DMD - Cognitive Impact (Pt. II) Thursday we meet with the intervention team at Matthews Elementary, so this seems like a timely follow up to my previous post skimming over some of the biological aspects of DMD's cognitive impacts with a discussion of observed academic issues and related case studies.
Prior to diving into a discussion of objective observations, though, I wanted to share some of our personal experience.
It's probably safe to say we noticed Talen's looming academic issues well before we had any inkling that he was suffering from a degenerative neuromuscular disease. Lisa deserves a lot of credit for putting Talen into the Bright Beginnings program. I'm not sure how well he would have fared in kindergarten without the benefit of that year's preparation.
Isobel, Talen's older sister, has excelled academically from early on, so there was always some concern on our part that maybe our expectations were out of whack, and when we inquired with people who claim authority on the subject, the response would always be some variation of, "Boys just develop slower than girls." It wasn't until kindergarten at Barringer, in Mrs. Abernethy's class, that someone started to recognize that the issues we were seeing. Mrs. Abernethy noted in our first quarter conference that Talen seemed bright and engaged, but that he was experiencing issues with retention and sequencing that gave her some concern.
Unfortunately, we had to move Talen back to Matthews before we had a chance to really investigate the issues with Mrs. Abernethy, primarily because the gap between Talen and his classmates was significant. Barringer is a magnet school for gifted children, and there was an element of "If my child can read and count to 100 in kindergarten he/she will write the definitive grand unified theory in college." Talen was starting to vocalize some concerns about the difference in ability, so we thought it best to put him in a classroom with a student body that was more representative of the normal population.
I say that it was unfortunate because once he was in Matthews there was a lot of resistance to investigation. He was dropped from speech therapy, despite our protestations. Halfway through the third quarter he developed pneumonia and was hospitalized, ultimately missing close to a month of class time. Once we were able to get traction with examining the cause of his deficit, the response we heard pointed back to the missed time as the cause. Had we enrolled him in Matthews at the beginning of the year, maybe the staff there would have had more data to evaluate and things would have started moving sooner.
Even after his diagnosis, there was resistance to the idea that his academic deficit had a biological source. A staff member mentioned in a meeting that DMD had a strictly physiological pathology, so I knew that I would need to equip myself with facts to substantiate my assertion that there was a cognitive element to the disease in some cases, and that Talen's academic profile fit the narrative created by research being done. Some of these notes were already included in the first post, but given the length of this posts I thought it best to split the items with academic relevance into a second post.
So, here are the relevant materials I have saved, along with a brief summary of each item:
- [http://www.parentprojectmd.org/site/DocServer/EdMatters-Parents_Guide.pdf?docID=2402](Introduction to Education Matters for Parents - PPMD)
- [http://www.parentprojectmd.org/site/DocServer/EdMatters-TeachersGuide.pdf?docID=2403](Education Matters for Teachers - PPMD)
- [http://www.parentprojectmd.org/site/DocServer/Learning_and_Behavior_Guide.pdf?docID=11001](Learning and Behavior in Duchenne - PPMD)
- [http://mda.org/sites/default/files/publications/Teachers_Guide_NMD_P-225.pdf](Teacher's Guide to Neuromuscular Diseases - MDA)
I actually printed a copy of each of these publications, along with a document on adaptive PE, and put them in a binder for Talen's kindergarten teacher. The first two "Education Matters" documents give a high level overview, touching on some of the current school of thought regarding the specific areas where children with DMD struggle.Much of the teacher's guide is aimed at physical accomodations, but it does establish the deficit in verbal processing and "working memory" that is underlying in most cases.
The "Learning and Behavior in Duchenne" is a slightly deeper dive into the subject, and summarizes a number of clinical studies that have been performed in recent years.
The "Teacher's Guide to Neuromuscular Diseases" is another summarizing handout, which takes an even higher level view of the challenges that kids with neuromuscular disorders experience in an academic environment.
[http://www.parentprojectmd.org/site/PageServer?pagename=Care_educational_assessments](PPMD - Recommended Assessments)
This page from the PPMD website discusses a number of assessments recommended as early assessments for children with DMD. We got some pushback on performing any official assessment by Matthews staff. Ultimately I dropped the issue when I was told that the result of any discovered issues would be removing Talen from his classroom into an EC environment, rather than any sort of tailored learning in his normal classroom environment. I'm still not certain, but I think that we made the right decision given our options. EC designation has a degree of stigma associated with it that I'm not sure we could have smoothed over with Talen.
[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1950302/](Investigation of Poor Academic Achievement in Children with Duchenne Muscular Dystrophy)
This study was the most thorough and descriptive research I was able to find. The study dives deep into the topic, so set aside some time if you are expecting to read it.
The study establishes the discrepancy between [http://en.wikipedia.org/wiki/Wechsler_Adult_Intelligence_Scale](verbal and performance IQ) and summarizes previous findings that children with DMD suffer from limited immediate verbal memory. It goes on to discuss a proposed cause for this discrepancy, a specific type of working memory labelled [http://en.wikipedia.org/wiki/Memory_span#Digit-span](digit span) which, when combined with proposed deficits in [http://en.wikipedia.org/wiki/Phonological_awareness](phonological awareness), would produce the archetypical academic profile for cognitive impairment in DMD.
The tables in this study are especially compelling, as they demonstrate the deviation between children with DMD and their siblings. Even taking into account potential confounding variables, there is a clear distinction between the groups. The resulting difference between groups on all standard tests and academic composite scores was statistically significant, with a p-value of 0.000 for most of the results.
