A Much Needed Update

Tylor had his yearly check up at Mayo in February.  Dr. Patterson is still very happy with his condition.  His spine is still looking good, his horizontal gaze is getting a bit slower and of course his vertical gaze is very slow like before.  He seems to be having more tremor issues than in the past but nothing to serious right now anyway.  The seizures are still an issue but we are thinking that is do to some changes in his environment.  So I am keeping a close eye on them and we will discuss at a later date if we need to adjust his medication.  He was pretty sleepy during the exam but the doctor was happy with out Ty responded to the test he preformed.

His G-tube was also changed on our visit.  She was very pleased with how good the site looks.  No infection or granulation tissue to report.  He is such a trooper when he gets it changed.  With his growth (now 6'-0") the track is in a upward position so it is a bit uncomfortable to have changed.  In time it may need to be repositioned.  Meaning another surgery.

As far as his diet they are concerned that his weight is still the same as it was a year ago.  So we increased his calorie count.  He takes one can of the old formula and one can of a new formula with more calories twice a day.  We don't want him to get to big for the simple reason that I still have to get him around but we also want to ensue that he is getting the amount of calories and nutrition his growing body needs.

Tylor also had reevaluation for PT, OT, and speech therapy.  They will be working on respiratory therapy, endurance, fine motor, and the Dynavox (his communication device).  I was given stretches to do at home and he needs to ride his bike more. Tonight he did pretty good with the stretches and as always loves riding his bike.

