M S U D Newsletter
Articles selected from: Vol. 9 No. 1, April 1991
This
issue features Dr. Holmes Morton and his unique Clinic For Special Children in
Pennsylvania.His interest in the high
incidences of Glutaric aciduria among the Amish in Southeastern PA and MSUD in
the Mennonite population in the same area led him to establish this non-profit
Clinic.The Clinic setting affords an
extraordinary opportunity to observe children with these disorders.
Clinic Visit
The first week in January
1991, Wayne, Shayla & I stopped at the Clinic for Special Children in
Lancaster County, PA. We met Dr. Holmes
Morton, the founder, at the home of an MSUD family the winter before. Now we were visiting his unique Clinic in
this temporary location.
Dr. Morton had just returned
from visiting a family. His slightly
rumpled look attested to his sixteen to twenty‑hour workdays. His devotion to his work and the families of
his patients is undeniable.
Stepping into the lab, we
were surrounded by high‑tech equipment.
Dr. Morton seemed in his element as he moved about the room explaining
his research to improve diagnosis and care for children with inherited
metabolic disorders.
We asked if he would run a
test on Shayla's blood. No problem -- he
could run it while we were talking. In
one hour, while we watched, he completed the test with a print‑out of her
current amino acid levels. He saved
some blood to check keto acid levels later.
A urine 2,4‑DNPH test showed a negative reaction. How efficient!
Amish
& Glutaric Aciduria
A Harvard Medical School
graduate and pediatrician, Dr. Morton developed an interest in this area of the
country during a research fellowship in metabolism at Children's Hospital in
Philadelphia. In June 1988, he
diagnosed Glutaric aciduria in a Amish boy who was previously identified as
having cerebral palsy. There were only
eight cases of this disorder documented in medical literature at that time.
With the help of local
midwives, Dr. Morton began gathering urine samples of Amish newborn infants to
test for Glutaric aciduria. He went
from farm to farm to check on children diagnosed or suspected as having the
disorder.
During this time he gained
the trust of the community and made an important friend, Rebecca Huyard. She is Old Order Amish and had fifteen years
teaching experience in Amish schools.
Five of her sister's seven children had become mysteriously ill. Two had died and the others were physically
disabled. Dr. Morton diagnosed their problem as Glutaric aciduria. Now Rebecca helps teach preventive care at
Amish social gatherings and is Dr. Morton's office manager.
Children with Glutaric
aciduria are normal at birth and usually healthy for the first few months of
life. Under the stress of common childhood illnesses, such as diarrhea or
infection, Glutaric acid builds up to toxic levels and causes life‑threatening
metabolic illness and brain damage. Untreated or undiagnosed infants may lapse
into a coma and die within a few hours after becoming ill with diarrhea or an
ear infection. Children who survive are
often left with paralysis and uncontrolled movements which is commonly referred
to as cerebral palsy.
Through his research and
clinical work, Dr. Morton believes the disorder is treatable and the severe
effects can be prevented. His strategy
for treating children with Glutaric aciduria is similar to that of caring for
children with MSUD. Recognizing the
condition before brain damage occurs is crucial! This is the reason the Clinic established a voluntary newborn
testing program.
Long term care involves
restricting protein, preventing acidosis and careful monitoring of blood
Glutaric acid levels during infectious illnesses. If hospitalization is needed, Dr. Morton admits the children to
Lancaster General Hospital directly under his care. The administration and medical staff of the hospital are very
supportive. Therapy has prevented
progression of brain damage.
Since diagnosing the first
case of Glutaric aciduria in Lancaster County, Dr. Morton has diagnosed 19
cases. Five infants were found in the
past year through the Clinic's newborn testing program. He estimates that 1 in 200 Amish infants in
Lancaster County will inherit the potentially deadly metabolic disorder. But Dr. Morton is there when needed, even at
the door!
Mennonites
& MSUD
We who are familiar with MSUD
will notice many similarities in these two disorders. While at the Children's Hospital, Dr. Morton cared for children
with MSUD. Many of these children were
from Mennonite families in the Lancaster area. There was an apparent need for a
more accessible and consistent source of medical care.
The Amish and some Mennonites
do not have automobiles or health insurance.
When these children become ill, careful monitoring is necessary
throughout the illness. Traveling to
Philadelphia and hospitalizing the sick child is stressful to the child and
family as well as costly. A Clinic
proposal appealed to the Lancaster area Amish and Mennonite families. Since the churches of the plain people
help pay family medical bills, the families solicited help from their churches.
A
Vision Becomes Reality
Dr. Morton envisioned a
clinic to provide diagnostic services and medical care in the community at
affordable prices. In April 1989, he
and his wife, Caroline incorporated a non‑profit organization called
Clinic for Special Children. Frustrated
in their efforts to get financial support, they applied for a second mortgage
on their home. Then an article about
this country doctor was published on the front page of the Wall Street
Journal on Sept. 20, 1989. More than
500 people from 43 states responded with contributions for the Clinic and the
dreams and needs of many began to become reality.
The Hewlett‑Packard Co.
donated the gas chromatograph/mass‑spectrometer needed in testing for
Glutaric aciduria. The Lancaster
General Hospital donated temporary office and lab space. The amino acid analyzer used for testing and
monitoring MSUD was purchased through donations from local Mennonite churches
and an anonymous donor.
These donations enabled the
Clinic to cut costs significantly. The
test for Glutaric aciduria at the Clinic costs $35 compared to approximately
$300 at major medical centers. Diagnostic
tests for MSUD at major medical centers run $200 to $400. A blood sample of a newborn can be
deliver-ed to Dr. Morton an hour or two after birth. An hour later, the test is completed at a cost of $45.
