, a condition of abnormally low blood
sugar that can cause short-term weakness, vomiting, seizures, and confu-
sion. Long-term effects of hypoglycemia include delayed cognitive and
4 NEWBORN SCREENING FOR GENETIC DISORDERS

Table 1.2  RUSP fatty acid oxidation disorders


Disorder Live birth prevalence
Long-chain 3-hydroxyacyl-CoA dehydrogenase 1 in 20,000
(LCHAD) deficiency
Medium-chain acyl-CoA dehydrogenase (MCAD) 1 in 20,000
deficiency
Trifunctional protein (TPF) deficiency 1 in 20,000
Very long-chain acyl-CoA dehydrogenase (VLCAD) 1 in 50,000
deficiency
Systemic primary carnitine deficiency (SPCD) 1 in 100,000

physical development, an increased risk of coma, and heart problems such


as an enlarged heart and the risk of heart failure. FAODs can also produce
metabolic acidosis, an accumulation of organic acids in the blood that
causes nausea, vomiting, and breathing problems, or hyperammonemia,
an excess of ammonia in the blood that can lead to brain injury and
death. FAODs sometimes cause damage to nerves in the hands and feet,
deterioration of muscles, and liver problems. Some FAODs, such as long-
chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, cause
health problems in pregnant women whose fetuses have LCHAD defi-
ciency. These women can experience hemolysis, which is the b­ reakdown
of red blood cells (RBCs), low platelet count, and liver damage. LCHAD
deficiency can also cause vision loss in infants.
Metabolic disorders can also take the form of amino acid metabo-
lism disorders, which are caused by the inability to catabolically break
down the amino acid building blocks of dietary proteins or the inability
to transport amino acids into cells for the anabolic production of proteins.
Table 1.3 lists the six amino acid metabolism disorders on the RUSP and

Table 1.3  RUSP amino acid metabolism disorders


Disorder Live birth prevalence
Classic phenylketonuria (PKU) 1 in 15,000
Citrullinemia type I (CTLN1) 1 in 40,000
Argininosuccinic aciduria (ASA) 1 in 50,000
Tyrosinemia type I (TYR I) 1 in 100,000
Maple syrup urine disease (MSUD) 1 in 200,000
Homocystinuria (HCY) 1 in 250,000
Symptoms and Diagnosis 5

estimated rates by which they affect newborns. Characteristic signs of


some amino acid metabolism disorders occur because of the abnormal
accumulation of harmful biomolecules in body fluids. Maple syrup urine
disease (MSUD) is named for the unusual smell it causes in the urine and
sweat of affected children. Children with phenylketonuria (PKU) often
have a noticeably musty body odor. Some symptoms of amino acid me-
tabolism disorders appear within days of birth and others appear in early
childhood. Symptoms among newborns include lethargy, nausea, vomit-
ing, seizures, and coma. Some infants have abdominal pain from liver
dysfunction. In early childhood, symptoms can include abnormal curva-
ture of the spine, osteoporosis, anemia, weight loss, vomiting, diarrhea,
and hypotonia, as well as an increased risk of stroke and high blood pres-
sure. Sometimes an amino acid metabolism disorder causes dislocation of
the lens of the eye, resulting in impaired vision. Children with amino acid
metabolism disorders are often at risk of developing intellectual disability
and sometimes display hyperactivity, irritability, extreme aggression, and
self-injurious behavior. The symptoms of amino acid disorders sometimes
persist into adulthood and can be triggered by infectious disease, surgery,
or changes in diet.
Table 1.4 shows two listings on the current RUSP that are catego-
rized as endocrine disorders. The endocrine system is composed of glands
throughout the body that produce, store, and release hormones for the con-
trol of growth and development, metabolism, reproductive processes, and
emotional states. Congenital hypothyroidism (CH) affects the thyroid,
a gland in the neck that uses dietary iodine to produce triiodothyronine
(T3) and thyroxine (T4) hormones that control short-term physiological
functions such as breathing, heart rate, and body temperature. Thyroid
hormones also affect long-term metabolic processes such as weight control,
cholesterol levels, and muscle strength. CH is characterized by an inability
to produce normal levels of T3 and T4 hormones. Usually, this is because
of the absence of the thyroid, but sometimes it is caused by an unusually

