My subject is genetic considerations
in neuromuscular diseases.
There are four topics that I would like to discuss.
The first is the classification
of neuromuscular diseases by their inheritance
patterns.
The second is problems and determination
of genotype Variable expression is
one diagnosis of carrier state is
a second.
The third topic is the value of prenatal
diagnosis in neuro muscular diseases,
and finally,
the impact of genetic counseling.
First,
the classification of normal street diseases by inheritance
patterns.
The disease is inherited in the mandalorian character
can be classified as autism or dominance,
autism and recessive and excellent
disorders.
On the first slide,
we can see that in autism all dominant
inheritance an affected individual
Need have only one gene of the given type,
an affected individual unless the result of a new
mutation has an affected parent
and affected individuals,
offspring is equally likely to be affected
and to be normal.
On the next slide are listed neuro muscular diseases
with autism.
All dominant inheritance.
They include facial scapula,
humerus,
neuro muscular disease,
hockey low fare and Jill muscular dystrophy.
Central core disease,
Neverland myopathy,
my atomic dystrophy or my atomic atrophy.
Most forms of My attorney.
Congenital Parramatta,
Tonia,
congenital,
all types of familial periodic
paralysis,
familiar hypertrophic pollen arthritis,
amyloidosis of the Andreotti or Portuguese
type.
Most types of hereditary sensory,
ridiculous neuropathy and acute
intermittent porphyria.
On the next slide,
in cases of autism or recessive inheritance,
we show that affected individual has the given gene
in double dose
relatives at risk are therefore generally
siblings for the offspring of
two carriers.
The probability is one quarter for being
affected and one half for being a
carrier for rare,
excessive,
there is an increased probability of
parental con Sanguinetti
on the next slide are shown diseases
with autism,
a recessive inheritance.
They include limb girdle,
muscular dystrophy,
Glycogen storage disease of two types,
types five phosphorus deficiency
and type seven possible fact.
Aquinas deficiency,
verdad,
nick Hoffman's disease,
Most types of cooking,
bull,
re Landers disease and rest and syndrome.
On the next slide.
In excellent recessive inheritance,
an affected individual has no normal
X.
Consequently the great majority affected individuals are
males,
affected individuals in the same family
are related through females.
A female carrier,
married to a normal male has an equal
chance of producing and affected
male,
A normal male,
a carrier female and a normal female
with each pregnancy.
The next slide lists neuromuscular diseases
with excellent inheritance.
They are Duchenne,
muscular dystrophy,
both of the severe type and of the mild or
Becker type.
The next object to be discussed.
Our problems in determination of genotype,
a common problem in genetic
diseases is that due to variable expression of a
single gene.
This slide shows a family with my atomic
dystrophy,
a disease which is often different in members of the
same family in this
diagram of this family
are plotted muscular weakness or
stiffness,
cataracts,
characteristic fishies and
mental slowness.
We can see nearly all patterns of these four components
in many neurological conditions in which the
same gene has different manifestations in
different members,
we are uncertain as to the cause
in my atomic district.
He,
however,
we know one factor that affects the symptom
pathology that is whether the
affected parent is the mother or the father.
Nearly all cases of my atomic dystrophy of
infantile onset have
the affected parent is the mother.
We surmised that this means that
the developing fetus
is suffers in some way when the
uterus which nourishes it.
It is also my atomic dystrophin and
type a second problem in
the determination of genotype is that of
carrier diagnosis and no place in
neuro muscular diseases.
Is this a more serious program a problem than
in the diagnosis of carrier state and
relatives of patients with Duchenne
muscular dystrophy.
The next slide shows a family shows
criteria for carrier diagnosis
and a woman relative of the Duchenne
patient is
definitely a carrier If more than one
relative is affected.
That is for example,
in considering they are a mother or a sister of a
patient,
she,
however,
is only probably a carrier if there's only one affected
son or brother and
has a serie um CPK elevation on
more than one occasion or a muscle biopsy
is abnormal.
The one there is often more
history more relevant data in a
pedigree in such a case than is evident.
Uh ah
an example is shown on the next slide.
This woman is definitely a carrier
because she has a brother,
her brother as well as sons who are affected
this individual.
Here,
her daughter may ask
a position about the likelihood of producing
affected sons.
The conventional advice is that since
she is the offspring of a woman who is definitely
a carrier,
That she has a 50 percent chance of being a
carrier in this family.
However,
this woman has three sons whom we shall
assume our normal because they are
past the conventional age of onset for this
disease.
Now,
if a woman who is definitely a carrier
has one half chance that any male
son is affected,
the chance that such a woman would have three who
are unaffected is one half Times 1/2
times one Half,
or 1 8.