For those who didn't take or don't remember statistics, a p-value of 0.005 is given as a very stringent measure of statistical relevance. Anything below 0.005 is usually assumed to have a strong correlation.
And I thought I'd never find a use for statistics.
Parents finding themselves in the same situation should take some time to read through these documents, because you can't rely on the diligence of educators. From a practical perspective, given their workload, the number of kids they have to attend to, and their relative pay maybe it's just not a reasonable expectation.
The last note I'll leave on the subject is that you will hear a lot about IEP's, and a lot of parents seem to cling to this idea that, "If only I could get an IEP, my child would get the help he needs." You see it frequently in the PPMD forums and it is reiterated through PPMD and MDA brochures. I would caution parents of children with DMD, or any disease with similar impact, against this kind of rigid thinking. Ultimately the goal of the IEP process is to legally codify accommodations made for children with disabilities. It doesn't stipulate what those requirements might be, and pressing the subject with recalcitrant school administrators will result in the minimum level of services required by law. Keep in mind that you will be dealing with people who are well versed in the school system's bureaucracy, and unless you are prepared to spend most of your free time becoming versed in that language you will become frustrated.
In my opinion, the IEP process becomes a useful tool when physical accommodations become a more pressing concern, given their more easily quantifiable impact. Academic issues can be open to subjective interpretation, and the school administrators can interpret that information in a manner that suits their whim. There are appeals and external processes in place that you can take advantage of, but it is normally easier to appeal to the school's desire to educate and work in concert with, not opposed to, the administrative staff.
DMD - Cognitive Impact (Part I) For the first six or eight weeks after Talen's diagnosis, my need to research the disease was consuming. I still have a 2GB dropbox full of articles I saved for later review, and I've only scratched the surface in porting those articles to the site I started putting together.
I read articles about the current understanding of the disease, and boy, did I read articles about treatment options. In my mind, there was something lurking somewhere in the corner of some forgotten study or trial that held the key to pulling my kid out of this mess (Spoiler: There isn't, or if there is I haven't found it yet).
What I didn't spend a lot of time on initially was the peripheral impact of the disease, which has received less attention in the past than the physical impact of DMD from a research perspective. I had some understanding that the affect existed from skimming through articles, but when I ran into some resistance to the idea that DMD had anything more than a physical effect in a discussion with Talen's school, I knew a more diligent investigation was warranted.
Since the 1960's, medical research has started to conclude that there might be some correlation between DMD and some degree of cognitive impairment. The discovery of [https://en.wikipedia.org/wiki/Protein_isoform](protein isoforms) helped explain why a coding deficiency for a structural protein can cause cognitive issues. For those uninterested in going down the genetic rabbit-hole, the short version of the currently held theory is that mRNA can selectively include regions of a gene during transcription/translation, producing a number of proteins with varying structure and function from the same basic genetic code.
(For the biology nuts, there's a list of [http://www.dmd.nl/isoforms.html](dystrophin isoforms here). I would be a liar if I said I've read about it at any real length, though..)
I'm going to dip into the weeds here for a second.
The Dystrophin gene is known to produce at least 7 distinct isoforms, possibly more. Of those, it is believed that some degree of cognitive impairment can be predicted when mutations affecting the expression of the dp71 and dp140 occur. The ability to predict the degree to which genetic mutations will affect something as dynamic as cognition is a science that is still developing (from what I have read). From the little bit I have read, there is even some degree of contention regarding the degree to which phenotypes (the observable characteristics defined by our genetic composition) are controlled by genotype versus [https://en.wikipedia.org/wiki/Epigenetics](epigenetic factors) beyond the genome, so these discussions should be put to some scrutiny. However, scientists believe that there is some relationship between the location of mutations and their impact on cognition, and the expression of isoform proteins is key to this theory.
From left to right in the diagram are observed IQ ranges correlated with missing dystrophin isoforms. The [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008803](source study here) discusses at some length the validity of measuring the impact of cognition by isoform change versus exon deletion or duplication.
The correlation is loose, though. Boundaries for IQ even within the specific isoform groups are a range, with a margin of error, so it should be taken as a tendency and not a ceiling on a child's ability. Getting back out of the weeds, research has loosely categorized DMD patients into four clustered phenotypes: * Early infantile DMD (Very poor motor and intellectual outcome) * Classical DMD (Intermediate intellectual and poor motor outcome) * Moderate Pure Motor (Normal intelligence and delayed motor impairment) * Severe Pure Motor (Normal intelligence and poor motor outcome)
Diagram on the left [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0004347]((Source)) breaks down the distribution of 70 randomly selected DMD patients into these four phenotypes, omitting 5 outliers that were included in the study.
The study, titled Clinical Heterogeneity of Duchenne Muscular Dystrophy (DMD): Definition of Sub-Phenotypes and Predictive Criteria by Long-Term Follow-Up, identifies some loose correlation between specific mutations and these four phenotypes for anyone who is interested in the result but not excited by mapping out isoform coding regions for the dystrophin gene.
In Talen's case, the deletion occurs between exons 48-54, which is represented only slightly more in the early infantile and classical clusters than the moderate pure motor, and only minimally in the severe pure motor cluster.
