A new year, a new direction

As I say Happy New Year I can only pray for the best and a very happy one to each and every one of you



Again, I am so sorry for the delay in updates ( I feel like I start every update with this apology) but after reading the information we have been handed, I hope you can imagine what we have been going through – AGAIN ~ de ja vous and forgive us for keeping ya’ hangin’!



I could swear we just lived this nightmare and only a short year ago (almost to the date that we were first diagnosed/misdiagnosed with MPS VI). I couldn’t imagine how I was going to live through it once, but now TWICE?! My head has been spinning and my heart aching as I’ve tried to get a “grip” on this new diagnosis (at the least to learn how to properly pronounce it) and to gain some sort of control of our new situation that has no treatment or cure for our little one.



Just before the holidays we received this email from Dr. Whitley;

Cami and Mike,

I just received two pieces of information that provide important, preliminary diagnostic results. We can discuss this more fully when you return to Minneapolis and/or when we have more final results.

1.) In my lab, sequencing of the SUMF1 gene found NO mutations.

While this test is not perfect, this is a very, very strong indication that Trey does NOT have multiple sulfatase deficiency (MSD).



2.) The blood tests from Dr. George Hoganson were essentially normal except for deficiency of N-acetylgalacosamine-6 sulfatase and this would be consistent with the diagnosis of Morquio syndrome type A (MPS IVA), an MPS condition that has skeletal problems (the kind he is demonstrating), but does NOT have mental retardation as part of the disorder. While Trey would have the skeletal problems we are seeing and these need some long-term attention, the risk for other problems (such as heart, brain, etc.) are very, very, very low or "nil".

Morquio syndrome is much more like Maroteaux-Lamy syndrome is some respects, except that:



a) Joints tend to be "too loose" rather than showing progressive contractures and tightening.

b) The other problems of heart and brain that occur in MPS VI, do not occur in MPS IVA.



We are still working on getting the skin fibroblasts out to two labs for additional confirmation, and I am setting up mutation analysis for the MPS IVA gene; all of this additional/final confirmation will take another month. However, the results we now have all fit together and are consistent with the diagnosis of MPS IVA and I think we should be 95% confident that this is the diagnosis for Trey.



The impact is that:

1.) We can consider stopping Naglazyme infusions.

2.) We will pay attention to long-term skeletal issues, especially the hyperlaxity of joints (including the spine).

3.) Enzyme replacement therapy for MPS IVA is being researched at BioMarin, but clinical trials have not been started.

4.) Bone marrow transplantation has been done in only a very, very few patients long ago, and the improvements were considered equivocal; so, we cans discuss this but I think you will decide this is not a good option for Trey.



I hope this is happy news for you, and that you have a Merry Christmas.

Warm regards, Chet



In a follow-up email to answer a few of my questions Dr. Whitley writes;

1. Additional enzyme measurements from cultured skin fibroblasts, and 2. DNA sequencing of the MPS IVA gene...in a few weeks. If these are all consistent, then we have a very firm diagnosis. In the meanwhile, I am relatively confident that Trey has MPS IVA, and that you can stop Naglazyme infusions now.

Warmest regards, Chet







Now for the latest…from those two emails’ and with the advice of Dr. Whitley, Trey underwent his last Naglazyme infusion on December 17th, 2008. 42 weeks of infusion for nothing! No, even I can’t imagine!!!



When I reach for the positive in all of this, this is the best I can come up with …We could have been properly diagnosed a year ago and still been waiting for a treatment to be discovered for our baby, in the meantime watching this horrid disorder take a toll on his body,

OR

We could be misdiagnosed (as we were) and been given the hope (false as it may be) that this new infusion therapy could drop Trey’s GAG levels by approx. 70% and that we would be on our way to fixing what is wrong in his little body with the results being anything less than positive.



Hummmm….so wait and worry or “think” that what you are doing is working wonders for your child and that, “at least there is a treatment for our son’s disorder where as many of the other MPS disorders have nothing…those poor parents, how must they feel just waiting for a treatment”?! We were spared a year is the best I can come up with ?!?