Dr. Patterson Trip to Notre Dame

March 2, 2012 - Marc Patterson, M.D. Chair - Division of Child and Adolescent Neurology, Professor of Neurology, Pediatrics and Medical Genetics, Director - Child Neurology Training Program Mayo Clinic. Dr. Patterson is board certified in psychiatry and neurology (with special qualification in child neurology and in neurodevelopmental disabilities). Dr. Patterson is on the Scientific Advisory Board for the National Niemann-Pick Disease Foundation.  When my frail bark starts from the shore, Far out across the unknown tide; May some good angel guide me o'er, In safety to the other side! David Fletcher Hunton Grand Haven Daily Tribune,February 15,1902 At some point or another, most of us realize the frailness of the bark upon which we sail. For many, steeped in a cultural denial of death and blessed with good health, this realization comes late. But, in the realm of rare diseases, the awakening to pure vulnerability often comes at an early age and well before the 72 years Hunton had secured when he wrote this verse. When this awakening comes, it often appears as an “unknown tide” – in waves of unanswered questions and grief. Then, it is vital, not to sink into hopelessness or denial, but as another poet sets it, “to take arms against a sea of troubles.”1 In our species, we first take up arms against the dark and unanswered troubles by naming them and pushing away speechless sorrow. The great botanist and father of classification, Carolus Linnaeus, was called “God's registrar” and he wrote about the significance of classification, which always begins at the boundary of the unknown deep: “The first step in wisdom is to know the things themselves; this notion consists in having a true idea of the objects; objects are distinguished and known by classifying them methodically and giving them appropriate names. Therefore, classification and name-giving will be the foundation of our science .” (Systema Naturae ,1735. Trans., M. S. J. Engel-Ledeboer and H. Engel (1964), 19.) On March 2, Dr. Marc Patterson visited the students and faculty of the CRND and delivered a seminar, which would have pleased old Linaeus, “An introduction to neurometabolic disease.” Last year, Patterson taught an in-depth class on NP-C disease; this year, he placed NP-C in the broad framework of metabolic diseases of the nervous system, focusing on the common characteristics which substantiate the working classification:“inborn errors of metabolism (IEMs).” This delicate phrase names the general class of more than 5,000 distinguishable disorders, which are now visible and subject to relational analysis and systematic experimentation.  Dr. Patterson explained IEMs as "genetic disorders in which absence or malfunction of the gene product perturbs the internal milieu." He described a variety of gene products, all of which are subject to errors that potentially manifest in the appearance of disease: enzymes, structural proteins, transporters, channel constituents, receptors, and transcriptional and translational factors. Given the number of factors that can be deranged in the process of gene transcription and translation, Patterson explained how the percentages of people affected by some form of rare disease quickly mount up. In the United States about 1 in 10 people has been estimated to suffer with a rare disease. Still, there is a significant problem with the undercounting of rare diseases.  According to Patterson, underestimation of disease prevalence may occur because of overreliance on classic disease profiles. These can blind us to the atypical presentations resulting from mild, complex, and combined genetic errors. Additionally, where the observable expression of a disease is developmentally staged or results from multiple downstream effects over time, we miss in our estimation of disease prevalence. Patterson illustrated the problem with an Italian study of Fabry Disease. The study found an actual incidence of 1:3,100 versus a previous estimate of 1:50,000 in a region of Italy because it captured atypical, mild and late-onset cases, which were previously overlooked. Compared to the classic profile of Fabry, atypical cases in this region ran 11:1. Underscoring the complexity of genetic unfolding and the general inadequacy of the models, Patterson summarized, "Whatever we're thinking, however complicated you think a system is, it is really much more complicated."  Dr. Patterson's review of IEMs outlined known genetic mechanisms, molecular mechanisms, and the correlations between genotypes and phenotypes. He illustrated particular disorders and described symptomatic manifestation for the audience. The genetic mechanisms underlying IEMs include loss-of-function mutations, gain-of-function mutations, regulatory mutations, multiple downstream effects, and mutations based in epigenetic influences and Mosiacism. Examples of small molecule diseases take in amino acidopathies, organic acidopathies, urea cycle defects, fatty acid oxidation defects, disorders of oxidative phosphorylation, porphyrias, and neurotransmitter disorders. These conditions are associated with phenotypic presentations, including severe life threatening neonatal catastrophes, milder episodic dysfunction and cerebral organic acidemias. Examples of large molecule diseases comprise sphingolipidoses, mucopolysaccharidoses, neuronal ceroid lipofuscinosis, and glycoproteinases. These conditions share phenotypic traits such as progressive neurodegeneration, organomegaly, dysostosis, coarsening of the features, ocular changes, and cutaneous lesions. Many of the small and large molecule diseases share a common problem of deficiencies in enzymes, cofactors (these activate enzymes) or enzyme transporters. Complex IEMs include congenital disorders of glycosylation (CDG), childhood ataxia with central hypomyelination (CACH - vanishing white matter disease) and Cockayne's syndrome. These complex disorders are characterized by combined symptoms of large and small molecule diseases (i.e., features of slow deterioration with episodic decompensation).  According to Patterson, critical factors for diagnosing and treating IEMs currently embrace history, examination, presentation, and investigation. Elements to be considered in the patient's history include membership in an at-risk population, consanguinity, multiple miscarriages, and certain problems during gestation. Neonatal issues may also give an early indication to genetic disorders (eg., jaundice, organomegaly, acute encephalopathy). Beyond infancy, other signs may aid diagnosis: dietary preferences and aversions, unusual odors, episodic decompensation, mimicking static encephalopathy and problems with developmental progress (eg., too slow or significant regressions). Patterson predicted that in the future, genetic testing will play an increasing role, although he noted social concerns and the importance of understanding that an identified genetic issue might not actually manifest phenotypically until late in life. During this highly technical presentation, Dr. Patterson made a special point of conveying to students his testimony on the art of medicine. Given the daunting scope of IEMs and the very real suffering signified by each of them, it was helpful to hear Dr. Patterson's philosophy on treatment. He is after all, a practitioner. He faces the daily challenge of nurturing the inner resilience of his patients and their families as the waves of unanswered questions beat against them. I want to emphasize one thing to you. There are no untreatable disorders. We can treat everybody. We can help everybody – however rare their disease. Whether or not there is 'a curative' ...there is almost no curative therapy for anything - or [often no] disease modifying therapy. Just by giving people good general medical care, you make a huge difference. You've got to educate them about the disease. You've got to educate their networks about the disease. And, learn from them – it's a two-way process. You've got to support their nutrition, make sure they're fit, make sure they've got all the support that society can get. And, that can be a nightmare – navigating your way through the different systems that exist. Does it make a difference? Yes! Cystic Fibrosis. You've all heard of it. One of the most common recessive, lethal diseases in the Caucasian population. When I was a medical student starting in the '70s, hardly anybody survived their teen-age years. Now, the median survival is up into the 40s and its getting up towards 50! Is there a curative therapy? Well, there was just a paper published about a disease modifying therapy. But [until now] there's been nothing! So, what changed? People developed specialized clinics. They started to get aggressive about treating these children. They developed protocols. They updated them. They tracked progress. And, they made a huge difference in the survival from this disease. So, that's a great model for all rare disease. You can make a huge difference. You shouldn't be a nihilist. You can help all of these people make a big, big difference. That is probably the most important message of this talk. Thus, the brilliant lodestar of the healer appears above the dark sea - attend its light and chart a course across the sea of uncertainty that is rare disease medicine. tagline: Patterson, Marc C. Classification: Angel of Mayo. 1 William Shakespeare, Hamlet, 3.1 .

