- The Washington Times - Sunday, September 12, 2004

Rare disorders have become anything but rare. Collectively, these few thousand illnesses afflict an estimated 25 million Americans or almost 10 percent of the U.S. population.

Yet, when broken down, that’s fewer than 4,200 patients per disease; a far cry from the more than 400,000 Americans who die from cancer annually or the 700,000 who succumb to heart disease each year.

But the statistics offer little comfort for those who are afflicted with the diseases.

“In the Orphan Drug Act, which was passed in 1983 to encourage research on rare disorders, the federal government defined a rare disorder as one that afflicts fewer than 200,000 people,” said Abbey Meyers, president of the National Organization for Rare Disorders Inc. (NORD), based in Danbury, Conn.

She said both NORD and the Orphan Drug Act were created as a result of a recognition in the 1970s that drug companies were unwilling to finance research into treatments for disorders that were not prevalent.

“The companies said the market was too small, that they couldn’t make any money,” said Mrs. Meyers, whose children have a rare, genetic disease that she declined to identify.

She explained that the Orphan Drug Act provided pharmaceutical firms with government incentives, such as tax breaks or exclusive marketing rights, to encourage research into treatments for relatively uncommon diseases.

Dr. Stephen C. Groft, who heads the National Institutes of Health’s Office of Rare Diseases, said, “The Orphan Drug Act led to the development of 260 products, which have been approved by the U.S. Food and Drug Administration” as treatments for rare disorders.

“But despite all the advances that have been made, there are still thousands of [rare] diseases that need additional focus and research activity,” Dr. Groft said.

Dealing with disease

For the most part, these so-called rare disorders have tongue-twisting names like myelodysplastic syndromes, aplastic anemia, lymphangioleiomyomatosis (LAM), cystinosis and Alpha-1 anti-trypsin deficiency.

Sue Byrnes of Cincinnati acknowledges that she had never heard of LAM when her daughter, Andrea Byrnes-Bollner, got a diagnosis for it a decade ago.

“LAM is a rare, fatal lung disease that mostly affects women in their 20s and 30s. My daughter was 22 when she was diagnosed,” Mrs. Byrnes said.

“LAM is marked by smooth muscle cysts that invade the lungs and destroy healthy tissue.”

Before being diagnosed with LAM, Mrs. Byrnes-Bollner had lost a kidney. It was only later that she learned that the renal failure was a complication of LAM.

When she initially checked with NORD, Mrs. Byrnes could find evidence of only nine U.S. women who had LAM. Today, about 1,000 report having it, she said.

Finding others with a similar disease can be difficult because only a few dozen of the disorders are widely known.

Those include hemophilia, which affects 10,000 men; tuberculosis, which strikes 25,000 yearly and has a high cure rate; and cystic fibrosis, a disorder that afflicts more than 30,000 children and young adults in the United States.

Many Americans would recognize the term West Nile encephalitis, which is a serious, sometimes deadly disease in which the mosquito-borne West Nile virus causes a swelling of the brain.

And they also probably would recognize the diseases of bulimia, Bell’s palsy, botulism, cerebral palsy, smallpox and typhoid, all of which are included on NORD’s rare-disease database.

But it is doubtful that they would know diseases such as West Syndrome, Whipple’s disease, Buerger’s disease, yellow-nail syndrome, empty sella syndrome or Job (as in the Old Testament) syndrome.

Although many of these rare diseases are serious, if not deadly, most Americans are in the dark about them.

Moving ahead

But there is progress.

University of Florida researchers have been using gene therapy targeted to the uterus to treat breathing problems in unborn mice suffering from a rare, inherited respiratory-muscle disease thought to afflict between 5,000 and 10,000 humans worldwide.

The condition is a deadly form of muscular dystrophy known as Pompe disease. It’s caused by a defective gene that fails to produce sufficient levels of an enzyme that normally breaks down glycogen, which is used to store energy. In some cases, the enzyme is not produced at all.

