Monday, May 23, 2011

Our Journey to get the Diagnosis

I wanted to give some details about this journey we have taken and how we got our diagnosis. We are a family of six. My wife, Becky, and 4 children. By my standards, we are a normal family and sometimes subnormal.  All seemed to be going well in our household. We have fun together and we work hard. One of our family mottos is "we can do hard things". We enjoy the outdoors and traveling to new places. We have big plans for our children and want them to be happy.  Things started to change the Fall of 2008.

It all began around October 2008 when my oldest daughter, Sydney, was having foot surgery by Dr. Flake. The anesthesiologist noted an abnormal ECG rhythm and recommended she see a pediatric cardiologist. We went and saw Dr. Rockow in Flagstaff. He did and ECG and an echocardiogram and diagnosed her with Wolfe-Parkinson White Syndrome and a mildly enlarged heart (rule out cardiomyopathy). He recommended that the entire family have a cardiology workup.

Seth came with us to the appointment and he recommended that we check him today. He stuck the electrodes onto his chest and his ECG showed high voltage. His ECG showed an enlarged heart.  His echocardiogram was normal.  Dr. Rockow recommended that Seth have a genetic and metabolic/endocrine workup. We took him to a local endocrinologist/pediatrician--Dr. Barela--who started the workup.

It was during this time that Seth developed a dissociated nystagmus in his right eye. His eye would start moving laterally very fast. We took him to Dr. Miles who recommended we see a pediatric ophthalmologist. We took him to Phoenix to see Dr. Leverant. She was very concerned that there might be a tumor pressing against his optic nerve and ordered an MRI of his brain and orbits. Phoenix Children's Hospital required us to pay $500.00 before they would schedule the MRI.  This nearly blew me away.  I am in medicine and I understand billing, co-insurance, co-pays, deductibles, etc, but in this situation where there was a concern of a brain tumor, it just didn't seem and feel right.

It took 10 days to get the MRI. These 10 days seemed like years. The days could not come fast enough. I was nearly useless. I had trouble concentrating and doing my daily routine. Work was challenging. I was wondering around aimlessly like the Children of Israel in the wilderness. My son, my little boy potentially had something terribly wrong.

Finally, the news came. Dr. Leverant called me and said there was no tumors noted, but there were several small “cysts” in the corpus callosum. She said these looked “benign”. I consulted a radiologist friend Dr. Berges who disagreed. He said these looked more like white matter lesions.  I called Dr. Leverant and told her that I had gotten a different opinion from a local radiologist.  She had the MRI reviewed by a pediatric neuroradiologist who concluded they were corpus callosum cysts.

By this time, the labs had come back from Dr. Barela.  He stated that Seth had a chronic metabolic acidosis and he wanted him to be admitted to Phoenix Children’s Hospital to try and put all of this together.  On January 21, 2009, Seth was admitted.  Becky and Seth
went to the hospital.  I stayed with my other children.  Becky called with updates.  She said her experience in the hospital was not going well. The first person Seth saw was the business manager who said we needed to pay $1000.00 before we could leave the hospital. This was the second time this hospital came for their money before services were rendered.  Again, this just didn't seem or feel right.

Seth finally saw the pediatric attending physician. It was over 24 hours post admission that they finally drew blood.  Becky was frustrated.  She said Seth was running around the hospital riding a tricycle and happy as ever. The appearance he presented was not a sick little boy with a chronic metabolic acidosis and brain lesions. His appearance was that of a happy 2.5 year old little boy who wanted nothing to do with this hospital.

I was now getting frustrated and decided to go down and help Becky.  I had my good friend Jay stay with our kids and I left for Phoenix.  I arrived about 36 hours post admission and they finally did some labs.  They stated that his metabolic acidosis had resolved.  One by one the specialists came by to see him. Seth saw a pediatric neurologist, geneticist, and several residents. He was discharged with absolutely no answers. The neurologist agreed with the radiologist reading of “benign cysts”.  The attending physician never ordered another ECG or had a cardiologist consult.  He never consulted Dr. Leverant regarding his eye.  They completely disregarded the high lactic acid level.

