Sad News

11 August 2017 at 04:53 | Posted in Circadian rhythm | 7 Comments

I have some very sad news. Beth MacDonald, also known as delayed2sleep, the founder and co-author of this blog, has passed away.

Beth had suffered from DSPS since childhood. As an adult she worked for many years as a school teacher, one of the most lark-oriented professions. On only a few hours of sleep she would force herself get up early to work, making up for it with a long nap in the early evening. For most of her life she did not know of the existence of DSPS. But when finally diagnosed, she made it her life mission to be sure that no one would have to struggle in the way she did.

She was for many years one of the most prolific and helpful posters on the Nite Owl mailing list. Despite having no formal scientific training, she steeped herself in the circadian science literature. In 2005 she started this blog, which she asked me to join as co-blogger in 2010. Starting in 2007 she was very active in editing the Wikipedia articles on circadian disorders. In 2011 she became one of the founding members of the Circadian Sleep Disorders Network, a patient support and advocacy organization, where she served for many years as secretary. She was also very active in the Facebook circadian groups (as Nina Beth) and on other online venues.

A someone put it the other day, Beth was the “heart and soul” of the online circadian disorders community. She was unfailingly generous with her time and energy. In my experience she was one of the kindest and nicest people I have ever met. I think I can speak for the whole community in saying she will be terrible missed.

In recent years Beth and I have focused a lot of our energy towards helping the work of CSD-N, so posts on this blog have been less frequent, although still appearing on occasion. It has been a source of happiness for both of us that so many people have found this blog to be useful. People have often told us that this was the first place where they learned that their sleep problems were due to a real disorder.

I should note that when posting on this blog, Beth maintained her anonymity, posting as delayed2sleep (or just “D”). I had to do some serious thinking about whether to break that anonymity. But in the past few years she had told me she was thinking of using her own name, as she did on CSD-N and in her other advocacy work. So I felt it appropriate to use her real name here. At the very least, she deserves to be known for the good work she has done.

I have been pacing back and forth for a good half hour hesitating to press “publish” on this post. Partly, it’s the finality of it. But there is something else, which, if Beth were here, she’d get a good chuckle out of. You see, Beth was an amazing proofreader. If you wanted something checked over for a misplaced comma or a dangling participle, you’d ask Beth. And I am sure this post has a few mistakes that could use Beth’s eagle eye. But as hard as she was on her own mistakes, she was always forgiving of the mistakes of others. So I’m not going to worry.

I do plan to continue this blog. Due to my CSD-N work and other obligations, posts may not be frequent, but I will try to post when possible, sometimes cross-posting on CSD-N. For certain, the blog will remain up as long as I am around.

And with that, I will press “publish”.

Farewell, Beth, my co-blogger and my friend.

James Fadden (aka LivingWithN24)

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N24 Awareness Day 2016: Genetics, the new face of N24 and DSPS.

23 November 2016 at 05:26 | Posted in Body clock, Circadian rhythm, Clock genes, DSPS, N24 | 4 Comments

I got my genes tested this month, and what I found out puts a new face on my understanding of N24 and DSPD.

faces2

The first human genome was sequenced in 2003 and cost 2.7 billion dollars.  Over the years researchers have improved their technique and reduced the cost dramatically.  Recently Veritas Genetics announced it had reached the goal of the under $1000 genome, offering a full genome sequence to anyone for $999.  Still very expensive but quite a drop from 2.7 billion!

Other companies also offer a more limited but still useful form of genomic testing.  One of these is 23andMe which offers testing for $99-$199.  Rather than plunging into the deep end  of whole genome sequencing, I thought I’d go with 23andMe to confirm that I could get useful information with less expense.  I am very impressed with what I was able to find out from 23andMe.

The method of 23andMe is based on analysis of what are called single nucleotide polymorphisms (SNPs).   Most of the human genome is identical from person to person, which is why we are all humans and not horses or banana trees.  SNP analysis focuses on variations in the genome of a particular common type.