Table 1.4  RUSP endocrine disorders


Disorder Live birth prevalence
Primary congenital hypothyroidism (CH) 1 in 3,000
Congenital adrenal hyperplasia (CAH) 1 in 10,000
6 NEWBORN SCREENING FOR GENETIC DISORDERS

small or deformed thyroid, an abnormally located thyroid, or a failure of


the pituitary gland to stimulate thyroid function. Newborns with CH
often have coarse facial features, a swollen tongue, jaundice, ­hypotonia,
umbilical hernia, and a characteristically hoarse cry. ­Symptoms of CH in
infants include lethargy, excessive sleeping, poor feeding, failure to gain
weight, and constipation. Left untreated, CH can lead to goiter, abnormal
bone growth, and intellectual disability. Congenital adrenal ­hyperplasia
(CAH) is a group of genetic disorders that are associated with dysfunc-
tion of the adrenal glands, a pair of glands located just above the kidneys
that produce hormones for the control of metabolism, blood pressure, the
immune system, and stress response. Adrenal glands also produce precur-
sors that are converted into estrogen hormones in ovaries and androgen
hormones in testes. CAH results from an error in the anabolic synthesis of
hormones by the adrenal glands. Female newborns with CAH often have
atypical or ambiguous external genitalia despite having normal internal
sex organs. CAH is the most common cause of intersex among individu-
als born with two X chromosomes. Newborn males with CAH appear
normal or have an enlarged penis. Symptoms of CAH that appear in in-
fancy include vomiting, dehydration, and failure to gain weight. During
early childhood, symptoms often arise because of an imbalance of electro-
lytes in the blood, and include shock, coma, and a risk of sudden death.
Mild forms of CAH are characterized by rapid growth during childhood,
early onset of puberty, severe acne, and an increased risk of infertility.
Three genetic disorders among the RUSP core conditions affect
the process by which hemoglobin inside RBCs delivers oxygen to tis-
sues throughout the body and removes carbon dioxide waste from them.
Table 1.5 lists the hemoglobin disorders and the prevalence of each among
live births. Sickle cell disease (SCD) is characterized by abnormal hemo-
globin that causes RBCs to adopt a crescent shape that prevents them
from circulating as well as normal disc-shaped RBCs. Beta thalassemia

Table 1.5  RUSP hemoglobin disorders


Disorder Live birth prevalence
Sickle cell trait (SCT) 1 in 65
Sickle cell disease (SCD) 1 in 7,000
Beta thalassemia 1 in 100,000
Symptoms and Diagnosis 7

results from a failure to produce normal levels of hemoglobin. Newborns


with SCD or beta thalassemia appear normal but develop chronic hemo-
lytic anemia within a few months that causes fatigue and lightheadedness
and an increase in heart and respiration rates. Infants with SCD or beta
thalassemia often develop an enlarged spleen, which causes weakness,
rapid breathing, accelerated heart rate, extreme thirst, and pain on the
left side of the abdomen. Damage to the spleen and other tissues compro-
mises the immune system, which causes an increased risk of opportunistic
infections. Children with hemoglobin disorders often grow more slowly
than healthy children and have a delayed onset of puberty. SCD causes
sickle cell crises, during which moderate-to-extreme pain occurs in the
chest, abdomen, lower back, arms, joints, or bones. Sickle cell pain is
often associated with fever, vomiting, dehydration, breathing difficulty,
joint swelling, and neurological symptoms. Other symptoms of SCD in-
clude vision loss, leg ulcers, stroke, and heart problems. Sickle cell trait
(SCT) is much more common than SCD, and the distinction between
the two disorders is that SCT is characterized by RBCs that carry a mix-
ture of normal and abnormal hemoglobin, whereas SCD RBCs contain
only abnormal hemoglobin. SCT usually does not cause symptoms, but
it can do so under conditions that favor RBC sickling, such as low oxygen
availability or vigorous exercise.
The 10 RUSP genetic disorders listed in Table 1.6 are categorized as
other disorders because they do not form a cohesive group in terms of