The whole visit was a complete waste of time and money.  The only benefit was that of Dr. Theresa Grebe who wanted to do some further genetic testing on him.  She ordered a chromosomal microarray panel on him and wanted us to see her again in a few weeks to go over the results. We followed up with her and she said everything was normal.  She ordered some more testing and wanted spine x-rays and renal ultrasound.  We saw her again in 6 months.  She recommended we follow up again with a neurologist.  We made an appointment with Dr. Sweetman who recommended that we get another MRI. She was not satisfied with the “cysts” diagnosis.  We had the MRI done on 12-17-09.  Once again, Phoenix Children's Hospital requested $500.00 before they would schedule the MRI.

By this time, I was thinking that maybe all this was an acute illness that had caused this and that everything was ok.  His dissociated nystagmus had resolved. Seth’s only continuing problems were he was very clumsy and had some speech delay.  Maybe he was just a little behind.  I see this all the time with my medical practice.  His clumsiness was so bad and he had hit his head so many times, that we bought him a small bicycle helmet that he wore everywhere.  I do have to admit, I was not as anxious to get the results back this time. It was Christmas time.  We had a great time together as a family. We went and got our Christmas Tree from the forest as we usually do. The kids were very excited. I had not heard any news from Dr. Sweetman, so I called her and asked if she had gotten the report back.  She apologized and said that Seth’s MRI was worse.  She stated that these were not benign cysts. She called them “lesions” and that they had gotten larger and there were new lesions in the basal ganglia.  She had no idea what it was and was referring us to a pediatric neurogenetic team at St. Joseph’s Hospital in Phoenix.
By now, this journey was taking a significant toll on our family. Financially, it was costing a lot of money. It was during a time when the White Mountain Apache Tribe was not paying their insurance.  I have terrible health insurance with a very high deductible.  The medical bills were piling up. The uncertainty of Seth’s diagnosis was also challenging.  All sorts of questions come into your mind.  Is your son going to live?  Do other family members have this?  Was there something I did or took that caused him to have a genetic defect?  How am I going to carry on?

The appointment with the pediatric neurogenetic team at St. Joseph’s Hospital took about 2 months.  With great anticipation to find out what was wrong, Becky, Seth, and I traveled to Phoenix for the appointment.  As we sat in the exam room, Seth was sitting on my lap and drawing pictures in my journal.  The team finally came in.  There was several doctors. They all introduced themselves. Dr. Vinod Narayanan was the head of the team.  There were residents, medical students, a nurse practioner, and a geneticists.  I’ll never forget the first words that came out of Dr. Narayanan’s mouth.  He said: “I have reviewed your son’s medical history and I have looked at your son’s MRIs and I have showed it to all of the attending pediatric neurologists, and we have never seen this before.  I have no idea what is wrong with your son.”

He did a thorough history and physical which took almost 2 hours.  He also said that both MRI’s showed white matter lesions, not benign cysts.  Something was causing the destruction of his white matter and they had no idea what it was.  We felt like Dr. Narayanan cared and took a deep interest in finding out what was wrong with Seth.  He told us he was going to put Seth’s MRI on a server for the pediatric neurology and radiology world community to look at and give some input.  He was also going to order some more tests.  The anticipation quickly turned to discouragement, despair, and consternation. The most distressing emotion aroused by the impending unknown came over me.  This emotion was fear.  I had been governed by this emotion for most of my entire life.  The situation was completely out of my hands, or was it?

I couldn’t just sit back and do nothing.  I wanted to help my son if I could.  I began to research.  I spoke with my radiology friend, Dr. Berges.  He offered to have a colleague of his, a pediatric neuroradiologist, in Indiana look at the films.  Grant’s colleague was not sure what was going on either.  It was clear by this point that Phoenix Children’s Hospital clearly mis-read the first MRI.  It was clearly a white matter disease of some type from the beginning.  She recommended we try and get in contact with a specialist in Amsterdam by the name of Marjo Van der Knaap, M.D., Ph.D a pediatric white matter specialist.

I also spoke with my cousin, Sharlene who is an ER physician in Utah.  She had a good friend at Harvard who was chief of Neurosurgery that she got me in contact with.  I spoke with him and sent the MRI’s to him.  He was very kind to view these films, but had no input about what it was.

I also had been reading about Dr. Van der Knaap and read about a family whose family was devastated by the loss of 3 infants to a white matter disease.  They have created a website called  I contacted the father and sent the following email:

April 30, 2010


I read about your story and I was touched and thought I would send an email to see if you might be able to help.

