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Fats are made
up of long chains of carbon atoms. They are referred to as very
long, long, medium and short chains depending on the number of those
carbon atoms. Very long fats >20 or more carbon atoms, long 18-14,
medium 12-4, short <4. Each chain length has specific dehydrogenase
enzymes that cut off 2 carbons at a time when functioning normally.
Hence, MCAD = Medium Chain Acyl CoA Dehydrogenase deficiency. In
that disorder fats with carbon lengths between 12 and 4 cannot be
broken down and toxins build up. Aside from MCT oil, most medium
chain fats in our diets come from the normal breakdown of very long
and long chain fats that are found in meats and dairy products.
So we really cannot completely avoid eating these, and we would
not want to because fats are critical to the normal development
of our nervous system and hormone synthesis. So we eat wisely—lean,
low fat meats and fish, veggies, fruits, etc. Avoid saturated and
trans fats as much as possible. Avoid too many simple carbohydrates
that create obesity—instead use complex carbohydrates like
whole grains, brown rice, etc.—natural sources of essential
(meaning we need to eat sources) fatty acids include canola, soy
and walnut oils, salmon, etc. There are several Web sites that list
fat chain lengths (i.e., www.nutritiondata.com).
We often monitor comprehensive free fatty acids (C8-26) every 3-6
months, to make sure that the essential fatty acids stay in normal
range because they help with immune function, nervous system function,
hormones, growth, etc. We usually encourage our patients to avoid
Olean and completely fat-free or nonfat foods. The bottom line though
is that you need to monitor the saturated fats and foods with lots
of long and very long chain fats. A metabolic dietitian is really
critical in helping you with good diet choices.
Lynne Wolfe
Metabolic NP
LAWPNP@comcast.net
I have a daughter
who was diagnosed with MCAD. Has anyone been told that their child
carries two different mutations and that because of the two different
mutations the MCAD is 'mild?' We still have her on a three- to four-hour
feeding schedule, but I'm wondering why does having the two different
mutations make a difference?
Many people
with recessive genetic conditions (needing mutations in both copies
of the gene to have the condition) have two different mutations.
There are many places on a gene where a mutation can occur and two
different mutations only reflect the parents’ individual genetic
backgrounds. In the case of MCAD, it happens that the A985G mutation
is by far the most common, and about 80% of patients have TWO copies
of this mutation. So your daughter is not considered 'mild' because
she has two different mutations, but because we know something about
the nature of those mutations individually. The T199C is a newly
discovered mutation that was only detected when states started screening
for MCAD at birth. That meant that all these kids were diagnosed
with MCAD before they ever had the opportunity to get sick and be
diagnosed that way. Many of the kids diagnosed by newborn screening
might NEVER have become ill from their MCAD, or only have been diagnosed
much later in life during a very severe viral illness. The T199C
mutation has not been seen in a child who was diagnosed by her symptoms,
but is showing up a lot in kids diagnosed by newborn screening and
so that implies that it is a mild mutation. Studies of the mutation
and what it does to the enzyme show that it only mildly disrupts
the way the enzyme works and so the enzyme works pretty well under
normal conditions. If anyone is interested in reading a scientific
journal article about MCAD mutations, below is an abstract from
Andresen et al. American Journal of Human Genetics, 68, 1408-1418.
With the exception of the T199C mutation, the best guide to whether
your child is mild or not is her clinical picture and not her mutations.
That is, how long can he/she generally fast before getting hypoglycemic,
has she/he experienced normal childhood illnesses without needing
special support, or did a cold or sinus infection put her into the
hospital? Does she need cornstarch at night or a nighttime snack
to avoid hypoglycemia in the morning or can she make it through
without trouble? These are questions I'd encourage you to discuss
with your metabolic team and are better indicators of how mild or
severe she might be. Also, if your child was diagnosed years ago,
they might not have identified the second mutation. The A985G mutation
is so variable. Case in point: we just diagnosed a little girl with
MCAD who is homozygous (has two copies of the same mutation) for
A985G. She didn’t get hypoglycemic until she had an operation
and had been fasting and then vomiting for 36 hours! So you really
can't make any predictions by using the mutations alone. I encourage
all of you to discuss your questions with your metabolic team and
a genetic counselor (if he/she is not part of the team already).
You cannot depend on the mutations alone to predict how your child
will do. This is not a black and white issue in terms of what is
mild and severe, and having a label of 'mild' or 'severe' isn't
necessarily helpful either. There's so much variability with MCAD
(and other FODs); there are obviously other factors, but they're
not clearly understood. But we don't need to understand exactly
what makes one child more sensitive than another to treat that child
appropriately. I think it's best to realize that everybody who has
children with MCAD (or other FOD) have that common bond over the
diagnosis, but beyond that, each child is an individual. As with
any medical condition, there are common ways to treat, but management
really needs to be individualized. So talk to your doctors and nutritionists
about your children and ask about the thinking behind their management
decisions so you'll have a good sense of your team's approach to
care.