Table 1.6  Other disorders on the RUSP


Disorder Live birth prevalence
Critical congenital heart disease (CCHD) 1 in 500
Hearing loss 1 in 500
Cystic fibrosis (CF) 1 in 2,500
Spinal muscular atrophy (SMA) 1 in 8,000
X-linked adrenoleukodystrophy (X-ALD) 1 in 30,000
Glycogen storage disease type II (GSD II, Pompe) 1 in 40,000
Classic galactosemia (GALT) 1 in 50,000
Severe combined immunodeficiency (SCID) 1 in 50,000
Biotinidase deficiency (BTD) 1 in 60,000
Mucopolysaccharidosis type I (MPS I) 1 in 100,000
8 NEWBORN SCREENING FOR GENETIC DISORDERS

body systems affected or underlying causes. Biotinidase deficiency (BTD)


is a defect in the metabolic process by which the vitamin biotin is recy-
cled. Symptoms appear in infancy or early childhood and include hypo-
tonia, seizures, breathing problems, hearing loss, vision loss, and delayed
development. Cystic fibrosis (CF) results from a defect in the process by
which chloride ions are transported across cell membranes. Newborns
with CF accumulate thick and sticky mucous in their lungs, which leads
to breathing problems and infections. Mucous also blocks the release of
digestive enzymes from the pancreas, causing malnutrition, poor growth,
and weight loss.
Critical congenital heart disease (CCHD) is a group of disorders that
result from errors in the formation of the heart during embryonic devel-
opment. According to the Centers for Disease Control and Prevention
(CDC), about one in four babies are born with a CCHD that requires
surgery or other medical procedures during the first year of life. Exam-
ples of CCHD include tricuspid atresia, in which there is a defective
or missing tricuspid valve between the right atrium and the right ven-
tricle; hypoplastic left heart syndrome, caused by underdevelopment
of chambers and valves on the left side of the heart; transposition of
the great arteries (TGA), characterized by a reversal of the positions of
the pulmonary artery and the aorta; coarctation of the aorta, caused by
an abnormal narrowing of the aorta; and tetralogy of Fallot (TOF), in
which four heart defects cause the heart to deliver oxygen-poor blood to
the body. Newborns with CCHD develop symptoms within a couple of
days, including heart murmur, low blood pressure, rapid breathing, and
low levels of oxygen in the blood. Untreated CCHD can lead to shock,
coma, and death.
Congenital hearing loss occurs in a variety of forms with severities that
range from mild hearing loss to profound deafness. Congenital hearing
loss can be syndromic, which means it is part of a genetic syndrome that
produces symptoms in multiple body systems, or nonsyndromic, which
means that symptoms are limited to hearing loss. Congenital hearing loss
can also be categorized as conductive hearing loss, which occurs when
sound waves cannot properly travel from the outer ear to the middle ear
before being relayed to the brain, or sensorineural hearing loss, which is
caused by dysfunction of the inner ear or the nervous connection between
Symptoms and Diagnosis 9

the ear and the brain. Congenital hearing loss and CCHD are the most
prevalent genetic disorders on the RUSP.
Classic galactosemia (GALT) results from abnormal catabolism of
the sugar galactose. Galactose is a component of lactose, a primary con-
stituent of milk and other dairy products. Infants with GALT who ingest
­galactose through mother’s milk display lethargy, jaundice, and abnor-
mal bleeding. Continued galactose consumption leads to a failure to gain
weight, liver damage, opportunistic infections, and intellectual disability.
Glycogen storage disease type II (GSD II or Pompe disease) is caused by
a metabolic defect that results in an abnormal accumulation of the com-
plex sugar glycogen in cells throughout the body. Infants with this disease
show symptoms within several months of birth, including hypotonia,
failure to gain weight, breathing problems, and an enlarged liver. With-
out treatment, life-threatening heart problems will occur. Mucopolysac-
charidosis type I results from errors in sugar catabolism. Newborns with
this disease often have abdominal hernias, characteristically coarse facial
features, and a hoarse cry. Symptoms such as excess fluid accumulation
in the brain, heart problems, swelling of the liver and spleen, and airway
constriction occur in infancy or early childhood.
Newborns with severe combined immunodeficiency (SCID) have an
impaired immune system that is unable to fight infections by fungal, bac-
terial, or viral pathogens that lead to symptoms such as rashes, chronic
diarrhea, hypotonia, fever, hearing loss, vision loss, intellectual disability,
and risk of death. The most common type of SCID affects males much
more frequently than females because it is caused by alteration of a gene
located on the X chromosome. X-linked adrenoleukodystrophy (X-ALD)
occurs predominantly in males for the same reason. There are three forms
of X-ALD that vary in severities and ages of symptom onset. Two forms of
X-ALD affect the nervous system, causing symptoms such as learning and
behavioral problems, vision loss, eating difficulties, and impaired mobil-
ity. All three forms affect the adrenal glands, which results in weight loss,
vomiting, and an increased risk of coma.
Spinal muscular atrophy (SMA) is a neuromuscular disease that af-
fects proximal muscles, such as those of the shoulders, upper arms, hips,
and thighs. There are five types of SMA that can be distinguished by age
of onset and severity of symptoms. Newborns with type 0 SMA cannot
10 NEWBORN SCREENING FOR GENETIC DISORDERS