The genetic code is a sequence of DNA nucleotides which we label with the letters A,T,G or C.   So part of the code might read like this: …CTGAATGCAGT…  An SNP refers to a situation where one letter of the code differs from person to person.   So while one person may have the sequence CTGAATGCAGT  another may have the sequence CTGAATTCAGT.   Notice the only change is that the letter G in the 7th place has become a T.   Typically one SNP will be more common in the population than the other.  So, for example 90% of the population may have a G, which would be referred to as the major (more common) allele.   The T would be called the minor allele.  (Allele is another word for genetic letters.)

So if you sign up for 23andMe you send them a vial of your spit, and 4-6 weeks later they send you a link to their site where they give you information about a selection of your SNPs and what they mean, as well as some other genetic information.

Most of the information you get from 23andMe, at first glance, seems pretty basic.  They tell you where your ancestors came from and a list of various genetic traits: is your hair likely to be curly, can you taste bitter foods etc.  Interesting but hardly world-shaking in most cases.

But in addition to this pre-analyzed information 23andMe also allows you to download a file containing the raw data: a long list of the actual SNPs and your results.   These you can upload to certain web sites such as Promethease for detailed analysis, or if you know what you are doing and what you are looking for you can look through the raw data yourself.  That’s when the fun begins.

And I knew just what I wanted to look for.

In 2014 Daniel Kripke et al. published an article called, Circadian Polymorphisms in Night Owls, in Bipolars, and in Non-24-Hour Sleep Cycles.  You can get the full text at the link below.

https://synapse.koreamed.org/DOIx.php?id=10.4306/pi.2014.11.4.345

The study identified several SNPs statistically associated with N24 or DSPS.   Not all of the SNPs studied by Kripke et al were tested by 23andMe but three of the most important ones were.

In the case of N24, Kripke et al. were particularly interested in variations in a gene called BHLHE40, or basic helix-loop-helix protein E 40.   The protein produced by this gene plays a major role in the molecular clock.

http://www.uniprot.org/uniprot/O14503

The study found that subjects with N24 were statistically more likely to have one or two C alleles instead of a T at a portion of the genome labelled rs908078, which is part of the regulatory sequence for this gene.   Looking at my 23andMe data I found this line:

rs908078        3       5024771 CT

So, yes indeed I did have one C allele.  It might have been even more impressive if I had two, as some of the N24 subjects did, but one C is still interesting.

But I developed N24 as an adult, following chronotherapy. Before that I had DSPD.  So if there is a genetic predisposition it might be even more likely to show up in genes associated with DSPD.  Kripke et al found two such genes and corresponding SNPS.

The first is a gene called NFIL3 (nuclear factor, interleukin 3 regulated).  It also plays a role in the circadian clock.

https://www.ncbi.nlm.nih.gov/gene/4783

The SNP for NFIL3 is rs2482705, and people with DSPS are more likely to have two G alleles. So looking at my data file I find this line.

rs2482705       9       94182502        GG

So, yes, GG.  I can cross out another letter on my bingo card.

The other gene is RORC (retinoic acid receptor-related orphan receptor C).  This gene has many functions and is not well understood, but one of its roles is also in clock regulation.

http://www.genecards.org/cgi-bin/carddisp.pl?gene=RORC

The associated SNP is designated rs3828057.  People with DSPS are more likely to have a GG allele.  Going back to my data file I search for that string and find this.

rs3828057       1       151780177       CC

You might at first think that was a miss, but remember the structure of DNA.  It consists of two strands linked together in a helix, which run in opposite directions, the sense strand and the antisense strand.   A C in the sense strand matches a G in the antisense strand, and vice versa.  An A matches to a T.  So CC is actually equivalent to a GG in this case.  It simply means one group tested the sense strand and the other the antisense strand.

So we have another hit.