What do we, as his parents, take away from this information? He very clearly doesn't fit into the early infantile cluster. He has had some difficulty in school, but he has also had some pretty big chunks of lost time since kindergarten. The school resists requests for testing to the extent they can (by non-threateningly threatening to pull him from his class and put him in an EC classroom with the more profoundly mentally handicapped children if we did demand it and testing did reveal a deficit), so we don't really know for certain if his academic issues are sourced from actual cognitive impairment or external factors.
I have my opinion, which I'll cover in part two along with some less neurobiological, more academic and real-world learning material on the subject of DMD and cognition.
I noticed recently that a lot of the research on exon skipping has started to focus on a new, non-morpholine based compound named Dantrolene, which is currently FDA approved as a muscle relaxer.
The first few times I came across it I knew I had heard the name before, though if I'm being honest, names start to blur together at some point. I did eventually remember where it was that I had first heard of Dantrolene, though.
You're thinking about sticking this in your ryanodine receptor right now.
Little tired, so this is likely to devolve quickly, but here goes...
Where I remembered reading about Dantrolene was from [http://www.parentprojectmd.org/site/DocServer/ANAETHESIAINdmd.pdf?docID=5661](a PPMD article on anesthesia induced rhabdomyolysis). For the most part, kids with DMD are not too unlike normal kids when it comes to protocols for treatment, but there are a couple of key differentiators that you have to be aware of as a parent. One is that there is a list of inhaled anesthetics which shouldn't be administered to your kid, or he might have a bad time. I don't remember the list off hand, just that it exists (and google can do the rest). In the event of anesthesia induced rhabdo (or is it malignant hyperthermia, who knows?) doctors can prescribe Dantrolene and it may or may not help.
What's funny is I kept thinking it was some drug I read about that was being used in combination with Utrophin to hook nNOS molecules, but that must have been something else.
Pretty underwhelming stuff until you look at recent research like [https://www.ncbi.nlm.nih.gov/pubmed/23241744](this), [https://www.sciencedaily.com/releases/2012/12/121212141804.htm](this), or [http://journals.lww.com/neurotodayonline/Fulltext/2013/02070/Dantrolene_Improves_Exon_Skipping_in_Duchenne.7.aspx](this) all of which has been published in the last month. Researchers ran a screen on thousands of small molecule drugs looking for candidates and Dantrolene has emerged as a promising candidate for combination therapy with exon skipping compounds.
Pretty cool stuff, if they ever move forward with clinical trials...
We went to our follow up appointment at Levine's Pediatric Orthopedic Surgery on Wednesday (Feb. 13th), and Talen got the green light to get back up on his feet and start walking. Of course he had to immediately give it a go, and he was shaky but demanded to walk out of the doctor's office.
Pics after the jump...
Ok, I'm attempting to attach the pics to this post in the ios blogger app. Am I doing this right? Oh my god.
One small step for Toomee
He is struggling with walking for more than a short distance, and the stairs are more of an issue now than ever, but given the six weeks off of his feet and the degree to which the DMD accelerates the decline in muscle tissue during periods of inactivity, it seems almost miraculous that he is even standing.
He seems to want to keep his foot turned outward right now, which you can somewhat see in the picture above. Lisa is going to be scheduling visits with Scott at the MDA clinic to see about physical therapy. Hopefully the struggle to get fully mobile will just be a temporary thing. If I'm being honest, though, my biggest fear regarding this whole situation is that the fracture and subsequent period of time off his feet will trigger a rapid decline in mobility that he won't be able to recover from.
I tend to be pessimistic though. Talen only seems to be capable of looking on the bright side, so I'm trying my best to follow his lead.
War never changes...
He's back in school now, and that's a whole other bag of worms. He has been working hard to get a handle on literacy skills, and before the break he was making pretty big improvements. It's hard to say how much this might set him back.
But worries and doubts aside, the main point is that he's back upright and out of the wheelchair. If there is a silver lining to be had, it came in the form of a discussion with the orthopedic surgeon.
I asked her about the nature of Talen's break. It seemed very abnormal to me, and she agreed that it was not typical. I asked a number of questions about the general lack of bone density in kids with DMD, because I had been told by one neurologist that DMD patients frequently suffer from [osteopenia](http://en.wikipedia.org/wiki/Osteopenia) caused by the muscular systems inability to stimulate bone growth (similar to how a sunflower will generate a thicker stem when subjected to wind or some other outside interaction).
The orthopedic surgeon told us that with Talen's late diagnosis that he probably wasn't suffering from any sort of osteopenia, that it is typically seen in kids who are so severely affected that their diagnosis occurs very early.
We will be meeting with his pediatrician at some point to check vitamin d levels and other indicators that will verify, but this is promising news.
If you're anything like me, you get all hot and bothered about eukaryotic initiation factors and you're just dying to read more about exon skipping. The rest of you need to get with the program. Here are some links for anyone interested in diving deeper into exon skipping.
