Ruled Out: Neurotransmitter Disease & More

I'd like to start with an important tip for any patient or parent thereof: be aware of your lab work. It is vital to know the following about labs:

1. When is the sample collected? (This is frequently used in the identifier like: 4/20/09 AFP.)
   
2. When is the sample sent out? (Many labs can't send out after 3PM so it may be next day.)
3. When is the sample received? (Usually the day after it is *sent*, but not always. Fresh samples may have to get there within 2 hours otherwise it is void. Other things, such as clotting and contamination can also void the test--and they won't always tell you!)
4. What is the substance? (plasma, red blood cells, white blood cells, cerebrospinal fluid, urine, tissue, etc.)
5. What lab is it being sent to? (Essential for follow-up. Don't trust your send-out lab.)
   
6. What is the turnaround time? (If weeks, do they count business days only? 2 weeks may actually mean closer to 20 days.)

This may sound anal-retentive to a lot of people out there. But, when it's your kid's life on the line, it is not. When a child has an approximately five-year life expectancy, even a few days delay is intolerable. I can't even tell you how many times (safely 10+ times) this knowledge about Bertrand's labs has shaved days or, such as today, weeks of uncertainty in B's case.

Today, after our Primary Childrens Medical Center lab said to give results a few more weeks, I followed up with Medical Neurogenetics, Inc., the Atlanta based laboratory running the neurotransmitter metabolites panel for Bertrand. Turns out that they had already faxed the results back LAST WEEK. The paper was just sitting in a pile somewhere at PCMC waiting to be scanned in--which can take weeks. So, I had the results faxed directly to Dr. Longo.

Dr. Longo being the fabulous clinician (AND researcher) that he is, and in spite of being out of town at a conference, let me know within minutes that the result was normal and that Bertrand's purine panel returned normal again as well. He is now thinking about next steps. (I call Bertrand my man of mystery!) But, the normal neurotransmitter metabolite panel means Bertrand doesn't have a pediatric neurotransmitter disease such as:

• Succinic Semialdehyde Dehydrogenase Deficiency (SSADH)
• Tyrosine Hydroxylase Deficiency (TH)
• Aromatic L-Amino Acid Decarboxylase Deficiency (AADC)
• Guanosine Triphosphate Cyclohydrolase I Deficiency(GCH I, GTP
• Cyclohydrolase, GTPCH)
• Sepiapterin Reductase Deficiency (SR)

As mentioned before, the normal purine panel means no Lesch-Nyhan, but it also rules out quite a few other diseases, such as those listed below in case you are curious.

Disorders of Purine Salvage

• Lesch-Nyhan syndrome
• Adenine phosphoribosyltransferase deficiency

Disorders of Purine Nucleotide Synthesis

• Phosphoribosylpyrophosphate synthetase superactivity
• Adenylosuccinase deficiency

Disorders of Purine Catabolism

• Myoadenylate deaminase deficiency
• Adenosine deaminase deficiency
• Purine nucleoside phosphorylase deficiency
• Xanthine oxidase deficiency

Disorders of Pyrimidine Metabolism

• Uridine monophosphate synthase deficiency

Letter from an Allgrove's Researcher

Below is the response from Dr. Marzieh Salehi, one of the few doctors in the world experienced with Allgrove Syndrome. This is one of the diseases Bertrand is being tested for. She mentioned testing for a fasting cortisol and running an ACTH stimulation test (neither of which we've done), after which (if results are consistent with Allgrove) we can move to genetic testing.

Keep in mind Allgrove (a.k.a. Triple A Syndrome) is rare. Let's put it this way, when I first researched it, the wikipedia entry was one line. It's a long shot that B would have it. Allgrove was first described in 1978, but since then, according to Dr. Salehi, there are maybe 80 reported cases in the world. (Although, many likely die before ever getting diagnosed.) So, yeah, it's rare.

Dear Ms. Might,

Dr. Poretsky forwarded your e-mail to me to respond. I’m afraid that I would not be able to help much given the lack of experience with the pediatric population affected with this condition as well as lack of knowledge with non-endocrinological aspects of this disease. There are not many people who know about this condition as the total number of cases reported in the world is about 70-80, so the most expertise regarding diagnosis and management generally comes from Neuromuscular Clinics. We collaborated with Dr. Henry Houlden from London, UK. for genetic testing in our case and I know that Dr. Felicia Axelrod, who is running a dysautonomia clinic at NYU, New York, has an extensive experience with these patients, so she will be a good source of information.

Your son has the key features suggesting the diagnosis of Allgrove Syndrome as you pointed out, however, he does not have to have all the features together, cases with tear abnormality or achalasia without any other problems have been well described and adrenal insufficiency may never been developed or come late (not until 20s and 30s of age). Based on what you mentioned it is reasonable to start with something more than fasting levels of cortisol; perhaps, ACTH stimulation test (high dose and low dose) that could be monitored every 6-12 months depending on general status.

Best regards,

Marzieh Salehi, M.D.
Division of Endocrinology, Diabetes and Metabolism
University of Cincinnati, College of Medicine
The Vontz Center for Molecular Studies

Speech Therapy: Session 4/28/09

At speech therapy with Meghan, B continued to show off his new-found steadiness. (Thank you, neurontin!) We discussed visual schedules at length and also Bertrand's diet, which has greatly improved. (Thank you, neurontin!) Meghan will be coming with us to UCAT for communication device selection on May 6th. Until then, I'll continue working on Bertrand's flashcards, and I'll post photos soon.