My son, Seth who is now almost 4, has been diagnosed with an unknown white matter disease that has been progressing since 2008. No one seems to know his disease is or how to treat it. He has had multiple tests and seen multiple specialist.

I was told by a friend who is a radiologist that Dr. Marjo van der Knapp is someone who we should try to get in contact with.

If you have any suggestions, I would appreciate it.

Thank you.


I received the following email back on May 2, 2010:

Hello Newell,

This is Mike again. Gabriella and I are very sorry to hear about your son Seth. I know this is a very difficult time for you. I believe the best course would be for me to forward our email correspondence on to Dr.Van der Knaap. If this is ok with you please let me know if this is okay.

Best regards,


I did not hear back directly from Dr. Van der Knaap, so I researched her and found some of her research papers which had her contact address. I sent her the following email:

May 9, 2010

Dear Dr. Vanderknaap,

My 3 year old son, Seth, has a white matter disease of unknown etiology. I was told by Dr. Mary Edwards Brown and by Mr. Salsbury to contact you to see if you would be able to help. I will give you a brief medical summary and correspondence from his pediatric neurologist (Dr. Narayanan) at St. Joseph's Medical Center in Phoenix, AZ. Also, I will provide you with a link to his MRIs:

Thank you Dr. Vanderknaap.


Newell and Rebecca

The following day May 10, 2010, much to my surprise I received the following email back:

Dear Newell and Rebecca,

Thank you for your note. I would be happy to look at your son's MRI. The website contains only some of the images and in the wrong format. Please send me a CD with the MRIs in DICOM format, together with your contact details and a print-out of this e-mail. I have given my full address below. I will then let you know what I think as soon as I can.

Best regards,

Marjo van der Knaap

This was literally a shot in the dark, but I hit the target.  I was so touched by someone who is regarded as the world specialist in white matter diseases who would be so willing to help at no cost. I’m sure her time is precious and she was so willing to help. She sent back the following letter:
Dear Newell and Rebecca

Thank you for sending me the MRIs of your son Seth.
The first MRI was obtained on 19-01-2009. The images show a bilateral lesion in the white matter of the gyrus cinguli, where the white matter enters the genu of the corpus callosum. The diffusion-weighted images still show restriction of the diffusion in the rim of the lesion on the right and in the entire lesion on the left. There is no enhancement after contrast.
A new MRI was obtained on 17-12-2009. The lesion on both sides has become larger and there are now several small satellite lesions. The diffusion-weighted images show decreased diffusion in the rim of the lesions and increased diffusion in the central part of the lesion. There is no enhancement after contrast.

My first thought would be that it could be a mitochondrial disease. Mitochondrial disorders may start with focal lesions and frequently display restricted diffusion in the rim of the lesions. In mitochondrial disease lesions may come and go. I would start with assessing blood in CSF lactate and consider a muscle biopsy or functional mitochondrial studies.
The images are not compatible with any of the classical leukodystrophies, such as metachromatic leukodystrophy, Krabbe disease or Alexander disease. The images are also not compatible with a diagnosis of vanishing white matter disease.
Please keep me informed of further test results. I am always willing to look at follow-up MRIs.

Best regards,
Marjo S. van der Knaap, MD, PhD
Professor of Child Neurology
VU University Medical Center
The Netherlands

I forwarded the letter to Dr. Narayanan who called me and said, “I was about to send her an email and ask her myself if she would look at the MRI’s”. We then set up further testing including a lumbar puncture, MRI of brain and spinal cord, MRA of brain, MR spectroscopy, and additional blood work. Dr. Narayanan also wanted to enroll our entire family in a study to have our genome analyzed by a company called TGen which we agreed to do.  One of the amazing things about this experience at St. Joseph's Hospital was they did not ask for money before they would treat our sweet little Seth!!!  In fact, once we got the bill, they offered financial assistance and significantly reduced our bill (something Phoenix Children's Hospital was unwilling to do).  I am so thankful for St. Joseph's Hospital!  One of the unfortunate things of this century is that St. Joseph's Hospital's Children's Services and Phoenix Children's Hospital recently merged.  
During the summer of 2010, we were on vacation in Utah.  We went on a family hike with my brother Kevin’s family to Stuart Falls in Provo Canyon.  My oldest daughter Sydney had just come out of a cast because she fell down our front stairs and broke her foot.  It required surgery.  She was not in the best shape, but never has been in good shape. While we were hiking, I noted she was having a difficult time hiking and was breathing very heavy.  She has had her own problems and had a cardiac ablation done in 2009 for her Wolfe-Parkinson White Syndrome.  The ablation was unsuccessful but they stated if she ever did go into a bad rhythm, she wouldn’t go over 150.  I checked her heart rate and it was between 170 and 180.  She was so fatigued and this was the first time she had presented like this.  She had done soccer and hikes with are family.  She rides her bike around our house and she had never had these symptoms.

