Hereditary Blindness

and Deafness
Hereditary Blindness
and Deafness
The Race for Sight
and Sound

Todd T. Eckdahl
Hereditary Blindness and Deafness: The Race for Sight and Sound
Copyright Momentum Press, LLC, 2017.

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 Abstract
This book presents examples of hereditary blindness and deafness that
illustrate the large variety of genetic diseases that affect vision and hear-
ing. It describes seven hereditary eye diseases, three genetic syndromes
that cause deafness, and four types of nonsyndromic deafness. The book
describes the diagnosis of hereditary blindness and deafness in children and
adults. It explains the patterns of inheritance of blindness and deafness,
and illustrates each with family scenarios. The practice of genetic test-
ing is described, which can provide information that prospective parents
can use to make reproductive decisions. The book presents treatments
and therapies for hereditary blindness and deafness such as hearing aids,
cochlear implants, and corneal implants. It describes future prospects
for diagnosing, treating, and curing hereditary blindness and deafness,
including experimental drugs, stem cell therapy, preimplantation genetic
diagnosis, and gene therapy.

Keywords
autosomal dominant, autosomal recessive, blindness, deafness, genetic
disease, hearing loss, hereditary blindness, hereditary deafness, nonsyn-
dromic deafness, sex-linked, X-linked, syndromic deafness, Y-linked,
vision loss
 Contents
Acknowledgmentsix
Introductionxi
Chapter 1 Symptoms and Diagnosis1
Chapter 2 Causes and Contributing Factors17
Chapter 3 Treatment and Therapy45
Chapter 4 Future Prospects51
Conclusion59
Glossary61
Bibliography67
Index69
 Acknowledgments
I am grateful to my friend Malcolm Campbell for encouraging me to take
a leap of faith for this project, and for 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. 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 of 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 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
Kent Desormeaux is a jockey who won over 5,700 thoroughbred horse
races and set the U.S. record in 1989 for most wins in a year with 598.
Kent won the Kentucky Derby three times, the Preakness Stakes three
times, and the Belmont Stakes once. In 2008, he had a chance to win
them all in the same year, which is called the Triple Crown. He had
already won the Kentucky Derby and the Preakness as his 9-year-old
son Jacob cheered him on at the Belmont Stakes. As his father raced for
the Triple Crown, Jacob was in his own race for sight and sound. Jacob
could not hear the thundering hooves heading down the home stretch
and strained through his glasses to see his father lose his bid for the Triple
Crown because Jacob was born with Usher syndrome, a hereditary dis-
ease that caused him to be profoundly deaf and to slowly lose his sight
by adulthood. Jacob has since gained ground in his race for sound with
cochlear implants that allow him to hear, but he is losing his race for sight
and is becoming blind.
More than 350 million people worldwide have moderate to severe
hearing loss or are profoundly deaf. About 1 in 1,000 babies is born
with moderate to profound hearing loss, and about half of the cases have
genetic causes, with the other half being due to nongenetic factors such as
maternal infections, drug or alcohol use during pregnancy, or premature
birth. About 30 percent of hereditary hearing loss is syndromic hearing
loss, during which partial or total hearing loss is caused by malformations
of the external ear and is accompanied by problems with other organ
systems. There are over 400 genetic diseases that cause syndromic deaf-
ness. Usher syndrome is an example of syndromic deafness because it
causes mild to profound hearing loss and a progressive loss of vision from
retinitis pigmentosa. Other examples of syndromic deafness are Alport
syndrome, which causes mild to profound hearing loss, kidney disease,
and vision loss, and Waardenburg syndrome, which causes mild to pro-
found hearing loss and developmental abnormalities. About 70 percent of
hereditary hearing loss is nonsyndromic hearing loss, which is a partial
xii INTRODUCTION

or total loss of hearing that is not accompanied by other symptoms.

Nonsyndromic deafness is caused by the dysfunction of genes that con-
trol the development and function of the middle ear or the inner ear, and
is categorized according to the pattern by which the genes are inherited.
Forty million people in the world are living with blindness. Among
adults, genetic diseases such as congenital glaucoma, corneal dystro-
phy, and age-related macular degeneration are the leading causes of
blindness. The prevalence of blindness in children ranges from 0.3 in
1,000 for countries with low childhood mortality rates, to 1.5 in 1,000
for countries with high childhood mortality rates. About 75 percent of the
approximately 1.4 million blind children in the world live in the poorest
regions of Africa and Asia. More than 60 percent of childhood blindness
is caused by hereditary eye diseases such as congenital cataracts, congeni-
tal glaucoma, and retinitis pigmentosa. About 2.5 percent of all children
are affected by amblyopia, a hereditary eye disease that usually affects one
eye and causes visual impairment or blindness in the affected eye. Color
blindness is also a hereditary eye disease, and it affects about 8 percent of
males and 0.5 percent of females.
The chapters of this book present types of hereditary blindness and
deafness that exemplify the large variety of genetic diseases and conditions
that affect vision and hearing. Chapter 1 describes the primary symptoms
of seven hereditary eye diseases, three genetic syndromes that typify syn-
dromic deafness, and four examples of nonsyndromic deafness. It describes
the diagnosis of hereditary blindness and deafness in children and adults,
and considers the health complications that accompany these conditions.
Chapter 2 explains the inheritance patterns of hereditary blindness and
deafness. It presents scenarios by which these conditions are inherited in
families, and explains how genetic testing can provide information that
prospective parents can use to make reproductive decisions. Chapter 3
presents treatments and therapies for hereditary blindness and deafness
such as hearing aids, cochlear implants, and corneal implants. Chapter 4
describes future prospects for diagnosing, treating, and curing hereditary
blindness or deafness, including experimental drugs, stem cell therapy,
preimplantation genetic diagnosis, gene therapy, and genome editing.
 CHAPTER 1

Symptoms and Diagnosis

This chapter describes examples that illustrate the large diversity of ge-
netic diseases that affect vision and hearing. It presents the symptoms and
diagnosis of nonsyndromic hearing loss and three examples of syndromic
deafness. It illustrates hereditary blindness with information about the
symptoms and diagnosis of seven hereditary eye diseases, chosen for their
prevalence and their varied effects on the visual system. Throughout this
chapter and book, the terms hearing loss and vision loss will be used to
refer to the effects of diseases that are not complete deafness or blindness.

