Pyroluria

One of my favorite subjects is vitamin B6 (pyridoxine) which has proven to play an vital role in the world of epilepsy and autism. Not only has pyridoxine been heavily researched and documented, it has an impact on Mira's temperament and to a certain degree, her seizure activity. We have gone through many trials with pyridoxine, ultimately deciding to leave her on a regular dosage of it, since last August. It is difficult to pinpoint exactly why and how pyridoxine helps her, since it is a complex vitamin that performs so many different enzymatic functions.

Hence, this question of why, is what fuels my continual research into pyridoxine and its relationship to epilepsy. Years ago, when I first read about Pyridoxine Deficiency, I was astounded to learn that the lack of a simple vitamin could be the root cause of some cases of catastrophic epilepsy. Biotin, folic acid, and a few other basic vitamins are also implicated in epilepsy and autism, which there are plenty of case studies and research to support such claims. However, pyridoxine deficiencies, dependencies, and connections to seizures have always been a focus of mine personally, since again, they help Mira in some capacity.

About a month ago, I was looking for additional pyridoxine/epilepsy connections, beyond what I have found in the past (PDE, homocystinuria, etc.) and discovered something I had never heard of: pyroluria. As it turns out, pyroluria goes by a host of different names, including pyroluria, pyrroluria, pyrrole disorder, kryptopyrroluria, hemepyrrole, Mauve Factor, malvaria, and more recently, HPL (hydroxyhemopyrrolin-2-one). First of all, why so many different names? That question led me down a serious rabbit hole of interesting research that dates back to 1929. But first things first.

What is pyroluria? The concept behind pyroluria seems to be pretty straightforward, however its relevance and prominence in mainstream medicine is very elusive, possibly because it is called by so many different names. I can't remember where exactly I first read about the term pyroluria, but a quick Google search led me to Wikipedia's excerpt on orthomolecular psychiatry, where it describes pyroluria, hystadelia, and histapenia, which are two other 'syndromes' I had never heard of. I was instantly hooked on where all of this was headed, so I started to dive deeper and ended up at a website called orthomolecular.org and its associated medical publication, entitled the Journal of Orthomolecular Medicine. In all of my years of reading, I had never heard of any of this, which required me to have a history lesson before I went any further.

Before we start talking about pyroluria, let's step back and ask a more important question: what is orthomolecular psychiatry or orthomolecular medicine (OM)? It is a branch of alternative medicine that believes that the root of many diseases is an imbalance or deficiency of nutrients, specific to an individual's biochemistry. You can get a brief overview of OM here, taking Wikipedia (or any other open-source forum for that matter) with a grain of salt. I focused in on pyroluria in particular, which ultimately led me to Carl Pfeiffer's article on schizophrenia - Pfieffer being one of the 'founders' of OM research. His article focused on the relationship between pyridoxine, zinc, and manganese and schizophrenia. 

Initially, the researcher in me was interested in the medical background of pyroluria, but the skeptic in me kept a close eye on how and where all of these studies on this relatively obscure syndrome, were stemming from. This particular article on schizophrenia was published in, along with nearly all other articles having to do with pyroluria, the Journal of Orthomolecular Medicine, which is not a mainstream publication. It is more of an isolated 'fringe' collection of studies and abstracts by a core group of biologists, chemists, researchers, doctors, and other relevant contributors, all working toward a common theme that revolves around the principles of OM, at least that is the way it is described by critics. Much of the criticism for these types of alternative medicine publications is redundant. Rejected by mainstream medicine, these researchers chose to start their own exclusive collection, collaborating only internally, within their own 'bubble', which ultimately means one should discredit most, if not all of this type of research, since well, it's not actually considered 'real medicine'. At the end of the day, I kept reading simply out of curiosity.

As it turns out, Carl Pfeiffer wrote an entire book on the subjects of pyroluria, histadelia, and histapenia, which can be downloaded here. It's an interesting overview of the research and extent that Pfeiffer and his colleagues had gone to investigate and implement their therapeutic approaches, offering up some cheesy cartoons for comic relief along the read. I was interested in pyroluria, so initially skimmed ahead to page 139, which didn't go into a whole lot of detail, other than some anecdotal information on symptoms, which could honestly be attributed to a host of different syndromes or situations. Pfieffer has written two other books, both centering around the idea of OM and the treatment of various ailments, neither of which I have read.

