Hello. My name is Celeste Duder and I have been asked to speak about the genetic bases
of selected speech, language, and hearing disorders. I would like to thank Laurene
Cranford, co-chair of this conference, for inviting me to speak, and the rest of the
conference staff for doing such a wonderful job. (Start applause)
You may be surprised to hear that over 10,000 different genetic disorders have been
discovered. You will be GLAD to hear that I do not plan to discuss each and every one of
them, hence the “selected” part of the title.
I’d like to start with a little historical background. Since I am a doctoral student, I often
hear the question, “What does the literature say?” In the case of genetics, one of the
original pieces of “the literature” was this article, published 48 years ago. In it, James
Watson and Francis Crick proposed that the structure of DNA is in the form of the nowfamous double helix. Personally, the part of this discovery that I find most inspiring is
that they were awarded, along with Maurice Wilkins, the Nobel Prize in Medicine in
1962. . . And look! Their article was only one page long. On our next slide, we see
today’s applications of the double helix model.
Every living cell in your body contains your genetic code. This is because every cell
nucleus contains your chromosomes. Each species has its own number of chromosomes.
The fruit fly, for example, has 8, while humans have 46. As you see, a human
chromosome looks like two separate strands, joined by a structure called the centromere.
One set of strands are typically shorter than the others. These two arms are called the p
arms, from the French word petite. The longer two arms are called the q arms, because q
comes after p.
In humans, the chromosome are numbered in descending order of size, so chromosome 1
is the longest, and chromosome 22 is the shortest. Chromosomes are made up of genes,
which are shorter segments of DNA molecules. Genes use a code composed of 4 bases—
cytosine, thymine, adenine, and guanine, abbreviated A, T, G, and C. When the Human
Genome Project announces that they have sequenced the human genome, what they mean
is that they have a list of roughly 3 billion As, Ts, Cs, and Gs in the correct order. Which
means that reading the genetic code by itself would be only slightly less exciting than
reading the phone book.
So why do genes and their sequence matter so much? Because genes produce proteins.
Why are proteins important? Because proteins are what cause cells to perform specific
functions during development. Proteins can change an undifferentiated cell to a neuron;
they can instruct cells where to migrate in an embryo; later they control sexual maturation
and aging. Certain proteins cause the plaques and tangles found in the brains of people
with Alzheimer’s. So the next challenge of the Human Genome Project lies in identifying
the proteins produced by the genes they have sequenced, and understanding what can go
wrong.
Today we will discuss the different ways genetic disorders can be expressed. Some are
produced by single genes, some by whole chromosomes, and the multifactorial disorders
are thought to have both genetic and environmental components.
First we turn to the single gene disorders. Some are autosomal dominant, which means
they are caused by a mutation or an alteration in a single copy of a pair of genes. Children
inherit one copy of each chromosome from each parent. So a parent with an autosomal
dominant disorder has a 50% chance of passing on that mutated gene copy to each child.
AD disorders can also be caused by brand new mutations, in which case there is almost
no risk of recurrence. AD disorders vary in their severity, and in some people are nonpenetrant, meaning the person exhibits no symptoms of the disorder. Examples include
achondroplasia, hereditary colon cancer, and neurofibromatosis type I.
This picture of a young girl with achondroplasia is courtesy of Dr. Robert Shprintzen at
Upstate Medical University in Syracuse, NY. Dr. Shprintzen is a professor and speechlanguage pathologist who has written two excellent books on genetics and
communication disorders. All of the photographs I will show you come from his book on
syndrome identification.
Achondroplasia is a syndrome that causes short stature and disproportionately short
limbs. Mean adult height is about 50 inches, or just over 4 feet. The mutation is on the
fibroblast growth factor receptor 3, which has been mapped to the short arm of
chromosome 4. The craniofacial system is affected, as you can see from the broad,
prominent forehead and the depressed nasal root. Children with achondroplasia may
exhibit an open bite, conductive hearing loss due to chronic middle ear effusion,
hoarseness, and hypernasality.
