COVER STORY:In search of a cure

Cynthia Frank remembers the pain. It was as if her bones were breaking one by one.

As a child, she complained often to her parents, who assured her it was nothing serious. Just growing pains, most likely. But when the San Francisco native turned 13, doctors finally delivered the hard truth.

Tests revealed Frank, whose father is Jewish, suffered from Gaucher disease, a genetic disorder that primarily affects Ashkenazi Jews. There was no cure, no treatment and no hope.

“They said my bones would disintegrate,” she recalls, “and I’d be in a wheelchair.”

Neither happened, thanks to remarkable strides in the treatment of Gaucher.

Today Frank, 41, leads a fairly normal life, though she must maintain an expensive medication regimen and endure bouts of severe pain.

In a way, she is lucky. Gaucher is one of the milder Jewish genetic diseases. Few patients die from it.

But there are others. At least a dozen conditions, like Tay-Sachs, cystic fibrosis, Niemann-Pick and Canavan’s disease, kill without mercy, the victims almost always children.

Why the Jews? Actually, Jews are no more prone to genetic disorders than anyone else. Every ethnic group has its own unique genetic land mines, and according to researchers there are more than 10,000 genetic diseases in the medical literature.

“Everybody on the planet is a carrier for six to eight disorders,” says Cecilia Fairley, a genetic counselor at UCSF. “But any disorder can happen in any population.”

Tamar Jacobs of San Jose knows all too well about the nightmare of those disorders. Her daughter Renette died 20 years ago from a mild form of familial dysautonomia (F.D.) that went undiagnosed. “Mild,” because Renette managed to live to age 32 (most F.D. patients never see their 20th birthday).

Her mother, who later found out she carries the gene, recalls: “Renette always had feeding problems. She threw up a lot. She was very pretty, very sweet, but when she cried she had no tears. But the doctors always said she’ll be fine.”

Renette failed to develop normally, however. “Everything was hard for her,” says Jacobs. “People thought it was a character flaw. She didn’t mix with the regular children. Walking was hard. She sweated incredibly. She had bad posture and scoliosis.”

Though Renette managed to finish high school, she struggled for much of her life, eventually moving to Israel and working as a hotel receptionist. But the disease gradually eroded her autonomic and sensory nervous system, and one night she died following a fainting spell.

Her body forgot to breathe.

“If someone had been in the house,” says Jacobs, “she could have been revived.”

Today Jacobs looks back in sorrow. During her daughter’s lifetime, doctors could not pinpoint the cause of Renette’s strange symptoms, including the inability to feel pain or cry tears. The term “familial dysautonomia” had not yet been coined, and the study of Jewish genetic disorders had only recently begun.

Nearly all of the serious Jewish genetic diseases are classified as lysosomal storage disorders that affect metabolism.

It is not the same kind of metabolic trait that makes someone gain five pounds after eating an apple fritter. Lysosomal storage disorders involve metabolism on the cellular level.

Greg Stewart is senior director of neuroscience at Genzyme, a Boston-area pharmaceutical company developing treatments for these kinds of diseases. He offers an easy-to-understand explanation of lysosomal storage disorders.

“Cells normally break down the byproducts of biochemical function,” says Stewart. “They stick the stuff in the lysosome, which is like a little garbage bag in the cell.”

Patients with lysosomal storage diseases lack a certain enzyme that helps their cells take out the trash.

“The only thing the cell knows how to do then is make more lysosomes to store the garbage,” adds Stewart. “The cells become filled with little garbage bags.”

That causes different organ systems to malfunction, enlarge or break down. Each of the genetic diseases affects particular organs of the body. With Gaucher patients like Frank, the liver, spleen and bones are impacted. Some Gaucher patients develop 20-pound spleens (a normal spleen weighs under a pound).

And if the affected organ happens to be the brain, as Niemann-Pick type A, then the victim, invariably a young child, is handed a virtual death sentence.

“The kids I see are either in developmental delay or regression, organ system failure or metabolic crisis,” says Dr. Greg Enns, director of the biochemical genetics program at Stanford University. “Kids with a metabolism problem are ticking time bombs. If they get flu or tip out of balance, they can go into coma, develop high levels of acid in the blood and spiral down to where the body fails.”

Adult carriers of those genetic disorders are not doomed themselves. Human DNA contains two copies of every gene, and as long as one copy is even 20 percent functional, i.e., minimally producing the enzyme in question, that individual will remain healthy. But if he or she procreates with another carrier, with every pregnancy that couple has a 25 percent chance of having a sick baby.

Thankfully, modern genetic testing has diminished those odds considerably.