NNPDF Family Conference 2011

This year the NNPDF Family Conference was held in Norfolk, VA at the end of July. Sy and I took Tylor along with Sy's Mom and Stepdad. We drove down, it took us about 18 hours. We arrive in Norfolk around 6:30am and I couldn't believe it the hotel had one room ready for us. So the five of us crashed for a few hours before hitting the sites.

Norfolk is beautiful! The view from our room was of the Naval ship yard and the Bay area. We did a little site seeing our first day there but it was also the start of the conference so we couldn't do a lot.

It was so nice to see the families we met in Seattle. We had over 225 people attend this years conference which makes it the biggest one to date!! There were a lot of new families so it was great to connect and bond with them. It is crazy how you can connect with someone you never met just because of this horrible disease. Also this year there were about 26 kids there....all I can say is WOW! I loved seeing all the kids interacting with one another. Our children are so precious.

Well I guess I should get on with what we learned at the conference.

On Friday we heard from Dr. Marie Vanier, she has been researching this disease for three decades, Dr. Dan Ory, Dr. Steve Walkley, and Dr. Fran Platt. This group of doctors gave an overview of NPC Disease research, Support of Accelerated Research (SOAR) updates, Updates on Miglustat and Cyclodextrin as therapeutics for NPC and combination therapy for NPC.

On Saturday we heard from Dr. Marc Patterson, Dr. Kasturi Halder, Dr. Dan Ory, and Dr. Denny Porter. This group talked about medical and clinical update. The topics included: NPC intro adn overview, assistance of undergrads in charaterizing clinical progression for NPC, biomarkers for NPC, development of the NIH Cyclodextrin clinical trial.

Through out the weekend we also did a lot of brainstorming on how to raise money for research for National Niemann Pick Awareness Month in October. We got to listen to the famous Humorist, Carol Ann Small, we learned about an iPad can help our children communicate with us better and of course we had a beautiful banquet dinner to end the conference.

Carol Ann Small

I talked with Dr. Kasturi Halder, she is the Director at the Center for Rare and Neglected Diseases at the University of Notre Dame, about sending Tylor's medical records for the students to review. She was glad to take my information becasue with so few cases they are always looking for new NPC families. I am in the process of gathering all the medical records, I am only waiting on one doctor to get back to me.

I also talked breifly with Dr. Denny Porter, from NIH, about getting Tylor down there for the the NPC Natural History Study. He told me he would be glad to see Tylor and to call Nicole, his assistance, to set up the appointment. Nicole and I talked shortly after we got back. She explained that they would be performing all the test Tylor has had over at the NIH. That means more EEGs, MRIs, another skin biopies and spinal tap, a lot of blood with be taking, eye and hearing exams, and much more. So at first I thought do I really want to put Ty through all this again??? This information they gather from Tylor may help in the future and who knows maybe we will find out how it is processing in him. So we deceided to go for it. So Jill, Ty's Stepmom, Tylor and I are leaving Decemeber 4th and will return on December 9th!! We will keep you posted on how this go down there.

Well know on the the fun stuff...

After the conference we toured around Norfolk. We went on the SS Wisconsin and we drove on the Chesapeake Bay Bridge/Tunnel. That was so cool and weird at the same time. We also visited Grandma Mulgrew's brother in Maryland. We spent a day in D.C. and also got a little bit of relaxation time in before we had to go home. Here are some pictures!!

Virginia Beach

The fishing pier in Virginia Beach

Ty on the SS Wisconsin

See how the bridge goes under the water

Sy and Ty at the Capitol

Tylor and I with the Wright brothers

Eating Crab on the beach

July 14th-Mayo check up

Tylor's last check up was very uneventful, but we like them that way!

