Kathleens World

During the first three years of our effort's to find out what was "wrong" with our most affected son, Tim, we were met with constant frustration. It went something like this:

• Tim, born in October of 1994, full term, had a severe case of hyaline membrane disease, requiring NICU care with respirator and liquid surfactant. The neonatologists were mystified as to why this occurred. Luckily, he survived.
• Immediately after bringing Tim home from NICU, we noted he was very "floppy", had poor sucking, and needed to be handled very cautiously.
• He had numerous episodes of sudden dehydration.
• At age 8 months, he began physical, oral/motor and speech therapies. Feeding issues resulted in constant attention to weight gain (Tim is very low weight).
• At age 14 months, his physical therapist agreed with my observation that something more was going on with Tim than simple developmental delay.
• During this time, our pediatrician, who was a close family friend, allowed us to pursue investigation, even referring us to a geneticist, while also saying he thought everything was fine.
• At 18 months, Tim was diagnosed with a severe to profound bilateral sensorineural hearing loss, meaning he was deaf.
• At age 2, we went to Mayo Clinic, where all known disorders were ruled out, and the suggestion of mitochondrial disease was made. This was something we suspected through our own "internet investigation" and the use of the OMIM database.
• At age 3, a fluctuating hearing loss was confirmed, and Tim was enrolled in a full time hearing impaired preschool, with one on one support for his physical needs.
• More hospitalizations for dehydration occurred.
• In January of 1998, we chose a new pediatrician, who immediately referred us to Atlanta (Dr. John Shoffner) for a mitochondrial muscle biopsy.
• September, 1998: a Complex I and IV mitochondrial defect was confirmed.
• Mitochondrial mutation 4216 T-to-C transition in the ND1 gene associated with LHON and insulin resistance and a second mutation of 14687 A-to-G, a transition in the tRNA for glutamic acid that has been reported in a patient with myopathy and respiratory failure confirmed in our youngest son. These are in addition to four shared polymorphisms between two of the brothers. However, only the younger suffers from severe cardiac and pulmonary involvement. He actually has QT syndrome and hypertrophic cardiomyopathy, also know as HCM. Tim has actually improved his health status as he has aged.
• January, 2012: Our geneticist suggests that our youngest son be evaluated for possible channelopathy. As he has not diagnosed this himself, he is working on a referral for us. Certainly another muscle biopsy looms, at least for this son.
• We have moved from IL to Madison, WI to be closer to a major medical center/Children's Hospital. This is something that we should have done many years ago. The level of care is *much* better, and making it to regular therapies is a lot easier without an hour and a half drive each way.
• Parents: you cannot predict the course of your child's disease progress by what has happened to myself or any of my children.

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What is Mitochondrial Disease?
Here's an analogy to help you understand the way mitochondria disease works in people affected by this disease: If the power in your home goes out, your food will spoil, your air conditioning and heating won’t work, and you’re left in the darkness. The mitochondria is the part of the cell responsible for energy production and it is like the power supplier that provides energy to your home. If the mitochondria, or power supplier, is defective, your body cannot function as it should. The brain becomes impaired, muscles start to twitch spastically, causing pain and then those muscles weaken, the heart (which is the body’s biggest muscle) does not pump correctly, vision becomes impaired—the list could go on and on. For many children and adults with mitochondrial disease, this is exactly what they experience.
To give you a more "scientific explanation", look at the top picture on the left of a mitochondrian, showing you the basic structure of a mitochondrian, which are present in every cell in our bodies.

Mitochondria are the powerhouses of the human cell; they convert the energy stored in sugars and fats into adenosine triphosphate (ATP), the essential energy molecule of all animals. This energy production is carried out on a complex folded inner membrane of the mitochondria (see the picture above). Every muscle cell is filled with mitochondria, combinging sugars or fats with oxygen to yield water and ATP. Without this ATP, we would die, having no "power" left. Mitochondrial cytopathies have a diverse range of symptoms, and span many (all) organ systems. There is such a large number of biochemical and genetic defects, that currently a predictable clinical course does not exist. Using the description above, the analogy of a power supplier not supplying enough energy is a good one. The mitochondrian in the above picture is only one of many in your cells. The reason people manifest with SO many different problems is based on the percentage of "bad" mitochondria that get assigned to that part of the body. In our own family, some kids obviously have a higher percentage of bad mitochondria in their muscles than some of their siblings, while others have more brain (neurological) problems. The chart on the left (second picture down) shows you a basic idea of how this can happen. Keep in mind that men do not contribute mitochondria, but that does not mean that only Mom causes mito disease, as there can be mutations. 

