a
Leukocyte or
White Blood Cell
(greatly magnified)
(Image
derived from WikiMedia Commons Source)
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The goal of the Leukocyte Adhesion Deficiency, (L.A.D.), web site is to increase awareness and understanding of L.A.D. The information on the site is presented in a patient-friendly, plain language format that we hope makes it easier to understand.
Since we couldn't eliminate all of the medical jargon when talking about L.A.D., we provided a medical dictionary search that can be accessed from anywhere on the site. To look up a medical term, just double-click on a word or select a phrase from the web site that you would like defined, press the "ENTER" button and confirm your request. To learn more about how it works, click here.
If you wish to view the site in another language, we also provided links to translation facilities. They can be viewed by clicking here.
We hope you find the information on the site helpful. Now, let's see if we can answer some of your questions.
What is Leukocyte Adhesion Deficiency?
Leukocyte Adhesion Deficiency or L.A.D. is a very rare genetic disorder that affects the body's immune system.
L.A.D. occurs when a patient's white blood cells or leukocytes are unable to produce a protein called CD18. In some cases, the leukocytes do not produce enough CD18. In other cases, normal or near-normal levels of the protein may be produced but might be defective and not function properly. CD18 is necessary for leukocytes to "travel to the site of an infection"... more on this later.
To date, only about 300 cases of L.A.D. have been identified worldwide. However, the actual number of cases may be significantly higher because many patients may be misdiagnosed or go undiagnosed due to the medical community's current lack of familiarity with L.A.D.
Since L.A.D. is a genetic disorder it is considered a Primary Immunodeficiency, (P.I.) and is NOT contagious.
What do we mean when we say "travel to the site of an infection"?
Even though leukocytes are constantly circulating through your bloodstream, they are not always in the right place at the right time... at least not in sufficient quantity. So, when you develop an infection, a signal or message is sent out from the affected area.
The message is passed to the blood vessels where it is "seen" by leukocytes that happen to be going by at the time. Leukocytes in a healthy person receive the message, activate and begin to move into the affected area by "sticking" or adhering to the blood vessel wall with tiny CD18-based, velcro-like "hooks". The image at the top of the page may help you visualize these "hooks".
Then they slowly "crawl" through the blood vessel wall, migrate to the sight of the infection and get to work. This migration is also called chemotaxis.
How
Leukocytes "Get to Work"...
Courtesy
the Hospital Practice web site ...
What happens in a person with L.A.D. is that the message goes out and is "seen" but the leukocytes are unable to successfully activate and "grab" or adhere to the blood vessel wall because they lack the necessary "hooks". Sometimes the "hooks" are present but may be defective and not work properly.
Since these leukocytes cannot adhere, because of missing or defective "hooks", they experience an "adhesion deficiency", which is where the disorder gets its name. Without the ability to adhere, leukocytes cannot make their way to the site of an infection to protect the body, which can lead to the symptoms described in the section entitled "What are the symptoms of L.A.D.?".
For more information about how the immune system protects the body from infection, click here to view "Anatomy of a Splinter". This link is provided courtesy of CellsAlive.com.
Are there different types of L.A.D.?
Yes, there are actually several different types of L.A.D. They are broken down into what are called genotypes and phenotypes. Genotypes are genetically different types of L.A.D. This means that L.A.D. can be caused by a number of genetic errors. Within each genotype, there can be one or more phenotypes. Each phenotype describes how the genetic defect affects each patient.
There are currently two general genotypes of L.A.D. that have been identified. They are designated, L.A.D.Type 1 and L.A.D. Type 2. A third LAD type was recently described...it has been tentatively designated L.A.D. Type 3.
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L.A.D. Type 1 - "Classic" |
Genotype - the genetics of this type of L.A.D.:
L.A.D. Type 1 is described in technical terms as the "deficiency of beta chain (CD18) of LFA- 1, Mac 1, p150,95". In other words, the protein mentioned earlier does not get produced in either the correct quantity or the correct form.
Phenotypes - how this defect can affect the patient:
L.A.D. Type 1 "Classic" currently has two known phenotypes: Severe and Moderate.
Severe - is probably best described by an almost to total lack of the CD18 protein on the leukocytes of the patient. This, in turn, causes the symptoms of this phenotype to be more severe or acute. The severe phenotype, is a very serious disease and should be considered potentially life-threatening.
Moderate - is probably best described as a decrease in the expression of the CD18 protein on the leukocytes of the patient. This, in general, may cause the symptoms of this phenotype to be less severe or acute. However, this phenotype can still be life-threatening, if not aggressively managed.
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L.A.D.
Type 1 - Novel or Variant
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Genotype - the genetics of this type of L.A.D.:
This form of L.A.D. tends to be caused by unique, extremely rare, genetic defects that are classified as L.A.D. but can't necessarily be considered "Classic" L.A.D. In some Novel or Variant patients, the CD18 protein may be produced at normal or near-normal levels but may not function correctly... in other words the CD18 is present but still cannot "stick" or adhere to the blood vessel wall thus resulting in an "adhesion deficiency". For specific genetic information on a Novel or Variant case, please visit this page.
