4 yr old/many issues/mitochondrial disease??

[kass]

Dear Doctor,

Thanks so much for the information you provide here for those in need of it. I have a 4 yr old daughter whom we are very concerned about and are attempting to find a diagnosis for so we know better how we might be able to help her. Her doctors here suspect something mitochondrial and are recommending we go somewhere for a fresh muscle biopsy, but considering the travel and surgury needed, I am looking for feedback from others before making this decision. Any feedback you can offer will be appreciated.

Brief history:
Normal pregnancy (my second) and uncomplicated labor and delivery.
Reduced, but present, movement in the womb.
Mild problems with heat regulation while in the hospital.
APGARs good, but difficult to make her cry.
8 pounds 9 ounces at birth
Hairy patch at base of spine and birthmark to left of lower spine with undefined borders.
Doesn't really cry till over a year old.
VERY easy baby
Nursing difficulties and a FTT dx when she was 6 months that we were able to rectify by nursing her on both sides twice each feeding. Still a slow nurser. All early milestones mildly late.
First 18 months she is below the 2% in weight and height.
At one year ped dx'd her with hypotonia and decreased or absent DTR's. She was not weight bearing.
Therapy is started and she cruises at 19 months and walks at 21 months. She is very hypersensitive and dx'd with SI Dysfunction.
At 18 months she suddenly jumps to the 70th % in height and weight.
Dx'd at 2 with a moderate-severe speech delay, starts therapy.
She is seen by a developmental ped, a nuero and an ENT. Hearing eval discovers a mild loss and fluid behind the ear drums.
Surgury done to put tubes in, remove tonsils (enlarged) and adenoids (sleep apnea), and perform a muscle biopsy.
Muscle biopsy showes Fiber Type I Predominance.
Nueromuscular specialist seen. MRI, CPK and Basic Chromosome screen ordered. CPK and Chromosome normal, MRI shows delayed myelination in the periatrial white matter bilaterally.
DTRs in all extremeties consistently 0-1.
Feet pronating and inserts are made.
At 3 she is dx'd with a mild-moderate gross motor and fine motor delay. Therapy continues, PT is added.
Leg length and size discrepency is noted as her gait begins to change. (1/4" smaller on left)
Left sided weakness becomes more pronounced, although she is left side dominant.
While still delayed, she continues to progress.

Since birth she has had spells of intense, progressive lethargy lasting anywhere from 2 weeks to 3 months, and periodically has a strong, unusual odor primarily noticable on her head. In the last year she has had 2 stomach bugs, both of which led to mild dehydration. Her response to this was to become almost non-responsive and completely floppy. All illnesses since birth have taken her longer to recover from, although she has been a relatively healthy child. Eye exams have all come back normal, as did her pulmonary check up a year ago. She also has something thats been around for as long as we can remember...the palms of her hands and soles of her feet are very red and you can see the capilleries are close to the surface. Head circumference has been 100+% since she was 2.

In March of this year 2 things started happening that brings us to where we are now. She began walking less and less, asking to be carried or ride in a stroller, complaining of leg pain from the knee down (focus often seems to be around the knee joint, but no swelling or heat). Madison is hypo-senstive to pain, and actually appears to not feel pain internally, so when she complains it typically means something is hurting her very badly.

She also suddenly changed her eating habits.  Went from being a mouth stuffer to taking very small bites and eating and drinking very slowly. When she began taking a drink and then coughing and sputtering and having it come out her nose, an upper GI and swallow study were done in August....Upper GI showed mild reflux, and swallow study showed mild nasopharyngeal reflux, and mild velopharyngeal insufficiency. She is eating/drinking less and less till where we are now, which is only 6-800 calories a day and less than 12 ounces of fluid are being taken in. PH probe and endoscope were done last week...esophagus looks fine and biopsies were normal, and pH probe picked up mild reflux. The eating difficulties are not related to oral motor problems or sensitivities, but appears to be an attempt on her part to protect her airway (pulls chin to chest when she drinks, chews for a long time, takes breaks in between bites). She has not, and never has had any symptoms of reflux. Its assumed at this point that the GI reflux, as well as the nasopharyngeal reflux are a new issue. At this point our GI doc is seriously considering placing a g-tube to be able to ensure she is staying hydrated and nourished.

MRI of spine was done last month because new nuero suspected a tethered spinal cord, but the MRI was normal. She is still not potty trained and does not appear to know when she needs to go, and often times when she already has. MRI of brain was repeated also, and it showed improved, but still delayed myelin.

A fasting (overnight) blood draw was done 3 weeks ago, with the following abnormal results:
Hemoglobin 15.0 (ref range 11.3-14.5)
RDW 11.0 (ref range 11.5-14.5)
Glucose  67 (ref range 74-127)
Chloride   105   (ref range 97-104)
Calcium   10.3H  (ref range 0.7-9.0)
Albumin   4.4H  (ref range 2.4-4.2)
Free Fatty Acid    902   (ref range 239-843)
And the doctor mentioned that she was "spilling Ketones" also.
Pyruvate and Lactate have not ever been done.

Further, she has a brother who is diagnosed with autism, epilepsy, learning disabilities, Tourette's, dev delays, auditory processing issues, and has a congenital abnormality of the hippocampus.