After speech therapy, Bertrand and I hosted play group at our house! It went extremely well even if Bertrand fell asleep. And only Kevin and Lynn showed up. Quality over quantity!

Ruled Out: CLN1, CLN2, GM1

Ceroid lipofuscinoses, neuronal (CLN) are a group of fatal, autosomal recessive, progressive encephalopathies in children. They are characterized by psychomotor deterioration, visual failure, and the accumulation of autofluorescent lipopigment in neurons and other cell types. So, we're happy that CLN1, the infantile type (Santavuori-Haltia disease; MIM 256730), and CLN2, the late infantile type (Jansky-Bielschowsky disease; MIM 204500), have been ruled out!

GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder characterized by the generalized accumulation of GM1 ganglioside, oligosaccharides, and the mucopolysaccharide keratan sulfate. Since GM1 has important physiological properties and impacts neuronal plasticity and repair mechanisms, the release of neurotrophins in the brain and is fatal, we are glad that this disorder is also ruled out (again--this was a retest).

Today, I found out that Bertrand's purine panel results are back, but not what they are. I also heard from Kelly Schoch, a geneticist at Duke with Dr. Shashi. Kelly said that Bertrand's microarray came back normal! His karyotype should be back later this week. After that, the only Duke results we are waiting on are: Nieman Pick Type C, Ataxia Ocular Motor Apraxia, and Mitochondrial DNA Depletion.

I also shared with Kelly and Dr. Shashi the results of B's CSF ACTH. Dr. Longo has said, "I am still not sure about the increased ACTH: ACTH as prolactin [B's prolactin is also elevated] is inhibited by dopamine and that might be the problem. I would wait on the neurotransmitters to see HVA levels in the CSF." So, baby-roids are on hold for now. ;) Tomorrow I'll check on the status/turn around time for the neurotransmitter metabolites panel.

After all this, Dr. Book's office called to schedule a follow-up. Bertrand will be seeing Dr. Book, gastroenterologist, on June 29th--the soonest available appointment. She will be reviewing whether or not Bertrand may now need a liver biopsy, since so many tests are happily resulting as normal. We also scheduled an appointment with Dr. Grimmer, otolaryngologist, for May 26th to check for narrowing of the esophagus.

Orthopaedic evaluation

Early this morning, Bertrand and I went to the Salt Lake City Shriners Hospital for Children. Bertrand had an orthopaedic evaluation with Dr. Marcy Woiczik. Dr. Woiczik said that his bones looked good so far, but she wants to see another x-ray of his hips in 6 months. She is concerned that B's delay in walking may start causing hip abnormalities.

Dr. Woiczik referred Bertrand to the physical, speech and occupational therapy department at Shriners. He'll be having his speech therapy evaluation this Wednesday with Laura. On May 5th he'll be having his occupational therapy evaluation with Chris and his physical therapy evaluation wtih Cindy. These evaluations will determine the frequency of therapy.

The physical and occupational therapists will address the issue of equiptment. Dr. W mentioned that Bertrand may need braces for his feet, but the draw back is that his muscles may not strengthen properly. She also mentioned a stander--it looks very similar to a gait trainer. The therapists will determine which kind of device would best benefit Bertrand.

Overall, Bertrand seems to be doing well musculoskeletally. We just need to keep him like that and give him a little extra help with coordination/balance. Speech-wise, we'll see what Laura says this week. B and I, we're excited to get to work!

Ruled Out: Metachromatic Leukodystrophy

Bertrand's Arylsulfatase A test, which was sent out to Seattle, came back in today. The result was normal, therefore Metachromatic leukodystrophy (MLD, also called Arylsulfatase A deficiency) has been ruled out.

MLD is a lysosomal storage disease which is commonly listed in the family of leukodystrophies. Leukodystrophiea affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripherial nervous systems.

The remaining lab results, from blood drawn during his skin biopsy on 4/20/09, should be in this Monday. Bertrand's skin biopsy cultured well and is ready to be sent out from the ARUP lab to other labs for fibroblast testing.

Physical & Speech Therapy: Session 4/23/09

Today, Bertrand had a joint speech and physical therapy session. I gave both therapists copies of his occupational therapy evaluation from Annie Miller and his developmental evaluation from Maria Escolar at UNC. We discussed his impending evaluation at Shriners (the future of the gait trainer), his new hippotherapy (yes, they watched the video), our trip to UCAT (we'll be making another trip), and lastly Bertrand's amazing progress/mood shift thanks to his medication.

Both therapists were shocked at how talkative and happy Bertrand has become. They also couldn't stop mentioning how open his hands were, how fantastic his eye contact was, and how steady he was while sitting/standing. I am so happy that B's progress wasn't all in my head. Meghan and Kirtsten left our session singing the praises of neurontin.