Lisa
Genetic Counselor
(additional
comments from Lynne, Metabolic NP)
This is a perfect time to agree with Lisa’s comments above.
FODs, OAs, and many other biochemical disorders really cannot be
assigned a mild to severe label based on any DNA mutations alone
- we have to look at how each individual reacts. In Genetics, there
are two concepts that are critical. Phenotype = what the patient
looks like physically, biochemically etc., AND Genotype = what the
genes actually are. Most of the FODs have been studied to look for
matches between Phenotype and Genotype because IF the Genotype really
did dictate the Phenotype, we could manage disorders easily. That
is not the case at all. There really is not any Phenotype/Genotype
matches in any of these disorders. As Lisa said, each child is an
individual and will present with symptoms of their FOD depending
on their other Genetic predispositions, their environment, etc.
We are all still learning about these disorders and how genes dictate
our normal body functions. It will be a while until we can say for
sure what the real impact is of all the genetic mutations we are
still in the process of discovering. The difficulty is that humans
have normal variations in genes called Polymorphisms and they occur
in a predictable incidence in the normal population. When that is
all that is found in a patient who has a disease, and it is unlikely
that a common polymorphism is causing the disease but nothing else
has turned up, it is occasionally labeled "mild" for want
of any better explanation. However, it is more likely that either
the patient has a "private" mutation (unique to their
family) or a mutation that has not been previously discovered. We
have LOTS to learn about Genetic disorders.
Lynne A. Wolfe, MS, PNP, BC
Metabolic NP
LAWPNP@comcast.net
Low Blood sugar is a very important symptom for some
FODs. Normal blood sugar is 70-120, it might normally peak slightly
higher after a meal, until Insulin is released and drives sugar
into our cells to make energy. Infants are very prone to low blood
sugar for several reasons, the biggest being they don't have good
stores of Glycogen, the body's way of saving sugar for later use.
Most Metabolic Specialists protect Infants with FODs from low blood
sugar by having them eat every 4-6 hours. As we get older, develop
more Glycogen and some other hormonal things change, we become less
likely to experience low blood sugars—but
in children with certain FODs it is still possible. So, in the older
children, raw Cornstarch is used to provide a very slow release
of sugar over a long period of time, 6-8 hours. This is why yesterday,
I wrote that "under treatment" even those children with
FODs that are associated with low blood sugars, usually do not experience
low blood sugars. For sure, the only way to monitor for low blood
sugar accurately, if that is something your Dr wants monitored,
is to check it after 6 hours of fasting. If you check a blood sugar
while Cornstarch is still being absorbed or after you have given
your child something to eat or drink—the
blood sugar will appear normal even if it wasn't and then your Metabolic
Specialist has no way of knowing how best to treat your child.
Lynne A. Wolfe, MS, PNP, BC
LAWPNP@comcast.net
Metabolic NP
Can
you please address elevated ammonia issues and FODs? From my reading,
I believe that once a child is symptomatic from elevated ammonia
levels (i.e. vomiting), it must be treated. If it is not treated,
it may get worse and lead to more problems like lethargy, coma and
death.
Ammonia is a
normal chemical in our bodies from the breakdown of proteins. It
can come from the proteins we eat or from the breakdown of our muscles
and other body proteins that occur normally every day. Most Ammonia
is broken down further in the Liver into Urea, which leaves our
bodies in our urine. Ammonia levels can rise when the Liver is not
able to work correctly from an infection, or a metabolic disorder
affecting the enzyme function of the Liver. The Liver can be affected
by many Metabolic disorders. "Reye-like" Syndromes have
been associated with children who have undiagnosed Metabolic disorders,
especially FODs. It is believed that high Ammonia levels can contribute
to the lethargy we often see when children are diagnosed with Reye's
Syndrome. Ammonia levels can become very high and cause severe problems,
including coma and death, especially when the children are in an
unrecognized metabolic crisis. There is a very complete list of
the metabolic disorders that have been associated with "Reye-Like"
Syndromes, and how undiagnosed metabolic Disorders and true Reye-Syndrome
differ on the FOD Web site under Medical
Information. Ammonia is measured in a blood test. It is a technically
finicky test requiring fast, non-tourniquet drawing, sometimes arterial,
rather than venous blood, it must be put in ice immediately, and
run in a very short period of time or the results can be falsely
elevated. It is affected by when your last meal was eaten, how well
the Liver is working etc. For children with FODs this would not
be a routine test, but it would be considered if your child were
very ill and lethargic.
Lynne A. Wolfe, MS, PNP, BC
LAWPNP@comcast.net
Metabolic NP
Our
child was recently diagnosed with an FOD. How can I explain the
seriousness of the disorder to relatives, friends, teachers, etc.,
without alarming them?
