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Q: What fats do MCADers need to avoid?

A: 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., selfnutitiondata). 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

Q: 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?

A: 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.

Genetic Counselor

A: (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.

Q. Do you have information about the skin biopsy done for FOD diagnosis? How large is the area of biopsy, any sutures/steri strips? How long does it hurt afterwards? What is the average waiting time for results?

A. Skin biopsies taken for enzyme analysis require an amazingly small piece of tissue, 2-3mm. This can be accomplished with a Punch biopsy tool or scalpel. Usually the skin is numbed. Some Providers use some EMLA cream topically first. It should optimally be in place 30-60 minutes. (I personally write prescriptions for families and have the patch put on prior to arrival in Clinic. Then the child isn’t hanging around getting more nervous.) Some providers use a very small needle to put in some numbing medicine, like Lidocaine, right before the procedure. For enzyme analysis, it doesn’t matter where the tissue comes from so long as it is cleaned well, and not a pressure point that won’t heal well and may hurt more. On infants and small children, I like the upper, outside of the buttocks. It’s easy to hold them to get at this spot. They can’t see it or pick at it after it is done. Older kids will hold still, even if they aren’t happy. Under the arm is commonly used because even though the scar is very small, it will be completely hidden. Under the arm is also very important, if the tissue is to be looked at under the microscope for any reason. The wound is very small and doesn’t usually require stitches—sometimes steri-strips are used. Some type of dressing will be on top, a bandage, gauze or Tegaderm—it doesn’t really matter. It heals fast. It doesn’t hurt very long either. I think most kids just hate being held still, and are most upset by that, rather than the procedure itself which is usually very quick.

Results can take a while, several months sometimes. Bottom line is that the small piece of skin cells needs to grow large enough to get enough enzymes to test, that takes time, before any tests can even get done. Sometimes, skin cells grow slowly, and there is no way to speed that up. Patience is the word of the day. Waiting for results and answers will be hard.

Lynne A. Wolfe, MS, PNP, BC
Metabolic NP

Q. I have a question about low blood sugars and about not relying on them as an indicator of crisis. Hypoglycemia is not an indicator in all crisis situations. This is very important. I think this is a point that needs to be emphasized. Can someone elaborate on this?

A. The take home message from the Orlando Conference (Oct 2002) about low blood sugars was that for a long time, all FODs have been lumped together in a category of “hypoketotic hypoglycemia”—low ketones (or no ketones) and low blood sugar. Dr Roe, Dr Korson, Dr Rinaldo, Dr Winter, and the other speakers, all clarified that as we learn more about FODs, of which there are now 18 known, we are seeing different characteristics in each. Some, like MCAD and one type of VLCAD, are prone to low blood sugars—some are not. Also, in children who have had experiences with low blood sugar in the past, that may be their main red flag. And, infants and younger children tend to have more frequent low blood sugars than older children. HOWEVER, especially in children who are recognized and being treated, their symptoms may include lethargy, some other type of altered behavior etc., as they build up the toxic fatty acids during an acute illness or prolonged fast. You need to speak with your doctors to clarify what they feel is the most important concern for you and your child, based on their diagnosis and responses during illnesses.

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
Metabolic NP

Q. 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.

A. 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
Metabolic NP

Q. 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?

A. 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
FOD Family Support Group

Q. Why is carnitine suggested for some of the fatty oxidation disorders and what is its purpose?

A. 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.]

Q. What is the difference between Newborn Screening (NBS) and the acylcarnitine profile?

A. 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 (now retired) and Staff
Institute of Metabolic Disease
Baylor University Medical Center

Q. What is the difference between an Amino Acid and an Organic Acid?

A. 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 (now retired)
Institute of Metabolic Disease
Director, Mass Spectrometry Lab, Dallas, TX

Q. What does an elevated SGOT mean?

A. 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