Dr Korson's May Chat - Never Posted but Sent To Me after Editing

[Guest guest]

I was sent this about a month before the MDA Chat administrator retired. It was not ever posted to the MDA site so I am sending it as I know many of you have wanted to read this chat with Dr Korson.

Alice

Mon., May 17, 2004

Muscular Dystrophy Association (MDA) Chat

MITOCHONDRIAL (MITO) CHAT

Guest Host:

Mark Korson, M.D.

Dr. Korson's medical training at the University of Toronto was followed by a pediatric residency at Toronto's Hospital for Sick Children. He completed a genetics/metabolism fellowship at Children's Hospital in Boston. Dr. Korson was Metabolism Service Director at Boston Children's for ten years until October 2000. He is currently the Associate Chief of the Metabolism Service at Tufts-New England Medical Center and an Associate Professor of Pediatrics at Tufts University School of Medicine. His interests include the natural history of metabolic disease (treated and untreated) through childhood into adulthood, and the development of teaching methods for training physicians, residents and medical students and community professionals about metabolic/mitochondrial disease.

Information contained in this chat transcript is not intended to replace, and should not be interpreted or relied upon as, professional advice, whether medical or otherwise. Please consult your own health care professional for advice concerning the matter discussed herein.

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MODERATOR -- Welcome Dr. Korson. It's great to have you here.

DR. KORSON -- It is a pleasure to participate in this chat room!

QUESTION -- I was just diagnosed with multi-complex defects of OXPHOS consistent with a MELAS variant through muscle biopsy and other tests. The complexes and which gene I don't know yet. My doctor is planning on discussing it next visit. My plasma lactate level was 23 (NL 3-12) and though my pyruvate was high normal, the ratio was 28. Is this all considered pretty high and what is considered dangerous? I heard that lactic acidosis can be life threatening, how so?

DR. KORSON -- Elevated lactic acid levels are called "lactic acidemia", or "high lactic acid in the blood". Lactic acid levels that are high enough to change the pH of the blood and actually turn the blood acidic is referred to as "lactic acidosis." Lactic acidosis does not usually occur unless the the levels run greater than three times the upper limit of normal, and occurs usually when lactic acid levels climb quickly. Under those conditions, yes, the acidosis can be dangerous. Many patients run mild elevations and show no clear symptoms as a result. MELAS syndrome is associated with elevated levels only some of the time; I have patients with the MELAS mutations who have NEVER had an elevated level. That's a problem with the current inadequacies of our classification system.

QUESTION -- Are children with long chain fatty acids disorders (and on a normal diet) in need of EFA supplementation and if given essential fatty acids will they be able to properly metabolize them?

DR. KORSON -- If the child is following a "normal diet" (no fat restriction), then extra essential fats (EFA) are not necessary. Patients with fatty acid oxidation defects probably metabolize them slowly. However, under conditions of fasting or illness, when metabolic needs are high, patients with defects cannot metabolize them fast enough and run into trouble (develop symptoms).

QUESTION -- My daughter (17; Complex IV)has episodes of extreme irritability that seem clearly out of the norm and can last a couple of hours. Normally, she is very easy going. She is fasting intolerant, and the irritability sometimes responds to food, but not always. These cluster for weeks, sometimes alternating with days of extreme fatigue, drowsiness, and reduced muscle tone. Would you please give possible reasons for irritability in MITO and possible treatments?

DR. KORSON -- There are numerous causes for irritability, including 1) - pain (muscle cramps, nerve pain or neuropathy, headaches and migraine, abdominal distress associated with poor motility), 2) - numbness/tingling (neuropathy), 3) - seizures, 4) - dizziness (due to autonomic dysfunction), among others. Any of these will run together with other symptoms. There are therapies for each, but depend on making the current diagnosis of the cause. It may be worth giving a trial of pain medication consistently for 1-2 days first to see if it is pain, and if not consider one of the other causes.

