Scientists Identify Genetic Cause of Previously Undefined Primary Immune Deficiency Disease

September 24, 2009

Scientists Identify Genetic Cause of Previously Undefined Primary Immune Deficiency Disease

Researchers at the National Institutes of Health have identified a genetic mutation that accounts for a perplexing condition found in people with an inherited immunodeficiency. The disorder, called combined immunodeficiency, is characterized by a constellation of severe health problems, including persistent bacterial and viral skin infections, severe eczema, acute allergies and asthma, and cancer.

The team that made the discovery was led by Helen Su, M.D., Ph.D., at the National Institute of Allergy and Infectious Diseases (NIAID), and included collaborators from NIAID and the National Cancer Institute (NCI). The research is reported in this week’s New England Journal of Medicine.

“NIH clinicians have cared for people with unusual and difficult-to-treat immune disorders for decades,” says NIAID Director Anthony S. Fauci, M.D. “This study exemplifies their commitment to improving the lives of people with these diseases by trying to uncover the causes of these disorders and thereby better understanding how to treat them.”

Combined immunodeficiency is a type of primary immune deficiency disease (PIDD) in which several parts of the immune system are affected. This inherited disorder is characterized by increased susceptibility to bacterial, viral and fungal infections of various organs of the body. In some cases, susceptibility to cancers also may be seen.

There are 150 known PIDDs. Approximately 500,000 people in the United States have been diagnosed with a PIDD, while many more remain undiagnosed.

The NIAID and NCI investigators recognized that certain patients with an undefined form of combined immunodeficiency shared enough clinical features to make it likely that the cause might be a common genetic mutation. Originally, these individuals were thought to have a variant form of hyper-immunoglobulinema E syndrome (HIES), a disorder characterized by increased levels of a class of antibodies known as immunoglobulin E, superficial and systemic bacterial and fungal infections, and atopic dermatitis, also known as eczema.

This newly described group, however, had far more severe eczema than is typical in people with variant HIES.  They also had extensive and difficult-to-manage viral infections of the skin, such as warts, molluscum contagiosum—a type of poxvirus that only infects the skin—and herpes simplex. Some in this group also developed skin cancers, as well as lymphoma of the skin.

“Even though these individuals were diagnosed with a more uncommon form of HIES, they were still considered to have a mystery disease, because they had severe allergies and had developed cancers,” says Dr. Su.

Using a technique called comparative genomic hybridization, a process by which large amounts of DNA is fixed to a computer chip and analyzed for changes in the genes, scientists examined the genes in the tissue samples from five different groups:  the 11 individuals with the unknown immunodeficiencies, people with the variant form of HIES, people with classic HIES, those with other immunological diseases, and healthy individuals.

The researchers discovered that people with the unique form of HIES had mutations in a gene called DOCK8 that led to deletions in parts of the gene. The normal function of DOCK8 is currently unknown.

When compared with healthy individuals, the people with DOCK 8 mutations had fewer CD8 positive T cells, immune cells needed to fight viral infections; fewer antibody-producing B cells; and increased numbers of eosinophils—immune cells associated with allergy.

According to Dr. Su, these findings indicate that DOCK8 is essential for defense against viral infections and for preventing the development of cancer and allergies.

Although further study is required to determine if DOCK8 mutations occur in other people with similar disease symptoms, DOCK8 immunodeficiency syndrome may be a new PIDD. These findings mean that individuals with this rare disease will be able to receive a more accurate diagnosis. Identifying a genetic cause for the disease provided comfort to some of those diagnosed who had battled an unknown immune disease for years, according to Dr. Su.

“The study of inherited disorders and the genetic alterations that are responsible for their complex array of disease symptoms has often resulted in the discovery of causative genes that play a role in cancer initiation,” said NCI Director John E. Niederhuber, M.D. “The disease mutations found in this study in the DOCK8 gene exemplify that kind of important finding.  As with any discovery of a genetic defect, the challenge going forward is to develop a complete knowledge of the cascading pathways of biological function for which DOCK8 is responsible.”

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at or call NCI’s Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH)—The Nation’s Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit



Zhang et al. DOCK8 mutations underlie a new form of combined immunodeficiency with allergy, hyper-immunoglobulinemia E, lymphocyte dysfunction, viral infections, and cancer. New England Journal of Medicine DOI: 10.1056/NEJMoa0905506 (2009).