Pompe disease causes a gradual weakening of muscle and heart tissue when glycogen accumulates in muscles, restricting their ability to contract. Infants who develop Pompe disease usually die during their first year of life.

Animal research into Pompe disease — led by Dr. Barry Byrne, a pediatric cardiologist at the University of Florida, and Mary Rucker, a former graduate student — yielded some of the more successful findings to date for this breathing disorder, dramatically improving the ability of respiratory muscles to function.

The scientists injected a harmless virus — modified to contain copies of a therapeutic gene that produces the enzyme needed to break down glycogen — into the livers of eight mice three-quarters of the way through gestation and into the stomachs of three others.

The gene rapidly spread to its intended destination, the diaphragm, in five of the eight mice injected in the liver and in all three mice injected in the abdomen.

What’s more, the researchers found that the treated mice had enzyme-activity levels up to 10 times higher than normal, a sign that the gene was working.

An additional three mice that received a less-potent form of the gene had almost normal muscle function at 6 months old — compared to mice in a control group, the scientists said.

“What we wanted to know was whether early treatment had better outcomes,” said Dr. Byrne. Replacing the gene during intrauterine development, he said, “prevented the accumulation of glycogen in the diaphragm and improved the strength of that muscle.”

He cautioned that in-utero gene therapy poses potential risks to both the mother and the unborn child, so human clinical trials are not in the near future. University of Florida scientists are collaborating with researchers at the University of California at Davis on similar studies in primates.

Genzyme Inc. of Cambridge, Mass., is developing an enzyme-replacement therapy for Pompe disease that it hopes to have approved for marketing in the United States in 2005.

The company is testing a drug called myozyme in young children with the disease, said Genzyme spokesman Bo Piela. One study is testing the drug, an enzyme-replacement therapy, in infants younger than 6 months, and another is examining it in babies and tots 6 months to 3 years old.

“The studies are still under way. They could offer a lot of hope for patients,” Mr. Piela said.

Tiffany House, 21, of San Antonio, who has battled Pompe disease since she was 12 years old, has been taking experimental enzyme-replacement drugs for five years.

“I’m doing really well on it,” said the young woman, who is wheelchair-bound and must use a ventilator at night.

In 1999, Miss House and her mother, Marilyn, moved to Rotterdam, Holland, for nine months so she could participate in a Dutch drug trial.

“My younger brother and sister remained in the United States with my dad, while we were away,” she said.

Today, Miss House is a junior at the University of Texas at San Antonio and is contemplating law school. She is taking a medication that Genzyme hopes to market soon.

The work to find a treatment for Pompe disease is just part of experimentation going around the world in search of remedies for about 5,000 diseases that are largely unknown to the public.

Most, but not all, are genetic.

Genetic testing has helped prevent genetic disorders. The testing determines whether the parents are at risk for genetic abnormalities that could lead to disease. A Johns Hopkins researcher recently told Congress about 1,000 genetic tests that are in use or development.

Because of genetic testing, NORD’s Mrs. Meyers said fewer Jewish couples are giving birth to babies with Tay-Sachs disease, a genetic disorder of the brain that usually kills children by their fifth birthday. Most babies with Tay-Sachs never crawl, never walk and never talk.

Ashkenazi Jews, or those of Eastern or Central European descent, as well as French-Canadians and Cajuns, are at high risk for having the genes that cause Tay-Sachs. Prevalence in those populations is about 1 in 27, compared with 1 in 250 in the general population.

Because many Jews are undergoing genetic testing for Tay-Sachs before starting a family, most Tay-Sachs victims today in the United States and Canada are not Jewish, according to a recent survey by researchers at the University of California at San Diego.


Achieving success

Some of the greatest inroads in battling a fatal rare disease have come with cystic fibrosis (CF), a genetic disease that develops when children inherit two copies of a defective gene from their parents.