At our speech session next week, I will be working with Meghan on flashcards for B. These flashcards will contain photos of his objects: bottle, yogurt, exersaucer, book, etc. These will serve as an unsophisticated and inexpensive precurser to a tablet communication device. Depending on Kirsten's availability, Meghan may be the only therapist coming with us to UCAT to pick out a few switches/toys to assist Bertrand in effecting his environment.

For our next physical therapy session (5/4/09), Kirsten will be joining Bertrand, Matthew and I at the National Ability Center to observe his hippotherapy session. Kirsten has gotten to know Bertrand extremely well, so she should be able to provide excellent insight and assistance to Kim, the hippotherapist. Also, seeing Bertrand in a different environment may help Kirsten gain a better understanding of how surroundings affect him.

High ACTH, medical loose-ends & online early learning

While most of Bertrand's 4/14/09 and 4/20/09 labs are still pending, one more result came back. His CSF ACTH was elevated at 349--normal range 5-46. (His earlier blood ACTH was mildly elevated at 62.) This is cause for retesting and/or potential steroid treatment. Fortunately, I had Dr. Sakonju draw extra CSF, so it is easy to send out to a different lab for an ACTH retest. I am waiting to hear back from Dr. Longo about possible steroid treatment.

I am still waiting to hear back from Dr. Sakonju about yesterday's CT scan and what she thinks about the results we've gotten back from Bertrand's spinal tap. The results we have so far should be able to guide us in both additional testing and symptom mitigation. Chiefly, my concern is that if mitochondrial disease is still being considered, that we have enough time to schedule the Atlanta muscle biopsy with Dr. John Shoffner for the week of May 7-17th.

Dawn, a nurse from Dr. Book's office, called me back. Bertrand's liver biopsy has been canceled, not postponed. Dr. Book has no desire to see him in her clinic again, either. My positive spin interpretation of this is that she is happy with and confident in Dr. Longo's work with Bertrand. (Dr. Longo is in fact fantastic, so I could see how such faith would be well placed.)

Today marked the begining of Bertrand's cyberschooling. We signed up for a beta test of the Waterford Institute's new early learning software for two year olds (even though B isn't 2 yet). Bertrand loved it! He stayed glued to the computer for 17 minutes (longer than the recommended 15)! While many things (ABC games, etc.) are advanced for him, I think that exposure is good. We'll see how he does with it over the next 6 weeks. :)

CT scan, swallow study and more questions

Today, Bertrand and I got to radiology early so I could schedule his brain CT scan for June. Well, it turns out, we got there so early that they said, "we can just do the scan now." And, we did--without sedation! There are some motion artifacts but nothing so bad as to render the scan unreadable, according to Casey, the CT technician. I am so proud of my big boy for staying so still! I am looking forward to the CT scan's interpretation from radiology.

After the brain CT, Bertrand had his very first swallow study done. The result is oddly mixed. Yet again, they'd never seen anything like Bertrand before. On the X-ray it looked like his swallowing was fine, but he still aspirated. As some of you know, Bertrand jerks his head during feeding. The therapist also didn't like how he seemed to be taking breaks for breath or how his breathing sounded. (I have found his breathing raspy/loud but all the doctors say his lungs sound clear.) So, we are being referred to an otolaryngologist--an ear, nose and throat specialist (ENT). An ENT can use a scope to look down his throat and see if there is anything unusual such as narrowing, which doesn't show up in a swallow study.

I am waiting to get an ENT referral from Dr. Samson-Fang in order to schedule that appointment. I am also waiting to hear back from Dr. Sakonju. Bertrand and I ran into her at the hospital and she'll be calling me later today with the preliminary results from yesterday and her reading of today's CT scan.

Ruled Out: Mitochondrial Disease (*maybe*)

Calling the lab today to check on the status of Bertrand's 4/14/09 (still not in) I was surprised by what was in: some of today's lab results. Here they are.

• Creatine 173 (normal range <296)
• Cortisol 20.3 (normal range 1-23)
• Glucose 53 (normal range 40-70)
• Lactic Acid 1.0 (normal range 0.8-2.2)

The normal lactic acid doesn't completely rule out the mitochondrials (only with a muscle biopsy could we be sure), but it makes a mitochondrial disease highly unlikely.

The normal creatine makes a peroxisomal disorder unlikely. In particular, the normal cortisol and glucose make Allgrove unlikely as well. (However, another ACTH test is still pending--this could still lead to some symptomatic steroid treatment.)

Lumbar puncture, electromyography, etc.

Bertrand gets ready for his LP & EMG on the hospital bed.

Bertrand had his lumbar puncture (a.k.a. spinal tap) and an impromptu electromyography (EMG) today. While we'll start getting results back tomorrow (such as lactate) for labs run on the cerebrospinal fluid (CSF) tomorrow, we have the EMG results now.

The EMG of his arms/hands and legs/feet confirmed what we learned from the nerve conduction study. Bertrand's peripheral nerves show signs of demylenation. In his arms/hands he has what would be classified in adults as carpal tunnel syndrome. Just like his daddy! (Except in B's case it is not due to the compression of the median nerve, but the demylenation of it).

Based on this and some other information, Dr. Sakonju (B's neurologist) and I discussed a trial course of Valium. Bertrand is currently prescribed Valium in case of seizure only. These smaller doses of Valium would be taken before physical therapy or activity so he could get the most out of it. We'll see.