Lisa said his height and weight are good. He weighs 123lbs and is a whopping 5'-11"! His tube feedings are going well and he continues to eat orally. After a little more discussion about his eating habits she suggested we keep everything the same unless something were to change.

The G-tube specialist looked at the site before changing the tube, she commented on how good the site looks. There is no skin break down, no scar tissue, and no leakage. The tract has moved due to Tylor's growth but she didn't have any concerns to warrant a GI investigation. So she changed the tube and sent us on our way.

Dr. Patterson continues to be impressed that Ty is remaining stable. His seizures are under control, he is down to about 15 per month were before he would have anywhere from 35 to 45 per month. He was very alert during the exam....smiling and laughing when appropriate. The doctor contributed Ty's stability to the care we provide and the reduced seizure activity. So unless something changes we will see them again in six months.

More on Histone Deacetylase Inhibitor

University of Notre Dame Press Release Claims Breakthrough


A paper claiming a breakthrough in the fight against Niemann-Pick Disease Type C (NPC) appeared in a recent issue of Proceedings of the National Academy of Sciences (PNAS). The paper, coauthored by Olaf Wiest and Paul Helquist of the University of Notre Dame and Frederick Maxfield of Cornell University, says the use of an unspecified histone deacetylase inhibitor corrects the damage done by the genetic disorder NPC and allowed once-diseased cells to function normally. Follow this link to view an abstract of this paper at PNAS: http://www.pnas.org/content/early/2011/03/15/1014890108

To help understand the press release issued by Notre Dame on March 21, the NNPDF consulted three respected experts in Niemann-Pick Disease Type C: Dr. Dan Ory of Washington University, Dr. Marc Patterson of Mayo Clinic, and Dr. Denny Porter of the National Institutes of Health. Follow this link to view the Notre Dame press release dated March 21, 2011: http://www.eurekalert.org/pub_releases/2011-03/uond-bin032111.php

Daniel Ory, M.D., Washington University School of Medicine, and Chair of the NNPDF’s Scientific Advisory Board, responded to our inquiry:

The results are promising, but represent an early step in the process of identifying effective compounds for NPC. More cell studies are needed to understand the mechanism [and] mouse studies should be pursued….there is a long history of compounds that are effective in reducing cholesterol in cultured cells but do not have benefits in animal models, so we should be cautious in extrapolating such results to humans.

Marc C. Patterson, M.D., Chair of the Division of Child and Adolescent Neurology at Mayo Clinic, also a member of the NNPDF’s SAB, further cautioned against making premature assumptions:

The work was done in cultured fibroblasts, so one should be very cautious about extrapolating these data to animals or humans. Moreover, the work was done in cells expressing one or two I1061T NPC1 mutations, and may not be relevant to other mutations; it was not effective in an NPC2 mutant cell line. Of note, the late Dick Pagano showed dramatic reversal of trafficking abnormalities and filipin staining in NPC fibroblasts in which rab 7 and 9 were overexpressed, but much more modest results in transgenic mice with NPC1 mutations and rab overexpression.


Mouse studies could certainly be justified, but it would be premature to assume that this approach will be applicable in humans with NPC.

Another of the NNPDF's SAB members, Forbes “Denny” Porter, M.D., Ph.D., of the National Institute of Child Health and Human Development at the National Institutes of Health (NIH), stated, “It is always good news to have a potential new approach to treating NPC. Cells are the starting point, but to translate this to a potential therapy more work needs to be done.”

The paper by Wiest, Helquist and Maxfield does not name the specific histone deacetylase inhibitor. Histone deacetylase inhibitors (referred to as HDAC inhibitors) are a class of compounds that interfere with the function of histone deactylase. HDAC inhibitors have a history of use in psychiatry and neurology as mood stabilizers and anti-epileptics.

One HDAC inhibitor, valproic acid, was considered as a possible treatment for NPC, but results have not been overly promising.

Yiannis Ioannou, Ph.D., Department of Genetics and Genomic Sciences at Mount Sinai School of Medicine, also a member of the NNPDF’s SAB, made the following statement regarding his recent study of valproic acid and NPC:

We have just concluded our mouse studies on valproic acid and have evaluated its effect on cells from a number of NPC patients and on the NPC mouse. Unfortunately, the results are not great.