QUESTION -- My infant son has a diagnosis of a partial defect of Complex I and a suspected fatty acid oxidation disorder (elevated long chain fatty acids/carnitine deficiency), all diagnosed through a frozen muscle biopsy. His doctor (who evaluated the frozen biopsy, sent to him from Boston) has recommended a fresh biopsy to investigate the results. What further information could be gained from a fresh biopsy? Or more importantly, why can't the fresh muscle biopsy wait? We are concerned as he has been through so much already (G-tube placement complications, frozen muscle biopsy surgery, several hospitalizations, etc).

DR. KORSON -- If the quality of the result is not in question (e.g., no concerns about the technique or the processing of the specimen), then there seems to be a real problem in your son's respiratory chain. Complex I defects are often associated with fatty acid oxidation impairment, further supporting the diagnosis. I am not sure that another biopsy is needed right now. The approach to management will not change all that much, although further information may help point toward slight changes in vitamin or cofactor therapies. Mitochondrial DNA studies should probably be performed to evaluate a possible DNA mutation that has been found to be associated with complex I defects, especially if there is a family history suggestive of an energy problem.

QUESTION -- My 18-year-old son is on the autism spectrum, and has deteriorated physically, developed movement disorders, and lost an awful lot of weight. He is 6 feet tall and only weighs 61 kg (lost 1 kg from a cold recently but regained it). He was 67 kg nine months ago. He eats a lot and eats good food but won't eat red meat.

My son's extreme fatigue, cramping from toes to hips when walking leisurely, and inability to get up out of a chair gets worse as the day goes on and is very scary at night resembling paralysis at times, yet he can still speak, but appears breathless and complains of chest pains.

He had an appointment with a neurologist at our local hospital last week and was told that he should see a psychiatrist because the neurologist didn't know what was wrong and couldn't recommend any treatment or further testing.

Any ideas?

Would MCT oil help keep weight up? I give him CoQ10 300 mg/day in divided dose and basically follow the MITO cocktail with the exclusion of carnitine, because for some weird reason he looses even more weight when taking carnitine.

DR. KORSON -- A percentage of patients with "autism" have underlying metabolic/ mitochondrial disease. And a percentage of metabolic/mitochondrial patients have autistic-like features. It is worth having your son evaluated by a metabolic physician to consider underlying causes for his "autism" since the features you describe are not typical for autism; mitochondrial disease should be considered. Also remember that anyone who has a sleep disturbance (characterized by restless sleeping, snoring, sluggishness when waking up on your own) can suggest sleep apnea which is often associated with significant fatigue during the day; fatigue can improve significantly when the sleep problem is addressed. And mitochondrial patients are at risk for sleep apnea.

QUESTION -- I have a 100 percent TPN-dependant daughter who has a "clinical" diagnosis of MITO who cannot receive CoQ10 (beacuse it has to be given through the gut and in oil). I have heard that there is a company in Japan that will possibly begin making a parenteral form of CoQ10 or that possibly it can be given through the skin as a patch. Do you know about either of these products or have more information?

DR. KORSON -- Yes, both of those products are in development. I know a pharmacist who tried mixing coenzyme Q10 in a lipid-based gel patched to the skin. The patient showed some clinical improvement for a brief while but blood levels of coenzyme Q10 did not seem to show an increase compatible with the dose he was taking, so I don't recommend trying this.

QUESTION -- My daughters carnitine level is normal but she has lots of autonomic symptoms. Could extra carnitine help keep her blood pressures up? We've been bolusing saline through her central line for diastolic less than 40.

DR. KORSON -- In general, the cardiologists seem to approach autonomic-based blood pressure issues by 1)-providing more fluids on a regular basis (not just in response to low pressures), 2)-providing fluids PLUS extra salt (to retain fluid and regulate blood pressure), 3)-doing the above and treating with medication (such as Florinef) which help retain fluid and stabilize blood pressure). I don't believe carnitine helps but there is so much we don't know, so to give extra carnitine a trial is reasonable. By the way, even patients with "normal" carnitine levels can show a benefit from supplemental carnitine.