Bertrand will be seeing Dr. Sakonju again for a follow-up on June 10th. Earlier that day he's scheduled to have a brain CT scan to look for calcifications in the basal ganglia. This may or may not be proceeded with depending on the results of his labs... for now, however, it is a go.

General anesthesia was used today, so Bertrand fortunately didn't have to go through the IV trauma or the blood draw trauma (it took 4 sticks). Some of the blood will be sent out to labs in Georgia and elsewhere, and if we don't get some clear answers within the next 6 weeks or so, a muscle biopsy will take place sometime in July.

A message from Bertrand

Subtitles included.

Day Out with Thomas the Tank Engine

Oh my! Bertrand and I, we are so excited. This morning we bought tickets to RIDE Thomas the Tank Engine at the Heber Valley Railroad on May 22. These tickets sell out quickly and are only available for May 21-25 (Memorial Day weekend). We've been wanting to go to the Heber Valley Railroad for quite some time, and this seems like the perfect opportunity. :) Bertrand loves Thomas!

Hippotherapy: Session 4/13/09

Spoiler: There's lots of a baby on a horse.

Bertrand on Drugs

Genetics, assistive technology & May travel

This morning, Dr. Vandana Shashi, the geneticist from Duke University, called me. She, being the amazing doctor that she is, presented Bertrand's case to the entire genetics section at Duke! She was able to use the video that Dr. Eddie Smith (neurology) took to showcase Bertrand's movements and features. They are still befuddled but, as a team, they came up with some other tests they'd like to have run for Bertrand's spinal tap next Monday. Here is the email she wrote to Dr. Longo aftee speaking with me.

Dear Dr. Longo,
I am the medical geneticist who saw Bertrand Might last week. Your note on him was very helpful. As you know, it has been a challenge to find a unifying diagnosis for his features despite so many people thinking about him. I hope you don't mind me doing this, but I have a list of tests below that may be helpful. We have met here as a group after evaluating Bertrand and had some suggestions for further testing. Some of these can be done in a stepwise fashion, if the ones pending now are negative, but as you may agree, for CSF studies it would make sense to do all at the same time. I have listed the suggestions below, with the understanding that you may have thought of these already.

1. CSF studies- in addition to the neurotransmitters, get amino acids (simultaneous plasma AA), glucose (plasma as well), lactate.
2. Skin biopsy- send out for mitochondrial panel (Baylor)
3. DNA for Batten's disease (NCL)
4. Blood for mass spectrometry for the carbohydrate deficient glycoprotein disorders (Greenwood)
5. Urine creatine
6. MECP2 sequencing if microarray is normal
7. Urine polyol
8. Chromosome breakage studies

His mother told me that Allgrove syndrome and Menkes are being considered as well.
Please let me know if I can do anything else.

This afternoon, Bertrand and I went to The Utah Center for Assistive Technology (UCAT). At UCAT, Bertrand was evaluated by Scott. We tried a bunch of switches, switch adapted toys, and other goodies. Bertrand was not in the most receptive mood (he was pooping), so we'll try to go back sometime next week with Matthew. This is really Matthew's area. A lot of the programs and toys are so simple, it may be cheaper (and more fun) to rig things ourselves.

In our very first apartment, over 6 years ago, Matthew used X-10 to wire everything from the lights to the tv, stereo, coffee pot... you name it. We could turn it all on or off remotely--via web. At the time, I rolled my eyes. Now, we have to do it again, but for Bertrand, so the project will include placing mounted wireless switches in his crib, play areas, and eventually his gait trainer. I think Bertrand's daddy, grandfathers and uncles will have a blast with this!

At UCAT, I was fortunate enough to find out from Scott that there is a new cyber Pre-K in Utah! I gave him my email so I could get more information. I just love the cyber school concept. I'd been introduced to K12 before, and think it'd be a perfect fit for a special needs child like B. Since they have open enrollment here, I am going to see about putting him on the waiting list now, so, if he makes it to age 3, he could attend the cyber Pre-K.

Lastly, I finalized some of the dates we'd be visiting our family in Georgia. We'll be in the peach state from May 7 through the 17th to attend Bertrand's Uncle Booj's commissioning ceremony. Mother's Day will be spent at St. George Village with B's great grandparents, Bud and Rosina. We'll also be spending some time in the Blairsville area riding trains and playing with friends and cousins on Lake Nottley. Maybe we'll even swing by Augusta--who knows? :)

Well-baby check and more test results

Things have been moving so quickly since we got back from North Carolina (and finishing taxes *shudder*) that I've been a bit lax on the updates. Here are some things you've missed.

• 4/13/09 Bertrand had his first hippotherapy session. His horse was named Captain Brownie, but B was more interested in Patches, the barn cat. :) We can't wait until the next session on May 4th! I'll post pictures and video later.
• 4/14/09 Bertrand had a skin biopsy, from which he has recovered beautifully.
• 4/15/09 Bertrand went to the Salt Lake City library to meet with his play group and participate in a baby read-along. We had fun in spite of the weather. Later that day, we all went to see Judith, our family counselor, for almost the last time. She thinks we are coping amazingly well and that we should write a book some day!