I did however, go back and read some of the other chapters on copper toxicity and ironically, homocystinuria, both of which have to do with pyridoxine and zinc, of which Pfeiffer and others have used extensively as therapeutic agents in their studies. Copper toxicity and ASD have been the focus of countless studies in the last 20 years, including this one, another one here, and yet another one here. Much of the research that Pfeiffer (and others prior to that, since the late 1920's) has some validity in contemporary, mainstream medicine, only the identifiers and names are perhaps different. Zinc for instance, is a strong copper antagonist and does have some significance in creating a proper zinc/copper/manganese balance in the body, at least from what I have read.

After absorbing as much as I could stand regarding the concept of pyroluria (and considering I initially started on this journey reading about other pyridoxine connections) I have mixed emotions about all of it. The relevant historical research that attempts to establish a connection between pyrroles (which some claim to not even exist), epilepsy, and autism is somewhat vague and isolated to a handful of articles, beginning in the 1950's. Perhaps this is due to the lack of real examples (Pfeiffer only offers 1 or 2 patient cases in his book) and the absence of controlled studies on the subject. Perhaps the understanding of pyroluria was merely in its infancy, with Pfeiffer being limited by the technology and resources accessible at the time. Perhaps pyroluria goes by so many different names, that the spectrum is so vast it is difficult to pinpoint a particular study that encompasses all of these early ideas. There are some legitimate associations between mineral toxicities and zinc/manganese/pyridoxine therapies that are recent and relevant. Ironically, some of the current research references the early works of Pfeiffer, Hoffer, O'Reilly, and even contemporary pyroluria researchers, including Dr. Dietrich Klinghardt, who continues to beat the drum for those who are willing to listen. 

I have just been diving into this over the past month and will continue to read more. If you are interested in getting an overview of pyroluria, which is referenced as the Mauve Factor in these articles, I would encourage you to read the following two part series and form your own opinion on it:

Discerning the Mauve Factor - Part 1

Discerning the Mauve Factor - Part 2

Happy reading and I will post a follow up on this soon.

Research

Over the past 11 1/2 years, I have ventured down countless avenues in regards to epilepsy and autism. The process of researching anything can be overwhelming at first, but when you get to the root of an issue or idea, there are usually extensive references to back up specific claims or concepts of any given article. This is particularly true when it comes to medical research. Some of the full length articles I have read over the years have lengthy references, averaging 50-100 individual references per article, noting past writings and/or studies that were documented, that relate to a particular statement within the article at hand. Buried within the references are a plethora of additional research (depending on what you are actually researching), often leading me down a further rabbit hole, but on occasion, guiding me to further either reinforce or dismiss an idea that might be relevant to my family.

However, internet-based research is a minefield, full of hidden agendas, inaccuracies, and just blatant falsehoods. Let's just take the idea of zinc, which coincidentally, I have been researching exclusively over the past month. In the past, I've read a considerable amount regarding homocystinuria, Neuronal Ceroid Lipofuscinosis (NCL), pyroluria (which is a long future post in itself), the history of schizophrenia, and a host of other pyridoxine specific disorders, some of which directly involve dietary minerals, particularly zinc, manganese, and magnesium. If you read this article, albeit which is very brief and not all that informative, there is a reference (reference number 4) to the statement:

'Zinc deficiency has been found in infants with autism spectrum disorders. Some patients with autism may have immune dysfunction, an zinc is sometimes given to enhance immunity. However, the Autism Treatment Network's supplements study found that many children may be receiving too much zinc'. (4).

Granted the title, 'An Unofficial Guide to Autism Supplements' sums it up fairly well, thus my skepticism goggles were fully focused. It was the last sentence that caught my attention, since it went against everything that I had read in the last few weeks prior. If you follow through to the actual referenced article, which is located here, (it can be found in a host of other locations) you will note that it says absolutely nothing about the Autism Treatment Network, nor anything about children receiving too much zinc. In fact, of the 50+ articles and abstracts I have read in regards to zinc deficiency, I have not read anywhere that zinc toxicity was an issue, in any of the controlled research thus far, in fact, the exact opposite has been documented. There is actually considerable research linking zinc deficiency with Autism Spectrum Disorders (ASD) and some studies going so far as to establish an association of the severity of symptoms with the extent of zinc deficiency. These inaccurate and misleading references are rampant on the internet. The reference actually belongs after the first statement, here:

'Zinc deficiency has been found in infants with autism spectrum disorders. (4). Some patients with autism may have immune dysfunction, an zinc is sometimes given to enhance immunity. However, the Autism Treatment Network's supplements study found that many children may be receiving too much zinc'.