Symptoms and Complications of Hereditary Deafness

The types of symptoms and health complications that arise from heredi-
tary hearing loss and deafness depend on which parts of the auditory
system are affected. The outer ear includes the fleshy parts that we see,
the ear canal, and the outer layer of the eardrum. An underlying piece
of cartilage forms the shape of the outer ear, which directs sound waves
into the ear canal. The ear canal is formed by cartilage and bone and a
layer of skin that is protected by ear wax. Sound waves travel through
the ear canal and cause the eardrum to vibrate. The middle ear transmits
vibrations of the eardrum to the inner ear through a series of three deli-
cate and precisely positioned bones commonly referred to as the hammer,
the anvil, and the stirrup. Vibrations of the stirrup are passed on to a
series of fluid-filled compartments in the inner ear until they arrive at the
cochlea, which contains specialized hair cells, named for the hair-like
projections called cilia that extend from their surfaces. Hair cells use cilia
to transduce the mechanical signals of fluid vibrations into the electrical
2 HEREDITARY BLINDNESS AND DEAFNESS

signals of nerve impulses. The cochlea is also part of the vestibular sys-
tem, which provides overall body balance and spatial orientation. The
vestibulocochlear nerve sends impulses from the inner ear to the brain,
which processes them as sounds that we perceive. Hearing occurs either
through air conduction or bone conduction. Air conduction occurs when
sound waves that enter the ear canal cause the eardrum to vibrate, which
leads to vibration of the bones of the middle ear. During bone conduc-
tion, sound waves that travel through the bones of the skull are detected
by the cochlea. Bone conduction is also facilitated by the mastoid bone
located behind the ear.
The perceived loudness of a sound depends on the ability to hear and
on the intensity of the sound. The decibel (dB) is a unit named after Al-
exander Graham Bell that measures the relative intensity of sounds, and it
is defined as 10 times the logarithm of the ratio of the intensity of a given
sound to the standard threshold of hearing, which is set as the minimum
intensity that most people can hear. A value of 0 dB does not mean there
is no sound, but that the sound pressure is equal to the standard. The
standard threshold of hearing causes a pressure change that is about one
billionth of the standard pressure of the atmosphere, which illustrates the
sensitivity of human hearing. Because the decibel scale is logarithmic,
there is a 10-fold increase or decrease in intensity between sounds that
differ by 10 dB, a 100-fold increase or decrease for 20 dB, a 1,000-fold
increase or decrease for 30 dB, and so on. For perspective, a whisper is
about 20 dB, a conversational level is about 60 dB, train whistles are about
100 dB, and a very loud rock concert can be over 120 dB. The hearing
threshold is the minimum intensity of sound that a person can hear. The
normal hearing threshold ranges from 10 dB, which means that a person
can hear a sound that is one-tenth the intensity of the standard, to 15 dB,
which is an intensity that is about 32 times higher than the standard. As
shown in Table 1.1, the severity of hearing loss is categorized from mild
to profound. Adults with hearing loss greater than 40 dB and children
with hearing loss greater than 30 dB are said to have disabling hearing
loss. Total deafness occurs when a person has profound hearing loss or
cannot hear sound at all, regardless of its intensity.
There are about 360 million people worldwide who have disabling
hearing loss, which is about 5 percent of all people. About 10 percent of
 Symptoms and Diagnosis 3

Table 1.1 Severity of hearing loss

Severity of hearing loss Hearing threshold (dB)
Normal 10 to 15
Slight 16 to 25
Mild 26 to 40
Moderate 41 to 55
Moderately severe 56 to 70
Severe 71 to 90
Profound 91 or higher

people with disabling hearing loss are children, and one-third are 65 years
of age or older. Data from the United States demonstrate that the preva-
lence of hearing loss increases with age. Two percent of adults aged 45 to
54 have hearing loss, compared to 8.5 percent of those aged 55 to 64 years,
25 percent of those aged 65 to 74 years, and 50 percent among people
75 years or older.
Hearing loss can be congenital, which means that it is present at birth,
or it can develop later in life, during childhood or adulthood. Hearing
loss can also be hereditary or acquired. Acquired hearing loss can occur
at any stage of life, including embryonic and fetal development. Infec-
tions during pregnancy such as syphilis, rubella, herpes, toxoplasmosis,
or cytomegalovirus are responsible for about 30 percent of congenital
acquired hearing loss. The risk of congenital hearing loss is also higher
among infants that have low birth weight, jaundice, or oxygen depriva-
tion. Acquired hearing loss can occur in infants, children, and adults from
infectious diseases such as encephalitis, measles, mumps, chicken pox,
meningitis, or the flu. Trauma to the head or the ear, repeated exposure to
occupational or recreational loud noise, and side effects of some medica-
tions can also cause acquired hearing loss.
Hereditary hearing loss is categorized as syndromic or nonsyndromic.
Nonsyndromic hearing loss is a partial or complete loss of hearing that
is not associated with symptoms involving other parts of the body, and
it accounts for about 70 percent of the cases of inherited hearing loss.
Nonsyndromic hearing loss can be categorized according to four patterns
of inheritance (Table 1.2), which are explained in Chapter 2. Within each
of these categories, the age of onset, progression, and severity of hearing
4 HEREDITARY BLINDNESS AND DEAFNESS

