Amazing genetics…

Posted by Karen - February 5th, 2012

Posted by Karen

A few days ago our National Geographic magazine arrived in the mail.  This month, February 2012, the cover story was about dogs, and how the incredible variety of breeds of dogs has been found to be attributable to just a few genes.  If I may summarize the article, it seems that despite the fact that dogs come in so many different shapes, sizes and colours and with such varying hair lengths, hair textures, temperaments, skills, etc, there’s not actually much genetic variability among dogs.  Their DNA is mostly the same from dog to dog.

So what does that have to do with Fibrodysplasia Ossificans Progressiva, which is the subject of this blog?  I’m getting to that, so don’t “hound” me (ha ha, sorry, I couldn’t resist).  Thinking again about dogs…  Say you focus on the dog’s coat.  The author of the article, Evan Ratliff, points out that among dogs, “three or fewer” genes determine whether a dog has “a coat that’s long, curly, wiry, or a combination.  If none of the three genes are mutated, the dog will have the short, smooth coat of breeds like beagles and basset hounds…” (p. 43)  Wow, and more wow.

So, generally speaking, the specific example of dogs shows that a change in a single gene can have a big whopping effect.  Which now brings us to human variability, particularly in the realm of genetic and chromosomal disorders.  Unlike the canine example described above, many human disorders have been found to be caused by the interaction of a bunch of genetic mutations, or by deletions or substituations of entire genes, and even by abnormalities of entire chromosomes.  I understand, for instance, that multiple sclerosis is thought to be due to the interaction of a number of genes, and probably with environmental contribution as well.  Another example is that of Down’s Syndrome, which has been known for some time to be caused by an extra chromosome (each chromosome containing many, many genes).

So let’s turn now to FOP.  If you have it, as my 7 year old daughter Miranda does, you know well what this genetic disorder is about.  But not everybody knows everything that FOP does, so I’m going to run through a checklist.  In no particular order, here’s what you get from FOP:

1. Differences in the big (or “great”) toe.  Just about everyone with classical FOP has big toes which are missing the first joint down from the tip of the toe.  Or, maybe you could say that the joint is there, but it’s abnormal and non-functioning, so people with FOP can’t bend their toes at that joint.  Additionally, the big toes are slightly (and sometimes not so slightly) smaller than would be expected, and angled inward toward the other toes (sometimes just a little, sometimes a lot), causing a bunion-like protrusion on the ball joint of the foot.  This big toe business is an absolutely characteristic feature of FOP, and often leads to diagnosis before anything else is observed.  (NOTE – there are a small number of people with “FOP genetic variants” which cause everything from very little toe difference at all to big toes which are completely missing).  To have a look at some FOP toes, click on this link to the International FOP Association’s website:  http://www.ifopa.org/en/symptoms.html

2. The thumbs of people with FOP are often a bit different as well.  When Miranda was born, her thumbs were clasped into her palms – sort of in imitation of her big toes.  Some people with FOP have thumbs affected this way, and some seem not to.

3. Subtle differences of all the fingers and the wrists.  I can’t exactly pinpoint what’s going on here, but when I look at the hands of people with FOP, things seem a little unusual.  The thumbs seem to be rotated a bit, and the finger joints seem to be a tiny bit larger than you would expect.  The heels of the hands, right at the wrists, seem to protrude a bit as well.  This stuff is really not very noticable, but if you know what you’re looking for, you see it.

4. FOP causes “exostoses” (small bony bumps) on the shin bones just below the knee.  They’re asymptomatic, just…  Present (in many, but not all people with FOP).  I remember noticing these on Miranda before we got her diagnosis, and I pondered what they meant. 

5. Hips.  Apparently people with FOP have abnormalities in the hip sockets which you can see on x-ray if you know what you’re looking for.  I also know one woman who thought her 10 year old daughter’s gait looked unusual from behind, and she pushed her doctor to look into it – this lead to a train of inquiry which resulted in an FOP diagnosis 2 years before the condition became symptomatic (call me impressed by THAT very observant mom).

6. Ribs and vertebrae.  The rib joints of people with FOP are slightly different to the norm, and neck vertebrae in people with FOP are often fused or partly fused right from birth.  In Miranda’s case, she could move her neck well, except for bending her neck backwards.  She HATED “tummy time” as a baby because she couldn’t get her head up off the floor, leading a physiotherapist at the time to think she had weak neck muscles.  Said physiotherapist was astonished when, a few months later, Miranda was able to sit up completely normally and on schedule.