breathe or swallow on their own, and usually die within 6 months. Type 1
SMA causes infants to have muscle weakness, movement deficiencies, and
feeding problems. Severe respiratory problems cause most infants with
type 1 SMA to die within 1 year. Type 2 SMA causes breathing problems,
respiratory infections, scoliosis, contractures, and loss of independent
ambulation. Type 3 SMA and type 4 SMA affect ambulation but are less
severe and have little effect on life expectancy.

Newborn Screening for Genetic Disorders


Newborn screening involves clinical laboratory procedures that measure
biomarkers, a term that refers generally to any indicator of normal or
pathogenic processes, including physical measurements such as body
temperature and heart rate, but which refers in the context of newborn
screening to the presence of metabolites or proteins that correlate with
RUSP genetic disorders. Many tests for biomarkers can be conducted on
a newborn blood sample taken with a heel stick procedure that carries
little risk and causes minimal discomfort. Usually the blood sample is
taken 24 to 48 hours after birth, but because the results for some condi-
tions, such as PKU and CH, are inconclusive during this period, a second
sample is often taken after 2 weeks. The blood is spotted onto paper and
sent to a clinical laboratory for analysis. Most states retain dried blood
spots from newborns for at least a year and some states retain them for an
indefinite period. Archived blood spots are sometimes used for retesting
for a genetic disorder. They are also made available to families for other
health-related tests or for the identification of a missing or deceased child.
Sometimes, unused blood spots are used with permission from the family
for biomedical research.
The results of newborn screening blood tests are usually available
within 2 weeks. Health care providers are most often able to report to
parents or caregivers that the screening results are negative for all the
tested conditions, but sometimes they must relay a positive or borderline
screening result. A borderline result is between negative and positive re-
sults and is usually followed up with a second test. A positive screening
result is described as failing, out-of-range, or abnormal. Because a positive
screening result does not necessarily mean that the newborn has a disease,
Symptoms and Diagnosis 11