Table 1.2 Worldwide prevalence and symptoms of hereditary deafness

Hereditary deafness Prevalence Symptoms
Autosomal recessive 110 in 100,000 births Mild to profound hearing loss
nonsyndromic deafness
Autosomal dominant 30 in 100,000 births Mild to profound hearing loss
nonsyndromic deafness
X-linked nonsyndromic 2 in 100,000 births Mild to profound hearing loss
deafness
Mitochondrial <2 in 100,000 births Mild to profound hearing loss
nonsyndromic deafness
Alport syndrome 2 in 100,000 births Mild to profound hearing loss,
kidney disease, eye disease
Waardenburg syndrome 2.5 in 100,000 births Moderate to profound hearing
loss, developmental defects
Usher syndrome 4.5 in 100,000 births Mild to profound hearing loss,
vision loss

loss vary widely. Nonsyndromic hearing loss can be congenital, or it can

develop during any stage of life. It is important to distinguish between
prelingual hearing loss that occurs before a child learns to speak and
postlingual hearing loss because they present very different challenges to
language acquisition. After hearing loss onset, the severity might remain
stable, or it might progressively worsen with age. The severity of nonsyn-
dromic hearing loss ranges from slight to profound in each of the four
inheritance categories, and it can affect either one or both ears. Hearing
loss can affect the full range of pitches that a person can hear, from low to
high pitches, or it might affect only part of the range.
A genetic syndrome is an inherited disorder that causes symptoms in
multiple body systems. Hearing loss that is part of a genetic syndrome is
called syndromic hearing loss, and it accounts for about 30 percent of in-
herited hearing loss. More than 400 genetic syndromes cause hearing loss,
along with a very large variety of problems with other systems throughout
the body. Alport syndrome is an example of syndromic hereditary hear-
ing loss that occurs at a rate of about 2 in 100,000 births, and which also
causes kidney and eye disease (Table 1.2). An early symptom of Alport
syndrome that often occurs in infants is trace amounts of blood in the
urine. In older children and adolescents with the disorder, progressive
kidney dysfunction leads to more frequent and severe bleeding that is
 Symptoms and Diagnosis 5

detectable as discoloration of the urine. Adults with Alport syndrome

develop end-stage renal disease, which leads to a variety of health compli-
cations that include headaches, fatigue, sleep apnea, weight loss, nausea,
swelling of the extremities, respiratory problems, and high blood pres-
sure. Because Alport syndrome causes progressive hearing loss, people
born with the disorder have normal hearing as infants, but begin to lose
their ability to hear high-frequency sounds in late childhood or adoles-
cence. Later, they also lose low-frequency hearing, but they usually do not
experience complete hearing loss. Some forms of Alport syndrome cause
the onset of hearing loss to be delayed until late adulthood.
Waardenburg syndrome also causes syndromic hearing loss. It occurs
at a frequency of about 2.5 in 100,000 births (Table 1.2). The hearing
loss from Waardenburg syndrome is congenital, can involve one or both
ears, and ranges in severity from moderate to profound. Waardenburg syn-
drome is often associated with a white forelock of hair that is present at
birth or develops in adolescence. Other symptoms include premature gray-
ing before the age of 30 years, a low hairline that is closer to the e yebrows,
lightly pigmented skin patches, and wide-set eyes that are pale blue or two
different colors. Additional health complications of Waardenburg syn-
drome include severe constipation and a decline in cognitive ability. Some
types of Waardenburg syndrome also cause embryonic developmental
problems that result in cleft lip and palate, intestinal defects, or an abnor-
mal spinal column.
Usher syndrome is the most common disease affecting both hear-
ing and vision, and it occurs at a rate of about 4.5 in 100,000 births
(Table 1.2). There are three recognized types of Usher syndrome that
differ in the onset and severity of symptoms. Infants born with type
I Usher syndrome usually have profound deafness, whereas infants born
with type II have moderate to severe hearing loss that progressively wors-
ens over time. The hearing loss caused by type III Usher syndrome is not
present at birth but usually develops in late childhood or adolescence.
Both the age of onset and the severity of hearing loss vary widely among
people with type III Usher syndrome. All three types of Usher syndrome
are associated with retinitis pigmentosa, which results in visual impair-
ment and possible blindness. Early symptoms of night blindness and loss
of peripheral vision often progress to impaired vision, and to blindness.
6 HEREDITARY BLINDNESS AND DEAFNESS

The onset and severity of retinitis pigmentosa symptoms vary widely

among the three types of Usher syndrome, and among people with the
same type. Infants born with type I Usher syndrome often have trouble
learning to walk because the same inner ear dysfunction that causes their
hearing loss affects their ability to maintain balance. For the same rea-
son, problems with balance can arise later in life for people with type III
Usher syndrome.

How Is Hereditary Deafness Diagnosed?

