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Sickle Cell Disease

Sickle Cell Disease


The Evil Spirit of Misshapen
Hemoglobin
Todd T. Eckdahl

Sickle Cell Disease: The Evil Spirit of Misshapen Hemoglobin


Copyright Momentum Press, LLC, 2017.
All rights reserved. No part of this publication may be reproduced, stored
in a retrieval system, or transmitted in any form or by any means
electronic, mechanical, photocopy, recording, or any otherexcept for
brief quotations, not to exceed 250 words, without the prior permission
of the publisher.
First published in 2017 by
Momentum Press, LLC
222 East 46th Street, New York, NY 10017
www.momentumpress.net
ISBN-13: 978-1-94474-975-0 (print)
ISBN-13: 978-1-94474-976-7 (e-book)
Momentum Press Human Diseases and Conditions Collection
DOI: 10.5643/9781944749767
Cover and interior design by S4Carlisle Publishing Services
Private Ltd., Chennai, India
First edition: 2017
10987654321
Printed in the United States of America

Abstract
Sickle cell disease (SCD) is the most common genetic blood disorder in
the world. Millions of people in the world have SCD and about 300,000
babies are born with it each year. The reader of this book will learn about
the major symptoms of SCD, including chronic anemia, delayed growth,
spleen dysfunction, opportunistic infections, vision loss, leg ulcers, stroke,
and heart problems. The book explains how the primary cause of SCD
is a gene mutation that causes hemoglobin to polymerize in red blood
cells, making them adopt an abnormal sickle shape. Sickled cells carry
less oxygen and occlude blood vessels in tissues and organs throughout
the body. The reader will learn how SCD is inherited and how genetic
testing can provide information that prospective parents can use to make
reproductive decisions. The book presents treatments for SCD such as
pain medications, antibiotic therapy, blood transfusions, and bone marrow transplantation. Future prospects for diagnosing, treating, and curing
SCD are evaluated, including maternal blood screening, preimplantation
genetic diagnosis, gene therapy and genome editing.

Keywords
beta-globin gene, genetic disease, hemoglobin, incomplete dominance,
sickle cell anemia, sickle cell disease, sickle cell trait

Contents
Acknowledgments....................................................................................ix
Introductionxi
Chapter 1
Chapter 2
Chapter 3
Chapter 4

Symptoms and Diagnosis1


Causes and Contributing Factors9
Treatment and Therapy31
Future Prospects37

Conclusion43
Glossary45
Bibliography51
Author Biography..................................................................................53
Index55

Acknowledgments
I am grateful to my friend Malcolm Campbell for encouraging me to take
a leap of faith on this project, and on several others that 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. Iam
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 education 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 to understand that
I could pursue my love of genetics in graduate school. Thanks to John
Anderson at Purdue University, who taught me to conduct molecular
genetics research and to value undergraduate education. I appreciate the
environment that Missouri Western State University provided me for fol
lowing a path to becoming a science educator. I am grateful to my men
tors 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 classroom and the research lab. I appreciate the
many students that 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
There is a traditional belief among the people of the Igbo tribe of Nigeria
that evil spirits called Ogbanje bring anguish to families. The vengeful
Ogbanje are born as children who live with much pain and suffering, and
die early so that the Ogbanje can be reincarnated to torment the family
again. Igbo children described as Ogbanje experience chronic anemia,
fevers, leg ulcers, swelling of the hands and feet, and episodes of severe
pain. These symptoms are associated with sickle cell disease (SCD). Although the Igbo tribe, and many others in Africa, have known about
SCD for centuries, the first reference to SCD symptoms by western medicine was an 1846 autopsy of an African slave in the United States who
suffered from fever and respiratory illness. In 1910, a dental student from
Grenada named Walter Clement Noel visited Chicago cardiologist James
B. Herrick to report fatigue, dizziness, breathing difficulty and frequent
episodes of pain. Herrick recognized the symptoms of anemia and gave
the case to Ernest E. Irons, who noticed that many of the red blood cells
(RBCs) from the patient had an unusual shape that reminded him of a
sickle. Herrick published a paper in 1910 that described the sickle-shaped
RBCs as contributors to a new disorder that we now know as SCD. After
SCD was diagnosed in other patients, a pattern emerged that it occurred
most often in people who live in regions of the world where malaria is
common, and in people whose recent ancestry can be traced to those regions. An explanation for the connection between SCD and malaria was
not deduced until the cause of RBC sickling was understood.
In 1927, it was observed that RBCs taken from people with SCD could
be caused to adopt the sickle shape in the laboratory by depriving them of
oxygen. RBCs from most people could not be made to change shape under
the same conditions. However, the RBCs from people related to those with
SCD could also be made to adopt the sickle shape. These people were described as having sickle cell trait. Two articles published in 1949 described
SCD as a genetic disorder. James V. Neel and E. A. Beet reported that