further testing is required, with the goal of supporting or denying a dis-


ease diagnosis. Diagnostic testing involves more accurate chemical and
biochemical analyses of disease biomarkers as well as genetic testing,
which is explained in Chapter 2. False-positive results of newborn screen-
ing are not uncommon because screening tests are intentionally biased to
incorrectly identify a newborn with the disease rather than accidentally
fail to detect one who actually has an RUSP core condition.
Chemical biomarkers of RUSP metabolic disorders detected by blood
analysis include fatty acids, organic acids, and amino acids. One method
for detecting these biomolecules is a combination of gas chromatogra-
phy (GC) and mass spectrometry (MS). During GC, the sample is va-
porized to produce a gas that travels through a column whose walls have
a coating that retains the various chemical components of the sample
differently. The time of retention of specific molecules in the sample de-
pends on their physical and chemical properties and is a sensitive means
of detecting them. MS involves ionization of the chemical components in
a sample to produce charged fragments that accelerate toward a detector
while being deflected by an electric or magnetic field. The paths of the
fragments are determined by their mass-to-charge ratios, which can be
­compared with standard ratios of pure samples to analyze the chemical
composition of the sample. A method for detecting chemical biomarkers
that is gaining popularity is tandem mass spectrometry (MS/MS). MS/
MS involves fragmentation of the molecules in a sample and first-stage
MS separation of fragments with predetermined mass-to-charge ratios
that are further fragmented by molecular collisions or light before analysis
with a second-stage MS. Liquid chromatography (LC) combined with
tandem mass spectrometry (LC-MS/MS) is sometimes used to detect
chemical biomarkers of metabolic disorders.
Blood from a heel stick is also subjected to biochemical tests for en-
zyme deficiencies associated with several RUSP core conditions. One
way this is done is to directly measure blood serum enzymatic activity
using a prescribed metabolic reaction that produces either a change in
color that can be measured by a colorimeter or a change in fluorescence
that is detected with a fluorometer. RUSP core conditions that are de-
tected with this approach include BTD, GALT, mucopolysaccharidosis
type I (MPS I), and GSD II. Screening for some RUSP core conditions
12 NEWBORN SCREENING FOR GENETIC DISORDERS

is performed with an immunoassay that relies on the specific binding of


an antibody to an antigen. A common way to detect antibody–antigen
interactions is to label the antibody with a fluorescent tag that can be
detected by a fluorometer during an immunoassay. Some immunoassays
detect small molecule antigens, such as hormones that are elevated when
CAH or CH is present, whereas others detect macromolecules, such as a
serum protein at abnormally high levels because of CF. Newborn screen-
ing for RUSP hemoglobin disorders involves the detection of alternative
forms of hemoglobin. Isoelectric focusing can detect alternative forms
of hemoglobin as they migrate through a porous gel under the influence
of an electric field. Normal and mutant hemoglobin proteins migrate at
different rates during isoelectric focusing, producing characteristic bands
on the gel. An alternative screening method for hemoglobin disorders
is high-performance liquid chromatography (HPLC), which exploits
the differential retention times of alternative hemoglobin forms during
column chromatography. The results of newborn screening can be posi-
tive for SCD or beta thalassemia, but often a so-called trait result occurs,
which means that the newborn is a carrier for beta thalassemia or has
SCT.
Newborn screening for heart problems associated with CCHD in-
volves pulse oximetry, a painless and noninvasive method for measuring
the level of oxygen saturation in the blood. Small sensors are placed on
the right hand and across one foot, where they measure changes in the
absorbance of light by pulsing arterial blood. The hemoglobin proteins
in RBCs absorb light differently when they are oxygenated compared
to when they are deoxygenated. Pulse oximetry screening is usually per-
formed 24 hours after birth to allow the lungs and heart of the newborn
to adapt to the processes of breathing oxygen and circulating oxygen-
ated blood to body tissues. A typical follow-up diagnostic procedure for
CCHD is an echocardiogram, which is a type of ultrasound imaging
that can visualize problems with the structure of the heart or the way that
blood flows through it.
Newborn screening also involves a hearing test conducted by one of
two methods. The otoacoustic emission (OAE) test uses a tiny earphone
and microphone that are placed in the ear to detect the reflection of
sound directed toward the ear drum. An OAE test detects the presence of
Symptoms and Diagnosis 13

a variety of types of conductive hearing loss that occur when sound waves
cannot properly travel from the outer ear to the middle ear, where they
are processed for relay to the brain. The auditory brainstem response
(ABR) test also presents sounds to the ears with earphones but uses elec-
trodes placed on the skull to detect electrical nerve impulses that are pro-
duced during normal hearing. An ABR test detects sensorineural hearing
loss caused by dysfunction of the inner ear, or the nervous connection
between the ear and the brain. The results of newborn hearing tests are
available on the same day of screening. A failed hearing test results in a
referral for more exacting hearing tests that are usually conducted within
2 weeks. Newborns who pass hearing tests should continue to be moni-
tored for hearing loss during early childhood. Some infants fail newborn
hearing screening not because of congenital hearing loss, but because of
wax buildup in the ear canal, fluid in the middle ear from an infection, or
movement during the test.