(Links after the jump)
##Brief Synopses of Exon Skipping
[PPMD Exon Skipping Summary](http://www.parentprojectmd.org/site/PageServer?pagename=Advance_research_strategies_exonskipping)
MDA Exon Skipping Summary - (dead link)
Prosensa Exon Skipping Summary - (dead link)
##Leiden University Research Portal
##Recent PlosONE Articles
[This is actually about exon exchange, which would be the next step after exon skipping becomes an accepted therapy](http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0010894)
[Variants Affecting Exon Skipping Contribute to Complex Traits](http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002998)
[Targeted Skipping of Human Dystrophin Exons in Transgenic Mouse Model Systemically for Antisense Drug Development](http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0019906)
[Identification of Small Molecule and Genetic Modulators of AON-Induced Dystrophin Exon Skipping by High-Throughput Screening](http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008348)
##Recent News and Developments
[Exon skipping to restore gene expression is promising therapeutic strategy for muscular dystrophy](https://www.eurekalert.org/pub_releases/2013-01/mali-est011513.php)
[This is probably one of the more important items to air recently: Dantrolene Improves Exon Skipping in Duchenne Muscular Dystrophy Models, Raising Hopes for Combination Therapy](http://journals.lww.com/neurotodayonline/Fulltext/2013/02070/Dantrolene_Improves_Exon_Skipping_in_Duchenne.7.aspx)
[Clinical Trial to Create an Exon Skipping Tissue Bank](https://clinicaltrials.gov/ct2/show/NCT01772043)
[Dual Myostatin and Dystrophin Exon Skipping by Morpholino Nucleic Acid Oligomers Conjugated to a Cell-penetrating Peptide Is a Promising Therapeutic Strategy for the Treatment of Duchenne Muscular Dystrophy](http://www.nature.com/aj/formerly_published.html)
When you tell someone that your child has Duchenne Muscular Dystrophy, more often than not you get this blank look from them while they try to gauge your demeanor to figure out just how serious it is. Most people have at least heard of the disease, but the impact of DMD isn't something the average person tracks until it affects them, and it's difficult to reconcile that someone as happy and full of energy as Talen could be afflicted with a terminal wasting disease.
Once the severity sinks in, one of the first questions people ask is, "Can they treat it?" Currently the answer is, "Not really." There are a number of treatment options under investigation, and I have been attempting to catalog avenues of research at Toomee.org. I have not had time to work on it recently, but I'm committed to comprehensively logging all of the research that is publicly available.
However, there are a couple of items that I think are very close to being accessible which bear addressing specifically. I'll dive into details after the jump, but the two main avenues of investigation that we are excited about right now are exon skipping and utrophin upregulation. We'll dive about an inch deep into exon skipping here and talk about utrophin in another post.
Exon skipping (and genetic biology in general) can seem like a very daunting topic, and I don't want to seem dismissive of its complexity, but it is possible to gain a basic understanding of exon skipping without diving too deep into genetics. I think, at a minimum, you need to understand the following:
- The primary relevant function of a gene is to encode/create amino acids which are assembled into proteins.
- Encoding begins with one of four nucleotides (five if you count Uracil, which replaces Thymine in RNA but that's not really important for this discussion).
- Exons are sections of the genetic sequence used to encode protein (not technically accurate but we're not going to get into the details of translation and transcription here so it's good enough for a short discussion)
- The four base nucleotides are assembled in triplets to encode amino acids in sequence.
- These triplets have to be assembled in specific order or the result will be something other than the expected amino acid (and the protein chain cannot be completed)
- DMD is commonly caused (but not always, how is that for non-specificity?)by deletions known as frameshift mutations, meaning that the missing bases cause the remaining base sequences to combine into useless combinations.
- Exon skipping turns a frameshift mutation into an in-frame mutation by hiding chunks of genetic code from the translation/transcription process, which results in base pairs that are once again sequenced in triplets to produce actual amino acid chains that can be used to produce proteins (dystrophin for example).
There is a slightly more in depth article that is still meaningful to non-geneticists on the Leiden University site: [See more info here](http://www.humgen.nl/lab-aartsma-rus/index%20for%20parents.html)
Leiden University, which I had never heard of before Talen's diagnosis, is one of the earliest research institutions to investigate exon skipping through the use of morpholino oligomers. Bit of trivia here: morpholino oligomers use as their structural base an organic compound (morpholine rings) that are used as a fossil fuel additive. Chemistry majors are probably rolling their eyes here, but I still think it's fascinating that the same compound used in gasoline can be used to treat genetic mutations.
So it's worth noting that exon skipping isn't some magic bullet. The resulting protein that is encoded from the truncated sequence is still missing information, and you have to assume that all of the information is important to some degree. What makes exon skipping so attractive for a large group of DMD patients is that a large number of mutations occur in the middle of the sequence, and this part of the protein is largely repetition of the same sequence. Losing part of the sequence in the middle is usually tolerated better than losing pieces at either end. Since dystrophin's primary function is to anchor cell membranes, the shape of either end is important as it affects the protein's ability to attach to either layer. This is important to note, because if the mutation occurs early or late in the sequence, exon skipping probably won't be of any benefit (doesn't matter if you are in frame when you can't attach to hold the cells together).
If you've stuck with me this far, you might already be able to guess the biggest issue with exon skipping. In a large gene (2.6ish million bases in the dystrophin gene) there are a number of places that deletions can occur. Kids with DMD have deletions throughout the gene, with a substantial number clustered in the middle region of the gene. Exon skipping relies on masking or hiding the genetic information immediately prior to or after the deletion to restore the reading frame, so the targets for masking are myriad. Each specific mutation requires a specific compound to restore the reading frame, unless you mask a larger section of the gene than necessary.
In Talen's case, the deletion occurs from exons 48-54. Leiden University has given us a "Exon Skipping for Dummies" graphic that will let us determine which exons can be skipped to produce the desired results.