xii INTRODUCTION

people with SCD had two copies of a disease-causing gene whereas people
with sickle cell trait had one copy of the disease-causing gene and one normal version of the gene. We now know that the gene codes for one of
the two protein subunits of hemoglobin, the protein in RBCs that carries
oxygen from the lungs to cells and tissues throughout the body. In 1949,
Linus Pauling and Harvey Itano found that the hemoglobin of people with
SCD was misshapen. Because their discovery was the first time that anyone
had made a connection between the structure of a biomolecule and human
disease, SCD is known as the first molecular disease. Sickle cell anemia
is the most common member of the family of inherited blood disorders
collectively called SCD. The distinction among different forms of SCD lies
in the types of hemoglobin that are carried in RBCs. Whereas people with
sickle cell anemia have a variant of normal hemoglobin that results in RBCs
with impaired function, people with other forms of SCD have other hemoglobin variants that result in various levels of RBC dysfunction. Knowledge
of the molecular basis of SCD led to methods that rely on measurement of
the structure of hemoglobin by which the disease can be diagnosed.
Further research established that misshapen hemoglobin causes RBCs
to adopt the sickle shape and that the body recycles cells that have sickled
more frequently than normal cells. As illustrated in the figure entitled
Sickled Cells, normal RBCs are round and flexible, and they are able
to traverse the entire circulatory system for the delivery of oxygen to cells
throughout the body. Sickle-shaped cells are inflexible and can get trapped
in the smallest blood vessels, especially capillaries in the extremities and
spleen, causing the anemia and frequent pain episodes experienced by
Walter Clement Noel and millions of other people with SCD. Perhaps the
Igbo people of Nigeria would say that misshapen hemoglobin is the form
that Ogbanje evil spirits assume to torment children and their families.
Approximately 300,000 babies throughout the world are born each
year with SCD. The disease is more common among people living in
sub-Saharan Africa, South America, Central America, the Caribbean,
the Middle East, India, and the Mediterranean than in other parts of
the world, and among people with ancestors from these regions. For example, 1 in every 365 African American babies is born with SCD, compared to 1 in 16,300 Hispanic American and 1 in 58,000 white babies.

INTRODUCTION
xiii
Normal RBCs
flow freely

Normal RBC

Sickled RBC

Sickled RBCs
block blood flow

Sickled Cells Sickled RBCs compared to normal RBCs


Source: Adapted in 2016 by Todd T. Eckdahl from:
Left Image: www.public-domain-image.com/free-images/science/microscopy-images
/patient-with-sickle-cell-anemia-hbss.jpg
Right Image: By Diana Grib - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w
/index.php?curid=45979326

About100,000 people suffer from the disease in the United States, where
the overall occurrence is about 1 in 4,000 births.
The following chapters describe SCD, the most common genetic
blood disorder in the world. Chapter 1 presents the major symptoms
of SCD, including chronic anemia, delayed growth, spleen dysfunction,
vision loss, leg ulcers, stroke, and heart problems. Chapter 2 presents the
pattern of inheritance of SCD and explains how it is caused by mutations in a gene for one of the two protein subunits of hemoglobin. The
chapter presents several scenarios by which SCD can arise in families and
how genetic testing can provide information that prospective parents can
use to make reproductive decisions. Chapter 3 presents treatment and
therapy for SCD, such as medications to manage pain and improve RBC
function, blood transfusions, and bone marrow transplantation. Chapter
4 describes future prospects for diagnosing, treating, and curing SCD,
including maternal blood screening, preimplantation genetic diagnosis,
gene therapy and genome editing.

