Download Usher syndrome A report on the genetic disorder, its causes, and

Usher syndrome
A report on the genetic disorder, its causes,
and devastating effects.
By
Kathryn J Foley
Biology 5293
1
The five sense organs that people use to explore and navigate their environment are:
sight, hearing, touch, smell, and taste. For the majority of people these five senses function at a
level that allows the individual to live a normal life which includes mainstream education and
self-sufficiency as an adult. For a minority of people, however, this is not the case. Although the
exact number is difficult to calculate, the U.S. Bureau of the Census reported that in 2009 there
were 70,700 children ages 6 to 21 that had hearing impairments, 25,800 with visual impairments,
and 1,400 that were deaf-blind. (U.S. Census 2012) For these individuals, especially the deafblind, common everyday task can become difficult and self-sufficiency is nearly impossible
(Moller K et el. 2009). There are many different causes for these disabilities, including injury,
infection, and genetic disorders. One of the genetic disorders is Usher syndrome. Usher
syndrome (USH), which is an autosomal recessive genetic disorder that affects sight, hearing and
balance, does not have a cure and can have devastating results if not diagnosed at a young age.
This disorder is responsible for 50% of the deaf-blind population, as well as 3-6% of individuals
that are congenitally deaf, and from 8-33% of people with retinitis pigmentosa (RP), a
progressive retinal degeneration disease ( Yan D 2010).
The characteristics of Usher syndrome (USH) was first described in 1858 by Albrecht
von Graefe, a forerunner of the modern day ophthalmologist. He studied a family that had three
brothers that were deaf and had retinitis pigmentosa. (K12 academics n.d.) Years later a British
ophthalmologist, Charles Usher, established that the disorder was inherited, meaning that it is
passed on from parent to child (Millan J et el. 2011). He arrived at this conclusion after studying
69 cases of people that were deaf/blind and their families (K12 academics n.d.) Usher syndrome
is a recessive genetic disorder, which means that both parents must be carriers of the gene in
order for their offspring to inherit the disorder. This explains why the majority of children with
USH are born to parents with normal sight and hearing. Each parent will carry a recessive gene
on one of their chromosomes, yet will not have any of the symptoms. With each birth, two
individuals that are carriers of the Usher gene will have a 25% chance of having a child with
Usher syndrome, a 50% chance of having a child that is a carrier of the usher gene, and a 25%
chance of having a child that neither has Usher, nor is a carrier of the gene. (Campbell N 2008)
The individuals that are carriers of the Usher gene will not show any symptoms of the disease.
When a person who is a carrier reproduces with a person that does not have the Usher gene then
each child has a 50% chance of being a carrier and 50% chance of not having the gene. The
numbers of people world-wide that are affected by USH range, depending on population, from
3.5 to 6.2 per 100,000 persons born and in some populations, such as Israel, Finland, and the
Accadians of Louisiana, there have been carrier rates as high as 1 in 100. ( Yan D 2010) The
genes that are responsible for USH are carried on the autosomal chromosomes, which mean that
it is not a sex-linked disorder; therefore both males and females can be affected. Although
research is still being done, to date there have been nine different genes found that can cause
USH (Bonnet C et el. 2011) These genes are important for the normal development and function
of the ear and eye.
The symptoms of Usher syndrome are hearing loss, lack of balance, and loss of hearing
in the form of retinitis pigmentosa (RP), “a subset of hereditary retinal degenerations which
affects more than one million people worldwide” (Pelino C 2009). For most people with RP the
first signs are night-blindness, which usually occurs during teen-age years. This is followed by
loss of peripheral vision which in time will narrow down to “tunnel vision”, the ability to only
see straight ahead, and for some individual’s complete blindness (Pelino C 2009). The vision
loss is caused by the degeneration of the photoreceptors, rods and cones, which are light
sensitive receptors located at the back of the eye. For most people the rods are affected first,
followed by loss of functioning cones (Genetics Home Reference 2007).