Now that we're caught up, today Bertrand had a well-baby visit with Dr. Samson-Fang. He got 4 shots. She said he looked great and his tone had improved. We were, however, still referred to pediatric rehabilitation physicians, Dr. Judith Gooch and Dr. Teresa Such-Neibar, for help with Bertrand's tone and function. Dr. Samson-Fang also referred us to a dentist, Dr. Keller, to make sure B is on track orally. Bertrand's blood pressure came back high, so we'll be watching that.

I came in with several questions regarding Bertrand's diet, medications, and supplements. He'll start taking 100mg of Coenzyme Q 10 every day. And, we should replace some bottles with water--she mentioned that they sell thickened water on amazon.com. (It could be easier for him to swallow.) Bertrand's weight is still a concern, but we'll see what happens between now and his 18 month well-baby. A lot can happen after the lumbar puncture.

Lastly, we got some lab results back:

1. ACTH 62 (normal range 5-46)
2. Copper 64 (normal range 90-190)
3. Ceruloplasmin 19 (normal range 14-44)

Here is what Dr. Longo said about them:

ACTH is a bit high. We do not have a simultaneous cortisol (ACTH is superior in these conditions as a screening test): would repeat next week cortisol and ACTH: if still high, would give hydrocosrtisone replacement. Patients with peroxisomal disorders have ACTH levels in the hundreds. Bertrand also had normal VLCFA that excludes classic peroxisomal disorders. Would get RBC plasmalogens if ACTH is still high.

Not sure about Allgrove: high ACTH is seen in Allgrove. However, several of the other findings are usually absent in Allgrove.

So, I would repeat cortisol/ACTH next week when he comes in for the spinal tap. I will discuss with Dr. Sakonju to determine the studies to obtain on the CSF.

Skin Biopsy, Pharmacy, Lab Work & More

Bertrand saw Dr. Longo this morning for a skin biopsy. After applying local anesthesia to the area, Dr. Longo took a pencil eraser sized chunk out of Bertrand's right buttock. Bertrand slept through the actual biopsy portion. This is of course after he pooped on the table and proceeded to pee all over Dr. Longo's nice white lab coat. That about covers what Bertrand thought of the entire experience. ;)

After that Bertrand and I went on the great seizure medication quest. Two more pharmacies and still no meds. His prescription calls for a non-standard dosage because he is small. This has caused me grief. Finally, the University of Utah hospital pharmacy said they could make them... by Thursday. It's a good thing Bertrand doesn't actually need them yet!

After that we were off to the outpatient lab. And, yes. My son, he has the stigmata. They had to poke 4 times (both hands and both arms, no feet this time) to get all the blood they needed. We got two of our favorite lab techs (Joel and Renee) since it takes three people to hold Bertrand down. As tough as it was, we managed to get a lot of smiles from Bertrand--and draw the blood.

The labs (many are repeats) and expected turnaround times are as follows:

1. Copper: 1 week
   
2. Ceruloplasmin: 1 week
   
3. CLN1 & CLN2: 1 week
   
4. ACTH*: 1 week
   
5. GM1 (Seattle): 7-10 days
   
6. Arylsulfate (Seattle): 2 weeks
7. Purine Panel (Baylor): 7 days
   

The skin biopsy will be cultured for 2-3 weeks at the ARUP lab before being sent to the University of Alabama. From then it'll take an additional 2-3 weeks to run the tests.

*Adrenocorticotropic hormone (ACTH or corticotropin) is a test I requested.

Last Saturday Bertrand rolled off the bed, got hurt and cut his lip. He was screaming so loud and hard that his face was blue, but there were still NO TEARS. I finally had enough and spent a day researching that condition; it's called alacrima. It ranges from no tears to blistered corneas and can be caused by very few things, one of which is called Allgrove syndrome.

Allgrove is another VERY rare genetic condition. It is also called Triple A Syndrome because it is characterized by Alacrima, Achalasia (difficulty swallowing) and Adrenal deficiency. We know Bertrand has difficulty swallowing and choking--his swallow study is next Tuesday. The ACTH would measure the adrenal (un)responsiveness, which is why I want the result.

People with Allgrove can have ataxia, movement disorder, neuropathy, optic nerve atrophy, developmental delay, abnormal EEG, small head for height... all of which Bertrand has. About the only thing he doesn't have is failure to thrive--his "problem" with a lot of tentative diagnoses. :) Most interestingly, it disproportionally affects Puerto Ricans! This is the first disease for which we have a known genetic basis.

Treatment for Allgrove would be relatively simple: a steroid like prednisone. (And of course extensive therapy to try to work around the damage which has already occured.) However, it is worth keeping in mind that alpha-fetoprotein, ALT, AST, and oligosaccharides should all be normal for Allgrove. These are all elevated in Bertrand. Regardless, I am fostering that evil little emotion called hope again. :)

Pictures of Testing (4/6/09-4/10/09)

Electrode on an adorable little foot (nerve conduction study).

Bertrand becoming Frankenbaby (EEG) with his beanie bear.

Frankenbaby is almost complete!

He's alive! Frankenbaby wakes up in a rave--note the strobe lights.