I am so sad yet in the same breath angry that this has happened to us. How much of Trey’s insurance money did we use for “nothing”? Do we know for sure of the side effects (esp. in a child who was never supposed to be administered the drug in the first place)? How could they not catch the truly deficient enzyme? Why didn’t they look closer since the original lab (blood and urine) paperwork said to rule out MPS IV, MPS VI or a possible bone dysplasia? The questions go on and on and they eat me up inside, but it is what it is and now we’ve got to move forward (easier said than done, I am realizing daily).



I don’t mean to toot my own horn but I’ve been told that the “Head Cheese” at BioMarin wanted me to know that what I did by fighting for answers as expeditiously as I did, for not sitting back and have decisions be made for our child, by not waiting for answers but seeking them out for ourselves from Dr. Whitley in MN, that he thinks I am one remarkable parent and that he wishes all parents would be a proactive as us. I can’t tell you how good that made me feel after being questioned about what else I would hope to find in MN that I wasn’t finding here in AZ…seriously!



So this is what we are now 95% sure Trey has as the final pieces of the puzzle should arrive any time now.



MORQUIO SYNDROME

Morquio syndrome is an inherited disease caused by the lack of a specific enzyme that is essential in breaking down glycosaminoglycans, or GAGs. GAGs are composed of long chains of sugar molecules used in building bones, cartilage, skin, tendons, and many other tissues in the body. Individuals with Morquio syndrome are missing an enzyme used to break down a specific GAG called keratan sulfate. Incompletely broken down keratan sulfate remains stored inside the Morquio patient’s cells and begins to build up, causing progressive damage.

Infants may show little sign of the disease, but as more and more cells become damaged, symptoms start to appear. The more common form of Morquio disease is known as MPS IVA to distinguish it from the much rarer type B (MPS IVB), which is caused by the lack of a different enzyme. Individuals with MPS IVB have similar problems but tend to be less severely affected. Morquio syndrome is estimated to occur in 1 in 200,000 to 300,000 live births.



From what I understand there are at leas two companies trying to get the new ERT be developed in the US for MPS IV-a. The two articles are inserts of their progress. We are praying very deeply that this will all happen sooner than later.

Clinical development plan

In early 2009, BioMarin plans to begin enrolling a small number of patients in a Phase 1 clinical trial investigating a potential treatment for Morquio syndrome. Preliminary experiments indicate that the drug under investigation can reach the bones and other tissues that are impacted in Morquio patients.

* I spoke with a clinical advisor and he relayed to me that they now think that the 1st phase will take place out of our country and then return to the USA for phase II…I sure hope he’s wrong.

----------------------------------------------------------------------------------------------------------------------------------
Vivendy's Treatment for Morbus Morquio (MPS IVA) Granted Orphan Drug Designation...

Wed Sep 17, 2008 5:27am EDT

Vivendy's Treatment for Morbus Morquio (MPS IVA) Granted Orphan Drug Designation by FDA



BASEL ,
Switzerland-- (Business Wire)--

Vivendy Therapeutics Ltd. today announced that its enzyme

replacement therapy (ERT) for Mucopolysaccharidosis IVA, (MPS

IVA-Morbus Morquio) has been granted Orphan Drug designation by the

United States Food and Drug Administration (FDA). This designation,

following potential marketing approval in the future will give Vivendy

seven years of market exclusivity and could facilitate the recovery of

certain regulatory filing fees.



"This approval is an important regulatory step in the development

of our unique modified enzyme treatment for Morquio patients", said

Dr. Roland Toder, Vivendy's Chief Executive Officer, "We look forward

to a timely execution of our development program".



About Vivendy's Enzyme Replacement Therapy (ERT)

Vivendy's seeks to replace the lack of or deficient activity of

the N-acetylgalactosamine-6- sulfatase (GALNS) enzyme in MPS IVA by

administering a recombinant human GALNS enzyme that has been

specifically modified - potentially enhancing the efficacy of the

therapy in MPS IVA significantly. Compared to the native enzyme,

Vivendy believes that the modification has the potential to maximize

the delivery of the enzyme to efficiently clear the storage materials

in target tissues and organs.