So for the SNPs that were tested  by 23andMe I am 3 for 3 in having the alleles associated with N24 or DSPD.  I don’t want to make too much of this.   These are statistical associations.  It’s entirely possible to have either disorder and not have these genes or to have the genes and not the disorder.  Nonetheless, while I am not yet ready to shout BINGO!,  I find the presence of these genes intriguing.  We aren’t quite ready to trace their function directly to the disorder but that may come in time. The first step in that process is to know what genes are involved. The fact that these genes are ones we do know are intimately involved in regulating the circadian clock is a good omen for our future understanding.

But there is also more on the horizon.  Recall I mentioned 23andMe only tests a limited number of SNPs.   Kripke et al reported a total of 9 SNPs associated with N24.  While rs908078 was the one they focused on the most, the other 8 are also significant.  But 23andMe only tested for rs980078.  They did not test the other 8.  But a whole genome sequencing, if I am ever able to afford that, should give results for the other 8. That’s a lot more letters to put on the bingo card!

I don’t think we are likely to explain N24 or DSPD entirely based on genetics.  Developmental and epigenetic factors almost certainly play a role.  But the more we know about the genetic aspects, the better off we will be. I must also add that genetic studies are not always replicated and it may turn out that all of this is a Will-o’-the-wisp that I will have to retract next year.  But eventually real data will come out.  As one of my favorite fictional characters said, “the truth is out there.”

LivingWithN24 (James Fadden)

This post also appears on the CSD-N web site.  Please join CSD-N to help support research like this.

72. 2015 in review

20 May 2016 at 12:38 | Posted in Circadian rhythm | Leave a comment

The WordPress.com stats helper monkeys prepared a 2015 annual report for this blog.

Here’s an excerpt:

The concert hall at the Sydney Opera House holds 2,700 people. This blog was viewed about 24,000 times in 2015. If it were a concert at Sydney Opera House, it would take about 9 sold-out performances for that many people to see it.

Click here to see the complete report.

N24 Awareness Day 2015 or “How I spent my blogging vacation.”

24 November 2015 at 06:01 | Posted in Circadian rhythm, N24 | 4 Comments

10 years ago my co-blogger Delayed2Sleep started this blog to bring awareness of Delayed Sleep Phase Syndrome. I joined as co-blogger 5 years ago under the name LivingWithN24. We both have continued to blog about issues affecting people with both DSPS and Non-24-Hour Sleep-Wake Cycle Disorder (N24).

I have been very gratified at the number of people online who have told us how this blog has helped them.  For example several people have told me that the post on Charting the Course of N24 helped them make a sleep chart and get a diagnosis.  Others have said that the Melatonin: Less is Sometimes More post has helped them find a dose that finally helps their sleep cycle.

Today is N24 Awareness Day.  It is a day set aside by the online N24 community to help spread awareness of this condition.  This is the third annual N24 Day.

https://n24day.wordpress.com/

In going online at the DSPS blog to write up something for today, I realized I had not posted anything here since last N24 Day.  I had a twinge of guilt, but that soon went away.  I may not have blogged much this year but I have done quite a lot this year concerning N24 and circadian disorders, some of it on my own and some as Vice-President of the Circadian Sleep Disorders Network.

I hope to blog here more in the future but in the meanwhile I thought I’d use this post to update the readers on what I have been doing in the world of N24 and circadian disorders generally.  Some of the readers may already know about this, but many may not and for them I have a lot of useful links and information to share.

Zebra

But first a word about N24 Awareness Day.  The theme for this year is “Think Zebras!”  This comes from a saying taught to doctors “When you hear hoof beats, think horses, not Zebras.”  This means when faced with symptoms look for a common cause not a rare one.  The patient with a cough, fever and muscle aches is more likely to have flu than Q fever.

But this approach leaves people with rare disorders out in the cold.  Those of us with N24 truly are Zebras, and diagnosticians need to keep that in mind.  I have said more about this in my post on the CSD-N site, so rather than repeat myself I will give you a link (and while you are there consider joining.  It is a worthy cause.)

http://www.circadiansleepdisorders.org/info/N24zebras.php

So what else has happened in the world of N24 since the last N24 Awareness Day?  Well a few things…

I was honored this year to be asked to write an article on N24 for the journal Sleep Review.  I should thank Ed Grandi for connecting us, and Sree Roy, the Editor of Sleep Review, for her hard work.  The article is called “What You Need to Know about Non-24”.  It is published online and in digital and paper formats.

http://www.sleepreviewmag.com/2015/05/need-know-non-24/

http://alliedweb.s3.amazonaws.com/sleeprev/diged/201508/html5/index.html

I have been very gratified by the reception of the article by both patients and health professionals.   A friend recently told me it turned up in the waiting room of her sleep clinic.  So word is getting around about N24.