The diagnosis of hereditary deafness begins with careful examination of
the outer ear and the eardrum with an otoscope. A light source in the
otoscope illuminates the ear canal and enables the use of a magnifying
lens to check the condition of the outer ear and the integrity of the ear-
drum. Otoscopes often have a means to send a gentle puff of air to the
eardrum to check its ability to vibrate. The diagnosis of hereditary deaf-
ness also depends on several types of audiometry to measure how well a
patient can hear. During pure-tone audiometry, the patient listens with
headphones to a series of pure tones ranging from low to high pitch. Each
tone is presented with a gradual increase in volume, and the patient is
asked to report when sounds are heard. The pitch of sound is determined
by its frequency, which is the number of sound waves passing a given
point per second, and is expressed with the unit Hertz (Hz). The normal
range of hearing is from 20 to 20,000 Hz, and people usually speak
in the range from 500 (bass) to 3,000 Hz (soprano). Audiometry presents
the patient with a series of tones that cover the full range of frequencies
that most people can hear, and the results are summarized in a graph
of the hearing threshold in decibels as a function of tone frequencies in
Hz. The graph reveals the degree of hearing loss in the low-, middle-,
and high-frequency ranges. Pure-tone audiometry depends on a vocal
response from the patient that a sound is heard, so it is not used with
infants and young children. Behavioral observation audiometry is used
with infants up to about 6 months old, and involves careful observation
by an experienced technician for quick movements of the limbs, changes
in facial expression, or other indications that the child has heard a sound.
For children up to about 2 years old, visual reinforcement audiometry
 Symptoms and Diagnosis 7

is used, during which a child is rewarded with a pleasant visual stimulus

for turning in the direction of a sound. The hearing of children between
2 and 5 years of age is often tested with conditioned play audiometry,
which turns a hearing test into a listening game that children want to play.
Whereas audiometry measures overall hearing, other clinical tests as-
sess the functions of specific parts of the ear and nervous system. Tym-
panometry measures the function of the tympanic membrane (eardrum)
and the bones of the middle ear. An inserted probe sends a pure tone into
the ear canal and measures the intensity of sound that is reflected back by
the eardrum and the underlying middle ear bones while varying the air
pressure in the ear canal. Dysfunction of the middle ear reduces the frac-
tion of the tone that is transmitted through it, and increases the intensity
of the tone that is reflected back to the probe. Normally, sound is trans-
mitted best when the air pressure in the middle ear is equal to the ambi-
ent air pressure, and deviation from this indicates middle ear dysfunction.
The function of the inner ear can also be assessed with the otoacoustic
emissions test, which measures the soft sounds that are echoed back to
the ear canal by the inner ear when it receives external sounds. Because this
test can be used with patients of any age, it is particularly useful for the
detection of congenital hearing loss. The electrophysiology of hearing can
be measured with the auditory brainstem response test, during which
sounds are presented with earphones while electrodes behind the ear and
on the forehead detect the electrical signals that are produced in response.
The auditory brainstem response test provides detailed information about
the amplitude of the electrical signal produced by the inner ear, and the
speed at which it is transmitted to the brain.
The hearing in noise test is used to assess the ability of a patient
to distinguish speech in a noisy background. Recorded sentences are
played at increasing volumes without background noise, and the volume
at which the patient can correctly repeat the sentences half of the time is
noted. The test is repeated with background noise presented in front of
the patient and to each side. The results provide information about the
type of hearing loss.
An accurate diagnosis of hereditary hearing loss also involves making a
distinction between sensorineural hearing loss and conductive hearing
loss. This can be done with a conductive hearing test, which compares
8 HEREDITARY BLINDNESS AND DEAFNESS

the ability of the patient to hear a vibrating tuning fork pressed against
the bone behind their ear to their ability to hear it when it is placed just
outside their ear. For a patient with conductive hearing loss, the ringing
sound is transmitted better through their bones than through the struc-
tures of their ear. A patient with sensorineural hearing loss cannot convert
either source of sound vibrations into a nerve signal to the brain.
Whereas the diagnosis of nonsyndromic hearing loss depends solely
on clinical assessments of hearing loss and the functions of the auditory
system, the diagnosis of syndromic hearing loss involves evaluation of
other body systems. The diagnosis of Alport syndrome might begin with
the detection of blood in the urine of an infant. More commonly, the
progressive kidney dysfunction associated with the disorder is detected by
blood discoloration in the urine that occurs in childhood or adolescence.
Clinical laboratory analysis is used to confirm the presence of blood and
abnormally high protein levels in the urine, which are indirect measures of
kidney disease. Microscopic examination of a kidney biopsy provides direct
evidence of characteristic changes in the structure of the kidney in support
of a diagnosis of Alport syndrome, and is used to exclude other causes of
kidney disease. A clinical ear examination is also used to diagnosis Alport
syndrome and to rule out other causes of hearing loss such as damage to
the eardrum or infection of the middle ear. Audiometry is used to m easure
the hearing threshold for a series of frequencies ranging from low to high.
The onset of hearing loss for patients with Alport syndrome involves a
reduction in their ability to hear high-frequency sounds. Aconductive
hearing test can also be used to distinguish the sensorineural hearing loss
associated with Alport syndrome from conductive hearing loss. Because
Alport syndrome is hereditary, family history can contribute significantly
to its diagnosis, which can be confirmed by genetic testing.
Waardenburg syndrome causes hearing loss that ranges from mild to
profound, and can be present at birth or develop later. Audiometry is
used to measure the onset and severity of the hearing loss. A diagnosis
of Waardenburg syndrome can distinguish among the four types of the
syndrome that occur, the two most common of which are type I and
type II. Because the characteristic feature of wide-set eyes is found with
type I Waardenburg syndrome but not type II, careful measurements of
the angle of the eyes and the distance between the pupils are useful in a
 Symptoms and Diagnosis 9