While we were on vacation, I got a phone call from Dr. Narayanan.  He told me results of the imaging studies showed that the white matter lesions had enlarged and the MR spectroscopy showed high levels of lactate within the lesions of his brain.  His lumbar puncture showed low levels of 5-methyltetrahydrofolate, high levels of alanine and lactate. The results pointed to a metabolic disease likely a mitochondrial disorder.

What was the next step?  Dr. Narayanan wanted us to see Dr. Shoffner in Atlanta, GA a world renowned specialist in Mitochondrial Disease.  Dr. Narayanan thought the next step was a muscle biopsy.  This is what Dr. Van der Knaap recommended.  This is what all the studies recommend.   Becky and I agreed, we would go see Dr. Shoffner for Seth's muscle biopsy.

I began to research mitochondrial disorders. I also noted that Sydney and Seth have very similar characteristics in their facial features, short stature, learning disabilities, eye problems, speech, and personality. One of the common "red flag" symptoms of mitochondrial disorders is Wolf-Parkinson White Syndrome. Could Sydney have this too? Sydney has seen several specialists at Yale and the University of Arizona. She also had an MRI at the age of 10 or 11 which was normal.

I began to work up Sydney for a metabolic disease. I ordered the basic tests and her Serum alanine and lactate levels came back high. I spoke with Dr. Narayanan about this and he wanted to see her. We scheduled her for an MRI, MR spectroscopy, and lumbar puncture. The MRI was normal, but her lumbar puncture came back high for lactate and alanine. Her 5-methyltetrahydrofolate was low. It looked like she too had a mitochondrial disease and cerebral folate deficiency.

Dr. Narayanan told us that if Seth ever had acute neurological finding, that he would need to be seen immediately. He was at risk for having a stroke, seizure, or rapid decompensation. Well, this happened in early October 2010. Seth developed an acute dysarthria. I was very anxious that he had a stroke or his disease was progressing to areas of his brain that control his speech. I called his neurologist, Dr. Narayanan at St. Joseph’s Hospital, and informed him. He said we need to get an MRI as soon as possible to see. I arranged to have the MRI done here in Show Low with Dr. Berges. His MRI showed no stroke, but progression of his disease.

It is difficult to describe the feelings that you have as a parent as you watch your child...slowly die.  We were so thankful that we finally had a plan of action and that we were finding answers.  Dr. Narayanan started Seth on what's called the "Mito Cocktail", a combination of vitamins, amino acids, and co-enzyme Q10.

Syndey’s imaging studies were normal, but she too had low levels of 5-methyltetrahydrofolate in her cerbral spinal fluid and high levels of lactate in her blood and spinal fluid.

So our journey then took us to Atlanta, Georgia on December 7, 2010. We were scheduled to see John Schoffner, M.D. a world renowned pediatric neurologist who specializes in mitochondrial disease.  He had Seth scheduled for a muscle biopsy, lumbar puncture, and other blood work.  He also did a resting basal metabolic rate test. We had my parents and my brother Lynn come to Show Low and watch our kids. We had an enjoyable time in Atlanta, despite what we were there for.

Seth’s testing in Atlanta confirmed the mitochondrial disease and cerebral folate deficiency.  They put him on leucovorin, and increased his "Mito Cocktail" levels of l-carnitine, B vitamins, and Coenzyme Q-10.  His defect in his mitochondria was in Complex 1.  It is common for people with mitochondrial diseases to develop low cerebral folate levels.  This is treatable with leucovorin.  It is unknown whether the other supplements do anything to help the mitochondria.  Dr. Schoffner also stated that Sydney most likely had the same disease.

So here we are in May 2011.  Seth’s speech has gotten worse, but nothing else new.  He goes for a sleep study on June 3rd.  We hope for the best and expect the worse.

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