Phenotype - how this defect can affect the patient:
The phenotype(s) for this disorder may take a different path for each patient which may be similar to the Severe or Moderate phenotypes of "Classic" L.A.D. depending on the specific nature of the genetic defect(s) but it might also manifest unique symptoms. This phenotype may be life-threatening, if not aggressively managed.
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L.A.D. Type 2 |
Genotype - the genetics of this type of L.A.D.:
L.A.D. Type 2 is described in technical terms as a "genetic mutation in the specific transporter of fucose from the cytoplasm into the Golgi apparatus", which may lead to the "failure to convert GDP mannose to fucose".
Phenotype - how this defect can affect the patient:
Unfortunately, we are unfamiliar with the different phenotypes of L.A.D. Type 2. You might want to consider visiting the following link to the National Institutes of Health database for more information on L.A.D. Type 2.
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L.A.D. Type 3 |
Genotype - the genetics of this type of L.A.D.:
L.A.D. Type 3 has been described as due to a "mutation in the KINDLIN3 gene, which prevents the beta 1, 2 and 3 integrins from undergoing activation."
Phenotype - how this defect can affect the patient:
The "prevention of the beta-2 [integrin] activation leads to LAD Type 1 symptoms, (infections and poor wound healing), whereas prevention of the beta-3 [integrin] activation leads to Glanzmann's thrombasthenia (GT) symptoms", where the patients are prone to bleeding.
Does L.A.D. only affect people?
No, actually there have been cases where both dogs and cattle have been diagnosed with the disease. The type that affects dogs is called Canine L.A.D. or C.L.A.D. and the type that affects cattle is called Bovine L.A.D. or B.L.A.D. Recently there has been some research that indicates that L.A.D. may also affect cats. This type of L.A.D. would most likely be referred to as Feline L.A.D. or F.L.A.D.
What are the symptoms of L.A.D.?
There are many symptoms of L.A.D. Some differ with the specific genotype and/or phenotype of L.A.D. The symptoms listed immediately below are generally common to human genotypes and phenotypes of L.A.D.
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Recurrent skin infections - may be more frequent and severe in younger patients. |
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Sometimes significant internal infections - these may occur less frequently than skin infections mentioned above, depending on the Type of L.A.D. the patient has, their ability to manage it and their age. |
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Severe Periodontal disease - up to and possibly including complete tooth loss. |
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Delayed wound healing - this might initially present itself as delayed umbilical cord separation. |
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Candidiasis |
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Leukocytosis - an increased white blood cell count. This symptom may be more severe in younger patients and may decrease as the patient ages. |
Additionally, the following symptoms have been observed and reported in a patient with L.A.D. Type 1 Variant but may not be present in other forms of L.A.D.
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Enlarged spleen or splenomegaly. |
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Muscle, tendon and joint discomfort, pain and/or swelling. This is thought to be caused by either a significantly increased level of superoxides a.k.a. "free radicals" in white blood cells and the bloodstream or increased pro-inflammatory cytokine production. This symptom did not appear to be present when the patient was younger but has become evident as the patient aged and could be related to the patient's genetic variant. This "effect" seems to be similar to some autoimmune disorders where the immune system is in some way "over active" and may therefore adversely affect normal tissues. For specific case information visit this web page. |
Symptoms alone are not enough to tell you if you have L.A.D. since other diseases may have similar symptoms. The only way to know for sure if you or someone you know has L.A.D. is to be tested, usually by a research or hospital hematopathology laboratory.
The European Society for Immunodeficiencies (ESID) provides a diagnostic criteria web page that may be helpful. You can click here to view it.
PLEASE NOTE: If you have a laboratory perform tests to determine if you or a family member has L.A.D., please be aware that a widely used test, called "Flow Cytometry", while generally considered to be accurate, can yield "false negative" results in patients with a certain type of L.A.D. In other words, you might have L.A.D. even though this test indicates that you don't. Additional, perhaps genetic, testing may be required to receive a definitive diagnosis.
SPECIAL DISCLAIMER: The following information is provided for your convenience only and does not constitute a referral to and/or an endorsement of the company, GeneDx, its tests and/or practices by the authors of this web site. Only you and your doctor can determine if you should pursue the type of genetic testing described below with this or another company and if you do so, it is done at your own risk.
If you are interested in genetic testing, there is a company that claims to specialize in testing for rare hereditary disorders, including L.A.D. Type 1. A genetic test has the potential to provide a definitive diagnosis. At this time, we are unaware of anyone who has used this test and we have no specific information about its accuracy. From what we understand, the test is relatively expensive and may not be covered by insurance.
However, if you are interested in learning more about it, you can have your doctor use the following link to the company's L.A.D. testing information page by clicking this link Please be sure that your doctor reads all of the available documentation on the site and if they have any questions and/or concerns, have them contact the company directly.
What treatments are available for L.A.D.?
There are a number of treatments for L.A.D. and we emphasize the term "treatments". Currently, there is no cure for L.A.D., although L.A.D. is thought to be a good candidate for gene therapy, when that becomes available.
