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"Confetti Skin, Beauty Within" is our blog about ichthyosis and its effect on our lives. Rachel and our three boys are affected with the form of ichthyosis called "icthyosis en confetti, type 2".

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Life with Harlequin Ichthyosis: The Science Behind Harlequin Ichthyosis

If you type the word “ichthyosis” into your favorite search engine, the first page of results offers up a list of respected medical websites, charities and the long standing forum for families. And it turns out that when people are searching on Google for “ichthyosis”, almost half of the time they are looking for information about harlequin ichthyosis, the most severe form of autosomal recessive congenital ichthyosis (ARCI). The search results for harlequin ichthoysis which go beyond the respected charities and medical websites are, in our opinion,  a fairly even mix of rubbernecking-at-medical-pictures and glossed-over informational articles. At first glance, you would never know that 31 other varieties of ichthyosis even exist.

In today’s post, we will talk about some of the basic known science regarding harlequin ichthyosis. Harlequin ichthyosis was not linked to a specific gene until 2005, so some of this research is very recent. And that means several older publications (including textbooks) are out-of-date.

Our post today is the first in a series of posts specifically about harlequin ichthyosis. We have asked several of our friends with (or caring for an individual with) harlequin ichthyosis to write a guest post (or posts) about their experience, and we will update each post in the series with links as new guest posts are published.

So what is harlequin ichthyosis, exactly?

Harlequin ichthyosis, the most severe form of autosomal recessive congenital ichthyosis (ARCI), is a recessive form of ichthyosis caused by having a large chunk of the gene ABCA12 missing or misspelled. ABC stands for ATP-binding cassette. There are a boatload of ABC genes, and “A12″ just specifies which one of those genes we are talking about. An “ATP-binding cassette” is a fancy name for a gate in the cell’s membrane that works like an automatic sliding door. The door needs power to make the doors open and someone to stand on the mat and tell it to open simultaneously. No power, no open. No person on the mat, no open. So, the ABCA12 gate needs both energy in the form of ATP and something needs to be on the other side of the membrane. ATP is that energy molecule we all learned about in 10th grade biology. If you remember any cell biology in high school, you may have forgotten the details of something called the Krebs Cycle. (Too bad we all didn’t get this guy to teach us.) Short version -  it binds to something, becomes ADP and P and energy, and the energy is used to power the sliding door. If you read anywhere else about ABCA12, you might see people call it a “highly conserved gene“. This means that if you looked at the genes of a rat, a fish, a fruit fly, a porcupine or a human, each of those animals has this gene, and in every case, the gene has the exact same sequence. This tells us that this gene is really important and if it gets messed up, the owner of the mutation usually doesn’t live long enough to pass it to offspring.

What does the ABCA12 protein do?

Well, the way it’s supposed to work is that the ABCA12 protein uses energy to pump a lipid called glucosylceramide into small bags called “lamellar bodies” or “lamellar granules.” The dark purple layer of the skin is called the stratum granulosum because on a slide the cells look like they are full of speckled sand.

You may notice that lamellar ichthyosis, a different form of ARCI, shares this name. In lamellar ichthyosis, the same granules are affected, just in a different way than in harlequin ichthyosis. (And that’s another reason how different types of ARCI share some similar traits.)

Lamellar bodies have a bunch of different gates that pump in cholesterol and enzymes and other fats, but glucosylceramide is about half of the total. The lipids outside help make the skin waterproof and also help the skin cells stick together, like mortar holding brick a wall together.

Glucosylceramide inside the cell tells the skin to divide and grow. It is normally balanced with a similar lipid called ceramide, which tells the skin to stop growing. They are related — one is a giant fat molecule, and the other is the same molecule with a chunk of sugar attached. Inside the cell, ceramide + an enzyme = glucosylceramide. The glucosylceramide is too big to go through the cell membrane on its own, so ABCA12 makes a gate in a small sack and it gets pumped into the sack. Then the sack attaches to the cell membrane and ejects the contents. Once outside, one of the enzymes from the sack breaks off the glucose, leaving ceramide as the main lipid holding the waxy skin surface together.

 

 

What happens to the ABCA12 protein in someone with harlequin ichthyosis?

In 2005, at least 3 different articles came out linking mutations in ABCA12 to harlequin ichthyosis. One used fluorescent dye attached to immune system components that bound directly to the ABCA12 molecule. Basically, what they found was that in people affected by harlequin ichthyosis, the ABCA12 transporter protein never made it to the cell surface. This means that the lamellar bodies aren’t filling with glucosylceramide, they aren’t binding to the cell membrane and they aren’t dumping their contents outside the cell.

Instead, for a person with harlequin ichthoysis, the lamellar bodies remain in the cells, the enzymes that make the skin slough off never get out to do their job, the skin isn’t waterproof because the glucosylceramide isn’t outside the cell to get converted back into ceramide, and on top of that, glucosylceramide builds up in the cells, which tells the skin cells to divide and make even more skin.