(This was my second formal article on N24.  The first, which I don’t think I have linked to on this blog, is a report on N24 for the National Organization of Rare Disorders, which I co-authored with Dr. Katherine Sharkey a couple of years ago: http://rarediseases.org/rare-diseases/non-24-hour-sleep-wake-disorder/)

Another high point of the year was participating in an online course offered by Coursera called Circadian Clocks – How Rhythms Structure Life.   It was taught by two eminent circadian researchers, Martha Merrow and Til Roenneberg of Ludwig-Maximilians-Universität München. I am not sure if the course will be offered again, but if you have a serious interest in circadian rhythms I highly recommend it.

https://www.coursera.org/course/circaclock

Finally, another major event this year was the publication of new guidelines for the treatment of circadian disorders by the American Academy of Sleep Medicine.

http://www.aasmnet.org/practiceparameters.aspx?cid=116

A preliminary version of the guidelines was released earlier and interested parties were asked to comment.  The deadline for comments was very tight.  CSD-N submitted comments on the guidelines.  In addition to helping compose the CSD-N comments I also submitted additional comments of my own which we did not have time to incorporate into the official CSD-N comments.

The most important aspect of the AASM guidelines — both their strength and weakness — is that they are based on a strict interpretation of the concept of evidence-based medicine.  According to this approach only treatments which have been subjected to controlled clinical trials are given a recommendation.  And clinical trials have to meet a number of strict criteria to be counted.

This is often a useful constraint.  It avoids the recommendation of treatments which are ineffective.  It is particularly useful in the case of common disorders where clinical trials can be organized. (To give an example from personal experience, I recently suffered a bout of diverticulitis.  Antibiotics are often prescribed for this condition but at least 5 controlled trials have demonstrated that they make absolutely no difference in outcome.)

However, in the case of rare disorders such as N24, this restriction can be both a blessing and a curse.  Given the rarity of sighted N24s there are very few clinical trials, and those that have been done did not meet the criteria of the AASM.  Thus the guidelines give “no recommendation” for any treatment of sighted N24.   For N24 in the blind, melatonin agonists are given a “weak for” recommendation.

The good side of this is it amply demonstrates the urgent need for more studies of treatments for N24, particularly in sighted patients.  It is intolerable that there is no validated treatment for such a devastating disorder.

The bad side of this approach is that it discounts evidence such as case reports of the efficacy (albeit partial and with limitations) of treatments for sighted N24, in particular light/dark therapy or combinations of light/dark therapy with melatonin.  In the absence of clinical trials for a rare disorder, case reports may be better than no evidence at all.  Nevertheless it is true that in the absence of controlled trials we don’t know how effective such treatments are for sighted N24s as a whole. This is an issue I may discuss more in the future.

So that has been my past year of involvement with N24 awareness.  In summary, there is more attention being paid to this condition.  But we still have a long way to go.  We need better understanding of the underlying biology of N24 — which is still poorly understood — and we need validated treatments.

— LivingWithN24 (James Fadden)

70. This blog’s stats for 2014 – by WordPress

30 December 2014 at 15:47 | Posted in Circadian rhythm | 3 Comments

The WordPress.com stats helpers prepared a 2014 annual report for this blog about Circadian Rhythm Disorders (CRDs).

Here’s an excerpt:

The concert hall at the Sydney Opera House holds 2,700 people. This blog was viewed about 23,000 times in 2014. If it were a concert at Sydney Opera House, it would take about 9 sold-out performances for that many people to see it.

Click here to see the complete report.

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