About Mucopolysaccharidosis (MPS) IVA

Mucopolysaccharidosis (MPS) IVA (MPS IVA, also known as Morbus

Morquio A) is a rare lysosomal storage disease characterized by a gene

mutation that causes a lack or deficient activity of the

N-acetylgalactosamine-6- sulfatase (GALNS) enzyme. This in turn causes

excessive lysosomal storage of keratin sulfate (KS) and

Chondroitin-6-Sulfate (C6S) which leads to multiple systemic skeletal,

spine and joint abnormalities as well as malformations of the chest.

Additionally, patients may suffer hearing loss, vision impairment, and

heart valve disease. Accurate epidemiological data regarding the rate

of incidence of MPS IVA is only sporadically available, but estimates

vary between 1 in 250,000 live births to 1 in 500,000 live births.





This was written by a mom who’s son, Eddie has MPS IV-a and her feelings about what’s to come…Sound familiar??? Ya think I could give her some insight on the weekly infusion’s?

Now that drug companies are starting the trials they will be covering the cost of that. However, Dr. Tomatsu is continuing his research to find a better, less evasive, and less costly way of getting the enzyme to children and adults with Morquio. The current way enzyme replacement therapy(ERT) works is that Eddie will have to have a 4-5 hour IV transfusion once a week for the rest of his life. This means that Eddie will have to go through something I don’t know if I could. This also means that with the $500,000 a year that the ERT will cost, that he will meet his insurance cap quickly. Dr. T finding another way to administer the enzyme is very important to us. We are thankful that he has come this far and hope that his research continues to make Eddie’s and our other Morquio friends lives a little easier. We are hoping you can help Eddie.

Thank You for all you do!

Jeni


Here are some questions and answers geared to MPS IV-a as answered by Dr. Tomatsu.
Q1. How can I tell my child is severe or mild? My affected child is similar to other Morquio kids?

Ans. The Morquio Registry paper has over 300 patients that have kindly contributed to the questionnaire. You may see some similarity and difference with your kids. Clinical severity is sometimes difficult to say exactly: at least we must see the information of growth chart, DNA analysis, enzyme assay, and keratan sulfate level.
We are very close to finishing “Growth Chart for Morquio Patients” with age. Once it is available, you may compare your kid with other Morquio kids.
Please keep the growth chart record as detailed as possible since at birth. We will also have more registry and biochemical data to be published.
Q2. How important to measure keratan sulfate (KS)?

Ans. KS is sort of sugar chain. Morquio patients can not digest KS since one of the enzymes to digest KS is missing in the body. Therefore, KS is accumulated in the body, especially, in the cartilage (bone) and eye cornea. The stored KS will destroy the cartilage layer (growth plate). Because of that, Morquio patients have a lot of signs and symptoms related to the bone. It is quite important to know how much KS is elevated in the body (urine and blood). KS level is age-dependent and it is the highest when the kids grow. There are two major methods to measure KS quantitively: one is to use antibody against KS and the other one is to use the very modern instrument (so-called, tandem mass spectrometry). Tandem mass spectrometry is very sensitive method and can measure KS even in a mouse.
Q3. When do we have to consider the surgical operation?

Ans. It is hard to predict when the appropriate time is. However, the most important operation is “cervical fusion” to protect against the unstable neck. From the registry data, around 30% of patients may require operations. The average age is around 9 years.
Q4. Is there any animal model of Morquio? How will you confirm whether any treatment is effective or not prior to human patients?

Ans. So far except human patients we only have three different types of Morquio model mice. No other animal models are known. Generally, we try to treat the animal model prior to human patients. Since there is no animal model except mice, we only use Morquio mouse model at this point. Our mouse model has a unique feature to produce inactive human Morquio enzyme. Therefore, we can treat this mouse model continuously for a long term without any problem. Generally, if we infuse the human enzyme into the mouse body, the human enzyme will be neutralized since the mouse recognizes it as a foreign body. We are treating Morquio mice by several different treatment methods to see the effectiveness. The most important issue is how to reach the bone especially, growth plate since the growth plate region does not have vessels.
Q5. We have glaucoma (or strabismus) on the eyes. Is that related to Morquio disease or not?