differential diagnosis. The hearing loss caused by type III Waardenburg

syndrome is accompanied by developmental abnormalities of the arms
and hands, including shortened limbs, abnormal joint function, fusion of
wrist bones, and webbing or fusion of fingers. Type IV Waardenburg syn-
drome also causes hearing loss, but is distinguished from the other forms
by its association with intestinal abnormalities that can be diagnosed with
a clinical test of bowel function or a colon biopsy.
The diagnosis of Usher syndrome is based on clinical evaluation of
hearing, vision, and balance. The presence of congenital hearing loss or
deafness is often checked with an otoacoustic emissions test. The presence
of congenital deafness indicates type I Usher syndrome, whereas moder-
ate to severe hearing loss is characteristic of type II. The progressive loss of
hearing that accompanies type II Usher syndrome and the onset of hear-
ing loss caused by type III Usher syndrome are monitored by audiom-
etry. Confirmation of retinitis pigmentosa also contributes to an Usher
syndrome diagnosis. Eye tests are used to detect the narrowing of the
visual field and the loss of visual acuity caused by the disease. Damage
to the retina is assessed by direct microscopic visual examination through
the pupil, and with a test that measures the ability of the retina to gener-
ate an electrical signal after receiving a light stimulus. Balance problems
that occur in young children with type I Usher syndrome, and which
develop later in people with type III Usher syndrome, can be detected
with a sensitive test that measures involuntary eye movements.

Symptoms and Complications of Hereditary

Eye Disease
The process by which the human eye captures light and transmits it to
the brain for vision begins when light passes through the cornea, a clear,
curved layer of tissues at the front of the eye that helps focus the light.
The cornea bends the light toward the pupil, which is an opening in the
iris that can be constricted (closed) or dilated (opened) to regulate the
amount of light that enters the eye. The iris contains pigment proteins
that block light from entering the eye and which determine eye color.
Light passing though the pupil is further focused by the lens, which is
composed of very long cells that are densely packed as fibers and which
10 HEREDITARY BLINDNESS AND DEAFNESS

contain proteins that make the cells transparent. Small muscles attached
to the lens can change its optical properties by making it thicker or thin-
ner, thereby focusing the image on the retina at the back of the eye. The
retina contains photoreceptor cells called rods and cones that convert
light information into electrical signals that are conveyed by the optic
nerve to the brain. Rods are specialized for distinguishing black and white
and for detecting low light, whereas cones are specialized for various col-
ors of light. The fluid in the eye is called the aqueous humor, and its level
is maintained by a filtration system (trabecular meshwork) located at the
angle of the eye where the pigmented iris meets the cornea. Human vision
is so complex that it is not surprising to learn the variety of ways that it
can be compromised. Injuries, acquired diseases, and inherited diseases
can cause moderate or severe visual impairment, including blindness.
The most common cause of partial or total blindness in one eye is
amblyopia, and it affects about 3 percent of children worldwide under the
age of 6 years (Table 1.3). Amblyopia is commonly called lazy eye because
one eye makes a much smaller contribution to vision than the other eye, but
this term is misleading because it implies that the problem would go away
with better effort and that the eye is solely to blame for it. The problem
is poor communication between the eye and the brain, and it starts when

Table 1.3 Worldwide prevalence and symptoms of hereditary

eye diseases
Hereditary eye
disease Prevalence Symptoms
Amblyopia 3 in 100 births Inability to focus one eye,
blindness in one eye
Cataracts 2.5 in 1,000 people Blurry vision, double vision,
poor night vision, blindness
Color blindness 80 in 1,000 male births Inability to distinguish colors
5 in 1,000 female births
Corneal dystrophy 9 in 10,000 births Blurry vision, blindness
Age-related macular 5 in 10,000 people Blurry central vision,
degeneration blindness
Retinitis pigmentosa 2.5 in 10,000 births Night blindness, loss of
peripheral vision, blindness
Congenital glaucoma 1.5 in 10,000 births Loss of peripheral vision,
blindness
 Symptoms and Diagnosis 11

the brain receives better visual input from one eye than the other because
of nearsightedness, childhood cataracts, or permanently crossed eyes. As the
brain continues to ignore input from the weaker eye, the function of the eye
gradually deteriorates from lack of use. The symptoms of amblyopia include
blurred vision, double vision, and poor depth perception. Amblyopia often
causes the eyes to move independently of one another, instead of coordinately.
A cataract occurs when the lens of an eye becomes opaque to visible
light. The resulting blurred and dulled vision worsens over time as the
cataract worsens, and can lead to blindness. Cataracts cause sensitivity
to bright light, poor night vision, double vision, and frequent changes
in the prescription for corrective lenses. Eventually, a cataract causes the
lens to adopt a yellowish color that tints the visual image and makes it
difficult to identify shades of blue. A congenital cataract is either pres-
ent at birth or develops within the first year. Congenital cataracts occur
at a rate of about 3.5 in 10,000 births and account for between 5 and
20 percent of worldwide childhood blindness. Age-related cataracts
result from a progressive change in the lens over 45 or more years. This
form of cataracts is responsible for almost half of the cases of blindness
worldwide, and occurs in about 2.5 in every 1,000 people. (Table 1.3)
Cataracts can also be acquired by an eye injury, by exposure to radiation,
as a health complication of diabetes, or as a complication of eye surgery.
Color blindness is the inability to distinguish colors, and it takes
a variety of forms that differ in symptoms and severity. The three main
types of color blindness are red-green, blue-yellow, and total color blind-
ness. Color blindness ranges from subtle and often unnoticed differences
in color perception to the complete inability to distinguish colors. The
most common form of color blindness is red-green color blindness, and
because it is caused by a gene on a sex chromosome, it affects males more
often than females, with a worldwide prevalence of about 80 males and
5 females in every 1,000 births (Table 1.3). The symptoms of red-green
color blindness depend on whether there is partial or total loss of the
perception of red or green. Most people with red-green color blindness
have partial loss of green perception, which makes yellow and green colors
appear redder to them, and makes it hard for them to distinguish violet
and blue. These are mild symptoms that do not have a large impact on
daily life. The two types of red-green color blindness that are associated
12 HEREDITARY BLINDNESS AND DEAFNESS