Two new cases of MSUD have
been diagnosed at the Clinic, one at 12 hours and the other at 20 hours of
age. Since the infants were well and
had low levels, therapy was started without hospitalization. Two older children with MSUD were treated
for dehydration at Lancaster General, put on IV's, closely monitored, and
recovered quickly.
Clinic
Raising
After Dr. Morton detected
Glutaric aciduria in a new born Amish girl, saving her health, the grateful
Grandparents made available a beautiful site for the new Clinic. We visited the building under construction
during January of this year. The
traditional timber frame building sits on sloping pasture land nearly
surrounded by trees. The long curving
driveway leads off a small country road.
It all bespeaks quiet, peaceful country life -- just perfect for these
people who avoid worldly, modern ways.
Here is an account of the
Clinic raising day. I summarized an
article from the Nov. 19, 1990 Wall Street Journal, adding remarks of
my own.
The Clinic was raised in the
traditional way, like the area barn raisings. One morning last Nov., over 50 men, most of them Amish and
Mennonite farmers, arrived at the site near Strasburg. They pounded stout oak pegs into holes at
the joints of hefty wooden posts and beams.
The men raised these massive timbers by standing shoulder to shoulder in
long lines of twenty or more men as volunteers steadied the beams with heavy
ropes. One hundred six people attended
the raising, offering help and moral support.
By noon, the first floor was
framed and the workers headed for the nearby farmhouse and lunch. They washed in buckets of soapy water on the
front porch, and then bowed their heads in a silent prayer of thanks to the
Almighty God who made this day possible.
The big kitchen held more than one hundred people at a time. This is where the Amish women prepared the
food for the hungry workers and their families and where folks sat eight or
nine to a bench eating soup from bowls held on their laps.
After lunch, twenty
carpenters straddled joists above the ceiling frame of the first floor and
pounded the next beams in place. No one
barked commands; this was real teamwork -- skills taught from generation to
generation.
In the middle of the
afternoon the rafters started going up.
Soon the finished roof frame completed the silhouette. By four o'clock it was time for farmers to
head home to do the evening chores. The
dream was coming true.
Ready
for Use
The Clinic is nearly
completed at the time of this writing and plans are to move into it in
April. Dr. Morton says, "I know I'll
spend the rest of my life working in this building. I believe we can prevent brain injury in the majority of the
children who have Glutaric aciduria. I
expect that over the next ten years the fate of 50 or more children will be
determined by the success or failure of the Clinic. That provokes a frightful sense of responsibility in me. That's what motivates my work."
I wrote this article using information from various sources including newspaper articles, a Clinic newsletter, personal contacts, and information supplied by Dr. Morton.
-- Joyce Brubacher
Editors note:
The
terms Amish and Mennonite may be synonymous to many of you. I feel it is important to clarify the
difference for medical reasons.
Although these two groups originate from the same areas of Europe,
particularly the Swiss Palatinate, the groups separated in 1693 and have been
separate identities for almost 300 years.
Amish still wear the distinctive plain attire but not all Mennonites
continue practicing this sign of separation from the world. Genetically there has been little mixing
until the past 30 to 50 years. Couples
always marrying within their own religious denomination result in extensive
intermarriage. Thus, inherited diseases
common in one group may be virtually unknown in the other -- such as the MSUD in
the Mennonites and Glutaric aciduria in the Amish. However this may be changing as today numbers of Amish are joining
the Mennonites.
April 12, 1991
Dear Joyce:
Last summer Tom Lundquist, a
senior medical student at Johns Hopkins Medical School, and I studied the use
of the urine DNPH test to monitor day to day control of MSUD. We had the help of Enos & Edith Hoover
and several other Lancaster County families who have children with MSUD. I long ago promised to summarize our
findings for your newsletter and regret that my busy work schedule has
prevented me from writing this letter before now.
Our reason for evaluating the
use of DNPH will be obvious to parents of children with MSUD. Because of the sensitivity of the disorder
to minor infections and small changes in diet, measurement of plasma amino acid
levels at monthly or quarterly intervals as practiced in most centers providing
specialty care, has limited value for the day to day management of the disorder
by families and local health care providers.
Parents have long recognized the need for a test which would allow the disorder
to be monitored daily at home in the same way that diabetics monitor blood
glucose levels. Several families have
used the urinary DNPH keto acid precipitation test to assess metabolic control
and have found the test to be practical for in‑home use and helpful in
the management of their children with MSUD.
We were asked by the MSUD Family Support Group to conduct formal studies
of the urine DNPH test, to verify its accuracy, and to comment upon the value
of the test for routine care.
Comments About The DNPH
Method Use In Our Study: Our purpose was to study the relationship
between the DNPH reaction in urine and the levels of keto acids and amino acids
in blood. We obtained twenty paired
blood and urine samples from children who have MSUD and used a Hewlett Packard
gas chromatograph‑mass spectrometer and an amino acid analyzer to measure
the branched chain keto acids and amino acids concentrations in the
samples. We monitored DNPH test each
day for 100 days in a 16 year old girl to gain insight into the day to day
changes in her metabolic control. We
also tested urine samples from 100 newborns to see if the test was often
positive in that age group.
The DNPH method we used is
the same as you have used and is described in Dr. Vivian Shih's book Laboratory
Techniques for the Detection of
Hereditary Metabolic Disorders.
The DNPH reagent was purchased from Eastman Kodak Company and 100 mg of
DNPH was dissolved in 100 ml of 2N hydrochloric acid. An equal amount (1 cc) of urine and the DNPH solution (1 cc) are
mixed in a clear test tube then after 10 minutes the cloudiness of the mixture
is noted. Although simply noting
whether the mixture is clear or cloudy provides the most information, we found
it useful and easy to score the cloudiness on a scale of 0+ to 3+÷0+
(clear), 1+ (very slight cloudiness), 2+ (cloudy but
possible to read print through), or 3+ (too cloudy to read print
through).