Harlequin ichthoysis is generally caused by large deletions or missense mutations in the ABCA12 gene. The protein it makes is a 3-forked molecule. 1 tine grabs the lipid, and the other two grab ATP. Once all 3 things are attached, the protein changes shape and shoves the lipid into the lamellar body. If there’s a mutation where the protein can’t grab the ATP, it can’t pump the glucosylceramide lipid through the gate. Likewise, if the pump can’t grab the glucosylceramide, it can’t push lipid into the lamellar bodies. Some of the research also suggests that the entire protein never even attaches to the lamellar body in the first place, and its absence means that there’s no way to tell the lamellar body to go dump the other stuff (enzymes that break keratin bonds and such) outside the cell.

In the picture below, the blue line is the cell membrane. All the red arrows are some of the places where harlequin mutations have been found. The purple triangles are where ATP attaches. The NH2 end of the molecule is where it begins, and in some cases of harlequin ichthyosis, up to 56 amino acids have been found missing here. In such a situation, it seems that the cell doesn’t even recognize the protein and doesn’t work at all, even though the “grabbing” parts of the molecule are not affected. While reading up on this, I found some speculation that the ABCA12 protein doesn’t trigger the lamellar body to bind to the cell membrane, that instead it triggers the cell to divide because the cell winds up thinking it is farther down in the epidermis than it really is, and various other possibilities about why a newborn affected with harlequin ichthyosis looks the way he does or why their skin grows so fast and gets so red. The articles I linked are all published between 2005-2011, so many of the answers still aren’t known.

Going beyond cellular biology: What does it all mean?

The previous sections of this post talked about how a mutation in the ABCA12 gene causes problems with the skin of an affected person. Once we get past the cellular level, here’s what winds up happening on a broader scale:

  1. The glucosylceramide buildup inside the cell tells the cell to replicate, so you get extremely fast skin growth.
  2. The lack of protein on the lamellar bodies means they can’t dump enzymes, so the skin cells don’t break down and fall off.
  3. The lack of protein on the lamellar bodies also means they can’t dump glucosylceramide, which then can’t turn back into ceramide, so there’s no “mortar” holding the cells together, which causes the skin to lose its waterproofing ability. (Or, for those more familiar with the term — the lack of protein on the lamellar bodies causes the affected skin to have an extremely high rate of transepidermal water loss.)
  4. Losing water through the skin from evaporation means losing heat as well. You need to take in more calories to generate the heat and maintain body temperature.
  5. Using calories on skin growth and managing body temperature means fewer calories for growth, so kids tend to be small and thin. And on a “macro” level in a newborn baby, those issues on the cellular level translate into these (very serious) problems:
  6. On a newborn baby affected with harlequin ichthyosis, the amniotic fluid keeps the baby moist so the top layer of skin doesn’t ever flake off. Once the baby is born, that top layer of skin dries out, shrinks and cracks. As it shrinks, it pulls the baby’s eyelids back (causing a condition called “ectropion”) and also cause the baby’s lips to flip inside out (a condition called “eclabium”). (And remember, ectropion is a common condition in other forms of ARCI.)
  7. Problems with the baby’s lips (“eclabium”) can make keeping the baby fed a problem. Combined with the baby’s higher nutritional and fluid intake needs, this can be a very serious combination.
  8. On the newborn, the cracking, shrinking skin can restrict breathing so a newborn can literally suffocate to death inside his own cocoon of skin.
  9. On the newborn, the cracks also open bloody sores, like deep paper cuts. If any of these gets infected, the baby can quickly become septic and die. Sepsis is an extremely high risk for the first month, but it can be a long term problem as well.

That’s our summary of what’s going on. We are not doctors or medical professionals. A doctor or nurse looking to confirm or consult on a diagnosis of harlequin ichthyosis should immediately contact FIRST, the Foundation for Ichthyosis and Related Skin Types because time is of the essence and specialized expertise is critical in caring for a newborn with harlequin ichthyosis.

Part 1: Life with harlequin ichthyosis: The basic science behind harlequin ichthyosis <–You Are Here
Part 2: Life with harlequin ichthyosis: Newborn Surprise
Part 3: Life with harlequin ichthoysis: In the NICU
Part 4: Life with harlequin ichthoysis: Going Home
Part 5: Life with harlequin ichthoysis: Ups and Downs in the First Year
Part 6: Life with harlequin ichthoysis: Toddler Years
Part 7: Life with harlequin ichthoysis: School Daze
Part 8: Life with harlequin ichthoysis: The Downs of Middle School
Part 9: Life with harlequin ichthoysis: The Ups of High School
Part 10: Life with harlequin ichthyosis: Moving Past School
Part 11: Life with harlequin ichthyosis: A Harlequin Pregnancy

We are always looking for questions and feedback about what we’ve written and what we have in store here. So please email us or leave a comment here if you have any questions or thoughts!

 

2 comments to Life with Harlequin Ichthyosis: The Science Behind Harlequin Ichthyosis

  • Pauline

    WOW, isn’t it all so technically complicated to understand. Thanks again Jenny. You are doing a fabulous job at putting others before yourself. Well Done.

  • sabedin

    Which kromozome carry the gene abca12

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