with the complete failure to perceive red or green have more substantial
symptoms. Blue-yellow color blindness affects males and females equally.
It can be caused by a diminished ability to detect blue light, which makes
blue appear to be greener, and makes it difficult to tell yellow and pink
apart. It can also be caused by the complete inability to perceive blue,
which makes blue appear to be green and yellow appear to be violet or
gray. Complete color blindness is the inability to detect at least two of
the three colors of red, green, and blue. People with this condition see
the world in shades of gray. Complete color blindness affects males and
females equally, and is extremely rare.
Corneal dystrophy refers to a collection of over 20 eye diseases that
cause the abnormal accumulation of foreign material such as dust, dead
cells, and bacteria in one or more of the five tissue layers of the cornea. The
symptoms of corneal dystrophies accumulate gradually during the first 20
years of life, and their severity varies widely. Some people with corneal dys-
trophy are asymptomatic, whereas others have severe visual impairment, in-
cluding blindness. Many types of corneal dystrophy cause corneal erosion,
during which the attachment of the outermost layer of the cornea to the un-
derlying tissue is compromised. The symptoms of corneal erosion include
mild to severe eye pain, light sensitivity, blurred vision, watery eyes, and dry
eyes. Corneal dystrophies usually affect both eyes equally. The worldwide
prevalence of corneal dystrophy is about 9 in 10,000 births (Table 1.3).
Age-related macular degeneration is the deterioration of the macula,
a small patch of densely packed rods and cones at the center of the retina
that controls the sharpness of visual images and enables visual perception
of fine details. Age-related macular degeneration is the leading cause of vi-
sion loss among the elderly. Its prevalence in developed countries is about
5 in 10,000 people (Table 1.3), and is expected to increase as the propor-
tion of elderly people rises. About 90 percent of the cases of age-related
macular degeneration are of the dry type, associated with the accumula-
tion of yellowish deposits underneath the retina that cause gradual loss of
vision in both eyes. The remaining cases are of the wet type and are char-
acterized by the abnormal growth of blood vessels beneath the macula,
which leak blood and serum that cause blurry and distorted vision.
Another cause of hereditary blindness is retinitis pigmentosa, which is
a collection of diseases that are characterized by degeneration of the retina
 Symptoms and Diagnosis 13

and the accumulation of excess pigment in visual sensory cells. Retini-

tis pigmentosa occurs at a worldwide prevalence of about 2.5 in 10,000
births (Table 1.3). It usually affects both eyes and gradually worsens vi-
sion over a period of decades. The onset of symptoms occurs during child-
hood, with difficulty seeing in low light that transitions to the complete
loss of night vision. Blind spots develop in peripheral vision that grow
and fuse, narrowing the visual field and causing tunnel vision. Progres-
sive degeneration of the retina later affects central vision, which negatively
impacts reading, driving, and facial recognition. The later stages of reti-
nitis pigmentosa are associated with the complete loss of vision. Many
people with retinitis pigmentosa are legally blind by middle age.
Glaucoma is a group of diseases caused by abnormal drainage of aque-
ous humor fluid through the trabecular network and into drainage ducts.
The gradual accumulation of excess fluid in the eye increases pressure on the
optic nerve, disrupting the transmission of electrical information from the
eye to the brain. Glaucoma usually affect both eyes, but not necessar-
ily equally. The most common forms of glaucoma are called open-angle
glaucoma, and they occur because the trabecular network at the angle of the
eye remains open, but the drainage ducts become clogged. Because the effect
takes years to occur, most people with open-angle glaucoma are over the age
of 50 years. The initial symptom of open-angle glaucoma is a slight reduction
in the field of vision, but with time, blind spots develop first in peripheral
vision and later in central vision. Some forms of open-angle glaucoma pro-
duce symptoms in infants, and are referred to as congenital glaucoma. The
worldwide prevalence of congenital glaucoma is about 1.5 in 10,000 births
(Table 1.3). Vision worsens gradually over a period of years, and without
treatment, is lost completely. Rarer forms of glaucoma called angle-closure
glaucoma are caused by a sudden closure of the trabecular network and its
associated drainage ducts. Angle-closure glaucoma causes moderate to severe
eye pain, eye redness, cloudy vision, and tunnel vision. Left untreated, it can
lead to permanently blurred vision, and often blindness.

How Is Hereditary Eye Disease Diagnosed?

The diagnosis of amblyopia is straightforward if the proper clinical
tests are performed as part of a visual examination. However, in most
14 HEREDITARY BLINDNESS AND DEAFNESS