The manner in which the DNPH
test is done is important, especially when the 0+ to 3+
scale is used. The urine and the DNPH
solution must be clear before being mixed.
If the urine sample is cloudy, it should be allowed to sit for 15 to 30
minutes to see if it will clear (or it could be centrifuged). The DNPH solution often has a small amount
of precipitate at the bottom of the bottle.
Avoid adding this precipitate to the urine sample. A clear, clean test tube of a standard size
should be used or it may be difficult to use the scale of cloudiness from one
test to the next. The test tube we used was an inexpensive clear plastic tube
that measures 1/2 inch across and is 3 inches high (12x75 mm). It is especially important to use equal
amounts of urine and DNPH. The
sensitivity of the test and the 0+ to 3+ scale depend
upon a 1 to 1 mixture of urine and DNPH.
Dr. Berry and others at
Children's in Philadelphia were initially concerned that the DNPH test was
insensitive. After some discussion it
was found that the DNPH method used by Children's called for only 4 to 5 drops of
urine in 3/4 to 1 cc of DNPH solution.
Using the Children's method a positive result would be obtained only
when very large concentrations of keto acids were present in the urine because
such a small amount of urine was used for the test.
Observations: The values 1+
and 2+ correlated with blood leucine levels from 5 to 10 mg/dl while
a strong 3+ reaction always indicated increased blood levels of the
keto acids and almost always predicted that the leucine concentration in blood
was greater than 10 mg/dl ( > 760 µM ).
We also found that during illnesses, concentrations of branch chain keto
acids increase in the urine in parallel with the rise of branched chain amino
acids and keto acids in the blood. The
DNPH reaction becomes positive long before ketones appear in the urine. Therefore it is a much more sensitive
indicator of poor control than keto‑sticks or Acetest tablets. The DNPH reaction is also much more
sensitive than the MSUD odor as a predictor of illness.
We found, as you had
reported, that excretion of keto acids increase 12 to 24 hours prior to the
onset of fever, diarrhea, and other clinical signs of infection. We also observed that the DNPH test is often
positive even when children with MSUD seem well. During an initial observation period with one girl, the DNPH test
was 2 or 3+ on 27 of 50 days and was often positive for several days
in a row. However, with simple changes
in therapy, the test was positive only 10 of 50 days and cleared rapidly with
minor adjustments in the intake of protein, MSUD formula, and bicarbonate.
The test is surprisingly
specific for the keto acids of leucine and isoleucine. DNPH precipitation does not occur with other
keto acids in the urine to any significant extent. Even urines that are strongly reactive with Acetest because of diabetic
ketoacidosis do not give false positive DNPH tests. We tested 100 urine samples from newborns and found only 1 weak
false positive.
There are a few circumstances when the DNPH result
can be misleading. After a meal, the amino acid levels in blood rise rapidly as
protein is digested and absorbed and then fall as the amino acids are taken up
into organs for use to make protein.
The rise in leucine after a meal is not always accompanied by a rise in
the keto acids in blood and urine. The
rate of conversion of the amino acid to the keto acid and the time of excretion
into the urine depends upon several factors including the amount of fat and
calories and protein in the food, and whether the person is metabolically well
or ill or dehydrated. The test is most
reliable when the first morning urine is tested or with a sample obtained at
least 4 hours after a meal.
Another important
circumstance that can produce a misleading result is the rapid fall of
isoleucine and the keto acids that occurs during the recovery period of an
illness. When a patient is on MSUD
formula alone and the branched chain levels are falling, the keto acids fall
more rapidly than the amino acids. Also,
isoleucine, which usually contributes about 30 to 50% of the DNPH precipitation,
falls more rapidly than leucine. For
these two reasons, the DNPH test may become almost clear when the leucine level
is still above 10 mg/dl. This is a time
when a blood amino acid measurement is useful to guide the re‑introduction
of protein and determine when isoleucine & valine supplements are needed.
It was our opinion that
clinical illness was more closely related to changes in blood keto acid levels
than the amino acid levels. Apparently
Dr. Scriver in Canada and Dr. Berry at Children's have also observed this. With
more research we may find that the management of episodic illnesses should be
focused upon blood levels of keto acids rather than amino acids. The DNPH test
may, with further study, prove to be a very good indicator of metabolic illness
and provide additional insight into the biochemical basis of episodic
illnesses.
Joyce, you will appreciate
that much of what we learned simply confirms what you and a few other parents
of MSUD children have known for some time -- the urine DNPH test is a simple,
inexpensive way to monitor the day to day treatment of children with maple
syrup urine disease. Routine use of the
test can provide parents and children with incentive for better dietary
management. More important, the DNPH
test can detect the rise of branched chain keto and amino acid levels in blood
that often accompany common childhood illnesses and allow parents or local
health care providers to make changes in therapy which will usually prevent
severe metabolic illness. Finally, our
preliminary studies indicate that in the newborn with MSUD, the DNPH test
should become positive between 48 to 72 hours of age and we expect there to be
a low false positive rate. The urine
DNPH test should allow families or local health care providers to readily
recognize MSUD in the newborn before the infant becomes severely ill or
damaged.
At the Clinic for Special
Children, we will continue to learn from such studies and gain new insight into
the biochemistry of MSUD and other biochemical disorders. Although we all hope that genetic research
will ultimately lead to new treatments for MSUD, we should recognize that none
of the children who now have MSUD will soon undergo gene replacement and be
cured of their illness. Gene
replacement will be of little benefit to those children who have severe brain
damage because of delayed diagnosis or poor biochemical management. Prevention of permanent damage to the brain,
the quality of the lives of these children, and in fact, their very survival,
depends upon an understanding of the biochemical basis of the disorder and upon
efforts to offer care that is effective, practical, and accessible to those who
need it.