If you are able to read the whole chart (I think my Ipad isn't cut out for updating blog posts), you will notice that each numbered exon is given a shape that fits with the exon preceding and following. Look at exon 58 for example. It fits right into the groove of exon 59 and exon 57. If you deleted exon 59, exons 58 and 60 don't fit together. However, if you were to hide exon 58, exon 57 will fit nicely into exon 60. This is the super simple version of how exon skipping works.
So look at 48-54 and pretend they were missing. 47 and 55 do not fit together, but 47 and 56 DO, so masking exon 55 would restore the reading frame for someone with Talen's mutation.
The number of kids who would benefit from any specific exon skipping compound is relatively small, which makes research and development less than enticing for pharmaceutical industries. The biggest target, exon 51, addresses somewhere around 13% of the DMD population, which is tens of thousands. Not a big money maker, so a lot of parents are being left out in the cold.
Luckily, Prosensa has in its preclinical portfolio a compound that will mask exon 55, and has recently received orphan status (preferential treatment) for all of its preclinical drugs, so we will likely see this go into clinical trials later this year if we are lucky.
This is without a doubt the most promising and likely available treatment option that is looming around the corner. The preliminary data from the exon 51 skipping trials seemed to show little improvement, but after several additional months researchers started to see statistically significant gains in children receiving treatment, versus declines in children on placebo.
This post turned into something way longer than I expected, so I won't get too deep into the current status or the trial results from exon 51 skipping, but I'll come back to it in another post. Suffice to say that we are excited and watching the interwebs for any news on Prosensa and exon 55 skipping.
The question of the day comes from Joann, who asks, "What the flip is up with the MD Care Act, and why are people posting pictures of sick kids on my Facebook telling me this is important?"
I'm kidding, that's not what she actually said, but it's a valid question nonetheless. Here's a history of the MD Care Act and why it's important right now.
(SPOILER: Advances in DMD research require funding and organization that would likely be lost if the act was not re-authorized. If you aren't a fan of rambling prose and bullet lists you can probably stop here. For the rest, details after the jump.)
The Muscular Dystrophy Community Assistance Research and Education Amendments of 2001 was sponsored by Rep. Roger Wicker from Mississippi's 1st district (currently serving in the Senate) and signed into law by GW in February 2001. If you are into reading legislative text and have some time to spare, here's the full text of the bill as it was signed into law:
[MD-CARE Full Text](http://www.gpo.gov/fdsys/pkg/BILLS-107hr717enr/pdf/BILLS-107hr717enr.pdf)
To be honest, I like the idea of reading the full text more than I like reading the full text, mostly because legislative verbiage is ponderous and inefficient, and I don't have a surplus of time to waste anymore evaluating what it really means to "provide for a broad range of research and education activities relating to biomedical, epidemiological, psychosocial, and rehabilitative issues, including studies of the impact of such diseases in rural and underserved communities."
Luckily [PPMD](http://www.parentprojectmd.org/) summarized the act on their site:
This legislation included 4 major points: * NIH would support [Centers of Excellence](https://www.wellstonemdcenters.nih.gov/index.htm) focused on muscular dystrophy. These Centers would have several components – basic research, extensive collaboration, shared resources, as well as, a clinical study. * CDC would establish programs focused on Duchenne muscular dystrophy. This would include improving diagnosis, data collection, and care considerations. * NIH and related government agencies would convene the research and clinical community to develop a research plan. * NIH and related government agencies would establish a steering committee to oversee progress (MDCC).
The act was re-authorized in 2008 and is currently up for re-authorization again in Congress. With the current political climate and financial difficulties that the US government is experiencing, eliminating funding for appropriations that the MD Care Act provides may be an appealing target for cuts since it is addressing the needs of a much smaller constituency than, say, erectile dysfunction (or cancer if you want to be serious).
I will go ahead and admit that the "4 Major Points" on the PPMD site are still a little vague, so here is a list of items that affect my family which are attributed to the MD Care Act: * Improvements to molecular diagnosis have made it possible to diagnose DMD in 95% of cases without the need for muscle biopsy, so Talen was diagnosed from a blood draw instead of having a piece of his thigh biopsied. * A number of new avenues for treatment have been identified and are under various degrees of development. Some examples:
- Myostatin inhibitors
- Stem cell/Myoblast transplantation
- Viral vector-based gene therapy
- Stop codon read-through
- Exon skipping
- Protein analog upregulation
- Applications have been developed for non-invasive ventilation and cough assistance in patients with DMD who require respiratory assistance
- Significant investigation has been committed to diagnosis and management of cardiomyopathy in patients with DMD, which has lead to the application existing pharmaceuticals like Eplerenone, Losartan, and Lisinopril to DMD populations.
- I don't think it's definitive yet, but there is indication that these drugs improve pathologies beyond the expected cardiac impact
- Quantifiable discoveries have been made to improve the understanding of cognitive impacts in DMD
- Can't stress how important this is, because it is real and observable, but DMD doesn't cause profound cognitive impairment so it is a fight to assert that Talen's academic needs are different from normal populations
- Recognition of decreased bone mineral content
- I think we know how relevant this is given recent events
- The standardization and development of multi-disciplinary treatment protocols for DMD
(Source: [MDCC Action Plan](https://mdcc.nih.gov/action_plan/2015-action-Plan-to-MDCC-508comp.pdf))
In a broader sense, the MD Care Act is responsible for a $463 million influx into muscular dystrophy research, with $192 million of that being earmarked for Duchenne specific reasearch.