countries, routine eye tests are not usually given until the age of 5 years.
The American Optometric Association recommends a comprehensive eye
examination for children at the ages of 6 months and 3 years. In older
children and adults, amblyopia often goes unnoticed because the brain
and the stronger eye compensate for the weaker eye. The diagnosis of
amblyopia depends on detecting a difference in vision between the two
eyes, or poor vision in both eyes. In older children and adults, visual
acuity is usually measured with a Snellen chart containing progressively
smaller letters or with a chart containing symbols for those who cannot
read. Visual acuity is measured in an infant by covering one eye and ob-
serving how well the infant can follow an interesting moving object. If
monocular amblyopia is present, the infant might try to remove the patch
to better see the object or outwardly display their frustration. Treatments
for amblyopia are most effective if the diagnosis is made at an early age.
A diagnosis of congenital cataracts begins with a comprehensive eye
examination. A key test is to measure the response to red light, which
is reduced or absent in infants with congenital cataracts. The opacity
of the lens is also measured, and microscopic examination of the eye is
used to directly observe the location and severity of cataracts. If there is
a family history of cataracts, then it is reasonable to assign the cause of
congenital cataracts as hereditary. If not, additional tests are performed
to attribute congenital cataracts to environmental exposure, infectious
disease, a metabolic disorder, or a genetic syndrome. The diagnosis of
age-related cataracts begins with a standard eye exam and is often con-
firmed by an ophthalmologist. A Snellen chart test detects the effect of
cataracts on visual acuity, and examination of the lens with an ophthal-
moscope after pupil dilation enables direct observation of the size and
severity of cataracts.
Several tests are used to quickly diagnose color blindness. Historically,
the most commonly used test is the Ishihara Color Test, which uses a
series of 38 plates that are composed of circles of various sizes and col-
ors. Each plate has a number or a shape that can be perceived by those
who can distinguish colors, but not by those who have color blindness.
It is easy to find Ishihara Color Test plates online, and although these
can be used for initial testing, a definitive diagnosis should be made by
an ophthalmologist. The Cambridge Color Test is based on the same
 Symptoms and Diagnosis 15

concept, but asks the patient to observe the orientation of the letter C.
Getting the correct answer depends on being able to make color distinc-
tions such as red versus green, or subtler distinctions such as violet versus
blue. Another test for color blindness, called the anomaloscope, presents
the patient with a circle formed by two different sources of light. The
patient is asked to adjust the brightness of the yellow light in the top half
of the circle and the proportion of red and green light in the bottom half of
the circle until the two halves appear to be the same shade and intensity
of yellow. People with color blindness adjust the anomaloscope differently
than people with normal vision. More specialized color blindness tests
have been developed to test graphic designers, photographers, or pilots
who depend on accurate color perception.
The diagnosis of corneal dystrophy begins with the observation that
the cornea has lost some or all of its transparency. Having a family history
of corneal disease contributes to the preliminary diagnosis. A definitive
diagnosis of corneal dystrophy is made by an ophthalmologist using a slit
lamp microscope to examine the cornea. A thin, bright sheet of light is
shined into the eye, and the ophthalmologist looks carefully at the nature
of the corneal defect to determine which of the over 20 forms of corneal
dystrophy is present.
Age-related macular degeneration can be detected during a regular eye
examination. Diagnosis of the dry form of macular degeneration requires
dilation of the pupils with eye drops and an ophthalmoscope to carefully
observe the retina at the back of the eye, looking for degradation of the
macula. The wet form of macular degeneration is diagnosed with more
specialized tests such as fluorescein angiography, which uses a fluores-
cent dye injected into the bloodstream to enable a detailed view of the
tiny blood vessels in the retina, and optical coherence tomography,
which can provide high-resolution images of the retina.
Retinitis pigmentosa can be diagnosed with clinical procedures that
are used during a comprehensive eye examination. An ophthalmologist
can use an electroretinogram to measure the ability of retinal rods and
cones to generate an electrical signal after receiving a light stimulus. The
visual field test presents objects to a patient with a fixed gaze in order to
map the visual field. Retinitis pigmentosa restricts the visual field in char-
acteristic ways that an ophthalmologist can recognize. Optical coherence
16 HEREDITARY BLINDNESS AND DEAFNESS

tomography and fluorescein angiography can reveal morphological

changes in the retina that are caused by retinitis pigmentosa.
Glaucoma upsets the balance between the production of aqueous
humor and its drainage, resulting in elevated pressure inside the eye. As
a result, the key diagnostic test for glaucoma is the measurement of in-
traocular pressure. Examination of the eye with an ophthalmoscope and
optical coherence tomography are also used to determine whether or not
the optic nerve has been damaged by glaucoma.
 Index
Page numbers followed by f indicate figures; those followed by t indicate tables.

Acquired hearing loss, 3 Cambridge Color Test, 1415

Age-related cataracts, 11 Cataract, 10t, 11
Age-related macular degeneration, Chorionic villus sampling
10t, 12 (CVS), 40
causes of, 2122 Chromosomes, 23
diagnosis of, 15 Clustered regularly interspaced
genes that cause, 3637 short palindromic repeats
treatment for, 49 (CRISPR), 56
Alleles, 23 Cochlea, 1
Alport syndrome, 45, 4t, 8 Cochlear implant, 4647
cause of, 19 Cochlin, 19
diagnosis of, 9 Color blindness, 10t, 1112
genes that cause, 32 causes of, 21
Amblyopia, 1011, 10t diagnosis of, 1415
causes of, 20 genes that cause, 3435
diagnosis of, 1314 Compound heterozygous
genes that cause, 34 genotype, 30
treatment for, 48 Conditioned play audiometry, 7
American Optometric Association, 14 Conductive hearing loss, 78
Amniocentesis, 40 Conductive hearing test, 78
Angle-closure glaucoma, 13 Cones, 10
Anomaloscope, 15 Congenital cataracts
Aqueous humor, 10 causes of, 2021
Audiometry, 6 diagnosis of, 14
behavioral observation, 6 genes that cause, 36
conditioned play, 7 treatment for, 48
pure-tone, 6 Congenital glaucoma, 10t, 13
visual reinforcement, 67 Connexin, 18
Auditory brainstem response test, 7 ConradiHnermann
Autifony Therapeutics, 52 syndrome, 21
Autosomal dominant inheritance, Cornea, 9
2425, 25f Corneal dystrophy, 10t, 12
Autosomal recessive inheritance, 23, 24f causes of, 21
Autosomes, 23 diagnosis of, 15
genes that cause, 3536
Behavioral observation audiometry, 6 treatment for, 4849
Blastomere biopsy, 5354 Crystallins, 36
70 INDEX