If you have suffered the death of a child(ren) and/or a near-death
episode, conveying that information to relatives, friends, teacher,
etc., will quickly enlighten them as to the seriousness of an FOD,
as well as to the ramifications of not diligently treating your
present FOD child. Not having the individuals panic after hearing
that information is a real balancing act, however.
One possible way of approaching this situation is
by having a talk with the individual explaining some of your concerns
and fears of coping with an FOD. After discussing how the disorder
has affected your family (death or near death of child), shifting
your discussion from death to focusing on your present child's FOD
concerns and needs, as well as on the hopefulness for a 'normal'
lifetime, may be a helpful way of keeping all those involved from
panicking. They are aware of what can happen, but their immediate
concern is to meet your child's needs while at school, daycare,
or in your home.
In your discussion, you can explain a few guidelines
that need to be followed (i.e. eat frequently, low-fat meals and
snacks, and possibly taking carnitine at certain times). Your guidelines
will vary depending on what situation your child is in (i.e. all-day
daycare, school, short-term babysitter). Some parents find it helpful
to have a complete schedule written out giving times for carnitine,
meals, etc. This way the caregiver does not need to make major decisions
about when to do these things. They may feel more comfortable if
everything is written down and explained. Be sure to highlight the
most important details, but try not to make it so detailed so as
to overwhelm the individual.
In summary, stressing the seriousness of the FOD is
important, but having the individual meet your child's needs is
the immediate concern. This balancing act may become easier over
time and as you feel more confident in discussing and actually working
through your child's well- and sick-routines.
Deb Lee Gould, Director
deb@fodsupport.org
FOD Family Support Group
Why is carnitine
suggested for some of the fatty oxidation disorders and what is
its purpose?
The production of energy
takes place in the mitochondria, the "power plants" of the cell.
Fatty acids are the preferred energy source for the mitochondria,
especially for muscle and heart cells. Entrance of most fats (i.e.,
long chain fats) into the mitochondria requires a carrier molecule
called carnitine. Once inside the mitochondria, the fats are metabolized
in a process called fatty acid oxidation to produce ATP (a chemical
form of energy).
Carnitine also serves a second important role in the
mitochondria where it functions to remove toxic organic acid (OA)
compounds. This scavenging function is important since high concentrations
of these OA compounds impair the mitochondria's ability to produce
ATP. After removing these compounds from the mitochondria, the carnitine-organic
acid compound is eliminated in the urine. This loss frequently leads
to carnitine deficiency if supplemental carnitine is not provided.
If carnitine concentrations are inadequate, entry
of fatty acids into the mitochondria are blocked. In addition, scavenging
of the toxic OA compounds is impaired leading to a buildup inside
the mitochondria. This results in a depressed production of ATP
and causes the person to exhibit signs and symptoms of low energy
production (i.e. floppy appearance, poor growth. weakness. lethargy)
and dysfunction of multiple organs including heart, muscle, liver,
and brain.
We receive a significant amount of carnitine from
foods we eat. The average diet contains approximately 100-300 mg
of carnitine derived mostly from red meats, poultry, and dairy products;
strict vegetarians have low carnitine intakes. Our bodies can also
synthesize carnitine from proteins we eat.
Newborns have less synthetic capacity to make carnitine
than children and adults. Carnitine has been added to most infant
formulas and is also found in mothers' breast milk. Carnitine is
supplemented in many of the special formulas designed to treat organic
acidemias. But usually additional carnitine, administered separately,
is recommended in the treatment of some of the fatty acid disorders.
Especially during times of illness and metabolic stress,
the defective enzyme results in a buildup of the toxic OA compounds.
These compounds bind to carnitine in the mitochondria and are then
excreted in the urine. This excessive loss may lead to a carnitine
deficiency if not adequately replaced.
[This information was taken from an article written
by Elaina Jurecki, MSRD & John Baker, MD of the Regional Metabolic
Center, Kaiser Permanente. Oakland, CA. It was printed in the Organic
Acidemia Newsletter August 1994.]
What is the difference
between Newborn Screening (NBS) and the acylcarnitine profile?
Tandem MS (MS/MS or tandem
mass spectrometry) is a technology that is used in various ways
to measure many different compounds. Specific tandem MS methods
can detect elevated levels of biochemical compounds in blood that
are useful for diagnosing many inherited disorders of metabolism.
It is important to realize that the different types of tandem MS
tests are designed to detect specific disorders and therefore may
not diagnose some diseases. Supplemental Newborn Screening is typically
done in conjunction with state newborn screening and may include
other tests in addition to tandem MS.To determine what your child
may be tested for, one should request an information sheet from
your testing laboratory. This should list what disorders will be
tested for, such as amino acid disorders, organic acid disorders,
fatty acid oxidation disorders or other types of disorders.