Thus,
in calculating the likelihood of this woman being a
carrier,
which should take into account not only the fact
that her mother was a definite carrier,
but also the fact that she has
ah if she were a carrier,
she,
she has not passed on this gene in three
opportunities to do so.
A third factor that might be considered is her CPK
status.
Known carriers have CPK
elevations in only two 3rd of cases,
and therefore this woman has a
normal CBK.
She has only 1 3rd chance on that basis
alone for being a carrier.
Thus,
the statement about her risk for being a carrier
should take into account the half chance based
on her mother,
the 1/8 chance based upon three out of three
Children being sons being normal
and the one third chance based upon her normal
cPK.
The analysis of the probability of
carrier status.
Taking into consideration multiple separate
probabilities is called.
Bayesian analysis.
Ah If Beijing analysis
considerations are included in the estimate of carriers
state the true value is often seem
to be lower than the figure commonly
given such individuals when
the the normal males in the family are not
considered.
The next subject to be considered is prenatal
diagnosis in their muscular diseases.
This lot reminds you that it's possible to withdraw
amniotic fluid surrounding the
fetus.
This can be done from the 14th week of pregnancy
onward,
this fluid contains cells which
are fetal in origin.
Such cells can be cultured and used
for examination of chromosomes or for
examination of enzyme activity.
The next slide shows three examples from
neuromuscular Diseases utilizing three different methods of
analysis.
Graph sums disease is a neuro muscular
disease in which the enzyme deficiency has been
identified Furthermore,
fibroblasts from patients are detective
lee abnormal.
In culture,
it is therefore likely that Ressam's
disease can be diagnosed in utero
based upon the same abnormality in
cultured amniotic cells.
Ah In the cases of Duchenne muscular
dystrophy,
ah prenatal diagnosis is less
successful.
However,
if the fetus of a
woman who is a carrier is female,
we can assure the mother that that
the resulting child will not be symptomatic.
It probably is worthwhile bringing up the possibility of
prenatal diagnosis in such circumstances,
We have found that many couples who
can a benefit who from
prenatal diagnosis
art considering these days utilizing
this procedure,
despite their beliefs about abortion in general
manifesting the suggesting
that individuals who may not accept
abortion on general grounds do wish to
take advantage of selective abortion where the fetus
can be proven to be defective.
In the case of Duchenne muscular dystrophy.
However,
the diagnosis of a male fetus does not determine whether
the child has Duchenne gene or
not.
The diagnosis of Duchenne in such a case Is
only 50% likely.
Some individuals who may be willing to abort
a Now a known
defective fetus may not be willing to abort
a fetus when the likelihood of
abnormality is only 50%.
A third possible 3rd method for diagnosing
prenatally is exemplified
by a genetic linkage.
This is a value in some families with maya tonic
dystrophy.
The next live presents the reason
for this possibility my platonic
dystrophy Locusts and the secreto Locusts are
linked.
To put it differently.
This means that the position that the
gene for my atomic dystrophy and the
gene for what is called the secret er
property are on the same chromosome.
The diatonic dystrophy Locusts can have
uh a Maya tonic dystrophy gene or
normal normal gene in that position.
The patient with monotonic dystrophy.
We know has one my atomic district you gene
and one normal gene at the homologous
position on another chromosome.
The secret er type determines whether
an individual secretes A.
B.
H.
Blood group substances in the body secretions such as
saliva.
The fact that the fetus secretes
such substances into the
ah amniotic fluid is the
basis for prenatal diagnosis involving
security types.
My blood group is a and I'm a secret er And
this means that I have blood group a not only on my red
cells but also in present in my
saliva.
Individuals who are blood group.
All secret what is
called blood group,
substance age in their body secretions and therefore it's
possible by testing and individuals red
cells and his saliva to determine
not only his A.
B.
O.
Blood group but also whether he's a secret er or not.
The helios at the secretary Locusts are
called big sc and little sc.
An individual with one or two big assay
genes secretes a.
Bh substances into his saliva.
Individuals who have only the little
sc gene are the ones who failed to secrete
these substances.
The next slide presents the criteria for
evaluating which couples may benefit
from prenatal diagnosis of my atomic dystrophy.
three criteria must be fulfilled.
These are stated here and
represented in the form of a pedigree which full
of one type which fulfills the criteria below
the first criteria is that the proposed notice must
have one big sc gene and one little
sc gene.
Now in order to in this family.
We have shown an affected man and his
wife who wished to have prenatal diagnosis
for their fetus.