Remember Tay-Sachs? That disease, once a terrifying specter hovering over young Jewish families, has effectively been eliminated, thanks to modern genetic testing and good PR.

Back in the 1960s and 1970s, the American Jewish community mobilized to spread the word on Tay-Sachs testing. “Everyone got involved,” says UCSF’s Fairley. “The lay community, rabbis, the media. Now the incidence of Tay-Sachs is lower in the Jewish community than in the general population.”

That is, the Tay-Sachs rate in the Jewish community fell from one in 3,600 live births to one in 300,000 today.

That’s the good news. The not-so-good news is that the Tay-Sachs screening model has yet to be duplicated with any other Jewish genetic disease. Part of the problem is bureaucratic.

“Every state does different screens,” says a frustrated Enns. “In California, we screen for four diseases. In Hawaii, they screen for 30. There’s no good reason why [there’s such a disparity]. Here we had an expanded program in progress; then the governor had all new programs scuttled. Now California has become the first state to start screening, then stop it.”

Fortunately, the state legislature came to its senses, recently restoring the expanded screening program. But in the year it will take to go into full effect, no doubt some babies will be born sick who otherwise might have been identified.

Even with the best screening programs, some families will suffer the heartbreak of a sick child. In Frank’s case, even if testing had been available, her parents would probably have skipped it. Having only one Jewish parent, Frank logically should have dodged the Gaucher bullet. But her mother is Swedish, and Swedes happen to be one of the other groups prone to the disease. As bad luck would have it, both her parents were carriers.

“I went through years of ‘Why me?'” she says. “I was very athletic, but my parents wanted to take me out of everything. As I got older, I got worse. My spleen got huge, and by my early 20s I looked pregnant.”

Frank tried to work, but constant pain forced her to give it up. She underwent a partial splenectomy, which, she says, improved her quality of life. “I had a waist again, my skin wasn’t yellow anymore and I could walk across the room without being exhausted.”

But an even more effective treatment came on the market: enzyme replacement therapy in the form of Cerecyme, a miracle drug for Gaucher patients.

“In 1990 I became a guinea pig,” she says, “part of the protocol. I’ve been doing an I.V. drip every two weeks for 14 years, with no side effects. I’m lucky.”

She still suffers, however. With her fragile bones, she broke her arm in what should have been a minor accident four years ago, and last September she was rushed to the hospital in excruciating pain. “My hips and back hurt so much I couldn’t breathe,” she says.

Just as stressful for Frank is the prospect of losing her health insurance, which currently pays the $180,000 annual costs of her Cerecyme.

“The only way to get insurance is to work full time,” she says, “but when I work full time, I get tired. And soon my COBRA runs out.”

Genzyme’s Stewart defends the high price tag of his company’s drug. “I consider Cerecyme the greatest biotech therapy to date,” he says. “When insurers see the efficacy, they should pay for this. But if a family can’t pay for it, we give it for free.”

Even more promising than enzyme replacement therapy is gene therapy, a concept that once seemed like science fiction but which is now on the verge of becoming science fact.

“It’s cool technology,” says Stanford’s Enns, explaining the proposed methodology. “Viruses are little syringes that inject DNA. So we hijack them, gut them and put in the gene we like, let them infect cells and replace the gene we want replaced. The problem is, we can’t exactly direct where to insert it. So far, there’s not a single disorder that has been cured by gene therapy.”

That may change soon. Stewart at Genzyme reports that his researchers have had great preliminary success

“I’m the world’s biggest cynic,” he says, “and I never believe a result until I see it repeated. The results we’ve seen with the gene therapy on Niemann-Pick are phenomenal. I couldn’t believe what I was seeing.”

What he saw in mice studies was the first apparent treatment for a Jewish metabolic disorder that broke the blood-brain barrier. It is the lysomal storage diseases that affect the brain, like Niemann-Pick, that are the most devastating. Stewart and his team managed to inject enzymes directly into the brain, correcting the inherent pathology.

But clinical trials on humans aren’t set to begin for at least a year, and those tests may take years before the Federal Drug Administration approves any new drugs. Meanwhile, genetic counselors like Fairley will continue spreading the word about genetic testing.

“Testing is really accurate, and Jews are generally well educated and proactive about health,” she says. “But this is not going to be successful unless all aspects of Jewish community are reached.”

And mothers like Tamar Jacobs can only pray that no family again should endure what hers did.

“It’s very sad,” she says. “Renette never complained. She was a little meek, very sensitive to other people’s pains, very forgiving. I loved her so much.”


A look at rare Jewish genetic diseases

Dan Pine

Dan Pine is a contributing editor at J. He was a longtime staff writer at J. and retired as news editor in 2020.