CHAPTER 1

Symptoms and Diagnosis


The abnormal shape, rigidity, and stickiness of sickled red blood cells
(RBCs) underlie two important pathological processes that cause the
symptoms and complications of sickle cell disease (SCD). One process
is occlusion, during which sickle-shaped cells block small blood vessels,
preventing the delivery of vital oxygen and nutrients to tissues and o rgans
and the removal of waste materials from them. Occlusion leads to both
sudden and long-lasting effects on tissues and organs throughout the
body, especially the bones, spleen, respiratory system, and nervous system.
The other SCD pathological process is hemolysis, by which cells that
have sickled are more rapidly destroyed than their normal RBC counterparts. The abnormal shape and rigidity of sickled RBCs cause them to be
filtered from the bloodstream by the spleen, after which they are recycled.
Occlusion and hemolysis are responsible for the primary symptoms of
SCD, which can be categorized as anemia, pain episodes, and opportunistic infections. They also lead to health complications of SCD such as
stroke, pulmonary hypertension, kidney disease, liver disease, and vision
loss. Diagnosis of SCD relies on tests to detect the misshapen hemoglobin
that leads to sickle cell formation.

Sickle Cell Disease Results in Chronic Anemia


Anemia results from a diminished capacity of RBCs to deliver oxygen
to tissues and organs throughout the body. A major symptom of SCD
is chronic hemolytic anemia, which is a long-term shortage of circulating RBCs caused by their premature destruction. RBCs are produced
from cells in the bone marrow called hematopoietic stem cells (HSCs)
that are released into the bloodstream where they circulate before being
recycled in the liver, spleen, or bone marrow. RBCs are red because they

SICKLE CELL DISEASE

carry hemoglobin, which also gives them the capacity to carry oxygen.
Oxygen is needed by cells throughout the body to extract energy from
food molecules that is used for cellular processes. Energy metabolism involving oxygen produces the waste product carbon dioxide, which is carried by the hemoglobin in RBCs back to the lungs, where it is exhaled
from the body. Hemoglobin is composed of four globin protein subunits
that are each bound to an iron-containing cofactor called heme. The rate
at which new RBCs are produced balances the time that they survive in
the bloodstream. The longevity of normal RBCs is part of an equilibrium
that maintains their concentration in blood. Normal RBCs survive in
the bloodstream for between 90 and 120 days before they are recycled.
Sickle cells are more fragile than normal RBCs, and can break open in
small blood vessels. They are also recycled faster in the spleen, liver, or
bone marrow. As a result, sickle cells survive only 10 to 20 days in the
bloodstream.
The fragility and premature recycling of sickle cells cause a shortage
of circulating RBCs, and result in chronic anemia. Anemia causes people
with SCD to suffer from fatigue because tissues throughout their bodies
cannot get enough oxygen to extract energy from digested food molecules
circulating in their blood. SCD patients might feel lightheaded or dizzy
because the brain requires a lot of energy and is therefore especially sensitive to reduced levels of oxygen. Anemia causes an increase in heart rate
and respiration rate as the body attempts to compensate for the diminished delivery of oxygen to tissues. Children with SCD often grow more
slowly than healthy children, and have a delayed onset of puberty as a
result of chronic anemia.

Sickle Cell Disease Causes Extreme Pain


The unusual shape of RBCs that have sickled and their increased propensity to adhere to vascular surfaces cause them to get lodged in small
blood vessels. The subsequent restricted blood flow is called ischemia.
The resulting oxygen-poor ischemic environment exacerbates the problem by causing more RBCs to sickle. For people living with SCD, tissue
damage from ischemia often causes a sickle cell crisis, which is the most
common reason that people with SCD are treated in an emergency room