QUESTION -- I am 38 years old, with a clinical diagnosis of MITO. I have started doing some walking for some exercise, but I am experiencing some bad leg cramps on the front outside of my calf and burning throughout the whole leg, especially down the back when walking. I have been walking for 6 weeks, two-three times a week, for one to two miles each time. Things are not improving; they are getting worse. I am trying to stay well hydrated and just started taking some magnesium supplements to see if that helps. Do you have any further suggestions? I have a fairly active job and am on my feet most of the day, but this is a completely new symptom for me. I am trying to cut down the length of my walks, bought new well-supportive shoes and am walking on a soft surface track. I am doing everything I can think of.

DR. KORSON -- Listen to your body. If one-two miles bring on symptoms, try half a mile then rest then another half-mile. The end point of your exercise should be reached before you develop (significant) symptoms. If you are more fatigued (i.e., "bad day"), reduce your expectations. If it is hot or humid out, cut it shorter or keep it indoors or work out in a cool-temp pool.

QUESTION -- My son is two years old and has LCHAD. He's been in the hospital for so called "vomiting viral attacks" almost every month for about six months now. I'm getting very concerned that something else may be wrong; it's not really always viral. Two people recently mentioned CVS to me. I haven't had a chance to look into it yet and wanted to know more about that or other areas to look into. Also, he takes Carnitor and MCT, canola and cod liver oil, but I've been reading up on CoQ10. Should he be on this and could it potentially help these acute illnesses?

DR. KORSON -- How was the diagnosis made? If an enzyme or DNA mutation diagnosis was not made, perhaps the LCHAD features are actually secondary to an underlying mitochondrial problem (LCHAD patterns in biochemical testing occur in complex I defects). By treating the mitochondrial disorder (including CoQ10), perhaps the vomiting will come under better control. If the LCHAD deficiency is a proven diagnosis, then try keeping him fed every 4-6 hours around the clock; this should help prevent catabolism and its symptoms. If he responds, then gradually increase the duration of overnight fasting to test his tolerance, remembering that during illnesses or periods of poor intake, he must eat/drink every four hours around the clock. By the way, make sure he doesn't have another cause of vomiting which sets things off like migraine or reflux.

QUESTION -- I am 41 years old and diagnosed with mitochondrial myopathy and encephalomyopathy. The muscle biopsy was not able to identify the particular problem. My doctor says I have symptoms consistent with MITO and that I have additional autoimmune problem. I have a big problem with exercise intolerance that puts me in crisis (weakness with encephalopathy). However, I have not given up on exercise and am trying a slow therapy program to build up my conditioning. I have an obesity problem and cannot seem to keep from gaining weight without activity. What are your thoughts on the value of an exercise program? And, do you think strengthening should be part of it? Please take into consideration that without exercise my weight and cholesterol go up.

DR. KORSON -- Exercise is important to maintain muscle tone, coordination, range of motion and prevent atrophy. As I mentioned before, you need to listen to your body and test its limits. Keep active with regular breaks and resting, modifying your exercise according to your daily status. On low energy days, poor sleep days, hot/humid days, cut back on your workout. On better days, increase it. The end point of your workout should not be pain or profound exhaustion. If you continue to gain weight, check for thyroid problems (a risk in mitochondrial disease) and/or cut further on calories -- you might want to consult a dietitian to help in this regard.

QUESTION -- I've heard that glycine is therapeutic for GA2? How does it work and what does it do? My son is seven years old.

DR. KORSON -- Glycine (an amino acid) and carnitine (a body cofactor) bind to various chemicals in the body. Carnitine binds with greater affinity (tighter bond) to some chemicals, glycine to others. Carnitine is generally the cofactor of choice for GAII; it binds some of the accumulating chemicals (like glutaric acid) and helps facilitate their excretion from the body. These chemicals in larger quantities often tie up an important body cofactor called Coenzyme A; by binding the chemical directly, the carnitine frees up the coenzyme A to do all it needs to do. Glycine does the same with certain chemicals, but I would have to research what benefits have been shown for glycine in GAII.

QUESTION -- My pulmonary function test indicated an early anaerobic metabolism and profoundly reduced carnitine levels and there was an indication in my labs which suggested the possibility of a mild MADD, GAII disorder (actylcarnitine elevations). Can the early anaerobic metabolism be caused by a MADD disorder alone - or is it more likely that a mitochondrial disorder is behind that problem?