-- Sincerely, Holmes Morton, M.D.
RESPONSES
TO THE NEW CLINIC AND THE USE OF DNPH
Enos
Hoover, the father of Edith Hoover, a 16 year old with MSUD, has been instrumental in starting the
Clinic for Special Children. As a
member of the board of directors, he represents families with MSUD
children. Following is Enos and his
wife, Anna Mae's recent experience with the Clinic's services.
We have found the services of
the Clinic a big help in keeping Edith's condition under control. We started using the 2,4‑DNPH test
regularly, and learned that her leucine was often slightly elevated (5 to 10
mg/ml). Also ph was low (5 to 7). So we started using sodium bicarbonate (20
gr/day) which keeps the urine ph at 7 to 9, and keeps the DNPH clear more
often. We also cut back on formula to
14 oz./day and give 24 cal./oz. when levels are low.
When we have a blood test
done at the Clinic we get results in 1 1/2 hrs. at a fraction of the previous
cost. Our new grandson's negative
diagnosis was made at 26 hrs. after birth!
Most of the midwives in Lancaster County are now using the DNPH on all
their newborns. So I believe we made
progress with MSUD in the past year.
The new building is ready at
this time. Much of the labor and some
materials were donated. I know we would
have used a local care center such as this earlier, but I suppose the time was
not right yet. It is really an answer
to our prayers, and we are sure it will also be a help to many younger parents
and special children.
Anne
Fredericks began taking her son to the Clinic and I asked her for her comments.
This is from her letter.
As to your question about Dr.
Morton, I feel that he has been an answer to our prayers. He is such a knowledgeable man but also a
very caring man, and Jeff really likes him.
We have had many problems, and he has been so supportive. We now use DNPH and check ph as well as
ke-tones. I just feel I have some
better ways to keep on top of his levels.
He takes so much time to explain things to us and to Jeff. We're all so thankful that Dr. Morton has
moved to Lancaster.
Peter
Shaffer and his wife Sharon from Kentucky have used DNPH for 9 years. Peter explains how they use it.
Ever since Jessica was
diagnosed 9 years ago we have used DNPH testing. DNPH is a chemical reagent that is mixed with urine. When it is negative it is a clear yellow. When it is positive, it becomes a cloudy
yellow. The more positive the more
cloudy. We rate our readings negative
or 1, 2, 3 or 4. When we reach the 4
level the DNPH test looks almost like mustard.
It is so thick you cannot see through it.
We use the DNPH as an
indicator of how Jessica is doing. We
do not use it alone. We also utilize
keto‑sticks. However, when we hit
a 4 DNPH, we are also hitting the highest reading on the keto‑stick.
We also pay close attention
to neurological symptoms such as the loss of balance, slurred speech,
drowsiness. In Jessica's case we have
seen high DNPH's with no neurological symptoms (very rare) and even
occasionally severe neurological symptoms, but low DNPH. Like most children, just when you have them
figured out, they change.
I
would like to share my experiences. (The
Editor)
At the symposium in Montreal
last year we learned that Dr. Charles Scriver's patients used DNPH for
years. Concerning his use of the test
for home monitoring he wrote, There are many ways of looking after a patient
with MSUD. This is just one of
them. I say this because two other
major centers don't subscribe to the monitoring of the keto acid, (and there
may be no difference in outcome). I
think the use of the test in the home gives the parent some sense of control.
Dr. Scriver's last statement
pinpoints the major advantage of DNPH as a tool in home monitoring. I have found it so helpful in my 26 years of
caring for children with MSUD. Frequent blood tests were not feasible as we
lived 160 miles from our medical center.
Correlating blood tests with
DNPH reactions in two children over a period of time helped me learn to judge
their amino acid levels quite accurately.
This took much of the guess work out of daily monitoring. I could implement diet changes at the first
sign of elevated levels and our children seldom needed to be hospitalized for
illnesses. It also aided me in varying
their diet.
I was given keto‑sticks
to use twice that I can remember when our children were sick in the
hospital. I was disgusted because they
were obviously sick, but the keto‑sticks showed no reaction. Later I did get some to try at home but
never saw a positive reaction. They
were totally useless for us. In
contrast to Peter's report, we have seen a very positive reaction with DNPH
frequently without neurological symptoms, usually caused by stress or from an
extra gram of protein eaten that day.
The test changes rapidly, sometimes in an hour on those occasions. Evidently there is a difference in how some
children respond to the different tests.
For many years I used two
test tubes each time I tested urine. I
would put 20 drops of urine in each and then add the reagent to only one of
them. If the urine was cloudy to start
with, I could watch both to see if the reagent was causing it to become more
cloudy. I never had a problem with this
method as taught to me by our doctor, Dr. Allen. I will always appreciate him introducing me to DNPH.
Shayla is 21 yrs. old and has
been responsible for monitoring her diet for several years. I would be very uncomfortable allowing her
this independence if she did not use DNPH.
She cannot tell if her leucine levels are elevated by how she feels
physically and has shown no distinct neurological signs with high levels for
years.
Our friends, Leon and Dianne
Kennedy have recently taken their second foster child with MSUD into their
hearts and home. I asked her how she
feels about using DNPH. Without a
moment's hesitation she answered emphatically, I wouldn't even consider taking
an MSUD child without DNPH! For some
of us, it is a necessity.