Here's the simplest way to explain what happens. The food we eat gets broken down and assigned in various fashion. The fats and sugars go through processing, and there's quite a bit involved in this. If you get into this stuff more, you'll hear all about the respiratory chain and ATP, which is the end result, or energy. The mitochondria in a cell have to go through five "complexes" to create energy. An error in any of those complexes is bad, but obviously there can be varying degrees of how big the error is, and where it occurs in the energy making process. Mitochondria are responsible for producing most of the energy that's needed for our cells to function. In fact, they provide such an important source of energy that a typical human cell contains hundreds of them. A mitochondrial disease can shut down some or all the mitochondria, cutting off this essential energy supply. Because muscle cells and nerve cells have especially high energy needs, muscular and neurological problems are common features of mitochondrial disease. MDA uses the third picture on the left to help illustrate.

Current Diagnosis Status in Our Family
One of our kids has a muscle biopsy confirmed Complex I defect in muscle (done in Atlanta with Dr. John Shoffner) with negative mtDNA southern blot, negative SSCP and sequencing of mtDNA (Complex I, Complex V, tRNAs, rRNAs). His symptoms included: Dicarboxylic aciduria; abnormal enamel development; moderate retrognathia; bilateral fluctuating hearing loss; motor and language developmental delays.

Further testing showed he shares the following specific confirmed polymorphisms in the MITOMAP with his brother: 10463T>C, 11719G>A, 11812A>G, 14233A>G.

This younger brother is much more medically involved, with a rather long list of issues:

• Hyoptonia
• Cortical Dysplasia
• Developmental Speech Disorder
• Migraines
• Prolonged Q-T interval on ECG
• Simple Dental Caries
• Abnormal Weight Gain
• BMI, Pediatric >99%
• Hypertriglyceridemia
• Hyperinsulinism
• Hypoventilation
• BiPap dependence
• Obstructive sleep apnea
• Cardiomyopathy due to metabolic or nutritional disease (hypertrophic cardiomyopathy) 

Danny also has two reported mutations in MITOMAP, 4216T>C* and 14687A>G

*4216T>C is a transition in the ND1 region which results in a tyrosine to histidine amino acid change with provisional mutation status being associated with LHON disease and insulin resistance.

*14687A>G is a transition in the tRNA for glutamic acid region with "Reported" status being associated with Mitochondrial myopathy with respiratory failure

I should perhaps mention here that the boys had this test done through a simple blood draw, which obviously we all found easier than a muscle biopsy. However, getting approval for this Genome Testing was not easy in terms of our insurance company. See "When & Where to Get a Diagnosis" later on this page for more info on the place our geneticist used.

When Should I Suspect Mitochondrial Disease?

As you read this, it may be nothing like what your child has. When should you investigate mitochondrial disease in your child, or even in yourself? Here are some "Rules of Thumb" of when to think mitochondria:
 

A "common disease" (i.e. autism, cerebral palsy, lots of others) has atypical features that set it apart from the pack. Three or more organ systems are involved. Recurrent setbacks or flares in a chronic disease occur with infections. Credit for above "rules of thumb" to Mitochondrial News, Spring 2000 Issue by Dr. Robert K. Navaiaux.

Problems That May Be Associated with Mitochondrial Cytopathies

Taken from Mitochondrial News, Fall 1997 Issue by Bruce H. Cohen, M.D.