Watson and Crick discovered the structure of DNA in 1953 and its impact on DMD was not felt until 1986 when Louis Kunkel identified the dystrophin gene. It was another two decades before any real application was made that leveraged these discoveries, but in the past ten years there has been a flurry of advances that hold a lot of promise for kids afflicted with DMD. I think we are right on the verge of some very major changes to the course of this disease, but the research necessary to move forward will wither on the vine if funding and oversight is not maintained through legislation like MD Care. Right now the hope that one of these treatment options will come to fruition very soon is the only thing that keeps me getting out of bed every day.
Does that fit in the box? ;)
Talen pushed the call button attached to his bed and the nurse buzzed back to ask if she could help him. Talen held the intercom up to his mouth and announced, "I need more morphine."
The nurse laughed and told Talen she was on her way.
Monday, in the afternoon after Talen came out of surgery, we started to see him returning to his normal personality. Somewhat. He was still a little irritable, and prone to demanding that select people leave his room, but he was starting to perk up again. Later that evening, while we were going to sleep, I heard him making the little beat-box noise he makes when he's happy and I started to think that things might be getting better.
That night the nurses were saying that if he could start weaning from morphine to lortab that we might be able to go home the next day.
The next morning I got up and walked the greenway to work. Lisa sent me pictures throughout the day. In a single day following his surgery, Talen was already getting out of bed and into a wheelchair. By lunchtime, he was rolling around the children's ward. I left work at 4:30PM when Lisa called to tell me that we were getting discharged. We ended up leaving the hospital around 7:30PM with a stack of pillows stuffed under Talen's immobilizer cast to keep his leg upright in the van.
Last Wednesday (1/ 23/13) we returned to the orthopedic surgeon's office at Levine's to follow up. At this point his leg seems to be healing fine. The doctor removed Talen's immobilizer case, but cautioned us that he won't be able to put any weight on his leg for at least another three weeks. We asked about returning to school, and the doctor said that the main concern is going to be getting him to the bathroom. If the school is able to make allowances for that he can return, but Talen pees a lot and Matthews Elementary seems to have a very limited capacity to provide resources.
We're not sure yet how this will affect Talen's mobility. All available information seems to indicate that extended periods of bed rest can trigger significant deterioration, but so far he still seems to have a lot of energy. I'm not sure if it's just my perception, but he certainly seems smaller, more frail than he did before the fall, much the same way he seemed to after his bout with pneumonia last year.
A part of me wanted to react like the world was coming down around me, and there was a few days there that I walked around with a black cloud looming over me. At some point, though, I realized that maybe I have some right to feel despondent, but in the meantime Talen was the one who had to cope with his leg snapping from slipping on a pair of pants in the hall. Yet here he was laughing and making poop jokes while I sat around like a teenager with a Cure record.
The Thursday after we got home from the hospital, I got home from work a little late and Talen was the only one still up. He asked me to play video games with him for a little bit before bed, so I sat on the floor and listened while he chirped about this thing or that. I leaned back and looked at him, happy as a little clam, and I told him, "Buddy, I think you're pretty awesome. I don't know if anyone else could have their leg hurt as badly as you did just a few days ago and still be as happy and upbeat as you are right now."
Talen looked thoughtful for a second and then he told me, "My leg wasn't hurt that bad..."
You reach this state of mind when you're looking at your son on the ground with his leg twisted back behind him at an unnatural angle that you can never fully enunciate. It's this perfect state of panic that threatens to overwhelm you, all while your forebrain is screaming at you to pull your shit together because someone is completely depending on you to take care of this.
I was hanging shelves in the upstairs closet when I heard "The Fall." One second Talen was running down the hall, then I heard a bang followed by crying, followed shortly after by Lisa screaming for me to come to the hall where I found the previously described scene.
The trip to the hospital was surreal. When you start to feel the panic rising in your throat you find that yelling at people can sometimes help push it back down, or I should say I sometimes do (and I think Lisa does also though she'll probably deny it). So we spent a lot of the trip from Matthews to Levine's Children's Hospital alternating between loud arguing and pestering Talen to make sure he wasn't going into shock. If you know Talen, you know that the only time he's ever really quiet is when he's sleeping, but he refused to respond to us in the van. The most we could get from him was an irritated gesture of finger to lips and a quick shushing...
The triage nurse was jabbing at a card with some smiley faces on it, asking about levels of pain. Talen was refusing to play ball and kept shushing the nurse. I let her give it her best shot before I told her, "Listen, he walked around for three days this summer with a broken arm and never gave us any idea he was in pain. Let's go ahead and call this a 10 so we can move along."
In the ER, we had a carousel of nurses and techs and doctors (oh my) come through to visit. There was quite a bit of frowning, some clucking of tongues, and more than a few pokes and prods as the medical staff began assembling their diagnosis. After a trip to the x-ray that left him breathless from crying, we got the news.
"It's a broken femur."
Talen went into meltdown-mode. Our friend had fallen at our house a year or so before and broken his femur (small world, right?), so Talen already knew what the implications were. Foremost among the concerns he voiced was a statement that keeps me awake at night still.
"Now I'm going to have to get a wheelchair, and I don't want to be in a wheelchair. Wheelchairs are for disabled people, and I'm not disabled."
It hit me right in that same place where it hurts when he tells me that he wants to be a fireman when he grows up or asks me what I think his wife will look like. What can you do in that situation? If you're a parent, you lie. I guess you have an obligation to say it's going to be ok even when you don't really believe it will be.