Symptoms and Diagnosis

or admitted to a hospital. Sickle cell crisis pain ranges from moderate to


extreme, and usually occurs in the chest, abdomen, lower back, arms,
joints, or bones. The pain might be localized or felt throughout the body,
and it can be either sharp or dull. Sickle cell pain is often associated
with fever, vomiting, dehydration, breathing difficulty, joint swelling,
and neurological symptoms. The duration of pain episodes varies widely,
with some lasting for several hours and others for days or weeks. There
is variability among SCD patients in that some have only a few pain
episodes and others have them as frequently as once a month. Sickle cell
pain results in inflammation that gets worse with each successive episode.
It can lead to organ damage or even life-threatening organ failure. Acute
sickle cell pain can also lead to chronic pain syndrome, which is when
acute pain causes complications that make the acute pain even worse. The
syndrome is associated with arthritis, collapse of vertebrae, and ulcers on
the lower legs.
Sickle cell crisis episodes can be categorized by the part of the body in
which the acute pain occurs. A bone crisis causes sudden pain in the bone
marrow that is actively producing new blood cells. There is a relationship
between the bones affected and the age of an SCD patient. During the
first eighteen months of life, the bones of the hands and the feet have
active bone marrow, and bone pain is often localized there, resulting in
hand-foot syndrome. During childhood, a bone crisis is most likely to
involve the longest bones, which include the humerus of the upper arm,
the femur of the upper leg, and the tibia of the lower leg. With the onset
of puberty, bone pain shifts to the vertebrae, especially those in the lower
back. A second type of sickle cell crisis is an abdominal crisis, which
occurs when people with SCD experience sudden pain in localized parts
of the abdomen, or general pain throughout the abdomen that can be
associated with nausea, vomiting, and diarrhea. An abdominal crisis can
be caused by disruption of the blood supply to any abdominal organ, including the liver, spleen, kidneys, and organs of the digestive tract. Finally,
a sickle cell crisis might be categorized as a joint crisis, which is characterized by acute pain in one or more joints. The interruption of blood flow
to the joints caused by sickled cells damages or destroys bone cells, and
results in inflammation of the joints. Hips are especially susceptible to a
joint crisis, but shoulders, knees, and ankles are also often affected.

SICKLE CELL DISEASE

A sickle cell crisis often occurs spontaneously, without warning, and


with no known cause. However, there are triggers known to provoke a
sickle cell crisis that people living with SCD learn to minimize or avoid.
One trigger is low oxygen levels, which can result from strenuous exercise,
dehydration, or breathing oxygen-poor air at high altitudes. People with
SCD should be cautious about flying in an airplane, even if it has a pressurized cabin, and should consider arranging for access to a supplemental
supply of oxygen. Other sickle cell crisis triggers include rapid changes
in temperature, sleep apnea, infections, and some medical procedures.
Strong emotions such as anxiety, depression, and anger have triggered
sickle cell crises as well.

Spleen Dysfunction Caused by Sickle Cell Disease


The spleen filters microbes from the blood and produces the white blood
cells and antibodies of the immune system. It also recycles RBCs, and in
people with SCD, this recycling function often overwhelms the system
and results in splenic sequestration. The entrapment of large numbers
of sickled cells in the spleen causes the organ to rapidly enlarge, resulting in the symptoms of weakness, rapid breathing, accelerated heart rate,
extreme thirst, and pain on the left side of the abdomen. A splenic sequestration event usually requires hospitalization, and can be life-threatening.
Repeated splenic events can damage the organ to the point where it stops
functioning. For children with SCD, acute splenic sequestration is the
second most common cause of death during the first 5 years of life.

Sickle Cell Disease and Opportunistic Infections


Damage to the spleen and other tissues compromises the immune system,
which causes people living with SCD to be more vulnerable to infections by pathogenic viruses, bacteria, and fungi. Although progress has
been made in developed countries in preventing and treating infections
in SCD patients, they are a more serious problem in less developed parts
of the world. As a result, infections are the leading cause of SCD death
globally. The most common infections in infants and young children with
SCD are Streptococcus pneumoniae and Haemophilus influenzae. These

Symptoms and Diagnosis

pathogens can cause pneumonia, an infection of the lungs that results in


coughing, fever, and breathing difficulty, or septicemia, an infection of
the blood that is associated with fever, fast heart rate, low blood pressure,
and breathing problems. Streptococcus and Haemophilus can also infect the
tissues surrounding the brain and spinal cord, resulting in meningitis,
with the symptoms of fever, sluggishness, chills, nausea, headache, and
back pain. Opportunistic infections in older children, adolescents, and
adults with SCD often occur in the lungs, kidneys, and bones. Bacteria
commonly involved include Streptococcus pneumoniae, Chlamydia
pneumoniae, Mycoplasma pneumoniae, Salmonella enterica, and Neisseria
meningitidis. In parts of the world where malaria is prevalent, infection
by Plasmodium falciparum is also an important opportunistic infection in
people with SCD.

How Is Sickle Cell Disease Diagnosed?