Unlike AD disorders, autosomal recessive disorders ONLY occur when both parents
carry one recessive copy of a particular gene, AND they both pass the recessive form to
their child. Someone who has only one copy of a recessive gene is known as a carrier and
is probably unaware of his or her status. These disorders are the reason why you should
not marry your cousin! Each person has somewhere between 5 and 7 mutations in his or
her genetic code, and if you are biologically related to someone, the chance that you
share the SAME 5 to 7 mutations is increased. Examples of AR syndromes include Usher
syndrome, sickle cell anemia, cystic fibrosis, Tay Sachs and PKU.
This slide is for the visual learners out there. It explains what we just discussed, namely
that AD disorders are present in one parent with a 50% recurrence risk for each
pregnancy. AR disorders must be carried by both parents and present a 25% chance for
having an affected child, and a 50% chance for each child to be a carrier.
Another form of single gene disorder involves the sex chromosomes, most commonly the
X. I heard a speaker at a genetics conference say once that the Y chromosome, the one
that causes maleness, is often quite large but actually contains long strings of “junk
DNA” that appear to serve no particular purpose. Why this might be, I have no idea….
X linked disorders can be dominant but are more often recessive. Females can be either
carriers or affected, while males are either affected or not. The recurrence risk varies with
the sex of the child. Male children of male carriers will not express the disorder, but male
children of female carriers are at 50% risk for being carriers. Female children’s risk will
vary, depending on whether their mother is affected or simply a carrier. Examples of sex
linked disorders include Fragile X, Duchenne muscular dystrophy, hemophilia, and
colorblindness. And here we have another discovery from a contemporary genetics lab….
In addition to single gene disorders, humans also exhibit chromosomal disorders, where
something goes wrong at the level of the entire chromosome. Chromosomes can be
repeated or completely missing, or they can exhibit structural abnormalities. These
include when PIECES of an entire chromosome are missing, repeated, moved to the
wrong place, or in the wrong order. The most familiar example of a chromosomal
disorder to SLPs and audiologists is probably Down syndrome, or trisomy 21. Others
include Turner syndrome, trisomy 13, trisomy 18, and Klinefelter syndrome.
This young man has Down syndrome. Though the entire chromosome 21 is repeated, it is
now understood that only a small segment on the long arm is responsible for the
syndrome. The clinical features of Down include mental retardation with later onset of
Alzheimer’s disease, microcephaly (disproportionately small head), macroglossia (large
tongue), small stature, heart abnormalities, and a transverse palmar crease, as seen in the
picture on the right. Otitis and middle ear effusion are commonly reported, often resulting
in conductive hearing loss. As for their language skills, young children with Down
syndrome benefit from aggressive intervention, but tend to show a plateau effect. The
average lifespan of a person with Down is approximately 35 years.
We turn briefly to multifactorial disorders. Some have proposed that certain syndromes
are caused by a combination of genetic and environmental factors, with a kind of
threshold effect. If your genes indicate increased susceptibility to a disorder, you might
develop it under specific environmental conditions, while a person without that
susceptibility would not. Fraser suggested that some cases of cleft lip and palate were
multifactorial, but others, including Dr. Shprintzen, argue that this type of causation can’t
be proven, because you can never isolate genetics from environment. He also thinks that
palatal development may be controlled by a single gene that we have yet to recognize.
The single gene and chromosomal disorders we have discussed are often referred to as
Mendelian forms on inheritance, after Gregor Mendel, the famous monk with the garden.
Let’s go back to high school briefly….remember when you learned geometry and that it
was all based on the theories of Euclid? And then someone came along and discovered
that Euclid wasn’t always right, and we now have non-Euclidian geometry? Same thing
with genetics. Mendel laid the foundation, but we have since discovered that inheritance
doesn’t always work in the ways he suggested.
There are four forms of non-Mendelian inheritance we will discuss. The first is
mitochondrial. Did I mention earlier that your chromosomes are located in the cell
nucleus? Well, that’s a lie. They are in the nucleus, but they are also present in the
mitochondria and can be inherited from there. Why do these disorders pass only through
women? Because the sperm cell does not contain mitochondria, while the egg cell does.
An example of a mitochondrial disorder is myclonic epilepsy.
The second form of non-Mendelian inheritance is mosaicism. Did I say that each cell in
your body contained the same chromosomes? That was a lie too, at least in some cases.