When & Where to Get a Diagnosis

Diagnosis of mitochondrial myopathies has been done only since about 1988. Fortunately the situation has improved dramatically for diagnosis in a local hospital. In the past I recommended going to only three doctors: Dr. Richard Haas in San Diego; Dr. Bruce Cohen (who has left Cleveland Clinic and is now at Akron Children's); or Dr. John Shoffner in Atlanta, GA. They are still the top guys in the field, but are no longer the only ones who can accurately diagnosis mitochondrial disease through muscle biopsy. Most major medical centers can offer help AND an accurate diagnosis. IF you are looking for a doctor for diagnosis purposes, try the UMDF (linked on this page) or call and ask for a metabolic physician. You can also try the genetics department of a Children's Hospital for a good referral. We are fortunate to live in Madison, WI, with the excellent care of the Waisman Center and their physicians at both the American Family Children's Hospital and the UW Hospitals and Clinics. 

Actually, now there may not be a need for muscle biopsies in everyone, though that's a matter for discussion with your doctors. Since we already knew that our kids had a confirmed mitochondrial disease because of the muscle biopsy done by Dr. Shoffner in the 90s, we've just been on the hunt for the error ever since. Two more muscle biopsies with Dr. Shoffner showed nothing wrong, one with a female sibling of Tim's, and one with me. But a muscle biopsy done elsewhere with me showed the opposite, and that I did, in fact, have a mito disease. Along comes TRANSGENOMIC Clinical Reference Laboratory. They are able to take blood, and in a process that I don't pretend to know how it works, read the whole mtDNA thing and tell what's wrong. It worked in our family, and they were able to find 4 matching mutations in Tim and Danny (the two tested) plus 4 more mutations in Danny. Here is the info on this lab, direct from their result sheet:
TRANSGENOMIC Clinical Reference Laboratory
12325 Emmet Street
Omaha, NE 68164
Phone 866-500-4363
fax 402-452-5459
CLIA# 28D103724

Back to how we handle things. Our doctors provide an "emergency protocol" letter that we can present to the first responders when any of the kids have a crisis. I really feel that we are working with a team that are doing all that they can to maximize the kids (and my) lives and to extend our lives.

SO--go where you must to get an accurate diagnosis, then interview doctors until you find those who are interested and willing to learn! The best way we have found to locate doctors is to contact the UMDF and ask them for guidance. If there is a support group in your area, they may send you there.
 
 

Diagnostic Testing for Mitochondrial Disease

1. Blood for mtDNA (PCR and Southern)
2. Blood and CSF for Lactate and Pyruvate, or Brain MR Spectroscopy
3. Urine Organic Acids (by GC/MS)
4. Plasma and Urine Amino Acids
5. Blood and Urine Carnitine
6. Brain MRI
7. Muscle Biopsy and Skin Biopsy, Neuropathology and Electron Microscopy, Mitochondrial Electron Transport Studies, Fresh (coupled) mitochondrial Polarography, Muscle mtDNA (PCR and Southern)

Taken from Mitochondrial News, Spring 2000 Issue, by Dr. Robert K. Naviaux

Carnitine: An essential thing to check in children with low muscle tone, frequent infections, slow weight gain.
Carnitine plays an important role in cellular energy metabolism!The mitochondria is the "furnace" of the cell. Fatty acids (fuel) must bind with carnitine to enter the mitochondria. Once inside, fatty acids are burned for energy. Carnitine then binds with the toxic waste by-products of metabolism, removing them from the mitochondria. The inner mitochondrial membrane is impermeable to fatty acids. Transport of fatty acids across this membrane can occur only when the fatty acids are attached to carnitine. Toxic waste products resulting from energy production are removed from the mitochondria by binding to carnitine. If they are not removed, toxic build-up occurs. Carnitine is a small molecule found in animal foods. There is little in a strictly vegetarian diet. This transport via the carnitine is the first step in turning fat into energy for driving muscle contraction or nerve cell firing. When carnitine is in short supply production of ATP is slowed. Only the L (levo) form of carnitine is safe for humans; the D form, which does not occur in nature, can be toxic.
Carnitine deficiency should be suspected if the any of the following are present:

Carnitine Deficiency is an often missed diagnosis, and can exist independently of mitochondrial disease. If you have a primary carnitine deficiency, treatment with Carnitor or another reliable replacement will bring about miraculous results. Check these links for more information on what carnitine is, and how it can be replaced in those with deficiencies.

Carnitine Defiency Syndromes: NORDFrom the National Organization for Rare Disorders

Mitochondrial disorders often have a carnitine deficiency along with them. Read up on the replacement supplement Carnitor at Sigma Tau's web page.