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The Second Coming of Gene Therapy

September 2, 2009

The Second Coming of Gene Therapy
For years, gene therapy produced tons of hype but no results. Recently, though, new approaches have yielded its first successes: breakthrough treatments for blindness, cancer, and the deadly bubble boy disease.
by Jill Neimark

“For the first two years of her life, my daughter, Katlyn, was knocking on heaven’s door every day,” says Daisy Demerchant, a 26-year-old mom living in Centreville, New Brunswick, just north of Maine. “Two months after she was born she started getting sick, and she never got better.” At six months Katlyn was diagnosed with “bubble boy” disease, formally known as severe combined immunodeficiency (SCID), which robs the immune system of the ability to fight infection. There are many causes of this disorder; in Katlyn’s case it was lack of the enzyme adeno­sine deaminase, or ADA, which rids the body of a natural toxin called deoxyadenosine. When the toxin builds up, it destroys T and B lymphocytes, the body’s infection-fighting immune cells. As a result, Katlyn’s immune cells were dying.

Treatment options ranged from risky to grim. One was a bone marrow transplant, in which imported donor cells could manufacture healthy T cells to fight invading germs. But bone marrow transplants can have lethal complications and often require drugs that further inhibit the patient’s immune system, leaving a window of vulnerability until the transplant kicks in. Another potential treatment involved injections of the ADA enzyme itself. But there was a risk Katlyn would develop antibodies to the drug, rendering it useless. Without any treatment at all, she would simply die.

While weighing their options, doctors put the little girl on protective antimicrobials and sent her to a hospital eight hours from her home. She became another fragile bubble baby sequestered from the world. “My husband quit his job building fire trucks, and we lived with Katlyn in the hospital for 15 months,” Demerchant says. The parents had to wear sterile gowns, booties, masks, and gloves, and the urge to touch their child—let alone hug and kiss her—had to be put on hold.

Just when it seemed as if Katlyn’s life might never improve, science and fate intervened. Her specific condition, called ADA-SCID, had long tantalized researchers seeking to repair genetic defects with a technique called gene therapy. Rare, deadly, and caused by a single gene mutation, it was a perfect proof-of-principle condition for anyone seeking to replace damaged DNA with genes that did the job. With all her troubles, little Katlyn Demerchant had been almost made to order for Fabio Candotti, a senior investigator at the National Human Genome Research Institute at the National Institutes of Health in Bethesda, Maryland.

Before Katlyn showed up at NIH, the doctors there were already well prepared: They had inserted healthy human ADA genes into a modified mouse retrovirus—a type of virus that can enter human cells and transfer new genetic material right into the DNA strands in their nuclei.

Once Katlyn arrived in May 2007, Candotti and his team removed stem cells from her bone marrow and exposed them to the engineered retrovirus, creating a human-virus hybrid. Then they injected the hybrid cells back into Katlyn. Like heat-seeking missiles, the retooled stem cells automatically found their way back home to the marrow. There, they began to specialize, creating all of the secondary or “daughter” cells that such stem cells normally produce—including healthy T cells with functioning ADA genes.

Everybody waited while Katlyn, still stuck inside the bubble, learned to walk on the floor of her sterile isolation room and to play through the protective window with a visiting dog named Toffee. On September 3, blood tests showed Katlyn’s immune system was being populated with robust, functioning T cells. She was so restored, in fact, that her parents were able to take her outside for the first time since she was an infant. “The first day we took her out she was really quiet and a little terrified,” Daisy Demerchant says. “The second time she started running around and asking us a million questions. She’d point to the sun, clouds, leaves, cars, everything imaginable, and ask us what it was. Ever since that day, she has never wanted to stay inside.”

Six months after her gene therapy transplant, Katlyn was so healthy that doctors let her return home to Canada. It can take a year or longer for the immune system to reconstitute itself in full, so Katlyn still takes antimicrobials as a precaution, but today she plays outside, even in the dirt, and is resistant enough to fly on a commercial plane.

The new DNA treatments for Katlyn Demerchant and other bubble babies are nothing short of remarkable, the culmination of a major push to perfect gene therapy for the disease, Candotti says. Across the ocean, in Italy, bubble babies with ADA-SCID are also being cured: A trial led by Alessandro Aiuti, a molecular biologist at San Raffaele Telethon Institute for Gene Therapy in Milan, restored the immune system in eight of ten children, while a ninth had significant improvement.

And bubble babies are far from alone. In Europe and the United States, gene therapists have restored vision in individuals suffering from a rare genetic disorder that inevitably leads to blindness. In Texas, a team has manipulated genes in order to put deadly cancers into complete remission. Building on these successes, gene therapy may soon be used to correct hereditary genetic diseases like cystic fibrosis, hemophilia, and Tay-Sachs and to activate the immune response against a wide variety of infectious diseases and cancers. Gene therapy and its adjuncts may help us trick the body into growing new tissue to rejuvenate arthritic joints, fix injured hearts, and speed the healing of wounds….Continued

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Campers aid area toddler

September 2, 2009

Campers aid area toddler

The Jeffery family is giving thanks to their newfound friends, many of whom they’ve never met.