Sarah P. Duke Garden (4/9/09)

Here are some pictures I took on my iPhone last week of my two favorite guys in the Sarah P. Duke Garden at Duke University (Durham, North Carolina). The pictures don't do the garden justice! It is a true gem. We are lucky that spring is also probably the best time of year to experience it. Thanks to Christopher for telling us about it!

What we learned

We promised an update on what we learned about Bertrand last week.

1. Bertrand can see, but his retina is beginning to cloud, and his optic nerve is beginning to atrophy. His vision is already degraded, and eventually, he'll be blind.
2. His ears are in good condition, but the auditory part of his brain is damaged. His hearing is probably poor. They recommended giving him up to 20 seconds to process what we're saying to him. Eventually, he'll be deaf.
   
3. His brain is experiencing frequent spikes in electrical activity. These spikes aren't seizures yet, but they will become seizures eventually.
4. His brain is not demylenating, but it's not mylenating properly.
5. His brain has had mild tissue loss.
6. His brain is growing new tissue, but the new tissue is not healthy.
7. His skeletal system is normal.
8. His heart and cardiovascular system are normal.
9. His nerves are showing signs of atrophy. Eventually, he'll be paralyzed and his senses will deaden.
   
10. His liver values are continuing their steady rise, but they are not yet in a range which indicates damage is happening.
11. He suffers from severe acid reflux.
12. He experiences a dull pain over his entire body (peripheral neuropathy). This is what makes him very sensitive to touch.
13. Cognitively, he is probably much more advanced than his tests indicate. They believe that he may actually be close to his true age cognitively, but this was difficult to measure through behavioral tests.
    

It's difficult to judge his life expectancy, but they feel has "more than months."

The damage acquired so far is permanent. Even if we were able to halt the progression right now, it's unlikely he'll ever be able to walk or talk. (But we're going to try walking and talking anyway!) In terms of treatment, stem cells can repair some of the damage, but only a treatment for optic nerve atrophy may be ready during his lifetime. There has been recent progress in reversing brain damage in rats with stem cells, but this is unlikely to be ready for humans within the next five years. Symptomatically, we should be able to stop the neuropathic pain and the reflux. After his lumbar puncture, we may be able to calm his movement disorder if we find he has a neurotransmitter imbalance.

Happy Bunny Day!

It feels so good to be home! The sky is so clear, the snow capped mountains beautiful, the grass and tulips and daffodils so bright! It is a good day to be alive. :)

Bertrand will enjoy a nice long walk with Mom, Dad and his dog after his morning nap (he went down early since he is back on East coast time). Bertrand got two new books and two new Elmo DVDs from the "easter bunny" along with beautiful cards, toys and cash from his grandmas. Quite the haul for the little guy!

And, the presents aren't stopping there. This morning Bertrand and I were looking at gait trainers. Since our insurance will cover 90% of the cost, Bertrand wants a top of the line Bronco Gait Trainer. He'd be able to use it until he hits 66 lbs and it would enable him to go off road!

Watch out, world. Here comes Danger Baby! :)

Shifting focus

Today's assessment was sobering. From reading the literature and speaking with experts, we already knew that Bertrand was unlikely to be eligible for the bone marrow/cord blood stem cell transplant. Still, as parents, we had to come to Duke and UNC. Parents are programmed to fight to the death, if necessary, to save the life of their child. It's as natural as breathing. I wouldn't have been able to live with myself if I felt I hadn't exhausted every option and every appeal.

But, now that we've run out of options to save his life, we can devote more of our energy to improving his quality of life. On this front, we've made great strides in reaching a definitive diagnosis beyond "neurodegenerative metabolic disorder." A final diagnosis may give us tools to help alleviate some of his symptoms. I'm very glad we finally discovered that Bertrand is suffering from neuropathic pain, and I'm optimistic that the Neurontin will be able to help him with it. That alone may make him into a much happier baby. Dr. Longo said that the lumbar puncture may reveal that another drug could help calm his movement disorder. The advice we received from the CDL will go a long way in improving his progress from therapy sessions. I'm looking forward to building a special computer for Bertrand that may help him break through the fog of his disorder to communicate with us.

It's a strange feeling to have finally run out of hope. But, the end of hope is also a form of closure. That's not to say we won't keep our eyes open for novel gene therapy and stem cell treatments coming through the research pipeline. But, as someone that does research for a living, I'm realistic about the timescales involved in such endeavors versus the timescales Bertrand has been given.

--Matthew

UPDATE: Matthew made this post while accidentally logged into Cristina's account.

More Clues. Still No Answer.

We just got back from our meeting with Dr. Kurtzberg. While we have many more data points now, we have no definitive answers on Bertrand's disease. The consensus is that he has something metabolic with a genetic basis, but they don't know what.

I am shell-shocked in spite of the lack of diagnosis. We now know that Bertrand's neurologic condition is already too far gone for him to be considered for a stem cell transplant even if he has a disease for which it would be considered an effective treatment. The chemotherapy itself would likely accelerate the progression of the disease.

Yet again, hope has proven cruel. Mitochondrial conditions (which while mitagatable in some cases, are fatal) are now at the top of the list. Doctor Kurtzberg wrote Bertrand a prescription for a seizure medication, for when he starts having seizures.