DR. KORSON -- MADD (multiple acyl CoA dehydrogenase deficiency) is also know as GAII (glutaric acidemia type II). MADD is a form of energy disorder affecting the function of the mitochondrion (it interferes with many reactions including one that involves delivering high energy electrons from the Krebs cycle where they are formed to the electron transport chain where they are used). So it could very well be the cause of your lab results.

QUESTION -- My 18 year old son has mtDNA mitochondrial Disease, severe Dysautonomia, severe Cyclic Vomiting. He also has exercise and heat intolerance. He receives monthly hydration for three days. The hydration really seems to perk him up. Why does he do so much better after the hydration?

DR. KORSON -- Several possible reasons. 1)-Autonomic dysfunction is often associated with blood pressure problems and fluids help. 2)-If there is sugar in the IV, the extra calories might help as well especially if he is not a good eater or has problems with his gut function. 3)-If this is migraine related, since underhydration and/or undernutrition can precipitate migraine (and vomiting), fluids can help. 4)-Whatever cyclic vomiting is, it seems to respond to fluids. Have you tried any of these on a regular basis as prevention: Regular fluids daily through a PICC line or central IV (autonomic), high-dose riboflavin daily (migraine), Periactin daily (migraine, cyclic vomiting).

QUESTION -- What sort of pre-conception or perhaps pre-natal technology is available to couples who have a child diagnosed with mitochondrial disease and wish to have another child? Is there any technology that can reduce or even eliminate the risk for future children? I have heard of pre-genetic implantation diagnosis (PGD), but did not know if mitochondrial disease can be identified through this procedure. We have one child with mito. and another who is unaffected. Our affected child's disorder has been identified as a nuclear mitochondrial disorder.

DR. KORSON -- If a DNA mutation has been identified as part of the diagnosis (very rare due to limits in our technology), then prenatal diagnosis or PGD are options. If only a respiratory chain enzyme diagnosis was made (vast majority of cases to date), many labs do not feel comfortable with the accuracy of the prenatal enzyme testing to make a prenatal diagnosis. That leaves looking for possible evidence from other forms of testing like ultrasound (e.g., if a small head -- microcephaly -- is part of the presentation).

QUESTION -- I just had a biopsy that said I had a profound deficiency of succinate cytochrome C reductase. I believe this is complex II/III. How does this present itself as far as symptoms and transmission? I also have three affected kids.

DR. KORSON -- There are a variety of clinical presentations that are possible with disorders caused by problems in complexes II or III. The majority of defects involving complex III and all involving complex II (depending on where the primary defect is) are autosomal recessive reflecting genetic abnormalities in the nucleus. A minority of complex III defects are caused by genetic abnormalities in mitochondrial DNA which is maternally inherited.

QUESTION -- Our son is now 7, was diagnosed in infancy with a rare terminal seizure disorder, muscle biopsy came out -- no MITO disorder. One year ago, his breathing became erratic, to a point that he can have apnea every 30-60 sec. for 30 sec to three min. He does not realize this and it happens continuously when he's awake and asleep with beautiful rhythmic breathing. He is now on 4-6 liters of oxygen through nasal prongs, 24 hours a day. For some unknown reason, this keeps him gong; without it, he is totally blue centrally within about a minute or two. His doctors decided that he is in brainstem failure due to a MITO disorder. How can this be since originally his test came back -- no MITO disorder? His quality of life is still good, though he gets tired. Less than a year ago, he was given two weeks to live, but he is our fighter. Any patients similar and what can we expect?

DR. KORSON -- Central apnea (brain failure to stimulate breathing) and peripheral apnea (due to obstruction and/or muscle weakness) can occur in mitochondrial disease. But there are other causes for apnea that are not mitochondrial in origin. If your son does not have a mitochondrial cause, there's your answer. If he does, then you should know that muscle biopsy results provide only one piece of information that helps determine a diagnosis. I have other patients who have confirmed DNA abnormalities that prove a mitochondrial diagnosis but the muscle biopsy results were "normal." The testing that currently exists for making a diagnosis is OK but not the most sensitive nor specific; we need to develop better testing.

MODERATOR -- Thank you Dr. Korson for your time tonight and his wonderful answers.

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