Indeed, most of the Jefferys’ supporters are members of the Bluewater Campers’ Association, which recently presented the St. Joseph’s family with a $7,200 donation, the second of such gifts since the club first heard of the family’s plight three years ago.

“I can’t tell you what this means for our family,” says Dennis Jeffery. “This will help a lot.”

And help is what the Jefferys need as their youngest son, three-year-old André, continues with his valiant battle with Severe Combined Immunodefiency Disease (SCID), an autoimmune disease that leaves him vulnerable to a host of life-threatening illnesses and renders most of his life to the confines of what is commonly known as a plastic bubble.

André was first diagnosed with the disease at the age of four months when the Jefferys brought him to see a Stratford doctor as the baby was covered in a rash that looked like he’d been splashed with scalding water.

André has been in and out of hospitals ever since.

Most recently, the sweet-cheeked young lad with soulful brown eyes, suffered cardiac arrest, his second one due to the havoc the 34 medications medications he takes daily are wreaking on his organs.

André is now at Sick Kids’ Hospital in Toronto where his mom, Sheila, keeps vigil as the rest of the family including seven-year-old sister, Monica, and nine-year-old brother, Donavon, hold down the fort in St. Joseph’s.

Naturally, notes Dennis, the emotional, financial and physical toll of André’s plight is difficult on everyone, especially André’s siblings who must spend a lot of time away from their beloved parents who, for a time, were at André’s bedside 24 hours a day.

“It’s hard to keep everybody together,” notes Dennis. “It’s been a difficult experience. I wouldn’t wish it on my worst enemy.

And when André and his mom are able to return home, the family will once again face the additional expenses of bringing Registered Nurses in to assist with his care. Plus, only 27 of the medications André requires are covered by OHIP.

At a recent meeting at the Bluewater Campers’ meeting room, club members presented the family with the $7,200 donation, as well as $50 gift certificates for Monica and

Donavon and a stuffed animal for André. It was clearly a proud night for members as one organizer put it: “For such a small number of people, this is an amazing amount of money.”

While learning André is currently grappling with kidney problems as he recovers from cardiac arrest, the Bluewater Campers vow to continue to help where they can – even though most of them were meeting Dennis, Monica and Donavon for the first time at the cheque presentation.

“It’s going to help me large,” says Dennis, who notes there are many changes on the horizon for the Jefferys including the possibility that they will have to sell their St. Joseph’s home, a community where both Dennis and Sheila hail from, and move to Toronto to ensure Andre continues to receive the treatment he needs.

Club member Deb Jeffrey, in thanking the campers, note the relatively small park – at 140 trailers – has raised nearly $20,000 in the past three years for the Jefferys and other community-based causes including $3,000 for Habitat for Humanity and $2,500 for the CT Scanner campaign at Alexandra Marine General Hospital in Goderich last year, and about $3,000 for the Jefferys two years ago.

The fundraising events, note organizers, were made possible through a slew of events, including silent auctions and golf tournaments with prizes donated by a vast number of area businesses and community groups. A special cake made each year proves to be a hot ticket item as well as it raised $350 during the first year, $550 the second and $1,400 this year.

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Mother’s tribute to hospital

September 1, 2009

(UKPA) – Sep 1, 2009

When it was suggested that her very sick daughter have a new bone marrow transplant procedure at Great Ormond Street Hospital (GOSH), Louise Moseley said she was just relieved that Ffion was not the first.

“I would have been more sceptical if she had been the first but other parents had been brave enough to say yes. She was so poorly we just thought that it had to be done.”

Ffion was just three weeks old when she developed skin problems that were so serious that she was regularly in hospital.

It was initially thought to be dermatitis but when Ffion was transferred to the Singleton Hospital in Swansea it was suggested the condition was likely to be caused by a problem with her immune system.

Ffion was three months old when she was diagnosed with the genetic condition Omenn Syndrome, a severe combined immunodeficiency (Scid), and admitted to GOSH.

“All I heard was ‘she needs a bone marrow transplant. It’s a fatal condition’,” said Mrs Moseley, 30, of Pembroke Dock, Dyfed. “It was a complete shock. I’d never heard of it because it’s such a rare condition.”

Too sick to have the chemotherapy needed for a conventional transplant, Ffion was given the new procedure using antibodies to prepare her for the transplant which she had aged five months.

Although she suffered complications afterwards, including Graft Versus Host Disease (GVHD) where the body attacks the transplanted tissue, Ffion was well enough to go home three months later and now only needs an annual check up.

“Not only did the BMT save Ffion, but her skin is now beautiful. You’d never know she is the same child that was so desperately ill in the past,” Mrs Moseley said.

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