Some people have both normal and mutated cells. If some of your reproductive cells (i.e.,
eggs or sperm) are mutated and some are normal, you may pass a disorder that you do not
express to your offspring. I couldn’t find any examples of disorders that are only
mosaicisms—the syndrome expressed would depend on the mutation in the cell.
The third form of non-Mendelian inheritance is uniparental disomy. This occurs when,
rather than inheriting ONE half of a chromosome pair from each parent, BOTH halves of
a chromosome are inherited from the same parent. We will see examples of this on the
next slide.
The fourth form of non-Mendelian inheritance is genomic imprinting, where the
expression of particular genes depends on whether they came from the male or female
parent. This sounds confusing, but I think these examples will clear things up.
Prader-Willi syndrome can be caused by EITHER genomic imprinting, when the father’s
chromosome 15 is deleted, OR from uniparental disomy, when BOTH copies of
chromosome 15 come from the mother. In either case, the end result is Prader-Willi
syndrome.
This boy has Prader-Willi syndrome, one of the hallmarks of which is hyperphagia and
obesity. Ironically, as babies, these children have severe hypotonia that leads to poor
feeding and failure-to-thrive. By their toddler years, however, the children will make
every attempt to engage in binge eating, and many parents have to install locks on their
kitchen cabinets and refrigerators. Most people with Prader-Willi have some cognitive
impairment and they may engage in self-destructive behavior, such as biting themselves.
Language delay may appear severe early on, due to the hypotonia, but there is often
substantial catch-up later.
Another example of a disorder that can result from imprinting or uniparental disomy is
Angelman syndrome. Angelman is caused by the EXACT same mutation that causes
Prader-Willi. But where Prader-Willi resulted from deletion of the FATHERS’s
chromosome 15, Angelman is caused by deletion of the MOTHER’s chromosome 15. Or
it can occur when both copies of chromosome 15 come from the FATHER (as opposed to
the mother in Prader-Willi). Interestingly, there is almost no overlap in the clinical
features of Prader-Willi and Angelman, as you’ll see on the next slide.
This boy has Angelman syndrome, clinical features of which include progressive ataxia,
hyperactive reflexes, cortical atrophy, seizures, and abnormal EEG results. People with
Angelman syndrome exhibit microcephaly, mental retardation, and a persistent open-
mouth posture with tongue protrusion. Hearing is typically normal, but speech and
language do not develop, which is another hallmark of the syndrome.
You think it’s tough being a speech-language pathologist or audiologist and having to
learn all this! Be glad you’re not a DNA molecule. One of my professors at Vanderbilt
used to say that it was a good thing we don’t have to know how our brains work in order
to use them. The same thing, luckily, goes for our genes.
Now we’re going to cover the “selected” speech, language, and hearing disorders from
the title. We’ve already discussed Angelman, so let’s move on to ataxia-telangiactasia.
These children are quite small, with hypernasal and dysarthric speech. This syndrome is
caused by an autosomal recessive mutation on chromosome 11. This syndrome is
especially devastating, because early development is normal with progressive
degeneration in childhood. Many children with A-T go on to develop leukemia or other
types of cancer.
This a boy named Patrick who had A-T. He was profiled in my local newspaper, and
that’s where this picture is from. He was diagnosed at age 5, though he presented only
with an unbalanced gait and articulation problems. At age 11, Patrick got a “balance
dog”, like a seeing-eye dog, to help with stairs. He was diagnosed with non-Hodgkins
lymphoma at 13 and underwent chemo. He had a bone marrow transplant at 14 and died
the following summer. Like ALS, this disorder is one that might first be picked up by a
speech pathologist, because one of the earliest signs is declining articulation skills in
children who were previously normal. About the only good news in A-T is that it is very
rare, with about 500 cases in the entire country.
One last speech disorder where the genes have been identified is Cornelia de Lange
syndrome. It is caused by a trisomy on the long arm of chromosome 3 in a number of
cases, though not all. These children exhibit short stature and mental retardation, though
IQ approaches normal in a few cases. Clefting is common, as are limb reduction and
missing digits. This slide shows a young woman with de Lange syndrome. Note the thin
upper lip and the shortened fifth fingers bilaterally.