7. Hearing problems.  About 50% of people with FOP have a degree of hearing loss, some to the point they require hearing aids.  It was originally believed that the hearing loss was caused by abnormalities in the ear bones, but more recently there’s been suspicion of a neurological contribution.  Miranda has one normal ear, and one ear with mild hearing loss at some tones.

8. Gastrointestinal problems.  A percentage of people with FOP seem to have issues with vomiting.  Miranda hasn’t had this problem, but Suzanne McCloskey, who shares this blog with me, has blogged in the past that her daughter Erin had to be investigated for this concern.

9. Seizures.  A minority of people with FOP have been documented to have a form of seizure problem.  This isn’t well understood, and is being researched.  We haven’t had this problem with Miranda.

10. Body hair.  Specifically, less of it.  You can see this particularly in the eyebrows.  Most people with FOP seem to have eyebrows which are kind of sparse, and sometimes even non-existent.  I don’t notice this very well in Miranda, but I’ve seen it in many others who have FOP.  I remember one woman with FOP commenting that she didn’t have to shave her legs often, because her leg hair just didn’t grow much.  (OK, so this disorder is good for at least SOMETHING.) 

11. Skull and facial shape.  There seems to be a characteristic FOP facial shape, which I would describe as long-ish and kind of narrow.  When people with FOP get together, many of them look related.

12. Finally, the kind-daddy issue of them all, the one that dwarfs all the rest of the stuff above into minor insignificance – FOP causes progressive swellings in the muscles, ligaments and tendons which become very warm, sometimes reddened and usually painful, and within those swellings, pieces of the tissue are destroyed and replaced by bone.  This eventually fuses the joints and prevents movement.  People with FOP are described as developing a “second skeleton”.  Bone imbalances then also lead to scoliosis, which is present in almost everybody who has FOP to one degree or another.  To make matters worse, flare-ups of FOP can be caused by even minor traumas, meaning people with FOP have to live carefully.  I’ve blogged often about Miranda’s FOP movement restrictions, which include a rigid spine, largely unmoving shoulders, a right elbow fused in an “L” shape and a partially fused left elbow.

Here we have Miranda and her friend Erin McCloskey, circa November of 2010. In both girls you can see some of the effects of FOP.

That’s really rather a lot of stuff.  I’ve got a list of 12 things above, and I know there are even a few more things (I didn’t even mention that FOP is known to have an immune system connection, for example).  But guess what – all of this crap is caused by a SINGLE genetic mutation.  One gene.  ONE.  And not only that, it’s caused by just a single pinpoint difference in one of the amino acids which make up the gene.  That teeny, tiny, miniscule change causes all the effects noted in FOP.  It just boggles my brain.  It’s almost unbelievable to me, except that I have absolute and complete confidence in the UPenn scientists who discovered the mutation and announced it in 2006.

A poster of the human genome at the FOP research lab at UPenn. The poster has the FOP mutation identified, but of course it's far too small to see in this photograph.

It also makes me think of the basic explanation of chaos theory – “if a butterfly flaps its wings in Japan, it causes a hurricane in California” (or something to that effect).  One little amino acid gets substituted for another at a baby’s conception, and the result is differences in toes, joints, body hair, hearing, movement and the body’s injury repair mechanism.  The genetic basis of FOP really is… well… amazing.

2 Responses to “Amazing genetics…”

  1. Geri-Lynne says:

    I recently read a book called Genetic Twists of Fate….a “dumbed down” version of the VERY complicated field…..it simply boggles the mind that a simple and sometimes singular switch can alter the course of a life….I have a hard time wrapping my head around it…it truly is amazing !

  2. Lara says:

    It is incredible that such a small change can wreak such havoc! I didn’t realize that sparse hair was a common FOP thing. I remember being surprised at Jaxon’s almost non-existent eyelashes at birth, though they have filled in reasonably now. (Our eldest, like both of us, has enormous long eyelashes that the nurses were drooling over when he was born!) I didn’t realize that finger and wrist differences were common either! Jaxon’s hands and feet were xrayed at 6 weeks as part of the genetics investigation and they found that the top bone in all his digits was short, though not noticeable to naked eye on some! I don’t think Jaxon has the exostoses but he does have bone spurs on both legs below the knee and Dr. K said that location for spurs was common in FOP but not the general population (as I had previously been told).



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