A word of caution‑‑DNPH
is an acid and must be handled with care and kept out of reach of
children. I've been told one can
get an acid burn from it. Though we've
never experienced that problem in over 23 years of use, I do advise
caution. Do clean up any spills
immediately, as it stains easily. It
should be kept in a dark bottle out of bright light, as light tends to weaken
the solution.
DNPH is not a miracle worker
but a very helpful aid in caring for persons with MSUD. It would be great if all parents would have
the opportunity to try it if they are interested. My thanks to Dr. Morton for his efforts in investigating 2,4‑
DNPH as a tool in home monitoring.
FAMILY
HISTORIES
This family history is about Jim and Renee Eck and their son, Cory, who has classic MSUD. I think Mrs. Eck expressed so well the underlying stress experienced by many families. Even when things are going well, there is always the next episode right around the corner. I admire so many of the couples I have had contact with for their courage in not being afraid to deal with these stresses. This reminds me so much of my son Mike's diagnosis. No one said it was easy.
-- Anna Toth
Jim and I were married in
1977. After five hard years of learning
about each other, we decided to have children.
In 1983, we had a healthy daughter named Crystal. After a year or so we decided to have
another child. Cory was born January
14, 1985, three days after our daughter's second birthday.
Everything seemed normal
until about the fifth day. Cory never
seemed to cry because he was hungry.
And most of the noises that he made seemed more like fidgeting or very
weak moans. On that fifth day, we were
being discharged from the hospital when I asked the doctor about him not eating
well and acting as if he were uncomfortable most of the time. I was told not to be an over‑excited
mother. (This was not my regular
doctor.)
On the first evening home
Cory had a seizure. I really wasn't
worried about it, because I have known of others to have seizures that were not
harmful. But I did not forget it. On the eighth day, Cory seemed a little
better, but I took him to see our regular doctor. Her conclusion was that Cory had a feeding disorder, and I was
shown how to force feed him. I did this
all through the night not getting more than four ounces of formula in during
that 10 hour period.
On the ninth day I took him
to Children's Hospital in Columbus, Ohio.
The doctor came to the same conclusion as our regular pediatrician, that
Cory had a feeding disorder. We were
sent back home doing the same thing as the day before.
On the tenth day, at around
5:00 a.m. in the morning, Cory had the second seizure that I noticed. I let him sleep until 9:00 a.m. and then
tried many ways to get him awake. I put
cold water on his feet and face; I bounced him around. I did everything I could think of, and it
did not work. I then took him to the
same doctor that saw him on the eighth day. She was surprised at the difference
in him. She called Children's Hospital
in Columbus, and he was admitted in a semicoma. Cory was put on IV's until they learned what was wrong.
On day twelve we were told
Cory had classic MSUD. At first I was
still very optimistic. I remember
thinking, we'll fix him up and send him home.
I soon learned it wasn't going to be that easy.
On the fifteenth day Cory
wasn't responding as well as they hoped, so they put him on dialysis for three
days. It did not work for Cory, so the
only other thing to do was to use IV's and wait.
Cory was admitted to
Children's Hospital on Jan. 22, 1985 and released March 22, 1985 to a very
unsure mother. Since that very rough
start we have unfortunately had a lot more rough times. Cory was in the hospital five times the
first year. From ages 2 to 3 he was a
lot more stable, hospitalized only two times.
At age four he had a lot of
ear infections and a lot of vomiting illnesses. He was also operated on for tight ham strings in his legs. They were released so he would hopefully be
able to walk and stand. It did help,
but he still had to have a lot of therapy.
He was hospitalized nine times that year. At age five he is back to ear
infections and vomiting and has been in the hospital eight times.
Cory turned 6 years old on
Jan. 14, 1991. On Jan. 8th he started
the new year in the hospital by having tubes put in his ears for the third
time. We are hoping that just because
he starts the year out in the hospital, that he won't make it such a regular
habit like in his past. For some
strange reason he likes it there. He
likes the attention he gets from all the nurses that all know him very
well. I think he thinks he has about
twenty mothers, and he can't choose which one he wants to keep.
I am grateful that this support group exists because I have called a lot of people on the parents' list for advice at different times. I would like to thank everyone for all the help they have given me. Even if you feel like you didn't help me, just having someone I could talk to that understood was a big help.
-- Thanks, Renee Eck
Our Special Story About Leanna
On April 3, 1985 at 3:58
a.m., I gave birth to a beautiful baby girl which we named Leanna Marie
Peters. My husband and I were so
excited because we had a son, and she just completed our family. We were discharged after three days in the
hospital. During the hospital stay, I
remember one of the nurses commenting on Leannna's sucking action. She thought it would be better if I nursed
her since she was not sucking very good with the bottle. I nursed her that night, and she seemed to
do well. She did well for a few days
until I noticed her sleep patterns to be a bit restless. She would frequently cry in her sleep and
make some very strange noises. I then
noticed she wanted to sleep more than to nurse, and it became an effort to get
her to suck.
A week after we were
discharged, I received a phone call from the office of the pediatrician who
examined her in the hospital at the time of birth. He was calling to let me know that one of her test results from
the newborn screening was a bit of concern to them, and asked that I bring her
in.
After examining her in his
office that afternoon, he instructed us to go directly to Massachusetts General
Hospital to be seen by Dr. Vivian Shih.
At that point in time, we were still not sure how serious the situation
was becoming. We went to Massachusetts
General Hospital, and she was examined by Dr. Shih who verified the diagnosis
as maple syrup urine disease. She also
informed us that our daughter was dehydrated.
Dr. Shih gave us a brief description of her disease and tried to answer
all our questions.
My first question to her was,
Can't you operate? Unfortunately, as
we all know, an operation does not work, just a constant diet of protein free
foods. At that point, we finally realized how serious her condition was and
started asking the questions, Why us, why her? But after much soul‑searching we realized we could handle
it and life would go on much as before.