The the first step is to determine
the HBO type of this
man's red cells and to determine
whether there is a B or H substance in his saliva.
If he does not have these substances in his libel,
then he is a non sequitur and
no benefit can be derived from this approach.
If we establish that he is a secret er then the
next problem is to determine whether he is a
hetero zygote as required
in this case.
This is done by analyzing his parents.
His mother turns out to be a non sequitur
and the only genotype
for a non sequitur is
uh the homos august little sc ST.
Thus uh this family feels uh
therefore this subject must have a little sc
gene because his mother had no other to give him.
And hence the first criteria is satisfied by this
family.
The second criterion is that the phase of
linkage must be known.
This means that we must be able to decide
whether the chromosome bearing the muscular
dystrophy gene in this family carries
the big sc gene or the little scg.
The man's mother is we,
as we is the one with must be dystrophy
and she has only little sc jeans.
Thus it's clear that in her case it was the
the diatonic dystrophy gene is on chromosome with a
little S.
E.
Jean
the third and therefore we can assume
that in most in all probability
the my atomic
dystrophy gene in her son is also carried
on his cross and was on with a little scg.
And thus the phase of linkage is
established.
The third criterion is that the the pra
positive spouse must not be big
sc sc.
The reason for that requirement is that if the
spouse had only big sc jeans,
then she could have transmitted only little big
sc genes to the fetus.
And no matter whether the fetus got the
chromosome with Moscow dystrophy on it or
not,
the security status would be positive.
This is a fortunate circumstance because this
woman is a non
sequitur.
Now in this family,
if the fetus is a
a non sequitur as determined by
a.
B.
H.
Assessment of the amniotic fluid,
then probably the child did inherit the
monotonic dystrophy gene uh from the
father.
If on the other hand,
the child has is a secret
er ah
then the chromosome from the
father ah contributing the
security type was the one without the district Eugene.
And most of my atomic dystrophy gene was presumably
not inherited.
Now,
the reason for saying probably rather than definitely
is that any two genes on the same
chromosome have a certain any too low signed.
Some chromosome have a certain risk of recombination.
Now,
from studies of segregation of diatonic
dystrophy and secretive type in families.
We know that there is a
11% chance that the
recombination will occur between the two lo sai
between any given parent and child.
Therefore the probability to be attached to this
prediction is not 100%,,
but 100 Percent -11%
or 89%.
Now suppose that the
wife in this case
was secreted positive,
then we would have to decide whether she
had too big,
too big sc jeans or only one.
We would determine that by looking at her parents.
If as in this case one parent was little
sc,
little sc,
we would know that this woman was a hetero saga.
If this were the case,
we could offer prenatal diagnosis in the sense
that if the fetus was non sequitur
then the child must would
probably have inherited the monotonic
dystrophy gene from the affected father.
However,
if the fetus was secret,
er we would be unable to
determine whether this is the biggest,
see jeanne had come from the
father or from the mother
and in this case we would have no information to relate to the
couple.
It's important to make clear clear to the
family in such a in this last
example that certain outcomes of
the test will not inform them as
to the likely this trophic status of the fetus.
The next slide shows that my atomic
dystrophy is linked not only to the secreto
Locusts but also to the Lutheran
locus.
The Lutheran locust determines what Lutheran
antigen is on the red cell surface
Lutheran A.
Or Lutheran B.
Now,
at the present time,
it's not possible to determine the Lutheran
status of the fetus because there is
no generally available
method for acquiring for obtaining
fetal red cells.
Nevertheless,
the linkage of my atomic dystrophy to Lutheran
maybe a value in detecting
ah who has inherited
the dystrophy gene after
birth,
but before the onset of symptoms here,
for example,
one of your patients has a with
monotonic dystrophy has a son.
Uh considering becoming a concert
pianist,
it may be constructive to determine whether he has
inherited the dystrophy gene.
And in such a case,
the if the
secret information is not uh
if this critter genotype do not permit this,
the Lutheran Jenna types may
notice however,
that the Lutheran linkage to my atomic dystrophy
is looser.
That is Recombination occurs
24% of the time,
Rather than merely 11% of the top.
And therefore,
the prediction made on the basis of the inheritance of
Lutheran Is not
accurate 100% of the time,
but 100% -24%
or 76% of the time.
Now,
how many couples?
One of whom has monotonic dystrophy
can be offered prenatal diagnosis
in this way,
from the incidents of various genotype
for security,
We can predict that
37.5% of us
individuals should uh
permit i prediction as to
the inheritance of multi
dystrophy in the fetus.
However,
the practical.