For patients with clinical symptoms or family histories
of inherited metabolic disorders, diagnostic tests for specific
disorders are much more appropriate than a general screen. The specific
tests, such as urine organic acids, plasma amino acids, plasma or
dried blood spot acylcarnitines should be determined and ordered
by clinicians based on the clinical symptoms.
Supplemental Newborn Screening by tandem MS: In our
laboratory, the Supplemental Newborn Screening is done by tandem
MS for amino acids and acylcarnitines. The test can detect more
than 30 inherited disorders of amino acid, organic acid and fatty
acid metabolism. It is an inexpensive screening test with dried
blood spots designed for screening healthy newborns at 2-3 days
of age. It is not recommended for the diagnosis of children with
clinical symptoms. Cut offs for normal levels of amino acids and
acylcarnitines in newborns are chosen to minimize false positives.
Approximately 1% shows some slight elevation of an amino acid or
acylcarnitine which causes us to request a repeat dried blood spot
card to see if the slight elevation is significant. Usually the
repeat is normal. The false negative rate is not known but is believed
to be very low. In order for this test to be inexpensive ($25),
it is highly automated. The quantitative results are analyzed automatically
by tandem MS computer programs for "normality" using cut offs established
for different groups of subjects. Although the screening is most
accurate for newborns it is still worthwhile to perform for older
infants if they were not screened in the newborn period.
Quantitative Acylcarnitine profile by tandem MS is
a more expensive test designed for the differential diagnosis of
fatty acid oxidation and organic acid disorders in children with
clinical symptoms or family histories suggestive of these disorders.
This can be performed on dried blood spots, plasma, postmortem blood
(or amniotic fluid with prior consultation). Because it is intended
for diagnostic evaluation, the cut offs used for acylcarnitines
are lower and every profile is examined by a technician for any
abnormalities in the mass spectrum, including peaks that are not
part of the quantitative analysis. Every profile is reviewed by
an experienced professional and reported with a professional interpretation.
The acylcarnitine profile does not include amino acid disorders.
Dr. Larry Sweetman, PhD and Staff
larrys@baylorhealth.edu
Institute of Metabolic Disease
Baylor University Medical Center
What is the difference
between an Amino Acid and an Organic Acid?
Amino Acids are the building
blocks from which proteins are made. They are chemical compounds,
which have an acid group and also a basic amino group, which is
why they are called amino acids. The proteins in our bodies and
our diets are made up of various combinations of about 20 different
amino acids. There are about another twenty amino acids which are
not usually part of proteins but have other roles in metabolism.
An example of an amino acid disorder is PKU in which the amino acid
phenylalanine cannot be metabolized properly.
Organic acids include a wide variety of chemicals,
which have an acid group but not an amino group. Included in the
organic acids are fatty acids, which come from the breakdown of
fats and oils. An example of a fatty acid metabolic disorder is
MCAD deficiency.
Some organic acids also come from the metabolism of
sugars. An example of an organic acid disorder related to the metabolism
of sugars is lactic acidemia. In the metabolism of many amino acids,
the amino group is removed to yield an organic acid. So there are
several organic acid metabolic disorders, which are due to defects
in the metabolism of amino acids.
An example is isovaleric acidemia, which is due to
a defect in the metabolism of organic acids derived from the amino
acid leucine. To make things more complicated, the disorder called
maple syrup urine disease has both elevated amino acids and elevated
organic acids derived from these amino acids.
Larry Sweetman, Ph.D
Institute of Metabolic Disease
Director, Mass Spectrometry Lab, Dallas, TX
larrys@baylorhealth.edu
Phone: (214) 820-4533
What does an elevated
SGOT mean?
SGOT (aka AST) is one the
liver function tests we monitor in children with FODs or OAs. It
is mostly found in the liver, but some can be found in the heart,
skeletal muscle, pancreas, kidney, lung, and white blood cells.
So it is not very specific to the liver. The liver enzymes SGPT
(aka ALT) & GGT are much more specific to the liver and if they
are OK - don't worry. On top of being not very specific to the liver,
SGOT also fluctuates day-to-day by as much as 10%, and it does change
depending on other things going on ~ for example if the muscle form
of CK (aka CPK) is elevated, the damaged muscle cells release SGOT
too. So it is very common to see elevated CK and SGOT together.
And yes, low elevations of both do occur in various FODs. One thing
to do is talk with your Doctor/Dietitian about checking to be sure
you or your child is getting enough overall calories. Sometimes,
adding extra calories (from carbohydrates) stops the muscle breakdown.
Most children with FODs and OAs need more calories than a child
at their same age might.
Lynne A. Wolfe, MS, PNP, BC
Metabolic NP
LAWPNP@comcast.net
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