Tishcon Corp. makes a a very stable Carnitine that was developed and patented by Sigma-Tau. Their products include L-Carnitine combined with Co-enzyme Q10, discussed below.

Feeding

For children with weight gain issues, supplemental feeding becomes important. We used to use Pediasure to keep Tim's weight up. He required six cans daily, which is a lot to drink. We used an NG tube to assist him. In the summer of 1999 he had a gastrostomy tube put in, which is a permanent "opening" in his stomach through which  we can do feedings. During that surgery he also had a venous port implanted. He lost this handy device to a staph infection in late 2000, but we may opt to replace it soon. It was under his skin, on a lower rib, and is inserted directly via catheter to one of his neck veins. That made blood draws and I.V. placements much easier. Tim was able to have his g-tube removed in February of 2007, when he finally was able to prove he could take in enough calories by mouth. He was aged 12 at that time!

There are currently diet trials being implemented, with reduced long chain fatty acid content. Recent data indicates that many patients with Complex I defects have secondary defects in long chain fatty acid metabolism. This can further inhibit oxidative phosphorylation.

Dehydration

Because Tim and Claire dehydrate VERY rapidly, we get them to the hospital at the first sign of serious trouble (dehydration, severe lethargy, confusion). Vomitting almost always means they need an IV WITH DEXTROSE as soon as possible. This addition of fluids and sugar helps them with that flaw in the energy cycle. We have seen them come back many times from the brink of death to their normal, albeight slightly frail looking, bubbly selves. For a year and a half Tim had an implanted venous port, which allowed for immediate IV access and avoided the need to find any other veins, as his collapse so easily. Unfortunately, due to the refusal of a home care nurse to use aseptic procedure, this central line developed a staph infection that resulted in the line having to be pulled. When it is replaced in the near future, you can be sure that no nurse will access our son without adhering to my strict criteria, as spelled out by the Infectious Disease Specialist.

Co-Enzyme Q10

Coenzyme Q10 is a very hyped thing right now. You can get it in face cremes, power bars, and numerous vitamins. But for those with mitochondrial disease, it is considered as a generally accepted effective therapy, although it may not be effective for an individual patient. It is usually prescribed is a dose range of 5-15mg/kg/day, not to exceed 200mg daily. It is important that you get your CoQ10 from a trustworthy source, not from an ad in a magazine. Generally, chain providers (such as Walgreens, Osco, etc.) will have forms of CoQ10 available without additives. Check with your doctor before beginning this therapy, and tell them the full ingredient list on the label. There is now a blood test that can be done to see if Co-Q10 will even help a person. We had the test performed on two of our kids, and have since discontinued the use for our kids. Still, there are a couple of trustworthy providers in the links at the end of this page. Despite the tests that showed CoQ10 would not benefit our kids, my neurologist has recently informed me of new studies that say absolutely everyone diagnosed with mitochondrial disease should be on CoQ10 AND Carnitor to help slow the progress of their disease. He says this with great conviction, and while I don't wish to advertise my neurologist (he is the head of a very respected dept and exceptionally hard to get into, I told him I would not use his name) I believe him. The problem for us is that the cost is so prohibitive. 

There are ways to address the costs associated with the many supplements associated with having a mitochondrial cytopathy, however, and I refer to them later.

The Idebenone Question

Idebenone is a molecule similar to Coenzyme Q10 that is not currently available in the United States. Some people do obtain it from foreign sources, though I would be extremely wary about this. You will hear about how it penetrates the brain better than CoQ10, amongst other miraculous claims. However, no ACTUAL studies have reported this yet. That said, there does not seem to be reports of anyone worsening (or improving) while on it either. 

The case reports written by doctors that claim improvements in strength, visual acuity and other neurologic improvements are to be taken with a grain of salt, as physicians do not write case reports on failed therapies. There was a study of Idebenone being conducted with patients who have Freidreich Ataxia, which is a disease that causes some mitochondrial dysfunction. This study did show cardiac improvement, but no neurological improvement, in pediatric patients.