• For NPC patient cell lines we have treated six different lines with valproate. Some cells responded positively; i.e., the cholesterol storage was cleared but some lines were completely resistant to the treatment. Upon analysis of our data it became clear that if the patient has a relatively mild mutation then they would respond to valproate, whereas if the mutation is more severe, then the cells don’t respond.


•With respect to the mouse study, we have treated about 25 mice with daily dosing of valproate. We can extend the life of these mice by about 10%. The mice live about 122 days on average vs. 108 days for the untreated mice.


At this point we don’t think that valproic acid would be beneficial for NPC patients.

Some years ago, valproic acid was given to a few NPC patients, including Stacey Vorpahl (1985-2004), the daughter of Gary and Barbara Vorpahl of Fort Atkinson, Wisconsin for the treatment of seizures. Barb, Vice Chair of the NNPDF Board of Directors, recently posted to the NNPDF listserv group about her family’s experience with valproic acid (as Depakote):

We did have Stacey on valproic acid (Depakote) for seizures when she first started having seizures. This was at age seven. Once she started Depakote we saw a rapid decline. One of the side effects is muscle weakness. It can also actually cause seizures at higher doses. She was on Depakote for about a year. She quit talking, needed a wheelchair, could no longer sit up or roll over by herself. We didn’t think she would survive to age 8 at her rate of deterioration. We thought the decline was from NPC but after comparing notes with other parents and seeing strange seizures that their children were also experiencing when doses were increased, we decided to gradually wean her off of Depakote and try another seizure medication. It was like bringing her back from the dead. We saw her strength start coming back, alertness level [sic], her talking never resumed but she did have strength to walk with assistance. I know others have had success with valproic acid but for Stacey it was a very negative experience. I was very surprised when I saw research coming out on valproic acid. It may work in mice but it certainly did not help our daughter even controlling seizures.

This summary was compiled by the NNPDF Central Office staff with thanks to the members of our esteemed Scientific Advisory Board. (March 31, 2011)

The National Niemann-Pick Disease Foundation (NNPDF) does not engage in the practice of medicine. It is not a medical authority nor does it claim to have medical knowledge. This site is an educational service of the National Niemann-Pick Disease Foundation and is not meant to provide diagnostic or treatment advice. Information contained or suggested on this Web site does not constitute medical advice. For all information related to care, medication or treatment, the NNPDF recommends consulting a physician to determine if information presented is applicable. Please review these additional cautions about medical information provided on the Internet.

Two Thumbs up for Ty

Tylor waiting for his last appointment

Tylor recently had his six month check up at Mayo Clinic.  We went up the night before so Ty could get a good night sleep and not have to get up real early in the morning.

We saw Lisa Epp, the dietitian, first. She was very happy with his weight!  He is maintaining a healthy weight but oral eating is becoming harder so she suggested we just feed him what he likes to eat. It doesn't have to a well balanced meal all the time since he gets all his nutrients through he G-tube. I told Ty hey how many people get the permission to be a junk food junking from their dietitian? Our main goal is to keep him eating orally as long as possible so the food we feed him needs to be something easy for him to eat...like Mac N Cheese, PBnJ, soups, spaghetti o's.

Next we saw Dr. Patterson. He again was please with how is doing. His progression is very slow...he is actually pretty sable right now. I think this is great considering the onset of symptoms started eight years ago.  We talked about starting Ty on Cyclodextrin.  Dr. Patterson explained that it would be given on an uncontrolled basis and that we don't know if it will help or hurt him. He also told us to look at the big picture...Ty's quality of life! Tylor is very happy, he loves to go to school and has tons of friends. Giving him the Cyclodextirn could possibly change this. After some more conversation we decided not to pursue getting Tylor on Cyclodextrin at this time. Dr. Patterson told us to keep doing what we are doing....Loving him and keeping him health. We can do that!!! 

Lastly Tylor got his G-tube changed. Penny said that the sight looked good just a little redness from the old tube being a little tight. She gave us some pointers on how to replace the tube with little to no pressure on Ty's belly. Then we were on our way!