Health Complications of Genetic Disorders Identified


by Newborn Screening
Because genetic disorders identified by newborn screening affect diverse
body systems, they cause a variety of health complications, many of which
impact the quality of life and some of which are life-threatening. The
RUSP core conditions CH, SCD, MPS I, and SMA affect bones and
joints, causing physical developmental delays, chronic pain, limited range
of motion, and loss of mobility. Digestive problems such as loss of ap-
petite, nausea, recurrent vomiting, gastro-esophageal reflux disease, and
chronic constipation occur with OADs, FAODs, amino acid metabolism
disorders, and CF. Liver disease and its associated health complications of
nausea, vomiting, abdominal pain and swelling, jaundice, and weight loss
can be caused by SCD, beta thalassemia, and GALT. Health complica-
tions associated with dysfunction of the immune system and the increased
risk of opportunistic infections by pathogenic viruses, bacteria, and fungi
accompany a variety of RUSP core conditions, including SCD, beta thal-
assemia, GALT, SCID, and X-ALD. Respiratory problems such as chronic
coughing, asthma, chronic obstructive pulmonary disease, upper respira-
tory infections, and pneumonia can occur in patients with FAODs, SCD,
14 NEWBORN SCREENING FOR GENETIC DISORDERS

beta thalassemia, CF, MPS I, and SMA. Heart problems are complications
of OADs, SCD, beta thalassemia, CCHD, GSD II, and MPS I and can
result in abnormal heart rhythms, stroke, heart failure, sudden cardiac
arrest, and the risk of premature death. An increased risk of seizures and
coma is associated with several RUSP core conditions, including OADs,
FAODs, CAH, and X-ALD. Some RUSP core conditions cause cognitive
developmental delays and intellectual disability, including OADs, amino
acid metabolism disorders, CH, GALT, and MPS I.
Index
Adrenal glands, 6 CFTR gene, 22
Advisory Committee on Heritable Chorionic villus sampling (CVS), 29
Disorders in Newborns and Chromosomal theory
Children (ACHDNC), 1 of inheritance, xii
Aldosterone, 36 Ciprofloxacin, 40
Alpha-keto acids, 20 Clustered regularly interspaced
Alternative RNA splicing, 17 short palindromic repeats
Amino acid metabolism disorders, 4 (CRISPR), 47–48
treatment of, 35 Coarctation of the aorta, 8
Ammonul, 35 Cochlear implant, 39
Amniocentesis, 29 Codons, 17
Anabaena variabilis, 45 Colistin, 40
Anabolism, 2 Colorimeter, 11
Antibody–antigen interactions, 12 Conductive hearing loss. See
Antihistamines, 40 Congenital hearing loss
Antisense oligonucleotide, 41 Congenital adrenal hyperplasia
Arginine, 35 (CAH), 6
Aspirin, 37 Congenital hearing loss, 8
Ataluren, 46 management of, 38–39
Auditory brainstem response (ABR) Congenital hypothyroidism (CH), 5
test, 12 Continuous positive airway pressure
Autosomal dominant, 25 (CPAP), 40–41
Autosomal recessive, 24 Copy number variations (CNVs), 19
Autosomes, 16 Corticosteroids, 36
Aztreonam, 40 Critical congenital heart disease
(CCHD), 8
Beta-globin, 22 heart surgery for, 38
Beta thalassemia, 7 Cryopreservation, 31
Biomarkers, 10 Cystic fibrosis (CF), 8
Biotinidase deficiency, 8
Blastomere biopsy, 30 Deletion mutations, 19
Blending inheritance, xi Diploid, 16
Blood transfusion therapy, 37 DNA microarrays, 23
Bronchodilators, 40 DNA replication, 18
Buphenyl, 35 DNA sequencing, 23
DNA testing, for genetic disorder, 23
Carboxylic acid, 2 Docusate, 40
Casanthranol, 40 Dominance, law of, xii
Catabolism, 1–2
Centers for Disease Control and Echocardiogram, 12
Prevention (CDC), 8 Endocrine disorders, 2
Centromere, 16 Enzyme replacement therapy (ERT), 41
70 INDEX