The other symptoms of USH are hearing loss and vestibular dysfunction, a lack balance.
To better understand the hearing loss associated with USH, it is important to have a basic
understanding of how the ear works. According to Campbell, the ear consists of three parts, the
outer ear, middle ear, and the inner ear. Sound waves are collected by the pinna, which is the
external part of the ear that is visible, and channeled up the auditory canal to the tympanic
membrane. This membrane separates the outer ear from the middle ear. The sound waves cause
the tympanic membrane to vibrate, which in turn cause the three small bones of the middle ear to
vibrate. These bones, the malleus, incus, and stapes transmit the vibrations to the oval window
which is located beneath the stapes. The vibration of the oval window moves the fluid which is
found in the part of the inner ear called the cochlea. It is within this “snail” shaped structure that
the mechanism of hearing takes place (Campbell N 2008). The inside of the cochlea has two
large canals which are called the upper vestibule canal and the lower tympanic canal. Separating
these two canals is the cochlear duct. Both of the canals and the cochlear duct contain fluid. On
the floor of the cochlear duct, the basilar membrane, is the organ of corti which contains hair
cells that are the mechanoreceptors of the ear. When the fluid is moved in the vestibular canal by
the vibration of the oval window it causes the basal membrane to vibrate which in turn causes
microscopic hair cells to bend. These hair cells send signals to the sensory neurons which carries
the information to the brain. Each hair cell has a bundle of rod shaped hairs projecting from it.
Each of these hairs has a core of actin filaments. (Campbell N 2008).
Studies have shown that the proteins made by the usher genes are important for the
normal development and cohesion of these hair bundles in the inner ear ( Yan D 2010). “The
USH proteins mainly colocalize in the stereocilia and at the synaptic regions of the hair cells of
the inner ear. Stereocilia are mechanosensing organelles located at the apical surface of both the
auditory and vestibular hair cells. The bending of the hair bundle by a sound wave opens
mechanically the gated transduction channels at the tip of the stereocilla, initiating the electrical
signal cascade for sound perception.” ( Yan D 2010). If the hair bundles are misshaped, then they
will not be able to function correctly and hearing loss will occur.
Within the inner ear are also the structures that are responsible for balance, the three
semicircular canals and the utricle and saccule. The three semicircular canals are each located at
a different angle and this detects the movement of the head turning. The utricle and saccule are
responsible for telling the body which way is up and also acceleration. The mechanism for this
is much like hearing. There are hair cells located at the base of the canals which respond to the
fluid when it moves and then sends signals to the nerves which carry it to the brain (Campbell N
2008) As in the organ of corti, when the structure of the hair cells are flawed, they can not
function correctly, thus the signals are not sent to the brain as they should be. Based on the age
of onset of these three characteristics, loss of vision, hearing and balance, and the genes that are
involved, Usher syndrome has been divided into three groups, USH1, USH2, and USH3.
USH 1 is the most severe form of the disease and accounts for 30-40% of all Usher
syndrome cases (Millan J et el. 2011). Persons born with USH1 will have profound hearing loss
from birth, as well as vestibular dysfunction. Persons usually will not begin to walk until age two
and many will never develop speech (Millan J et el. 2011). This form of Ushers is the most
frequent cause of deaf-blindness in humans (Yan D et el. 2011). Individuals with this form of
Usher syndrome will also begin to lose their eye sight usually before they reach puberty (Yan D
2010). For these reasons, early diagnosis is critical so that patients can get physical therapy and
cochlear implants; otherwise the ability to communicate can be lost (Bonnet C et el. 2011). For
USH 1 there have been seven genetic locations mapped on different chromosomes, with five of
the genes having been cloned. These genes are: “the actin-based motor protein myosin VIIa
(Myo7a, USH1B), two cadherin-related proteins, otocadherin or cadherin 23(Cdh23, USH1D)
and protocadherin 15 (Pcdh 15, USH1F), and two scaffold proteins, harmonin (USH1C) and sans
(USH1G)”. These proteins are found in the hair cells of the inner ear where they are present in
varying degrees at different times durning development ( Yan D 2010).