She remained in the hospital
for two weeks and required peritoneal dialysis. Her progress was slow at first, and I become a bit nervous every
time she spit up or fussed. We managed
to get through those two difficult weeks, and she has now turned into a very
outgoing and personable little girl.
We did encounter a setback
that caught us off guard when she was three years old because everything was
running smoothly. But as we all know,
those are the problems these children face every day of their lives. The setback was a stomach virus that caught
her on Christmas Eve. She was
hospitalized the day after Christmas.
She remained in the hospital for two days and was then sent home for
constant monitoring. Now I try to take
one day at a time and try to make her life as normal as possible.
She attends YWCA kindergarten and really enjoys interacting with other children. Her teacher has encountered some learning difficulties that we are trying to deal with at the moment. With the advice of her specialist, she is now seeing a psychologist at Massachusetts General Hospital who plans to administer a test at age six to determine what her learning disabilities are and how to handle them. We are hoping for the best, and realize the school years may require a constant effort for Leanna to keep up with her classmates.
-- Mary Ann Peters
An
excerpt from Mary Ann's letter to the editor
I just had a scary incident
when Leanna was sick. She had some type
of stomach bug and threw up once or twice.
But it caught me off guard when she saw worms and snakes in her
room. There was nothing there. Talking to her specialist, I found that when
MSUD children have high leucine levels, they may hallucinate. Other parents may be interested in this
information, especially if they haven't experienced it yet.
GENETIC
CAUSE OF CLASSIC MSUD
IN THE MENNONITE
POPULATION DISCOVERED
Alice T. Mazur, RN,
PNP;
Sheila Noone, RN;
Randall A. Heidenreich,
MD;
The Children's Hospital
of Philadelphia, PA
The year 1990 was a pivotal
year for the diagnosis and care of patients with maple syrup urine
disease. The mutation (changed gene)
responsible for classic MSUD in the Mennonite population was discovered. This exciting event was initially reported
by Dr. Matsudu of Kumamoto, Japan,
confirmed by Drs. Matsudu, Heidenreich,
Sefal et.al. of Japan, and Philadelphia, PA and Drs. Fisher, Fisher, Chuang and
Cox of Dallas, TX. The mutation is a
thymidine (T) to adenine (A) change in El alpha subunit of the gene. This change results in complete loss of
activity of the Branched‑chain ketoacid dehydrogenase enzyme leading to
symptoms of MSUD. As outlined in the
following paragraphs this information will directly impact individuals of
Mennonite faith and other individuals discovered to have the same mutation.
The gene is the fundamental
biological unit of heredity. Genes are
transmitted in pairs to individuals from their parents, one from father and one
from mother. Genes are located on
chromosomes which are in turn located in the nucleus of the cells of the
body. Inside the nucleus of each of the
body's trillions of cells are located 23 pairs of chromosomes. Coiled inside each chromosome is the body's genetic
material, DNA, or deoxyribonucleic acid, the blueprint for human life. Arranged along the chromosomes are the
genes, which are the fundamental units of heredity.
Genes instruct the body's
cells to make proteins and determine everything from eye color to
susceptibility to genetic diseases.
Each rung of the DNA twisted rope ladder contains a pair of four
chemical units known as nucleotides.
Adinine (A) always attaches to thymine (T) and cytosine (C) always pairs
with quanine (G). The characteristic
properties and fundamental activity of proteins, such as enzymes, depends on
the sequence of the nucleotides. Genes
act as indirect patterns for reproduction of body proteins, which are made of
chains of amino acids.
Classic MSUD in the Mennonite
population is due to a mutation of the sequence pattern of the
nucleotides. Individuals with MSUD, or
homozygotes, have inherited a gene with the mutation from both mother and
father. Those individuals who have
inherited one gene with the mutation from either parent, but who also inherited
a normal gene from their other parent are called carriers or are heterzygotes
of the disease.
It is not yet known whether
non‑Mennonite individuals with classic MSUD also have the same genetic
mutation. One individual with a variant
form of MSUD who was tested, did not have the same genetic mutation. There may be more than one genetic mutation
responsible for classic and the different variant forms of MSUD. Work is in progress both at the Children's
Hospital of Philadelphia as well as other centers to answer these questions.
Our studies have shown that
the longer the diagnosis is delayed, the more likely it is that there will be
some damage to the brain. Early
treatment is critical in these children for the best outcome. Newborn screening will help to identify the
children, but the results of testing will probably not be available for several
days and usually, the children will already have the symptoms. The usual symptoms are vomiting, poor
feeding, floppiness sometimes alternating with tightness of the limbs, arching
of the back and neck, excessive sleepiness, seizures, and the characteristic
odor of burnt sugar or maple syrup. It
has been estimated that classic MSUD occurs in 1 in every 176 live births in
the Mennonite population. The
identification of the MSUD mutation in the Mennonite population will help to
identify carrier status. Once two
parent carriers have been detected, they can seek early diagnosis and treatment
for potentially affected infants.
Infants have biochemical abnormalities on the first day of life, long
before symptoms occur, so diagnosis should be made quickly and treatment
started before serious complications occur.
Who should be tested? (1) All individuals who have family members
with MSUD should be tested for the gene mutation. (2) People marrying a known carrier.
What does the test
involve? The test is simple. Specimens can be obtained at home and
mailed. It involves pricking a finger
with a special sterile lancet, blotting several drops of blood onto a special
sterile filter paper and then mailing the paper to our office.
(NOTE: See under Genetics in the
Index for up to date information on this type of testing.)