Now, for my questions:
1. Does this appear to be a case that further investigation into mito is warranted?? Are there any other possibilities we should be investigating??
2. Is it normal for the body to begin burning fat from just an overnight fast??
3. Could very mild reflux, with no complaints of pain, possibly explain the eating/drinking issues??
4. At what point do we seriously consider a feeding tube for her, particularly if this is an issue that comes and goes??
5. Are there any further tests that you would recommend us have before we send her information to one of the doctors that are able to do fresh biopsies??

Thanks so much for taking the time to read this. I hope I have not overwhelmed you with information, just wanted to be sure and include the things that seem to be a part of whats going on with her. Our doctors here are really at a loss at this point, concerned but unable to help us.  Any information you could help me with would be greatly appreciated.

Sincerely,
Kass, proud mom to three amazing kiddo's

[CCF Neuro[P] MD, RPS]

Dear Kass:

Certainly, your daughter could have a mitochondrial cytopathy.  I was sure you were going to tell me that she had a dysraphic lower spine as the tuft of hair would be indicative of this disorder.  No, an overnight fast should not induce ketone body production in a normal child.  There are alot of tests that you could do, but I really recommend seeing a mitochondrial expert.  We do our own labs or send them to special places because we know they will do the proper testing.  It would be just replicating what someone else has done but maybe incorrectly.  The only places I would send my son to for a fresh muscle biopsy (I think the only way this should be done) is at the Scottish Rite Children's Hospital in Atlanta, UCSD, and The Cleveland Clinic.  I can't say for sure if your daughter has a mitochondrial disease, but it is a good place to start.  The people who do the testing are Dr. John Shoffner in Atlanta, Dr. Bruce Cohen at the Cleveland Clinic, and Dr. Navioux (sp) at UCSD.  I think we do it best along with Scottish Rite in Atlantic (but I am biased).  Dr Cohen is only seeing referrals who have done much of the paper work before hand.  I would contact his office for further information.  Your physician could e.mail him at ***@**** about what needs to be done.

But if your physician insists on testing then these are the things I would get:
After an overnight fast: lactate, pyruvate, ammonia, serum amino acids, serum free and acyl carnitine, urine organic acids, urine amino acids, urine free and acyl carnitine.  I would also get a MRS using 1 cm3 voxels covering the frontal lobes, brainstem and cerebellum.  

Keep me informed.

Sincerely,

CCF Neuro MD

[kass]

Thanks so much for your reply. It is with mixed emotions that we face this further testing..on the one hand there is relief in thinking we might finally know whats wrong, but on the other there is the fear of finally knowing whats going on. I appreciate having another opinion from you in making this decision.

Her nuero and I too thought for sure there would be some kind of spinal dysraphism, and felt like it explained some of what we were seeing with her, but the MRI suprisingly was completely normal. There is even family history of spinal dysraphisms as my mother had a lipoma when she was a child. Alas though, nothing showed up so this idea was abandoned. We are going ahead with seeing a ped urologist in December for possible urodynamic testing as it does appear that we may be dealing with some problems in that area (signs of a possible neurogenic bladder lately).

We are currently trying to make a decision about whether to go to Atlanta or Cleveland for this further testing. While I realize your bias (understand it too) could you tell me if there is anything that one facility/doctor would have over the other?? Are there any types of mito that one facility/doctor is able to diagnose that the other one might not be able to?? I had heard that Dr. Schoffner might not be able to dx if it is nuclear, a mutation or a secondary cause, but do not know if this is true or not, or whether this would be the case anywhere we go. Obviously, if we are to make this kind of trip we want to feel like there is a reasonably good chance that there will be some kind of better understanding when all is said and done.

Thanks also for the further test that need to be done. If I read your response correctly, they would all end up repeated when we see one of the mito experts, so if thats the case, then we will wait and not put her through it twice if its not needed.

Finally, do you have any recommendations on when the time is to do a g-tube for feeding?? Do you all have a criteria that you use or is it a case by case kind of thing??

Thanks again so much.....your help is greatly appreciated!!

Sincerely,
Kass

[kass]

I am sorry....just thought of something tonight and wanted to run it past you and see if it seems logical. I had mentioned that she has progressively been eating/drinking less and less over the last 7 months...well, lo and behold, she has now eaten almost normally for 2 days and I was at a loss as to what had changed. I think I might have figured it out though....she got IV hydration last Monday and Tuesday and I am thinking maybe as her system began to finally normalize because she was finally hydrated, it became less of a struggle for her to find the energy to protect her airway, thus she is able to eat better. In other words, we broke the cycle with the IV hydration and she was able to bounce back a little. Does this seem logical to you?? Its the only thing that has been different for her in the last week. Thanks for any thoughts you might have on this also.

Sincerely,
Kass

[CCF Neuro[P] MD, RPS]

Dear Kass:

Of the three institutions, there is little difference.  Whether the lesion is mitochondrial per se or nuclear really doesn't make much difference.  We do not know many of the nuclear lesions anyway.  The key is the electron transport assay, and the oxidative phosphorylation polarography assay and all three places do the former while we are the only institute that does both on fresh muscle.  G-tube placement is very individual and I would suggest that you get tested for a mitochondrial disease or metabolic etiology first as what you use to feed your daughter might be distinct depending on which disease(s) she has.  

Sincerely,

CCF Neuro MD