Studies done by Yan D et el. 2011, have shown that in mice mutations have been found
for all of the known USH 1 genes and studies have been conducted to see how the scaffold
protein harmonin (USH1C) affects the formation of the hair bundles in the inner ear. These
studies have shown that from birth to day 120, mice that were homozygous mutant (USH1c-/-)
“ showed progressively disorganized outer hair cell (OHC) stereocilia compared with the wellorganized pattern and rigid structure typical of normal stereocilia.” Normal stereocilia have a
‘V’ shaped bundle whereas the mutant mice displayed a more disorganized arrangement. ( Yan
D et el. 2011) Studies such as these have helped scientist understand the morphology of the
inner ear and how it works.
The second form of Usher syndrome, USH2, is also the most common and is
characterized by patients having intact vestibular responses, retinitis pigmentosa and hearing loss
of the higher frequency sounds that comes on slowly with age (Leijendeckers JM 2009).
Individuals with USH2 are able to develop normal speech and loss of eye sight usually does not
begin until age 15 ( Yan D 2010). As of this writing, three genetic locations have been found
that are believed to be responsible for USH2. These locations are USH2A, USH2C, and
USH2D. Of these three genes USH2a, which encodes for the protein usherin, has been shown to
be involved in 55%-90% of USH2 cases (Bonnet C et el. 2011). The USH2a gene is very large
and mutational screening has been done which shows that a mutation, c.2299delG accounts for
up to 45% of all the mutated alleles. Studies have also shown that the mutation c.2299delG
“appears to be an ancestral mutation of European origin which spread from Europe to other
regions of the world during colonization.” (Millan J 2011). As in USH1, these genes encode for
proteins that are present in the hair cells of the inner ear. Usherin is believed to be important for
the formation of ankle-links, which are filamentous lateral links that connect stereocilia at the
base (Adato A et el. 2005).
The third form of Usher syndrome USH3 is the rarest form worldwide, accounting for
only 1-6% of all Usher cases, with the exception of the Ashkenazi Jews and in the Finnish
population where this form makes up to 40% of all cases. (Vastinsalo H 2011) “USH3 is
characterized by progressive hearing loss, retinitis pigmetosa, and variable vestibular
dysfunction.” (Vastinsalo H 2011). With this form the symptoms of RP usually start to appear by
the age of twenty. Hearing loss is similar to USH2, with onset beginning in the first to third
decade of life, which allows the individual to develop good speech patterns before total loss of
hearing occurs. In 50% of USH3 cases vestibular dysfunction is present (Millan J et el. 2011)
USH3A, which encodes for clarin-1, is the only known genetic location for Usher syndrome 3
(Yan D 2010).
Clarin-1encodes for a protein that belongs to a large family of transmembrane proteins
that takes part in a number of functions which include; “regulating cell morphology, motility,
invasion, and signaling”(Geng R 2009). Although the exact function of Clrn-1 in the inner ear is
not known, studies using mice as models have suggested that it may play a part in hair cell
development and function. “Expression was most apparent in the spiral ganglion cells (SGCs)
and in the hair cells of the basal turn of the cochlea compared with the apical turns at early
stages.” (Geng R 2009). The study conducted by Geng (2009) also showed that expression of
Clrn-1 was present in the inner ear during all stages of development, from 16.5 days before birth
to 5 days after birth.
Many of the genes that are responsible for Usher syndrome have now been mapped, yet it
is apparent that the exact way in which they work together has not yet been fully explained.
