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Harlequin Ichthyosis Defines a Key Role for Abca12 in Lipid Homeostasis
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What is Harlequin Ichthyosis?
What is Ichthyosis?
The Ichthyoses are a family of skin diseases; the characteristic that they each share is that they cause the skin to build up and scale.
Your skin is alive; it is your body’s largest organ, With "normal" skin, the skin is constantly renewing itself, dying, and shedding (the average skin cell has a lifespan of 14 days).
One with this disorder; their skin does not shed therefore scales....
Warning: The pictures you are going to see are disturbing, so close your eyes if you have a weak stomach :)
-The disease is caused by defects in a protein called ABCA12, which is thought to function by transporting lipids within the cells of the skin.
-ABCA12 is simply the active gene in our skin cells. HI babies have defects in ABCA12.
-ABCA12 protein are essential for normal development of the skin, which provides a barrier between the body and its surrounding environment.
What most new born
babies look like
How does this happen?
-Ichthyosis is caused by a genetic defect, either by spontaneous mutation of a gene or through family inheritance. The symptoms may or may not be apparent at birth, but the genetic defect was present at conception.
-You cannot "catch" ichthyosis. You cannot do anything wrong to develop ichthyosis. It’s not your parents’ fault either. You were just born with it.
Newborn children affected with Harlequin ichthyosis are covered with plates of thick skin that crack and split apart. The thick skin plates can pull at and distort the infant's facial features
The tightness of the skin pulls around the eyes and mouth, forcing the eyelids and lips to turn inside out, revealing the red inner linings. The chest and abdomen of the infant may be severely restricted by the tightness of the skin, making eating and breathing difficult.
In Harlequin infants, premature birth is typical, leaving infants at risk for additional complications from early delivery. These infants are also at high risk for difficulty breathing, infection, low body temperature, and dehydration.
A Baby born with Harlequin Ichthyosis
The hands and feet may be small, swollen, and partially flexed. The ears may appear to be misshapen or missing, but are really fused to the head by the thick skin.
Treatment
As you can see from the pictures this disorder is very severe, and looks painful.
Constriction and swelling of the mouth may interfere with the suck response and infants may need tube feeding.
When a HI baby is born it is clear to medical staff that there is a problem with the new born.
Harlequin infants need to be cared for in the neonatal intensive care unit immediately.
Because there skin does not shed, it is very hard for the babies to maintain a safe body temperature.
Since they are unable to sweat in a hot environment and shiver in a cold environment, temperature in the room they are kept needs to be monitored.
In the past, Harlequin infants rarely survived the first few days of life. However, with recent advances in neonatal care and with new ways of treating HI babies, Harlequin infants can survive. There are survivors living today.
When your skin sheds, it’s practically invisible (unless you’re looking at it under a microscope) because it’s shedding in pieces that are so small.
With ichthyosis, the skin doesn’t follow the life cycle that it’s supposed to, and builds up.
In Ichthyosis, the skin cells reproduce at a normal rate, but they don’t shed as quickly as they should, and again produce a build-up.
Infants need to be bathed twice daily and use frequent *wet sodium chloride compresses* followed by application of bland lubricants to soften hard skin.
Overview
- I described a new genetic screen that we have used to identify a mouse model that develops the hallmarks of HI and carries a mutation in Abca12.
Most commonly used
lubricant.
-We have used this model to explain Abca12's significant role in the transport of lipids and cholesterol within the skin.
-I attributed specific transport functions to the protein and show that it can mediate the *efflux* of a number of different lipids from the cell including, cholesterol.
-I distinguished the break protecting the fatal mutation between homozygotes and heterozygotes mice.
Evaluation
Procedure
If I were to something different in my study I would use a smaller group of mice because I think the results would be more accurate.
Hypothesis
I also think that if I could change something I would inject some of the female mice with ENC; since the males were only injected I feel that the results may have been different if the females were.
- I used a total of 463 mice and 13 *polymorphic* markers
-Male mice were injected with a total dose of 200 mg/kg of *N-Ethyl-N-Nitrosourea (ENU)* in 3 weekly doses.
-Their first-generation (G1) male offspring were again crossed to the (G1) female
-I set up 40 G1 male mice to breed and generated 18 pedigrees that contained more than 20 G3 mice.
Problem Statement
I predict that if the the efflux of lipids and cholesterol related to Abca12 are not present in the embryo, then the keratin skin cells will be dehydrated.
Can genetics predict survival or for less severe cases a way to reduce the risk of this disorder?
How many of you have or have had dry skin?
Well if you have that is a form of ichthyosis!
The thickening of the *cornified* envelope produces a constrictive, tight and shiny epidermis resulting in limb *contractures*.
(A). Sections of epidermis at birth demonstrate severe thickening of the keratin wall.
Most people have ichthyosis and don't know they do. In small cases such as dry skin we treat ourselves with recommended lotions and creams.
One many are familiar
with is Eczema