Symptoms of CF, which is the No. 11 genetic killer of Caucasian children and young adults in the United States today, include persistent coughing and breathing difficulties; excessive appetite but poor weight gain; frequent chest infections; and potentially fatal lung damage.

The Cystic Fibrosis Foundation says CF causes the body to produce thick, sticky mucus that clogs the lungs. New research, reported this summer, suggests that the mucus might be pus, formed from broken-down white blood cells and bacteria.

“But that was one study that was small and preliminary,” said Allison Tobin, Cystic Fibrosis Foundation spokeswoman.

There has been a dramatic increase in the survival rate for those with CF in the past half-century.

“In 1955, when this organization was founded, most children with cystic fibrosis died before [entering] elementary school,” Ms. Tobin said.

By 1985, the average life span for a CF patient in this country was 25.

Today, survival is even better.

“About 40 percent of people with cystic fibrosis live beyond age 18, and the median survival age is 33,” Ms. Tobin said. She added that she’s heard of a “few” CF patients who survived into their 60s and 70s.

She points out that both survival and quality of life have improved for those with CF.

“We have a much greater understanding of the disease and how it works. We have 115 care centers accredited by the Cystic Fibrosis Foundation around the country, so patients receive better care, and there is now specialized treatment,” she said.

Ms. Tobin cited three drugs that have been especially beneficial for people with CF.

One is an aerosolized antibiotic, commonly called TOBI, “which goes right to the source of an infection.” Another is a mucus-thinning medication called Pulmozyme, and the third is azithromycin, a bronchitis treatment that she says “really helps” with CF management.

“Meanwhile, there are more drugs aimed at CF in the pipeline. About two dozen are currently undergoing clinical trials [in humans],” Ms. Tobin said.

Still deadly

Other rare disorders that remain deadly for those stricken are myelodysplastic syndromes (MDS) and aplastic anemia. Both are anemias, and neither is genetic or contagious.

Significant progress has been made in treating aplastic anemia in the past five years, specialists say.

The MDS are rare blood disorders characterized by malformed bone marrow cells that result in either abnormal blood counts or in blood cells that function poorly. They are primarily a condition of older adults. More than 80 percent of people affected are older than 60, although the number of cases in younger people has been rising in recent years.

Marilyn Baker, head of the Aplastic Anemia and MDS International Foundation, said MDS affect about 5 in 100,000 Americans overall, but 22 to 45 of 100,000 people older than 70. There are about 30,000 new cases annually, she said.

Until the early 1970s, Ms. Baker said, MDS was thought to be leukemia. Former Massachusetts senator and presidential candidate Paul Tsongas and scientist Carl Sagan died of the disease.

Aplastic anemia is a rare bone marrow disorder that results in unusually low levels of blood cells. Unlike MDS, the blood cells in aplastic anemia are not malformed. There is just not enough of them.

About 500 new cases are reported annually in the United States, and the condition is more prevalent among young people. In about 50 percent of cases of aplastic anemia, the cause is unknown.

Eleanor Roosevelt, physicist Marie Curie and Rep. Joe Moakley, Massachusetts Democrat, died of the disease, Ms. Baker said.

Fifteen years ago, aplastic anemia was universally fatal. Five years ago, it was 50 percent fatal.

But, today, thanks to bone-marrow transplants and an effective medication, an immunosuppressant known as ATG (antithymocyte globulin) with cyclosporine, 80 percent of cases of aplastic anemia are not fatal, Ms. Baker said.

“This success came about completely because patients participated in clinical trials,” she said.

Although clinical trials and new drugs remain the brightest of hope for those with rare disorders, they are no guarantee.

Ask Tiffany House’s mother, Marilyn.

She points out that Genzyme has ended distribution of a drug that Tiffany was taking to help her battle Pompe and replaced it with another drug in a smaller dose.

Mrs. House says she thinks that the current dosage is “insufficient” and that her daughter is “regressing.”

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