Whether it was an unintentional mistake or not, everything after the first statement is opinion. Personally speaking, opinion to me, often translates to mean 'agenda'. I tend to work backward and revert to the origin of the root article, which in this case, is hosted by the Pharmacy Times, which may or may not have a professional or financial interest in investing in OTC remedies. Taking another step backward, I looked at what the actual Autism Treatment Network (ATN) actually is, since it is obvious that the ATN is not part of the actual article referenced. As it turns out, the ATN has a long history of merging with other support/advocacy groups, including Autism Speaks, now falling under the umbrella entitled the National Autism Network, which on the surface, appeared to be just a provider directory for autism therapies.

Having never heard of ATN and its statement regarding zinc, I decided to try and understand who this group is. They appear to operating out of an unassuming corporate office park in Cary, North Carolina, offering an extensive national database of medical and therapy providers, which is certainly valuable for families new to the world of autism. After some additional digging, I was able to find some of the ATN's research on bio-medical therapies within their website, which makes no reference to 'children receiving too much zinc'. Going a step further and looking at their actual references, most of the articles are opinion-based links, with very few actual clinical references to anything. I wasn't impressed with the quality of references from the ATN and the fact that nowhere on their website is their any mention of their original statement as quoted on the Pharmacy Times, there isn't a whole lot of credibility with such groups, in my book.

My point is with all of this is when doing research, I always try to follow this simple protocol.

1. Do your homework. Follow up on links and references. Read multiple articles and find multiple perspectives, both positive and negative. Research anything that you might think is relative, but always follow up on the references. Articles tend to make broad-reaching generalizations, that often are unsubstantiated or simply not true. There are lots of opinions and you must carefully navigate which is which.

2. Be skeptical. I try to keep an open mind with everything I research, but at the same time, cautious of being overly optimistic or biased in my reading. For nearly every point, there is a counterpoint that is equally reputable. I try not to let emotion guide my reading and I always am skeptical in the sense that I feel that many articles are simply biased - some of what you read has a hidden agenda. I'm not sitting around wearing a tin foil hat, but rather being conscious of where the information and data is coming from.

3. Take a break. I read something almost every evening, which often leads to researching a particular subject to the point where I feel like I can form my own perspective on it. Investing so much time often gives me tunnel vision, without thinking of the counter to a particular subject - the best remedy I have found is to step away, get some perspective, and come back to it in a few hours, a few days, or a few weeks.

4. Bookmark, log, and/or archive your findings. I have been using this system for the past 5-6 years and it has been extremely helpful, as I tend to go back and look at certain articles I have read in the past that relate to what I am currently interested in.

If you want to read all about zinc and its connection to autism spectrum disorders, I would recommend the following articles:

Zinc and Its Importance for Human Health
Analysis of Copper and Zinc Plasma Concentrations in ASD
Infantile Zinc Deficiency: Association with ASD

March + April Update

These two pictures accurately summarize what has been happening in our world over the past two months. The creeping of March and the insanity of April. In the upper pic, you can see Mira slowly slouching in her chair, trying to slither her way to somewhere, out of her current position - whether she is uncomfortable, restless, or just wants to move - we are really never sure what she is trying to achieve when she does this. She does it at home, at school, in the car - pretty much everywhere.

Whatever the case, Mira's desire to creep out of her seat is how we all felt, trying to just get out of March. With no spring break plans and everyone getting stir crazy from the tail end of winter, I think we all needed a change of scenery. There wasn't anything particularly eventful about March, it just crept by at a snail's pace, simply because we didn't have a travel agenda for spring break, so there was nothing to gear up for, nothing to pack for, and nothing to really look forward to, except for well, April and warmer weather. Mira does not travel well and the boys were not interested in really going anywhere, so we decided to have a low-key spring break, which meant trying to occupy the time without going insane being at home.