As for language disorders with identified genes, we have already discussed Fragile X and
Down syndrome. You will notice that I have included autism with a question mark. Most
of the papers published on the genetics of autism theorize that there are a large number of
genes involved, perhaps more than 15. Some say chromosome 7 is definitely involved,
and some say 15. The article I refer to locates HOXA1 genes on 7p and 17q, and notes
that both are expressed in the hindbrain during neural tube formation. Interestingly, the
mutation in the HOXA1 gene is a single base substitution of guanine for adenine.
Williams syndrome is easily identifiable due to the so-called “elfin” facial features. It is
caused by a deletion from the long arm of chromosome 7. Children with this syndrome
display short stature, mental retardation, and remarkably preserved language structure
despite unclear content. They are often echolalic. I have a child on my caseload now with
Williams syndrome and one of his stock phrases is “Look at the little baby. He’s so cute.”
Nothing wrong with the structure, but he uses the phrase almost at random. Unlike
children with autism, these kids are very friendly, sometimes overly so. In addition, some
of them are musical savants. If you see a patient with Williams syndrome, ask about
musical ability. You may be pleasantly surprised.
For hearing disorders with identified genes, one great place to look is the Hereditary
Hearing Loss Homepage. This web address is NOT in your handout, so copy it down. If
you misplace the address, just type Hereditary Hearing Loss Homepage into a search
engine and you’ll find it.
Hurler syndrome is caused by a mutation on the short arm of chromosome 4. Like A-T,
children initially develop normally, but deterioration begins in late infancy. At 6 months,
there is slowing of motor development and all development stagnates by age 2. Hearing
loss is conductive.
Usher syndrome is characterized by hearing loss and retinitis pigmentosa, a visual
impairment with gradual (or in some cases, quite rapid) deterioration. There are 3
subtypes of Usher syndrome, depending on the type of hearing impairment. Type I is a
profound congenital loss, Type II is a sloping audiogram that is congenital, and Type III
is progressive hearing loss. My last look at the Hereditary Hearing Loss Homepage,
which was Monday of this week, indicated at least 7 different chromosome where
mutations that cause Usher have been reported.
As with Usher syndrome, the research on Waardenburg is proceeding rapidly. The HHL
homepage reported genes on five different chromosomes as causing it. The hearing loss is
congenital and sensorineural, and these children often exhibit chromia iridium—eyes of
two different colors. My husband and I were at a party this summer, where a couple
arrived with a beautiful little baby that had one blue and one brown eye, and a white
forelock. My husband’s aunt, who is an audiologist, asked me later to “name that
syndrome.” I couldn’t do it at the time, but it was Waardenburg. The parents, by the way,
did know of the diagnosis and were in touch with ENTs and audiologists.
The last syndrome we’ll discuss today is neurofibromatosis, abbreviated NF. Again, there
are several subtypes. NF I, seen on this slide, is caused by mutations on the long arm of
chromosome 17. Over 180 separate mutations have been identified that result in NF I,
and about half of all cases are new mutations, not inherited. Hearing is typically normal
in NF I, but café au lait spots and tumors are common. NF II, III and IV subtypes are
caused by mutations on chromosome 22 and include hearing loss, often secondary to
acoustic neuroma.
(Read cartoon)
As for treating genetically-based communication disorders, you can keep doing what you
have been. Namely, taking careful histories, referring as needed, and treating ethically
and to the best of your ability. It is a mistake to think that genetically-based disorders
can’t be treated—the literature has shown the children with Down syndrome, to pick just
one example, benefit from aggressive, early intervention. So do it!
Since this talk will NOT have answered all of your questions on genetics, or in case you
want to learn about all 10,000 genetic syndromes, here are some internet resources. The
Human Genome site is large and fascinating. The Genetic Alliance can help you find
support groups for patients and families with specific disorders. OMIM is the site for
researching a disorder that is new to you. Just type in the name, and a wealth of
information will appear. If you need a genetic counselor for a patient, see their website.
And finally, the KU Med Center has a wonderful page of resources that is well worth a
look.
If you are interested in reading material, please see Dr. Robert Shprintzen’s books. To my
great embarrassment, his name is misspelled in your handout, so please correct it.
Thank you very much for your attention. I will be happy to take questions, though I can’t
promise to answer any of them.