Ans. According to the textbook or common sense among doctors, we could say it is unrelated. However, the recent registry data or the information from the patient may change such concept. As Morquio patients live longer, these eye symptoms may be more popular. Therefore, we need more detail analysis before the definite conclusion of relation between Morquio disease and these eye issues.
Again, there is no statistical analysis made on these subjects. None of doctors and scientists know the clear answer. Since we have a schedule to the natural history program in a large scale from many Morquio patients, we may have more precise answers in the future.
Q6. The growth hormone will it work on a Morquio patient?

Ans. It will be unlikely to have a huge benefit by using the growth hormone since Morquio patients have sufficient growth hormone in the body. The fundamental issue of Morquio disease is caused by destruction of the growth plate with the accumulation of keratan sulfate in the cartilage cells. Therefore, we have to clear such storage material. Some patients have used the growth hormone in the past. However, till now, we have not noticed that huge benefits have occurred. Of course, there is still argument on when or how to treat the patient by the growth hormone since only few patients have used it so far.
Q7. Why is it so difficult to develop of Morquio A drug?
Ans. We have several reasons.

1. It is a very rare disease (1 out of 200,000-300,000 births). Therefore, only 1200 patients are suffering from Morquio A disease in developed countries. Therefore it is not so easy for the big company to have an interest to develop the drug.
2. It is systemic bone disease. It is a challenge to improve the bone lesions compared to other visceral organs like liver, spleen, kidney etc.
3. Enzyme deficient in Morquio patients is not easy to be purified since the enzyme is unstable.

In addition, we need to have detailed preclinical tests (mouse, monkey, rat etc.) to go forward to the clinical trial.
Q8. How much will enzyme replacement therapy or other treatment like gene therapy work on Morquio patients?


Ans. This is a very critical question but also it is very difficult to answer at this moment. Since we have never treated Morquio patients, we can not predict how effective it will be. Especially, many factors must be considered: age, clinical severity, the extent of storage material, current clinical situation, condition of the bone deformity etc. The effectiveness will vary by individual patient. Some patients will get more benefits but others will get less benefit. According to the other types of MPS patients treated by enzyme replacement therapy, to improve bone lesions, it will take time. Early treatment at an early stage will provide a more benefit. We are treating Morquio A mouse model at a different age currently. Gene therapy is still at quite an early stage on Morquio A, therefore, we can not predict any at this moment. We are currently under way of some other new treatments on Morquio mouse models. We hope that we can answer more clearly.
Q9. Why do Morquio patients have hypermobile joint (loose ligament)? And is there any help to put the wrist bands?


Ans. There are two possibilities: one is because of small bones on the hands and wrists. The other possibility is the connective tissue and ligaments surrounding wrists are severely affected. The wrist bands could be helpful to sustain the grip power. The drawing, writing, and the computer typing can help to maintain the function. All are supportive treatment. Indication of surgical procedures remains uncertain and its consequence is not clear since very few patients have received the operation so far.
Q12. What kinds of rehabilitation do we have to take? Any recommendation?


Ans. This is very important since the appropriate rehabilitation will maintain your skills and strength as well as physical activity. Generally, we recommend physiotherapy (swimming), diet therapy (refrain from overweight), fine motor skills (computer, any music instrument, drawing, writing), and walking if possible. Ultimately, each individual patient must find the most appropriate one by him or herself since signs and symptoms are different.
We are now summarizing the rehabilitation methods. Hopefully, we can put the methods in next version of educational CD.
Q. 13 How can we relieve the pain?


Ans. There is no universal method to relieve the pain. Also it depends upon how severe, how often, where, worsening or not etc. We are now summarizing the pain killer methods. Once it is done, we will inform it ASAP.

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We are still digesting all of this and have more to update you as far as what we are doing for Trey PT wise but I think this is more than enough for now…thx for caring



All the best in the coming new year,

Big hugs & lots of love, The Lanes



Christmas pictures-Go Cardinals