It began as just a limp — and then it puzzled doctors for seven years.
Back in 2003, Hollywood was Robert Zuckerman’s stomping ground. The acclaimed photographer, then 48, was at the peak of his career, preparing to shoot the promotional materials for the Disney blockbuster “National Treasure” starring Nicolas Cage and Harvey Keitel. He was too busy, it seemed, to notice his leg wasn’t working quite right.
“I walked into the music manager’s office, and he said, ‘Hey Robert, why are you limping?’” Zuckerman, now 59, recalled.
So he had himself examined. At first, the doctors thought it was multiple sclerosis; then, a herniated disk. But the symptoms just didn’t fit together: the immense fatigue, often after the smallest of excursions, the numbness in his toes, the urinary incontinence. A spinal tap, multiple brain scans and years later, Zuckerman was still without an accurate diagnosis.
But those symptoms, which usually present themselves when patients are between the ages of 35 and 60, suggest a classic case of APBD, or adult polyglucosan body disease. The disease is inherited through an autosomal recessive genetic mutation, which means that both copies of genes must have the mutation for the disorder to be expressed. It primarily affects Ashkenazi Jews. With fewer than 200 diagnosed cases worldwide, most of which are in Israel, APBD is relatively unknown even within the medical community. Such unfamiliarity leads to many misdiagnoses of more common conditions with similar symptoms, like prostate cancer, dementia, Lou Gehrig’s disease, Alzheimer’s, and MS. To make the symptoms easier to remember, the letters of APBD have been given alternative meanings: A for Ashkenazi, P for peripheral neuropathy (numbness in the toes), B for bladder issues and D for decreased energy. Research for treatment and cures is still in its infancy.
The only study designed to determine how the disease is inherited relied on a sample of just 380 Ashkenazi Jews and found that 1 in 35 had the mutation. This high carrier rate is similar to diseases for which preconception screening is readily available and encouraged, such as familial dysautonomia (1 in 30) and Tay-Sachs (1 in 25). The results of this small 2012 study, published in the journal Biochemical and Biophysical Research Communications, might not be statistically significant, cautioned Adele Schneider, medical director of the Victor Center for Jewish Genetic Diseases. She was not involved in the research but called it “a good start.” “If the carrier rate really is that high, then there is a problem with diagnosing patients,” she added.
The mutation occurs in the GBE1 gene and disrupts the glycogen branching enzyme (GBE) charged with the production of glycogen, the reserve energy stored in cells for use when glucose levels bottom out. Without normal GBE activity, misshapen glycogen forms long strands that can’t be used for fuel. The strands build up, causing damage to nerve cells.
There have been a number of cases in which APBD was diagnosed but only a single copy of the mutant allele was found; these have puzzled researchers. A potential breakthrough recently came out of Columbia University in New York, where neurologist Orhan Akman discovered a second mutation of the gene that generates APBD. This could explain positive diagnoses in people he had expected to be unaffected carriers.
“There was a group of patients who were not supposed to have the disease, but still did,” Akman said. “And this was frustrating for the patients and us.”
Akman expects to publish a study in mid-August.
The genetic mutation that causes the disease was first discovered in the early ’90s by Alex Lossos, a doctor and researcher at Hadassah Medical Center in Jerusalem. The largest strides in the research have only come in the last decade though, largely due to the APBD Research Foundation, which was founded in 2005 by APBD patient Gregory Weiss.
While neither a cure nor proven treatment regimen yet exists, researchers are making progress. APBD Research labs exist in Israel, the U.S., Canada, Spain and England, and Akman is developing a medicine, to be taken like cough syrup, that he hopes will slow down the progress of the disease and other glycogen storage disorders. APBDRF provided $26,000 for Akman’s initial research and committed $112,000 toward the mouse trials that he expects to begin this summer.
If it alleviates APBD symptoms in mice without causing grave side effects, the treatment could be ready for initial clinical trials in a year, Akman said.
“That’s very big progress considering the organization was founded less than 10 years ago,” Weiss said.
This May, APBDRF established an anonymous registry through Akman’s lab to diagnose and document potential carriers and patients of APBD. Upon request, the lab will send a saliva testing kit.
Zuckerman, who now zips around in an electric scooter, became heavily involved in the small organization soon after his diagnosis in 2010. He still appears atop IMDB’s rankings for photography, and insists that the scooter has put him at no particular disadvantage professionally. Still, much of his work in the film industry seems to have mysteriously dried up. It’s “frustrating and disheartening,” Zuckerman acknowledges. These days you’re more likely to find him on the other side of the camera, in brochures and videos for APBD awareness.