Enzymes, 2 symptoms and diagnosis


Escherichia coli, 45 health complications of, 13–14
Ethical, legal, and social issues newborn screening for, 10–13
(ELSI), 44 overview, 1–10
Ex vivo gene therapy, 47 treatment and therapy
Exons, 17 congenital hearing loss,
Experiments on Plant management of, 38–39
Hybridization, 50 heart surgery for CCHD, 38
hemoglobin disorders, 36–38
Fatty acid oxidation disorders OADS, FAODS, and amino acid
(FAODs), 3 metabolism disorders, 33–35
treatment of, 34–35 for other RUSP core conditions,
Five-prime cap, 17 39–42
Fluorescent in situ hybridization RUSP endocrine disorders, 35–36
(FISH), 23 Genome editing, 47–48
Fluorometer, 11 Genome-wide association study
Frameshift mutation, 19 (GWAS), 31
Gentamicin, 40
Gain-of-function, 18 Glycogen storage disease type II
Galactosemia (GALT), 9 (GSD II), 9
Gas chromatography (GC), 11
Gastrostomy, 40 HADHA gene, 20
Gel electrophoresis, 23 Haploid, 16
Gene expression, 15 Health and Human Services (HHS),
Gene modifiers, 31 1
Gene mutations, cause genetic Hearing aid, 39
disorders, 15–22 Heel stick procedure, 10
Gene therapy, for RUSP core Hemoglobin disorders, 2
conditions, 46–48 treatment of, 36–38
Genetic code, 17 Heterozygous recessive, 24
Genetic disorders High-performance liquid
causes and contributing factors chromatography (HPLC), 12
contributing factors for, 31–32 Homozygous dominant, 24
DNA testing for, 23 Homozygous recessive, 24
gene mutations cause, 15–22 Human genome, 15
inherited, 24–29 Human Genome Project and Celera
preimplantation genetic Corporation, 43
diagnosis, 30–31 Hydroxyurea, 37
prenatal genetic testing, 29–30 Hyperammonemia, 4, 35
conclusion, 49–50 Hypoglycemia, 3
future prospects Hypoplastic left heart syndrome, 8
experimental drugs for RUSP Hypotonia, 2
core conditions, 44–46
gene therapy for RUSP core Ibuprofen, 37
conditions, 46–48 Immunoassay, 12
newborn genome sequencing, In vitro fertilization (IVF), 30
43–44 In vivo gene therapy, 47
INDEX
71

Incomplete dominance, 26 Newborn genome sequencing, 43–44


Independent assortment, law of, xii Nitisinone, 35
Insertion mutations, 19 Nityr, 35
Intellectual disability, 3 Nonsense mutation, 19
Intersex, 6 Nonsteroidal anti-inflammatory drugs
Introns, 17 (NSAIDs), 37
Isoelectric focusing, 12 Nonsynonymous mutation, 18
Isoforms, 17 Nusinersen, 41
Isovaleric anemia (IVA), 19
Ivacaftor, 40 Online Mendelian Inheritance in
Man (OMIM), xii
Karyotype analysis, 23 Organic acid disorders (OADs), 2
Kuvan, 35 treatment of, 33–34
Organic acidemia, 2
L-glutamine, 45 Organic aciduria, 2
Law of dominance, xii Otoacoustic emission (OAE) test, 12
Law of independent assortment, xii
Law of segregation, xii PAH gene, 16
LCHAD deficiency, 20 Paired box 8, 21
Levothyroxine, 35 Palynziq, 45
Liquid chromatography (LC), 11 Particulate inheritance, xi
Long-chain 3-hydroxyacyl-CoA Pegvaliase, 45
dehydrogenase (LCHAD) Personalized medicine, 43
deficiency, 4 Phenolic acid, 2
Loss-of-function, 18 Phenylalanine hydroxylase, 16
Phenylketonuria (PKU), 5
Maple syrup urine disease (MSUD), 5 Piperacillin, 40
Mass spectrometry (MS), 11 Pituitary gland, 6
Maternal blood screening, 29 Pluripotent, 41
Medium-chain triglyceride oil, 34 Point mutation, 18
Mendel, Gregor, xi Poly(A) tail, 17
Mendelian inheritance, xii Polyethylene glycol, 40
Messenger RNA (mRNA), 17 Polymerase chain reaction (PCR), 23
Metabolic acidosis, 4 Pompe disease. See Glycogen storage
Metabolism, 1 disease type II (GSD II)
Missense mutations, 18 Positive screening result, 10
Mitochondria, 19 Preimplantation genetic diagnosis
Morphine, 37 (PGD), 30–31
Mucolytics, 40 Prenatal genetic testing, 29–30
Mucopolysaccharidosis type I, 9 Promoter, 17
Multiple carboxylase deficiency Proteome, 17
(MCD), 34 Pulse oximetry, 12
Mutagens, 18 Punnett square, 24
Mutations, 18
Reading frame, 17–18
Naproxen, 37 Recommended uniform screening
Neutral mutations, 18 panel (RUSP), v, 1
72 INDEX