Um In practice,
this figure is lower because of the lack of
availability of
affected relatives,
which permit a decision as to the phase of
linkage in the affected parent.
And last Only 10-20%
of couples of this type are
likely to be helped by this kind of
analysis.
The principles underlying prenatal
diagnosis or presymptomatic post
natal diagnosis by genetic linkage are important to
understand because we can confidently
predict that they will become of increasing
usefulness in the future.
This is because of the rapid increase in the
knowledge of the number of genetic markers and
because of the rapidly expanding knowledge
of the location of markers in relationship to
known disease entities.
The final topic I would like to discuss is the
impact of genetic counseling.
The data
that I'd like to draw upon deals with Duchenne
muscular dystrophy.
It's based upon A study
of 109 families with
Duchenne muscular dystrophy,
studied in Toronto at the hospital for
sick Children by Elaine Hutton
and Margaret Thompson.
And I use their data
with their permission thanks to their
generosity.
It will be available in published
form in the Canadian Medical Association journal in the near
future.
The question that it is to be asked is
do patients really use uh
recurrence risk risk recurrence information,
recurrence risk information in planning their families.
Their study shows that they do.
Indeed.
The first question to be asked is do they take
into account the
carrier status risk when
deciding how on their family plans
for further Children.
This table classify on this
table.
The female relatives of known Duchenne muscular
dystrophy cases are classified as too high
risk,
moderate risk or low risk.
For each class.
We show whether these individuals
have decided not to have further Children.
On the basis of the
risk figures they have been given.
We see that individuals given a high risk figure
were deterred In intent by 80
and 81% of the cases.
This is backed up by the fact that in 55% of the
cases the woman or her spouse were
sterilized,
individuals given low risk of the Cases were
deterred in only five of cases And were
sterilized in only 13% of cases.
Thus,
there was a good correlation between the risk
that was provided to the female relatives
and the deterrent effect of this
information.
The next question to ask is does the
risk provided affect not only
intent but also reproductive
performance.
In order to add to asked to answer
this question,
we need to look to not only not simply asked
the woman what she and her husband plan to do,
but actually count their lives born offspring
substitutes subsequent to the diagnosis of
carrier status.
The next slide presents these results
here again,
the female relatives are classified into the high risk,
moderate risk or low risk categories and in
this column we find,
we can tabulate.
The number of females apparently deterred by
this risk,
on the basis of not having had any live
born offspring subsequent to being
informed of what their risk was.
Those in the high risk category Were
deterred in 67 percent of the cases,
those in the lowest category,
Where you've heard in only 24% of the cases.
Thus,
we see that informing female relatives of the
risk figures appears to have impact not only
on their announced intent to have Children,
but on their actual performance.
Now,
if a if a clinic is effective
in there educational
efforts,
one might expect that there would be a
decline in the number of
families in the number of
new cases of Duchenne
dystrophy in subsequent years,
in which there was a positive family history.
This has been the experience in the Toronto group has shown him the
next lot.
In this column,
we list the year of ascertainment of the new case,
The number of the next call,
the number of cases ascertained In the 3rd
column,
the number of cases with positive family history
and in the final column,
the number of cases in which the mother was aware
of the positive family history at the time of
conception of the new case.
In the earliest year,
recorded
In 42% of cases,
the mother was aware of the positive family history,
where is in the most recent two years recorded
This figure had dropped to only 7-9
and thus the prediction about effectiveness
of genetic counseling is reflected in a
drop in the percentage of cases in
which the mother was aware of the positive family history at the time of
conception.
Thus,
the message is clear,
at least when dealing with clear cut with
extremely serious conditions.
People are influenced in their reproductive plans
by risk figures.
Hence it's the responsibility of physicians to make these
figures just as accurate as they can.
How where can you look for information to provide
this accurate information to your patients?
One source is the
book by victor mcusic entitled
dandelion inheritance in man.
This book lists For over 2000
human conditions
their inheritance patterns with a
statement as to how well known
how well established this inheritance pattern is
and a brief description of the
condition and the authoritative literature
citations.
A second useful reference is
the book entitled The principles of genetic counseling,
edited by written by Edmund A Murphy and
Gary a Chase.
This book explains the principles of
genetics underlying the calculation of
recurrence risk and in particular
details the problems associated with
carrier diagnosis for excellent
conditions like Duchenne muscular dystrophy and
takes into account the Bayesian analysis that I
alluded to briefly.
Hey,
a third valuable resource is the
uh birth defects uh
International Directory of Genetic services
uh published by the National Foundation.
Thus,
if you have difficulty determining the best
information for your family's
yourself.
There is help available in your region.