MSUD: THE IMPACT OF THE DISORDER
Gabrielle Weiss, M.D., Professor of Psychiatry, at McGill
University spoke on this topic at our 1990 symposium in Montreal. Several parents expressed their appreciation
and asked to have it printed in our newsletter. Due to its length, we did not print it in its entirety in the
Newsletter. This is the complete
article.
As a Child
Psychiatrist, I have worked for many years as a consultant to specialized
medical clinics for children with physical disabilities and chronic or terminal
illnesses. In this way, I have learned
over the years something about what is meant for the child to cope with being
handicapped in some way, or even terminally ill; what this meant to his or her
parents; how this affected the interaction between parents and child. I saw these issues as being crucial to the
emotional impact of the diagnosis and the subsequent course of the
disorder. However, I have worked only
with three families where one child had MSUD, and am therefore not a specific
expert for this condition, although I did learn some of the unique stresses,
frustrations and crises which MSUD children and their families undergo. In writing for parents of children with this
disorder, I want to emphasize that you, as the parents, and not I, the
professional, are the experts, and while I have much to learn about the
emotional impact from you, there is much expertise we can exchange which may be
helpful.
Let us turn to
MSUD specifically. Before the diagnosis
is made, parents go through a very hard time because the pediatrician may not
know at first why the newborn does not thrive.
But for this disorder, the diagnosis must be made within the first 10
days or so, if the infant is to survive.
Mothers are the
first to notice that something is wrong.
The infant is drowsy, is not sucking and is losing weight. The
pediatrician is puzzled and may change the formula. By the time the infant finally gets to hospital, he or she may be
in a coma. For the parents who have
been worried all along, this may be devastating. Now they do not know if their baby will live, and the parents may
be warned in the Intensive Care Unit that the baby could die, or live and be
retarded. Panic results during this
crisis, and it is normal for parents to hope for death on a cognitive level,
but on an emotional level, to nevertheless hope with all their hearts that the
baby will live. It is often a nurse who
smells the sweet (maple syrupy) smell of the urine, and finally laboratory
tests and dialysis are carried out and a diagnosis is made. Relief and concern follow on the parents'
part. Their infant improves but the extent of the damage to the brain is not
yet known, or is their ability to care for an infant with such a unique problem
known to them. Their baby has a life‑long
disorder for which a particularly rigid diet is essential; medical care will
always be required. What does all this
intense period of life, death and uncertainty do to the mother‑infant and
father‑infant bonding, which is essential for mutual attachment over the
years and the cornerstone of a healthy personality?
It is one of
life's miracles that most, in spite of the intensity of the upheaval, normal
bonding between parents and infant takes place. It is not easy for a few, and attachment only develops when some
of the fear of being unable to follow the routines required, and thus keeping
the infant alive, goes away. For some
of the parents, the strong bond made had much anxiety and guilt mixed in, which
may later become troublesome. Too much
anxiety and guilt, as well as the experience of both loving and hating their
baby (who has forever changed their lives and impinged on their freedom) may
benefit from professional help. These
feelings are universal, but some parents succeed in dealing with them by their
mutual support of one another, while others (less lucky perhaps in their own
early lives) make use of professional help.
When parents cannot cope and professional counseling is not available to
them, or not desired by them, serious problems between the child and parents
can result. These sometimes take the
form of extreme over-protection, which does not allow independence and autonomy
of the developing child, or there may be overt rejection, or a combination.
It is necessary
and difficult to come to terms with difficult emotions: ambivalence
(hating and loving the child at the same time); guilt (we, as parents,
gave our child this disorder, through our genes, why did we marry?); anger
at fate (why me?); fear (that as parents we cannot cope with a child
with so many special demands, or fear that we do not want to cope); sorrow
(for the child and the wish that the parents could have the disorder instead);
finally a sense of failure (at having an imperfect child).
Somehow, most
parents manage. Health professionals
who label any of these feelings disturbed have never had the experience. These feeling are normal, but have to be
worked through so that the child's development becomes as normal as is
possible. Professional help can be very
valuable.
I will now tackle
a few specific questions or situations which trouble parents of children with
MSUD, and which I have been specifically asked to comment upon.
Infants or
children who refuse the necessary formula
Many children
call the formula my milk and are revolted by the taste and smell. Even though they have had it all their
lives, they find it as distasteful as we do when we smell or taste it. This is not true for all children. Some have no problems and take their
milk's taste for granted. For those
infants or children who refuse it, disguising the taste with a flavor may help,
but not always. If the child refuses,
force‑feeding results and the battle is on. This battle can go on all day long, since the formula is
essential to life. It cannot ever be
skipped. Some of these children have
been force‑fed and survived it emotionally, still loving the mother who
had to do it. In time, children learn
that their mothers had no choice. Occasionally
a nanny, a grandmother or a friend is better than a parent in getting the child
to accept the formula. I think the
reason for this is that there is less anxiety in their attempts to feed.
Parents develop
all sorts of unique strategies to get the child to accept the milk. They are usually successful in the end. If this is not so, play therapy can be
helpful. For one child who refuses her milk, she became the mother in
play. She gave her baby this poison
and showed her need to be on the controlling side of the equation. She later set the rules for how she would
take the milk she needed: how thin, how thick, how much, how often, how
flavored.
What to tell
your child
Every parent will
get the advice to tell the truth, but it is more complicated than that. The truth has to be told in ways that are
meaningful to the child's developmental stage.
Amino acids, enzymes and genetics will mean something to the adolescent. The 2 year old only has to know he or she is
fine as long as he drinks and eats only some things. If the child does not comply, hospitalization and illness will
result. That not eating can be fatal,
cannot be understood until the child has a concept of the permanence of death,
which occurs between 5‑7 years of age.