Recommended uniform screening Sulfamethoxazole, 40


panel (Continued  ) Synonymous mutation, 18
amino acid metabolism disorders,
4, 20 Tandem mass spectrometry (MS/
endocrine disorders, 5 MS), 11
hemoglobin disorders, 6 Tauroursodeoxycholate (TUDCA), 46
organic acid disorders, 3 Tetralogy of Fallot (TOF), 8
other disorders on, 7 Tezacaftor, 40
treatments for, 39–42 Thyroid, 5
Regenerative medicine, 41 Tobramycin, 40
RNA polymerase, 17 Totipotent, 41
RNA splicing, 17 Tracheostomy, 40
Transcription, 16
Sapropterin dihydrochloride, 35 factors, 17
Segregation, law of, xii Translation, 17
Sensorineural hearing loss, 8–9 Transposition of the great arteries
Severe combined immunodeficiency (TGA), 8
(SCID), 9 Tricuspid atresia, 8
Sex chromosomes, 16 Triheptanoin, 44
Shunts, 38 Trimethoprim, 40
Sickle cell disease (SCD), 6 Trophectoderm biopsy, 30–31
Sickle cell pain, 7
Sickle cell trait (SCT), 7 Unfolded protein response (UPR), 46
Single-nucleotide polymorphisms
(SNP), 32 Vestibulocochlear nerve, 39
Sodium benzoate/sodium Voxelotor, 45
phenylacetate, 35
Sodium phenylbutyrate, 35 Whole genome sequencing
Somatic genome editing, 48 (WGS), 43
Spinal muscular atrophy (SMA), 9–10
Spontaneous mutations, 18 X-linked adrenoleukodystrophy
Start codon, 17 (X-ALD), 9
Stem cell therapy, 41 X-linked recessive, 28–29
OTHER TITLES IN OUR HUMAN DISEASES
AND CONDITIONS COLLECTION
A. Malcolm Campbell, Editor
• Sickle Cell Disease: The Evil Spirit of Misshapen Hemoglobin by Todd T. Eckdahl
• Auto-Immunity Attacks the Body by Mary E. Miller
• Huntington’s Disease: The Singer Must Dance by Todd T. Eckahl
• Nerve Disease ALS and Gradual Loss of Muscle Function: Amytrophic Lateral Sclerosis
by Mary E. Miller
• Infectious Human Diseases by Mary E. Miller
• Breast Cancer: Medical Treatment, Side Effects, and Complementary Therapies
by K.V. Ramani, Hemalatha Ramani, B.S. Ajaikumar, and Riri G. Trivedi
• Acquired Immunodeficiency Syndrome (AIDS) Caused by HIV by Mary E. Miller
• Down Syndrome: One Smart Cookie by Todd T. Eckahl
• Diseases Spread by Insects or Ticks by Mary E. Miller
• Autism Spectrum Disorder: He Prefers to Play Alone by Todd T. Eckahl
• Cancer by Mary E. Miller
• Muscular Dystrophy: I’m Grateful I’ve Proved Them Wrong by Todd T. Eckahl
• Diseases Caused by Dietary Problems by Mary E. Miller
• Infectious Human Diseases of the Intestine by Mary E. Miller
• Obesity: The Venus of Willendorf by Todd T. Eckahl

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