I don't know what else to say. Doctor Kurtzberg and the team at Duke have been amazingly kind, efficient, and knowledgable. They've given us many tools to improve Bertrand's quality of life for which we are grateful: toys, tools, tips and prescriptions.

We are very glad that we made the journey to North Carolina even though we are not leaving with a diagnosis in hand. The doctors at Duke will continue working with Bertrand's doctors at the University of Utah, sharing test results and brainstorming.

Bertrand will be undergoing a skin biopsy this Tuesday, April 14th with Dr. Longo and a lumbar puncture on Tuesday, April 20th with Dr. Sakonju at the University of Utah. Hopefully, this combined with the pending lab results from Duke will give us an answer.

Despite the grim prognosis we need to keep working toward a diagnosis. This will help us deal with Bertrand's symptoms and have a better idea about his life expectancy. Also, as we've been told yet again, this will help with family planning. :-P

Dr. Kurtzberg spoke a great deal on preimplantation genetic diagnosis. This is a method used for invitrofertilization by which embryos are genetically screened before being implanted. It has been sensationalized in the news because it makes selecting for hair and eye color possible. However, in practice, only parents who're likely to have children with life threatening disorders are actually using it so they can have healthy kids. Therefore, it should NOT be made illegal!

Almost done

We're waiting for our last appointment, with Dr. Kurtzberg.

Bertrand had his ophthalmology visit this morning. We were able to balance Bertrand on the razor's edge between asleep and awake for almost an hour, which means he finally had a eye exam without his movement disorder interfering. She was able to peer deep into his retinas for a sustained period.

The good news: the "cherry red spots" common in many lysosomal storage disorders were definitely not there. However, the optic nerve showed signs of "going pale." She said it was by no means severe, but that it wasn't exactly the color she expects to see in a healthy eye at his age. She also saw a cloudier reflection in his retina than she would have liked. She recommended an electroretinogram if he begins to exhibit vision problems.

The "graying" of the optic nerve had her concerned that he could be in the early stages of optic nerve atrophy, a condition common in some lysosomal storage disorders and some leukodystrophies.

Abnormal EEG, Dr. Escolar and Leukodystrophies

Today, Bertrand had an EEG in the morning. The results were "abnormal." We'll learn more from Dr. Kurtzberg tomorrow.

After that, he had more blood drawn and urine collected for more genetic and metabolic testing.

Next, we met with Dr. Escolar. She said Bertrand is the most difficult case she's ever seen. She's an expert on neurodevelopment and has seen over 400 patients with leukodystrophies. (Lysosomal storage disorders are a member of the leukodystrophy family.) She believes he fits the profile of a leukodystrophy.

What was eerie was that she was telling us about symptoms Bertrand will "eventually have" that will preceed seizures. She said that children with leukodystrophies have tendency to drift into "staring episodes," where they stare into space for minutes on end. As the leukodystrophy progresses, these episodes begin to have seizures at their end. Bertrand began having these staring episodes a couple months ago. At the time, we thought it was a sign of deep, intense thought. Now we have to be on guard during these episodes, and keep a diary of them.

Fortunately, Dr. Escolar was able to describe why Bertrand is so sensitive to touch: he has peripheral neuropathy. Apparently, it's common in leukodystrophies. Even more fortunately, there's a treatment for it that should give Bertrand much higher quality of life: Neurontin. We've got him a prescription, and we look forward to trying it once we get home.

We left Dr. Escolar's office around five in the afternoon, with enough daylight left to see the enchanting Sarah Duke Gardens. The walk around the garden helped us clear our heads after an overwhelming day.

Photo Update: Medical Imaging, Family, Easter Bunny

Bertrand with the Easter Bunny.

Bertrand, Matthew and I are exhausted. So, this is just a quickie update to let everyone know that his testing today went more smoothly than we could've expected. It the past few days have been a fun reintroduction to southern culture (the "north" in North Carolina is a misnomer.) While used to the sweet tea and y'alls, "Lil' Sugah Bugah" (translation: small sucrose mucose) was new to us as well as Bertrand--at whom it was directed! :) We had a great time with Bertrand's cousins, Ben & Luke, along with the Easter Bunny this afternoon!

Before Versed (sedative). He was mad--we tried to explain it was a gown not a dress.

After Versed (sedative). A very relaxed baby--still not happy about the dress.

Taking X-rays for skeletal survey. Bertrand's arm was still strapped onto a board with the IV.

Please note the "Save the Gonads" heart-shaped flexible lead shield. :)

At the Southpoint Mall play area. Bertrand was *not* happy that kids kept coming up to pinch his cheeks.

Matthew and Bertrand with Ben (right) and unknown child (center).

Matthew, Bertrand and cousin Kelly (Ben & Luke's mom).

Bertrand with great aunt Julie (Ben & Luke's grandma).

Ben & Luke chillin' on the Easter Bunny's "throne"--following Cristina's rebel lead.

Luke, Bertrand and Ben. (Ben & Luke loved helping with Bertrand's stroller.)

At Duke

Here's Bertrand at the Duke medical center. Today, he had a nerve conduction study. Apparently, this consisted of electrocuting him repeatedly, which he did not enjoy at all.