Deaf Community, 47 Hereditary blindness. See also

Decibel (dB), 2 Hereditary eye disease
Disabling hearing loss, 2 causes of, 2022
DNA microarrays, 39 contributing factors for, 4143
DNA sequencing, 39 experimental drugs for, 5152
Dominant allele, 23 future prospects for, 5157
Down syndrome, 21 genes that cause, 3338
Duane syndrome, 34 gene therapy for, 5457
genetic testing for, 3841
Ear canal, 1 inheritance, 2328
Eardrum, 1 preimplantation genetic diagnosis
Electroretinogram, 15 (PGD), 5354
Exons, 28 stem cell therapy, 53
treatment for, 4849
Fluorescein angiography, 15 Hereditary deafness. See also Hearing
Frameshift mutation, 29 loss
Frequency Therapeutics, 52 causes of, 1720
complications of, 16
Gain-of-function mutation, 30 contributing factors for, 4143
Gap junctions, 18 diagnosis of, 69
Gel electrophoresis, 38 experimental drugs for, 5152
Gene modifiers, 41, 43 future prospects for, 5157
Gene therapy, 5457 genes that cause, 2833
Genetic recombination, 35 gene therapy for, 5457
Genetic syndrome, 4 genetic testing for, 3841
Genome editing, 5657 hearing loss, severity of, 3t
Genome-wide association study inheritance, 2328
(GWAS), 41, 42 preimplantation genetic diagnosis
Glaucoma, 13 (PGD), 5354
causes of, 22 prevalence of, 4t
diagnosis of, 16 stem cell therapy, 53
genes that cause, 3738 symptoms of, 16, 4t
treatment for, 4547
Hair cells, 12 Hereditary eye disease
Hearing aid, 4546 complications of, 913
Hearing in noise test, 7 diagnosis of, 1316
Hearing loss, 26. See also Hereditary prevalence of, 10t
deafness symptoms of, 913
acquired, 3 Hereditary hearing loss, 36
causes of, 1718 Hertz (Hz), 6
conductive, 78 Human genome, 28
disabling, 2
hereditary, 36 Intraocular pressure, 16
nonsyndromic, 34, 4t In Vitro fertilization (IVF), 53
sensorineural, 78 Iris, 9
severity of, 3t Ishihara Color Test, 14
syndromic, 45
Hearing threshold, 2 Jackson Laboratory, The, 56
 INDEX
71

Lazy eye. See Amblyopia Rhodopsin, 37

Lens, 9 RNA splicing, 28
Lowe syndrome, 21 Rods, 10

Macula, 12 Sensorineural hearing loss, 78

Mastoid bone, 2 causes of, 1819
Maternal blood screening, 40 Single nucleotide polymorphisms
Maternal transmission, 28 (SNPs), 41
Melanocytes, 19 Snellen chart, 14
Mitochondria, 2728 Stem cells, 53
Mixed hearing loss, 18 Stem cell therapy, 53
Mutation, 29 Syndromic hearing loss, 45

Nonsyndromic hearing loss, 34 Totipotent stem cells, 53

diagnosis of, 89 Trabecular meshwork, 10
genes that cause, 3031 Trophectoderm biopsy, 54
Tunnel vision, 13
Open-angle glaucoma, 13 Tympanometry, 7
Ophthalmoscope, 14
Opsins, 34 Usherin, 33
Optical coherence tomography, 15 Usher syndrome, 4t, 56, 9
Optic nerve, 10 cause of, 20
Otoacoustic emissions test, 7 diagnosis of, 9
Otoscopes, 6 genes that cause, 33

Parkinsons disease, 53 Vestibular system, 2

Paternal transmission, 27
Phenotypes, 23
Photopigments, 21
PierreRobin syndrome, 21
Pluripotent stem cells, 53
Polymerase chain reaction (PCR), 38
Postlingual hearing loss, 4
Preimplantation genetic diagnosis
(PGD), 5354
Prelingual hearing loss, 4
Prenatal diagnostic testing, 40
Punnett square, 2324, 2428f
Pupil, 9
Pure-tone audiometry, 6
Vestibulocochlear nerve, 2
Viral vectors, 55
Visual acuity, 9
Visual field, 9
Visual field test, 15
Visual reinforcement audiometry,
67
Waardenburg syndrome, 4t, 5, 8
cause of, 1920
diagnosis of, 89
genes that cause, 3233
Whole-exome sequencing, 39
Whole-genome sequencing, 39

Recessive allele, 23 X-linked dominant inheritance,

Retina, 9 2627, 27f
Retinitis pigmentosa, 10t, 1213 X-linked recessive inheritance,
causes of, 22 2526, 26f
diagnosis of, 1516
genes that cause, 37 Y
treatment for, 49 Y-linked inheritance, 2728, 28f
 OTHER TITLES IN OUR HUMAN DISEASES
AND CONDITIONS COLLECTION
A. Malcolm Campbell, Editor
Genetic Diseases or Conditions: Cystic Fibrosis, The Salty Kiss by Todd T. Eckdahl
Gradual Loss of Mental Capacity from Alzheimers by Mary E. Miller
Hemophilia: The Royal Disease by Todd T. Eckdahl
Sickle Cell Disease: The Evil Spirit of Misshapen Hemoglobin by Todd T. Eckdahl
Auto-Immunity Attacks the Body by Mary E. Miller
Huntingtons 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

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