If you are going to give your child an unregulated supplement such as this, I highly advise you to be cautious. I wish, as much as the next parent, for some miraculous cure. But I also know that many people take advantage of suffering families. I recall the past enthusiasms about shark cartilage and other "guaranteed" supplements that would improve function and be the find of the century. Often these supplements come with other dangerous substances added into them. BUYER BEWARE!

Issues of Anesthesia in Mitochondrial Cytopathies

The full text of this article, written by Drs. Bruce Cohen, John Shoffner, and Glenn DeBoer is available online. But here, in a summary, are some things to keep in mind when a person with mito disease is going to have anesthesia:

1. The vast majority of patients with mitochondrial cytopathies have an uneventful surgery and anesthesia.
2. Patients rarely experience a complication with a simple elective surgical procedure such as a muscle biopsy or gastrostomy tube placement.
3. There are limited reports describing adverse events and outcomes in patients with mitochondrial diseases.
4. Patients with mito disease, on average, are "sicker" than an unaffected person undergoing surgery.
5. Patients with mito disease are at greater risk than unaffected people for side effects of some medications.
6. Adverse events reported include new neurologic problems such as a stroke, worsening of the overall neurologic status, respiratory difficulties, seizures, cardiac arrhythmias, prolonged coma and death.
7. Hypotonia (low muscle tone), bulbar dysfunction (weakness of the muscles that protect the airway) and relatively poor ventilatory function (decreased ability to breathe deeply and cough) are common in patients with mito diseases and pose an increased risk for perioperative pneumonia.
8. Malignant Hyperthermia (MH) is a life threatening, inherited syndrome triggered by potent inhalational anesthetic agents and/or depolarizing muscle relaxants. Muscle disease is ONE risk factor for MH. Many patients with mito disease sometimes have an associated disease that places them at potential risk for MH.
9. The risk of respiratory failure and worsening of neurologic function is often noted in patients with mito disease after "stressful" illnesses, including infections such as routine viral illnesses or pneumonia. Infections can occur with surgery, even minor surgeries.
10. Patients with heart rhythm problems are at risk for severe heart electrical conduction blocks, which can lead to death. Isoflurane may be a preferred inhalational agent as opposed to Halothane, because Isoflurane causes less disturbances in heart rhythms.
11. Although spinal anesthesia is safe, it should be used with extra caution in patients with neuropathies or myopathies, because of possible deterious effects on blood pressure and respiratory function.

Dealing with Supplement Costs

I know of almost no insurance company that will pay for the needed supplements for mitochondrial patients. Of course, insurers will weasel out of almost anything. I do find that persistence in matters can pay off though, so be prepared to keep fighting when it comes to them. Remember, they are staffed by human beings, though they try to hide this fact, and are quite good at it. 

The UMDF has an excellent article "Financial Help for Supplements" that is must reading for everyone who faces this issue. 

IN CONCLUSION...

This is a LOT of information. While almost all of it is negative and scary, you should know that my family is, for the most part, very normal. My older kids have gone on to lead productive, happy lives. I am happy to hear from families that find this site, and have communicated with hundreds of them over the years. I find that most ask the same questions, so let me tell you that if you are looking for a doctor in your area, or a support group, I want to direct you to the BEST follow-up out there. Things are so much better now than they were 12 years ago when we started out on this journey!

1. The United Mitochondrial Disease Foundation, or UMDF, is the one place you need to go for information. They can help you located local resources, and are "our" family that raise money for research, put on an annual conference for physicians and families, and sponsor support groups.

2. MDA, or the Muscular Dystrophy Association is known worldwide for it's support of "Jerry's Kids" but mito disease is one of the more than 40 diseases that falls under the MDA umbrella. If you or your child is diagnosed, contact your local MDA for support. The biggest benefit for kids is their annual Summer Camp, which my kids have loved.

3. Someone with way more ambition, time, and smarts than I did an awesome job with putting together the online MitoAction.org. It is an online site filled with all the latest news, supports, and answers to insurance issues, and anything else you can think of. Go there!

Contact Me

You can still email me. I love to get feedback from readers and do help when I can. But I tend to give the same answers to most who write; your BEST resources are:

1. United Mitochondrial Disease Foundation (umdf.org)

2. Muscular Dystrophy Association (mdausa.org)

3. MitoAction (mitoaction.org)