At this point I should explain for any non-parents, or any parents who haven't been to the ER, what happens when you take your child to the ER with any sort of laceration, broken bone, or contusion. You get THE QUESTION.
"So, how did this happen?"
The first couple of times you get asked, it seems innocent. But then they start asking your child, and if you respond for him they look at you like there's something wrong. You might dismiss it the first couple of times, but then they start asking your spouse. If you have other children there, you'll get, "So how did your brother/sister get hurt?" At some point you realize that they're not really asking how your child got hurt, they're asking if you beat your child. Once you realize what is really being asked, the constant repetition becomes tiresome. In any other situation, if someone were to ask me something equally repugnant more than once I would assume that it was because they didn't believe my answer the first time.
For posterity's sake, if there are any healthcare professionals reading this blog, I would like for you to pass this message along: Your ham-fisted attempts to probe for domestic abuse are obvious and unappreciated. I've heard the justification, and it's bullshit. If you truly need to know if I got mad and broke my kid's femur, you can probably wait until the initial crisis is over. We're not going anywhere, are we?
I actually started to lose it at one point when we got the question for the tenth or twelfth time. I think I was saved by my obsessive compulsion to interrogate doctors for specific answers and do my own independent medical research during downtime. I had gleaned from the orthopedic doctors that Talen had a spiral fracture in the upper part of his femoral shaft, so I decided to look up spiral fractures to try and gauge how long he was going to be off his feet. This was the first article I came upon:
Patterns of skeletal fractures in child abuse: systematic review
So I decided to keep my mouth shut, keep repeating my story, and maybe some day when everything was over I would be vindicated by hacking out some angry words on a little-viewed blog.
We were brought up to a room that night. While they were transferring him from the ER bed to the bed in the room, a tech showed up with a set of scales and waited patiently while Talen screamed bloody murder about being moved. Once we had him settled she started into the room. The nurse looked at her and shook her head. I sensed some mild degree of "Don't tell me how to do my job" starting to rear its head, so I weighed in.
"Are you planning on weighing him in this bed and subtracting the weight of an empty bed?"
Thoughout the night the nurse would come in to check on him. They had put him on a morphine drip, which hadn't completely made his pain go away, but at least he was talking again. At one point the nurse had come in to check on him and Talen was unhappy about being disturbed.
"I am going to fart in your face, and then I'm going to tape your face to the wall," he told the nurse.
"How about if I fart in your face first?" She asked. I was glad she had a sense of humor.
The next morning, the orthopedic surgeon came in and took Talen off to have his leg patched up. They set two nails in the bone to align the broken pieces, and told us that he would be off of his feet for 4-6 weeks. Seeing him laying in the recovery room was jarring. He looked so frail, not at all like the kid who is bouncing off our walls from the time he jumps out of bed until the time he passes out at night.
(Lisa's hovering, so I guess I've been on here long enough tonight. I'll wrap this up in another post)
I think it is probably fitting that 2012 transitioned to 2013 in a tempestuous fashion, given the earth shattering way that 2012 up-ended our lives. I had intended to get on a more regular schedule with updates and changes to the site, but life really hasn't been conducive to a quiet half hour or so at the keyboard. To catch everyone up with the Cliff's Notes version of events since Halloween:
- We went to Disney (thanks to some really awesome friends and family)
- I got promoted to Director of Core Systems and Telecommunications at CPCC
- The entire family got food poisoning at Showmars
- Then we all got the flu
- We got to see some of our favorite people over the holiday break (and Jordyn did drunk pushups)
- Talen went for his second visit at the MDA clinic (first in the full rotation)
- I wrapped up a project at another university in a less than satisfactory manner
- Pulled decent grades out at the last minute for fall semester, and signed up for Marketing Management and Professional Ethics for spring.
- Talen slipped and broke his femur while walking down the hall
- I went to ACUTA in Tampa and caught pneumonia
That should get everyone caught up in less than five minutes. I'll expand on the MDA clinic after the jump, and add posts on other pertinent items another time.
##MDA Clinic Visit 12/20/2012
This was our first visit to the MDA clinic during the actual "clinic" days at the CMC Neurology office across from CMC Main. The idea behind the MDA clinics is that the impact of diseases under the MD/ALS umbrella have a diverse range of pathologies, and patients benefit from access to a comprehensive range of specialists.
The Charlotte MDA clinic was already very busy when we showed up at around 8AM. We signed in and were taken back shortly by a nurse who weighed and measured Talen before talking to us about how the clinic works. In a nutshell, we have the option on clinic visits to speak with geneticists, dieticians, physical and speech therapists, social workers, respiratory therapists, and of course the neurologist. We opted to speak with the geneticist and speech therapist before seeing the neurologist.
While waiting in the lobby, we were visited by Allie and Barbara from the MDA. They were making the rounds talking about some of the things going on with the MDA, mainly the MDA Muscle Walk in March. I'm not sure if we're going to participate, but here's a link in case anyone is interested: MDA Muscle Walk
Our first visit was with Amy Wright, the clinic's speech therapist. Amy was super nice, but seemed surprised to see us. She confessed that most of the patients she saw were elderly patients who needed assistance using the phone, but still gamely listened while we talked about our concerns with Talen's verbal development.
Brief Historical Footnote: He had been in speech therapy from pre-k through the first half of kindergarten, but after we moved him from Barringer to Matthews Elementary the speech therapist at Matthews decided he did not require speech therapy. We were informed by the speech therapist at Matthews that his speech impediment was a ploy for attention. We're still a little cranky about the whole thing.