The basis for diagnosis of SCD is detection of misshapen hemoglobin
that causes sickling of RBCs. The misshapen form is called hemoglobin
S (HbS), and its structure and properties are described in greater detail in
Chapter 2. Biochemical analysis of a blood sample taken from a patient is
used to determine whether or not HbS is present, as well as other abnormal hemoglobin variants. Any genetic defect that produces a hemoglobin
variant is referred to as a hemoglobinopathy. Blood is drawn from a vein
in the arm in adults, and from a finger or heel in young children and infants. The most commonly used hemoglobin biochemical analysis methods are isoelectric focusing, high performance liquid chromatography
(HPLC), and electrophoresis. Each of these methods is capable of distinguishing between normal and abnormal forms of hemoglobin and therefore among the several forms of SCD. Chemical analysis of hemoglobin
is required in the United States as part of newborn screening, which tests
for about 30 harmful or potentially fatal disorders that respond well to
early diagnosis and treatment. If the screening test is positive for HbS,
genetic tests are conducted to determine whether one or more abnormal
hemoglobin alleles are present.
Other SCD diagnostic tests measure the ability of RBCs to adopt
the sickle shape. The hemoglobin S solubility test and the sodium

SICKLE CELL DISEASE

metabisulfite test reveal sickling of RBCs in a blood sample that has


been treated with chemicals that rapidly reduce the level of oxygen in the
blood. Examination of the sample under a microscope reveals sickling of
RBCs, which occurs at a high rate in patients with SCD and a low rate
in people with sickle cell trait. Looking for sickled cells in blood from infants younger than 6 months old gives a false negative SCD result because
infants still produce fetal hemoglobin that has not yet been replaced by
adult hemoglobin.
Diagnosis of SCD also occurs on the basis of symptoms that might
occur in infants and children. Unexplained episodes of severe pain in the
abdomen, chest, bones or joints, and swelling of the hands or feet might
indicate blockage of blood vessels by sickled cells. Fever can result from
opportunistic infections associated with SCD. Symptoms of confusion,
speech difficulty, and numbness can be cause for concern that SCD has
led to a stroke. Observation of these symptoms contributes to a diagnosis
of SCD that can be confirmed with the medical laboratory tests described
above.

Additional Health Complications of Sickle Cell Disease


There is a variety of health complications that are caused by the primary
symptoms of SCD. For example, blockage of the blood vessels that connect the heart and the lungs by sickle-shaped cells can result in acute
chest syndrome, the most common cause of death among children with
SCD over the age of three. Occlusion of the blood vessels might occur
spontaneously without a discernible cause, but it often follows an opportunistic lung infection because the associated inflammation lowers the
level of oxygen in the blood and causes RBC sickling. Sickle cell pain crises, the use of general anesthesia during surgery, and heavy doses of pain
medication have also been implicated as causes of acute chest syndrome.
Acute chest syndrome is associated with sudden and often severe chest
pain, coughing up of blood, shortness of breath, and fever. Repeated episodes of acute chest syndrome can lead to chronic lung disease.
About 30 percent of SCD patients have pulmonary hypertension,
which is an increase in the blood pressure of the large arteries that carry
blood to the lungs from the right side of the heart. The symptoms of