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Oral Antibiotics - usually used for maintaining the day-to-day health of the patient. |
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Intravenous Antibiotics - usually used when the patient suffers from a severe infection. |
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White Blood Cell Transfusions - again usually suggested when the patient suffers from a severe infection. Other treatments are usually used first since this treatment can have potentially significant adverse side effects. |
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Bone Marrow or Stem Cell Transplants - this is usually the treatment of last resort because of life-threatening nature of the procedure. However, this is currently the best chance that some L.A.D. patients have at a normal quality of life because it comes closest to a cure for L.A.D. But we must emphasize that the potential benefits must be carefully weighed against the risks and costs. |
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Permanent Gene Therapy - the best future hope for L.A.D. patients. The ability to actually replace the defective gene and provide normal quality of life. At last we heard, the ability to permanently replace a defective gene was 3-5 years away, but we're still hopeful that this is a conservative estimate. |
Are there any books that I can read about L.A.D.?
While there are no books that we know of that deal specifically with the topic of L.A.D. there are a couple that we have seen that discuss what it is like to live and cope with a chronic illness and/or hidden disability. If you are interested in either of these topics, you might want to pick up a copy of:
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Living
Well with a Hidden Disability: Transcending Doubt and Shame and Reclaiming
Your Life by Stacy Taylor, Robert Epstein |
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Sick
and Tired of Feeling Sick and Tired: Living With Invisible Chronic
Illness by Paul J. Donoghue, Mary-Ellen Siegel |
The following organizations/institutes, physicians and researchers
have worked to help diagnose and/or treat L.A.D. patients and many have been
active in
investigating the disease. The
links are
updated
when new information becomes available, some links may not be current.
PLEASE NOTE: These
links do not constitute a referral and/or endorsement of these individuals and/or
organizations by the L.A.D.
web site
and/or its
authors and
are
provided
only for
your
convenience.
There are many resources available to you to find out about L.A.D. The Internet is a great place to start. We have provided links to some of the Internet's most popular search engines.
Web Search Engines: Each of these links will search for L.A.D. related topics. A new window or tab will open with the results.
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Ask.com |
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Bing.com |
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Dogpile |
Medical Journal and Organizational Searches - usually more technical in nature but generally readable:
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National Institutes of Health / PubMed |
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LAD at JMF - LAD page |
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OrphaNet - LAD description |
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NIH Clinical Trials - current information clinical trials |
Genetic
Information -
for L.A.D. Type 1:
PLEASE
NOTE:
The
following links are provided for convenience to medical
professionals, students and researchers.
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University of Tampere - IMT - Bioinformatics Group |
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Online Mendelian Inheritance in Man (OMIM) - Reference 116920 |
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OMIM Reference 600065 - LAD 1 Molecule CD18 |
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GeneCard for gene ITGB2 or Integrin Beta 2 |
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Ensembl Gene Report |
If you or someone you know has L.A.D. then it makes sense that you would want to learn about it, in order to help you better understand it. But, if you don't have L.A.D., why would you want to learn about it?
Well, the answer to that question might surprise you. It turns out that the study of L.A.D. has provided valuable new insights that could lead to potential new treatments for "mainstream" disorders like:
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Heart Attacks |
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Stroke |
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Unstable Angina |
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Multiple Sclerosis |
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Rheumatoid Arthritis |
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Burns |
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Traumatic Shock |
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the Common Cold - to learn more about this research, visit this link... |
It really is amazing to think that the study of a very rare disease, in fact, one with only about 300 confirmed cases worldwide, may be leading to discoveries that could benefit countless people around the world.
We think that that's a pretty good reason to learn about L.A.D., don't you?
If you'd like to learn more about the role adhesion plays in our lives visit this Time magazine article by clicking on this link.
Why was this web site created?
This web site was developed because of the experience of an L.A.D. patient. L.A.D. had been a part of this patient's life since birth, but he did not know that he had L.A.D. until he was 31. Even then, he didn't know for sure which type of L.A.D. it was until he was almost 40. He had been misdiagnosed and gone undiagnosed for nearly 40 years!
So, one of the reasons this web site was created was to try and prevent that from happening again. We hope that this web site will increase awareness and understanding of L.A.D. We also hope that it will provide a more patient-friendly, plain language source of information about L.A.D.
Have more questions about L.A.D.?
If you have more questions about L.A.D. you might want to consider contacting some of the individuals/organizations listed in the "Who's worked on L.A.D." section above.
How do I use the MedlinePlus® medical dictionary search?
Since we couldn't eliminate all of the medical terms and technical jargon when talking about L.A.D., we developed a web site feature that let's you easily search the MedlinePlus® medical dictionary.
Just double-click on a word or select a phrase from the web site that you would like defined, press the "ENTER" button and confirm your request. The definition should appear in a new window. When you're done using the dictionary, just press the "BACKSPACE" key until you return to the L.A.D. web site.
PLEASE NOTE: Current searches are limited to 25 characters. This feature may not be compatible with all browsers. If it is unavailable in your browser you can click on the following link and enter the word or phrase directly into the MedlinePlus® Medical Dictionary
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