Hence, parents have to become skilled at telling the child what he needs
to know when he needs to know it, and in language that is understandable. The child has to learn that he or she can
never eat some things that smell so delicious.
One child whould have done anything to have scrambled eggs just once for
breakfast. Children eventually adjust,
but not without some anger and sadness, and a knowledge of being different from
others.
Learning
disabilities
These are
frequently associated with MSUD. They
may be the result of late diagnosis or intermittent poor control of blood
levels, sometimes as the result of intermittent infections. Learning disabilities may require special
remedial help and, for some, are associated with hyperactivity and poor ability
to inhibit impulses. Even when present,
the child eventually is likely to become self‑sufficient as an adult,
with or without completing college or even high school. Self‑sufficiency in adulthood may
depend on the child's emotional stability and independence as much as on the
degree of learning disability.
The parents go
through very upsetting periods every time their child has to have psychological
testing. They understand the day‑to‑day
variability of the child's cognitive functioning depending on blood levels,
which, at times, the school psychologist may not understand. A single bad test result, be it on reading
level or overall intellectual ability, may not be reliable. Parents of MSUD children have to educate
professionals on this. Their attempts
to do this may be misinterpreted by the professional as denial or over‑protection. It should be the physician's task to
interpret this variability of cognitive functioning to school authorities.
The thin line
between protecting a child and over-protection, leading to dependency
For parents who
have a child with MSUD, this thin line is not easy to find. While every situation is different, and a
mental health professional who knows the family well can be helpful, since he
or she is able to take a more objective stand, a few guidelines may be
helpful. It is normal to feel sad for
your child because of the life‑long restrictions of diet and uncertainty
about outcome in the future that the child will have to handle maturely. But it is a mistake to pity your child
excessively; some other illnesses are much worse. If a parent has too much pity for the child, the child will learn
to pity himself or herself. Nor can a
parent make it up to the child by giving material things or letting the child
get away with things. Upbringing has to
be the same as for a child without the disorder, except for the dietary
restrictions and accommodation to cognitive (learning) difficulties when
present.
Slowly, the child
with MSUD has to take responsibility for his or her own diet and this makes it
possible for the child to go to camp, sleep over at friends' houses, and to
visit relatives. It is an essential
part of child development to learn to leave home. The child who is excessively over‑protected and babied
does not develop the necessary sense of self to leave his parents. Because of the close bond between mother and
child, resulting from early necessary protection, some mothers require
professional help to learn to let their children grow up. Fathers can help a great deal since they are
usually not as closely tied to their children.
By becoming closer to their wives, fathers can enable them to allow ever
increasing independence in the children.
Family
interactions
What effect does
the child with MSUD have on the parents and on the larger family, including
grandparents? Where medical costs are
not covered (as they are in Canada), a financial burden may be experienced. There will also be an emotional burden on
the father to give out strength and stability to his wife and all the
children. Some fathers do a magnificent
job of shouldering these extra responsibilities. In some families, the father is more the breadwinner and not
closely involved with the mother and child.
Occasionally, he has not chosen this role but has felt pushed out and
unwanted in the close mother‑child bond.
When this happens, it spells trouble later, because father is needed to
facilitate the mother's allowing the child to grow up, even with the problems
of MSUD. In this situation, counseling
is often aimed at strengthening the marital bond, thus creating more space in
the mother‑child bond.
The brothers and
sisters of a child with MSUD may actually feel envy rather than pity. They may rebel in order to try to get more
attention. One brother told me that
when he was 8 years old, he wished he had MSUD. Special effort had to be made under the given circumstances to
provide sufficient attention to the normal children in the family.
Grandparents,
uncles, aunts and cousins (the large family) can, if available, be very
helpful. Cousins who are a similar age
can add to the necessity of socializing with children so that isolation does
not take place. (Of course, the child's
friends from the neighborhood or school play a similar role.) Grandparents and other relatives can help
bring about independence for the child with MSUD, by enlarging the number of
important people and providing places to stay away from home. Grandparents have to be careful not to be
too worried or to spoil their grandchild.
They can be very helpful to their children -- the parents -- when they are
supportive and not critical, and raise their children's self‑esteem as
parents.
Health
Professionals
We have a
particularly fortunate situation in Montreal.
The health professionals who care for the children with MSUD and their
families truly join the families, and in some ways become family members. Yet, at the same time, they can keep
sufficient professional objectivity, enabling them to give sound medical and
psychological help. Ideally, medical
care-givers need to tread this balance of being part of the family, with no
professional condescension, but rather with respect for the many unavoidable
hurdles. Yet, they need to keep sufficient
distance to accurately appraise why and when the family can and needs to use
their help. When psychologists or
psychiatrists are part of the team, much benefit results.
Families who do
not have good access to comprehensive medical or psychological care have to
become assertive advocates for their children until the required services are
found, a role requiring a degree of assertion for which parents may be ill‑equipped. Parent organizations, like this one, and
self‑help groups can be very valuable.
Parent groups have to avoid two patterns that are not always easy to
avoid. One is that parents can become
competitive with one another as to whose child is doing best. Another hurdle is that when an unfortunate
thing happens to one child in a particular family, it becomes a new threat to
all and could lead to more general pessimism.
Sharing all the possible worst things that could happen, but probably
will not, is not helpful. In spite of
these and other difficulties, parent organizations are enormously effective and
influence health professionals to understand the disorder, not only in terms of
the biological defect, but in terms of the psychosocial aspects of the child's
development. Parent organizations
provide the impetus for parents to mobilize better services at all levels for
their children. In getting together to
do this, they feel empowered and valuable.
Parents are our teachers, just as we share with parents our specific
medical and psychological expertise.
Parent organizations and meetings facilitate this interaction.
-- Gabrielle Weiss, M.D.