Various studies have found that USH1 and USH2 proteins work together to make up a “protein
network known as Usher interactome”. “The central core of the interactome is formed by the
PDZ domain containing the homologues harmonin and whirlin and the microtubule-associated
protein SANS, with the remaining USH proteins attached to this core.” USH 1 and USH2 genes
also interact in the eye, specifically in the ciliary/periciliary region of cone and rod
photoreceptors (Millan J et el. 2011)
Table 1. The three subtypes of Usher syndrome and their symptoms
Type 1
Profound deafness in
both ears from birth
Type 2
Moderate to severe
hearing loss from
birth
Vision
Decreased night
vision before age 10
Vestibular function
(balance)
Balance problems
from birth
Decreased night
vision begins in late
childhood or teens
Normal
Hearing
Type 3
Normal at birth;
progressive loss in
childhood or early
teens
Varies in severity
Normal to nearnormal, chance of
later problems
Until now, the main body of the paper has focused on the biological aspects of Usher
syndrome, but what about the social ramifications of this disease. Early detection, especially in
the case of patients with USH1, is critical so that proper help can be given to the individual, yet
often the disease is misdiagnosed. Other disorders such as Bardet-Biedl syndrome and MohrTranebjaerg syndrome can show the same clinical symptoms as USH, as well as rubella although
that is not as common today as it was in the 1970s and before (Millan J et el. 2011). Often
parents do not know to test for USH because there is no family history of it. At times it is not
until vision problems begin to occur that the correct diagnosis is made. Today there are genetic
test available for locate a few of the genes that are connected to USH, but much of the diagnostic
procedures are still based on clinical evaluations (Health n.d.) When diagnosed in time, patients
can use cochlear implants to help them hear and develop speech, if not then as the ability to see
and hear diminish, so will the ability to communicate to others (Pelino c 2009)
There are symptoms that a parent should watch for if they have a child that is born with
profound hearing loss. Because night-blindness is the first sign of RP, parents should observe
their infant and see if they can find their bottle in a darkened room (Davenport n.d.) Other signs
that are present as the child gets older are how well they can see outside at night. Do they
always need to hold onto a rail or an adult’s hand? The other symptom that should be a strong
indicator that a deaf child has USH is their balance and coordination. Many children with USH I
will have difficulty learning to crawl. They may prefer to roll or even have a “five-point” crawl
in which they keep their head on the ground (Health n.d.). Walking will also be delayed, often
until 18-24 months. Once the child learns how to walk and maneuver they have no problem
running and playing. Games that involve twirling are especially fun because these children do
not get dizzy (Health n.d.)
Today there is no cure for Usher syndrome. Cochlear implants have been used
sucsesfully in all three types of USH to aid in hearing loss. This allows the child to learn oral
language and for USH II patients they are often able to function well in mainstream schools
(Health n.d.). Although there is no treatment that will stop the progression of retinitis
pigmentosa there are optical devices available such as reverse telescopes, amophic lenses, and
mirrors that are useful in enhancing a patient’s functional visual field. To help with night vision
a wide-angle mobility lamp or “night-scope” can also be employed (Pelino c 2009). Other
studies have centered on vitamin A palmitate supplements and have found that a high daily
intake, (15,000 IU/Day) can slow down the progress of retinitis pigmentosa. There is however
risk involved with this high of a dose, one of them being a risk of birth defects, so women who
are pregnant cannot use this therapy (Pelino c 2009).
As an individual with Usher syndrome loses their sight, there are various ways in which
they can still communicate with the people around them. Tactile sign language is a form of
signing in which the deaf-blind individual places his/her hands over the other person’s hands so
that they can follow the movements (Deaf-Blind n.d.). Another way to communicate with nonsigning people is to use the screen Braille communicator (SBC). This is a small hand held
device that has a QWERTY keyboard on one side and a braille display on the other side. The
sighted person can type into the machine and it will be displayed in braille (Deaf-Blind n.d.).
Modern technology is making it easier to be able to communicate and to function.
Usher syndrome is a rare disease and therefore not as recognized, or well-funded as other
genetic diseases. But, because of the terrible trauma and isolation that it causes it is important to
continue to conduct, and fund, research that will help to better understand the genes involved.
As more information is learned perhaps a cure could be found using gene therapy. Even if the
best that can be hoped for is more accurate diagnoses procedures, this would help the patients
receive as much help as possible so that they could better prepare themselves for the future.
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