We managed to get through March, but it seemed as soon as April hit, everything shifted into high gear. I had to do a ton of traveling, mainly to Virginia and Massachusetts, which was difficult on Sarah. Adding to that, I don't think the kids had a full week of school in March or April. The slouching led to full-on fidgeting, and nearly ending up on the floor. I managed to juggle my work schedule around Mira's appointments, having to take some time off to go to some of them - ultimately it gave Sarah a much needed break from trying to do 12 things at once, while I was out of town for a majority of the month.

One of those appointments, in the middle of April, involved Mira getting an ERG, which is an electroretinogram, ordered by her ophthalmologist at her last appointment. The reason for the test was two-fold: first, Mira's vision is extremely poor, thus it was a precautionary measure to see if there are deeper underlying issues with the structural integrity of her eyes and second, because of Mira's very high myopia, her heterozygous mutation of TPP1 (and possible connection to NCL) the rationale was that an ERG may also reveal any clues to her having some NCL-like symptoms that might surface from the test.

I was very optimistic for the first half of the appointment, where they had to dilate Mira's eyes - the pics above were her in the waiting room, as we were waiting for the dilating drops to take effect. Mira was all 'dragons' and smiling a ton. Unfortunately, the second part, the actual exam, did not go so well. Mira became restless and irritable, as we had to stay in a room in completely darkness for about 20 minutes, so the eyes could fully adjust for the ophthalmologist/specialist could perform the actual ERG. Mira's last ERG was about 8 or 9 years ago, where she was being monitored for retinal toxicity while on Vigabatrin. The technology since that time has changed and the ERG can now be done without sedation, with a handheld device held over each eye. Not having to go through sedation is great. However, Mira did not have the patience, even for this non-invasive exam. It took all of my physical strength and the assistant's strength to hold her still while the specialist tried to get a decent reading for each eye. This process of trying to hold Mira's head still, in complete darkness, with her crying, trying to push her way out of her chair, for 20-30 minutes, was incredibly exhausting. Mira did not want any part of this and had checked out as soon as the lights were off. By the time we were done and back in the daylight, she was back to her pre-exam attitude, making dragon noises once again in the van on the way home. It was an exhausting experience and ironically, that was almost a month ago and we just received the results last week, which were normal. The good news is that there are no structural or degenerative issues that surfaced from the exam, yet her extreme myopia is still a mystery.

Our second appointment was just this past week, with endocrinology. We had a discussion at our last appointment with her endocrinologist, which was about 6 months ago, about stopping Mira's Lupron injections. We collectively decided to go ahead and stop them now, as Mira is almost 12 years old, which is more of an appropriate age for her to start puberty. The rationale for starting the Lupron injections in the first place, was to delay the onset of puberty, which Mira was showing signs of, at age 7 or 8, which is extremely early. We don't know why her endocrine and hormones are so out of whack - just another side effect of having a catastrophic epilepsy I suppose. We think it is the right decision to go ahead and let things run their course finally, although we have some trepidation as to what we should expect once her last injection begins to lose its efficacy. I have read and heard that some kids have a significant spike in seizures, with all of the hormonal shifts that tend to happen in puberty. Only time will tell.

Other than these two recent appointments (and one with neurology next week) it has been quiet in terms of Mira's diagnosis, medication changes, or anything medically speaking. We have not made any medication shifts with anything - she is still taking Lyrica, Fluoxetine, and pyridoxine, with the latter two helping with her irritability. We only added an iron supplement to potentially help with her fatigue. In terms of her disposition and demeanor, not much has really changed in the last few months. She has had good days and bad - Easter being a particularly bad day for her, having multiple intense tonic-clonics that made her very irritable and dystonic, which led to she and I staying home while Sarah, Eli, and Jonah went on an Easter egg hunt at a friends' house. She has had several bouts of dystonia over the past 2 months, complete with rigidity, seizures, and an altered, distant disposition we tend to see with her, lasting no more than 24 hours for each episode. She also had a few days where she was very quiet, wanting to just lean forward in her chair, hands over her ears, trying to seemingly shut everything out, just like in the picture above. And of course, we have had those days of inconsolable crying, where nothing makes her happy. After almost 12 years of this epilepsy journey with Mira, we never no what to expect.