Amy acknowledged that Talen had some obvious speech deficits producing certain sounds, but she said that the sounds he is having issues with are often the last sounds for kids to master. I think she was uncomfortable being asked to evaluate another speech pathologist's opinion, and in hindsight it probably wasn't fair to present it in that context. She admitted that it seemed off that he would be removed from speech therapy, but added that the guidelines are open to interpretation so there's not much to gain from pushing back too hard.
It's a petty sort of semi-vindication, but when you're having the kind of run we have had you take what you can get.
Amy gave us a referral to a private speech therapist, and we returned to the lobby to wait for the next specialist.
While we were in the lobby again I stopped by the clinical trials table to see what the Charlotte clinic was involved in. I skimmed over info about trials I've heard about with exon 51 skipping or Coenzyme Q10 and lisinopril while the girl working the table talked about some of the diagnostic trials available. We were asked to consider signing up for a trial where patients would be subjected to needle biopsy, with the material gathered to be used for research. I told the girl we would consider it, but if I'm being completely honest, right now I feel like Toomee is getting poked with enough needles. It might not make sense, but he sits so stoically for every pinch and poke (even though he hates needles) that I just can't bring myself to have him poked one more time than necessary. Maybe in the future he won't be getting jabbed as much, we'll see.
I think the geneticist we spoke with was actually a genetic counselor, and I sadly forgot to write down her name, but she was intelligent, well-informed, and very compassionate in discussing the genetic implication of the diagnosis, especially when Lisa broke down while we were talking about the possibility of inheritance. We already have the in's and out's of basic Mendelian genetics, so we skipped the whole discussion of what X-linked recessive disorders mean. This prompted the question about my background, which I'm starting to suspect is just empty flattery lavished on anyone who demonstrates an Intro to Biology level of familiarity with genetics. It's alright if it is, though, I still like it.
The genetic counselor sent Lisa to have blood drawn for screening. If Lisa tested negative, Talen's DMD developed spontaneously in utero, but if Lisa tested positive then the girls would need to be tested too at some point, since they could also be carriers. I think there's also a really rare third case, where the mother's blood tests negative but her ovum carry the mutation, but I couldn't find the citation for that if I had a gun to my head so I may just be making that up. Either way, I'll post the results of the testing in another update, maybe.
We wandered back to the lobby and waited...
As we started to get closer to noon, Talen started getting antsy, and I was getting anxious to get back to work. Lisa went to the front desk and asked if we could reschedule to come back and visit the neurologist on another date, and we were told to wait another 15 minutes and reschedule. 15 minutes later, we were told we would be taken back shortly. Scott, the physical therapist, ran past at one point on his way to twist one limb or another, and looked at us like, "What are you guys still doing here?" Finally we were taken back to see Dr. Bravver.
Dr. Bravver was very curt, but we knew to disregard this from our interaction with her over the summer. We wanted to talk to her about the issues that had come up during Talen's hospitalization for rhabdomyolysis back in October, mainly how to handle what seemed like a lack of protocol for dealing with kids with something like DMD in a general pediatric hospital. I don't know if we were cutting into her lunch hour or if she just found out that the Boris and Natasha spin-off got cancelled, but we were shut down pretty directly. The conversation went something like this (super paraphrased to suit my needs):
Me: ...So then we went to the emergency room and they told us that it looked like rhabdo, that if his total cpk was elevated that we would have to stay until it came down. I asked what is an acceptable cpk and they couldn't tell me.
Bravver: They can just call us.
Me: They said they couldn't get you.
Bravver: Then your pediatrician should be able to answer questions for them.
Me: I don't think my pediatrician is going to be able to field questions about a rare disease.
Bravver: DMD isn't a rare disease, 1 in 3500, etc.
Me: She told me she has only seen one other case before.
Bravver: You should get a new pediatrician.
Me: The diagnosing neurologist had only diagnosed one other case in 13 years.
Bravver: Whatever, kids with DMD are the same as regular kids, hospital should be able to treat them the same.
Me: Except for cpk.
Bravver: Right, except cpk.
Me: And AST/ALT.
Bravver: Yes, yes.
Me: And the anesthesia issues.
Bravver: Of course.
Me: Is there anything else?
Me: Ok, since I'm not going to get any help here, can I get results from any tests you have records for so we can build our own baselines?
After that, Bravver ran Talen through the normal physical tests (pull my arm, stand up from supine, run down the hall) and asked about whether or not we had seen an increase in falls (we hadn't). She then told us that given the increase in falls coupled with his age it was time to start him on glucocorticosteroids.
Now, I'm ok with starting him on prednisone/deflazacort. From what I've read, starting as early as possible is a good thing. But why ask us if he has had an increase in falls if you're just going to tell us he has no matter what we say?
To her credit, Dr. Bravver is on board with prescribing deflazacort. I guess more doctors are accepting it as a viable alternative to prednisone, but it is still technically not FDA approved for use in the US so there's some indication that prescribing deflazacort is a little progressive. I guess I could spend more time grousing about how ill Dr. Bravver seemed, and it would have been nice to have a more open exchange about how to handle the emergency room, but in the end the result was what we needed.
We left the clinic with the prescription for deflazacort in hand. Still haven't ordered it yet, though. We wanted to wait until after the holidays, and then Talen broke his leg...