After that, they drew lots of blood. One unusual factor that has always made drawing blood difficult is the fact that he clots almost immediately. In fact, his blood often clots in the tubing connecting to the syringe, which means he needs even more pokes. We're wondering if it's somehow related to the fact that his eyes have yet to shed a single tear--despite the fact that they do seem to produce ample moisture--another one of his strange symptoms.

According to the specialists he saw today, he's anomalous. While he's tested positive for oligosaccharides three times now, he doesn't match all of the symptoms for any of the known lysosomal storage disorders. This isn't necessarily cause for hope. Even if it's not a known lysosomal storage disorder, the fact that his body is accumulating oligosaccharides means that he'll still suffer the same effects.

The specialist he saw today is hypothesizing that it could be a neurotransmitter disorder, which is sometimes caused by a different but related kind of enzyme deficiency that is even rarer than lysosomal storage disorder. If he goes into that territory, he may be one of sixteen cases ever known. It's unclear whether a neurotransmitter disorder would be better or worse than an LSD.

The specialist also seemed to think a mitochondrial disorder more likely than a lysosomal disorder. Mitochondrial disorders involve a different kind of defect in the cellular metabolism, but they exhibit many of the same symptoms as LSD's. We really hope it's not a mitochondrial disorder, because mitochondrial disorders are even worse than LSD's. They can't be treated with bone marrow transplantation, and there isn't even the equivalent of an enzyme replacement therapy.

I'm heading out to Duke after I teach tomorrow, and I'll post more updates once I'm there.

On his way to North Carolina

Bertrand and Cristina took off early this morning, headed for North Carolina.

Apparently, Bertrand was a big hit with the North Dakota State University baseball team on the plane (pictured above).

In Good Hands

I met with a fellow professor, Guido Gerig, today. Professor Gerig is in both the School of Computing and the interdisciplinary Scientific Computing and Imaging (SCI) Institute here at the University of Utah. Coincidentally, Prof. Gerig used to be at UNC, joint between Computer Science and Psychiatry, and he knows many of the physicians we'll be seeing personally. He's even done research with several of them!

Prof. Gerig has many specialties and research interests, but one of them is advanced brain imaging and visualization, and he happens to have studied the brains of children with Krabbe's disease following bone-marrow transplantation. (Krabbe's disease is one of the lysosomal storage disorders for which Bertrand is being tested.)

Prof. Gerig assured me that Bertrand will be in the best possible hands at Duke and UNC. As parents, we can't ever hear those words enough.

Given how rare these disorders are, it's almost impossibly lucky to have a distinguished colleague so knowledgeable about Bertrand's condition.

RE: Genetic modification of umbilical stem cells for treatment of lysosomal storage disease?

Inspired by two other moms (Carrie and Chris) in the lysosomal storage disease community, I've been looking "outside the box" for possible treatments.

My first treatment concept involves altering the existing cord blood treatment for lysosomal storage disease to use a gene-modified version of Bertrand's own cord blood to minimize rejection and increase engraftment.

After a few weeks of looking into gene-modified umbilical cord blood research, I found a genetics & hematology expert at Harvard Medical School. He has done work with gene-modified cord blood for other diseases. The following is the prompt reply to the email I sent.

Cristina, this will depend very largely on the specific disease-causing gene, if found, and therefore the diagnosis. I would be happy to comment once you know this. There are not too many gene therapy trials open for metabolic diseases at this point.

FYI, this is the body of the email I sent.

I am the mother of a 15 month-old boy who is undergoing evaluation to determine which lysosomal storage disorder he has. Several such as Tay-Sachs and GM1 have already been discounted. I am jumping the gun a bit by looking at possible therapies--we are taking him to Duke University next week to be evaluated for a possible cord blood transplant (if his situation merits it). As you are well aware, there are many risks, such as rejection, associated with this treatment. With this in mind, I was wondering if you knew of anyone was capable genetically modifying his own banked cord blood to be used in the transplant? Your work with adenosine deaminase deficiency is the closest I've found. Even if a clinical trial comes too late for my son, I would like to know who is working in this area. It would make make the fight ahead of us easier knowing that others are fighting with us against this dreadful family of diseases.

Ruled Out: Mannosidosis & Fucosidosis

Both Mannosidosis and Fucosidosis are autosomal recessive lysosomal storage disorders. Mannosidosis is caused by deficient activity of the enzyme alpha-D-mannosidase. While in Fucosidosis the enzyme fucosidase is not properly used in the cells to break down fucose.

The last lab pending is for Krabbe disease. We should get the result for that back within the week.

Physical Therapy: Session 4/2/09

Normally parents shouldn't encourage scooting as a mode of mobility, but in Bertrand's case... well, we'll take what we can get. :) Any form of mobility would make Bertrand a happier baby. If he could develop sufficient hand control, there are even baby wheelchairs!

Bertrand Gets Adopted

In a shocking turn of events, Bertrand was adopted today by Angelina Jolie. Apparently, she saw his cheeks and thought he'd make a unique addition to her collection: Cambodian, Ethiopian, "Namibian", Thai, "French" (x2), and now Jiggly. We as parents didn't get any say in the matter. Angelina can just adopt whomever she feels like. Part of her U.N. ambassador perks or something like that. Matthew begged to be adopted too, but she said no.

Bertrand (above with Brad) spending quality time with his new family.