Symptoms and Diagnosis

pulmonary hypertension are tightness in the chest, dizziness, fatigue, and


extreme shortness of breath. The condition might arise suddenly, causing
respiratory failure and a life-threatening emergency. Pulmonary hypertension is a frequent cause of death among SCD patients. In the long
term, the increase in blood pressure can cause cor pulmonale, which is
an increase in the size of the right side of the heart that can lead to heart
failure. The complication of pulmonary hypertension occurs primarily in
adults living with SCD, who should get a regular electrocardiogram test
to check for its possible onset.
A stroke is damage to a region of the brain caused by interruption
of its blood supply, and strokes affect about 10 percent of SCD patients
over the age of three. Strokes in people with SCD occur when sickled
cells occlude the blood vessels that supply the brain with oxygen. The
acute symptoms of stroke are weakness or numbness of the extremities,
speech difficulties, seizures, and loss of consciousness. Stroke is often a
life-threatening medical emergency. The long-term effects of stroke include learning problems, impairment of the ability to think, speech problems, impaired vision, and one-sided paralysis. Small strokes might not
be noticed, but their cumulative effects can cause behavioral changes or
impairment of mental function. Cells that have sickled can also cause
blood vessels supplying the brain to weaken and rupture, resulting in an
aneurysm.
The unusual shape of sickle cells can cause blood to coagulate more
often than normal, which is referred to as thrombosis. When a blood clot
forms in a vein that is deep within the body, such as in the legs, the condition is called deep vein thrombosis. The condition might result in pain,
bruising, cramping, or swelling, but it can also occur without symptoms.
The seriousness of deep vein thrombosis comes from the increased risk
that a blood clot in a deep vein might break loose and travel to the lungs
and block the flow of blood between the heart and lungs. Risk factors
for deep vein thrombosis in SCD patients include acute chest syndrome,
pulmonary hypertension, pregnancy, orthopedic surgeries, and frequent
use of venous catheters.
Approximately 10 percent of people living with SCD have some form
of sickle hepatopathy, which encompasses several forms of acute and
chronic liver dysfunction. One form is hepatic sequestration, during

SICKLE CELL DISEASE

which sickled cells obstruct blood flow from the liver. As blood vessels expand with accumulated blood, they put pressure on the bile ducts, which
causes enlargement of the liver. Another form of liver dysfunction in SCD
patients is cholestasis, which results from stoppage of the flow of bile
from the liver to the digestive tract. Its symptoms are darkened urine and
light-colored bowel movements.
Another health complication of SCD is gallstones, which are deposits in the gall bladder of salt, cholesterol, or bilirubin, which is a product
of the breakdown of RBCs. The increased rate of blood cell destruction
caused by SCD promotes gallstone formation. Gallstones block the flow
of bile from the gall bladder to the digestive tract, causing pain, nausea, vomiting, abdominal pain, fever, and jaundice. Gallstones must be
passed on their own, shattered by ultrasound, or surgically removed. SCD
can also cause kidney complications. The environment of the kidneys
is relatively poor in oxygen, and this favors RBC sickling. The resulting occlusion of small blood vessels in the kidneys leads to sickle cell
n
ephropathy, which is one of the most frequent and severe complications of SCD. Some amount of kidney damage occurs in nearly every
person with SCD. Sickle cell nephropathy is associated with severe lower
back pain, fever, high blood pressure, and nausea.
Disruption of blood flow in men living with SCD can result in
priapism, which is a painful erection of the penis that can last for several
hours. RBCs that accumulate in the penis experience low oxygen, which
produces more sickled cells that exacerbate the problem. Repeated
episodes can damage the penis, leading to erectile dysfunction and

impotence. Priapism affects about 40 percent of men with SCD.


Occlusion of small blood vessels by cells that have sickled can also
result in damage to the retina, which is the light-sensitive layer of t issue at
the back of the eye. As a result, people with SCD can develop retinopathy
that leads to blurred vision, problems with color perception, and blindness. To compensate for the reduction in blood supply to the eye, extra
blood vessels sometimes develop in SCD patients that also impair vision.
Detachment of the retina is also a common vision complication from
SCD. Because of these vision complications, SCD patients are advised to
have frequent eye examinations.

Index
Abdominal crisis, 3
Acute chest syndrome, 6
Alpha-globin gene cluster, 9
Amniocentesis, 24, 38
Anemia, 1
Aneurysm, 7
Anopheles, 25
Autosomes, 19
Balancing selection, 26
BCL11A, 29
control element for, 42
Beta plus thalassemia, 18
Beta zero thalassemia, 17
Beta-globin gene cluster, 9, 1011
Bilirubin, 27
Black disease, 26
Blastomere biopsy, 39
Blood transfusions, 3335
Bluebird Bio, Inc., 41
Bone crisis, 3
Bone marrow transplants, 3335
Centers for Disease Control and
Prevention (CDC), 31
Cholestasis, 8
Chorionic villus sampling (CVS),
24, 38
Chronic hemolytic anemia, 1
Chronic pain syndrome, 3
Compound heterozygotes, 19
Cor pulmonale, 7
CRISPR/Cas technology, 4142
Cryopreservation, 40
Deep vein thrombosis, 7
Deoxygenation, 15
Emmaus Life Sciences, Inc., 3738
Ex vivo gene therapy, 4041
Exons, 11
Fetal hemoglobin (HbF), 33

Frameshift mutation, 13
Gallstones, 8
GBT440, 38
Gene modifiers, 27
Gene therapy, 4041
Genetic code, 11
Genetic testing for SCD, 2425
Genome editing for, 4142
Genome-wide association study
(GWAS), 28
Genotype, 20
Global Blood Therapeutics, Inc., 38
Haemophilus influenza, 35
Hand-foot syndrome, 3
HBB gene mutations cause, 1215
types differ in, 1518
HBB gene, 40
HbD-Granada, 17
Hematopoietic stem cells (HSCs), 1,
34, 4041
Heme, 2
Hemoglobin, 5, 912
Hemoglobin C (HbC), 15
Hemoglobin D (HbD), 16
Hemoglobin S solubility test, 56
Hemoglobin SC disease, 16
Hemoglobin SD disease, 17
Hemoglobinopathy, 5
Hemolysis, 1
Hepatic sequestration, 78
Heterozygous genotype, 19
Homozygous recessive, 19
Human genome, 9
Hydrophilic amino acid, 14
Hydrophobic, 14
Hydroxyurea, 3233
In vitro fertilization (IVF), 24, 39
In vivo gene therapy, 41
Ischemia, 2

56 INDEX

Joint crisis, 3
Leiden Open Variation Database
(LOVD), 18
L-glutamine, 37
Major histocompatibility complex
(MHC), 28
Malaria and SCD, 2527
Maternal blood screening, 25, 38
Mendel, Gregor, 19
Meningitis, 5
Meningococcus vaccination, 35
Missense mutation, 13
Monogenic, 19
Morphine, 32
Mutations, 1215
Newborn screening, 5
Nicotinamide adenine dinucleotide
(NAD), 37
Nonsense mutation, 13
Nonsteroidal anti-inflammatory drugs
(NSAIDs), 31
Occasional blood transfusions, 33
Opioids, 32
Opportunistic infections, 45
Oxidative stress, 37
p.Arg41Lys, 13
p.Glu122Gln, 16
p.Phe72LeufsX18, 13
Pedigree analysis for, 23
Penicillin, 35
Phenotype, 20
Plasmodium falciparum, 25
Pneumococcus vaccinations, 35
Pneumonia, 5
Preimplantation genetic diagnosis
(PGD), 3940
Prenatal diagnostic testing, 24
Priapism, 8
Pseudogenes, 10
Pulmonary hypertension, 67
Punnett square, 2022
Retinopathy, 8
RNA splicing, 11

Sensitive genetic tests, 3738


Septicemia, 5
Sickle beta plus thalassemia, 18
Sickle beta zero thalassemia, 18
Sickle cell disease (SCD)
additional health complications of,
68
blood transfusions and bone
marrow transplants, 3335
in chronic anemia, 12
contributing factors, 2730
diagnosis of, 56
experimental treatments for,
3738
extreme pain, 24
gene therapy for, 4041
genetic testing for, 2425
genome editing for, 4142
HBB gene mutations cause,
1215
types differ in, 1518
hemoglobin encoded by globin
genes, 912
improved prenatal diagnosis of,
3839
inherit of, 1923
and malaria, 2527
and opportunistic infections, 45
pedigree analysis for, 23
preimplantation genetic diagnosis
of, 3940
preventing, 3536
spleen dysfunction caused by, 4
treatment of, 3133
Sickle cell nephropathy, 8
Sodium metabisulfite test, 56
Spleen dysfunction, 4
Splenic sequestration, 4
Spontaneous mutation, 14
Streptococcus pneumonia, 35
Stroke, 7
Substitution mutations, 13
Tankyrase I, 28
Transcription, 11
Translation process, 11
Trophectoderm biopsy, 3940
Vasoconstriction, 29

OTHER TITLES IN OUR HUMAN DISEASES


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Genetic Diseases or Conditions: Cystic Fibrosis, The Salty Kiss by Todd T. Eckdahl
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Hemophilia: The Royal Disease by Todd T. Eckdahl

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Nerve Disease ALS and Gradual Loss of Muscle Function: Amytrophic Lateral Sclerosis
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Auto-Immunity Attacks the Body by Mary E. Miller
Brain Degeneration from Huntingtons Disease by Todd T. Eckdahl
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