Little Gavin’s infectious laugh could make hearts soar; it could also plunge him to the ground.
His baffled parents could not understand why his contagious humor also triggered a complete loss of muscle tone. They began to fear making him giggle.
Kristen and Fernando Lopez ushered their oldest son to the doctor. They tried tickling him to demonstrate these unusual episodes, but it didn’t work. The pediatrician assured the worried parents that everything was fine.
That was three years ago.
Little did the family know that their bright boy with big, soulful brown eyes was in the throes of a rare, genetic disorder called Niemann-Pick Type C disease (NPC). Elusive to diagnosis, it results in the progressive, catastrophic loss of nervous system function.
Colloquially, it is referred to as Alzheimer’s in children. But according to one of the world’s foremost child neurologists who has been studying NPC for 20 years, Dr. Marc C. Patterson of the Mayo Clinic Department of Neurology, it’s “much worse” than that. It robs little ones of their minds (dementia) and movement. And, ultimately, their lives.
Sitting in her Carrollton home, Lopez describes her son, now almost 6, as a “warm body” who can no longer run and play or share his hearty, trademark laugh. “He doesn’t say ‘Mom’ anymore,” she offers softly.
But he wasn’t always like that.
On April 14, 2004 Lopez, now 28, gave birth to Gavin nine days early. His arrival “was so unexpected, but so beautiful,” recalls the young mom, a customer service rep at the time. Like many babies, he came down with a prolonged case of jaundice. “No big deal, right?” says Lopez.
Although colicky, Gavin developed like any other healthy baby, hitting his milestones on time. By the age of 2, he was talking perfectly, “almost too perfectly,” recalls his mom. By this time, Gavin had a little brother named Ethan. Both boys were learning English and Spanish in their bilingual home. But, Lopez and her husband Fernando, a mechanic, started noticing differences in their sons. For instance, Gavin slept a lot during the day. There was the problem with his falling to the ground when he laughed. Then at 3, Gavin stopped running and jumping (his gait was unsteady and stiff), and he didn’t want to color anymore.
‘Running in circles’
There was no common denominator among Gavin’s symptoms (loss of intellectual function, clumsiness, speech issues, low muscle tone, seizures)—except that they were getting worse.
At his 4-year checkup, the doctor confirmed Lopez’s gut feeling and gave the family a referral to see a neurologist.
“I just knew something was wrong and I felt so guilty waiting so long,” she recalls, apologetically. “We were in denial.”
But several visits to two different neurologists (and a litany of testing, including blood work, spinal tap and MRI) would net the same results: normal.
“I felt like we were running in circles,” Lopez says.
By June of 2009, Gavin entered a seizure study and was diagnosed with gelastic cataplexy, a sudden and transient episode of loss of muscle tone. It literally means to “fall about laughing,” reports Patterson. “Except, it’s not very funny.”
Still, the doctors didn’t know what caused it.
Desperate, Lopez began conducting her own research online and came across a disease associated with cataplexy—“the worst of them all, NPC.” In fact, she found a YouTube video of a child exhibiting the disease and Gavin said, “That looks like me.”
Lopez took Gavin back to the neurologist and demanded to have her ailing son admitted to the hospital to be tested for NPC.
Soon, Gavin was surrounded by a team of medical experts at Children’s Medical Center of Dallas. Four days later, a pediatrics genetics expert, Dr. Lewis Waber, sat down with the family and told them that he thought Gavin exhibited some of the symptoms of NPC. “I think he does, too,” Lopez recalls hollowly. Two months later (after a skin biopsy – the only way to test for NPC) the family finally confirmed the grim diagnosis.
‘Becoming the expert for her child’
Waber, also a pediatrics associate professor at UT Southwestern Medical Center at Dallas, confirms that the variable disease is difficult to identify (it’s exceedingly rare, affecting only 1 in 150,000). There are many types of neurological conditions that can set off similar symptoms, but one commonality seems to be the peculiar problem of a child tilting his head back to look up (vertical gaze palsy), explains Waber.
There is no FDA-approved treatment or cure for NPC—a lysosomal storage disease (LSD) that prevents cells from processing and eliminating cholesterol and other lipids, leading to a cellular traffic jam that ultimately overloads the organs and attacks the brain. Parents are left to watch their child deteriorate rapidly before their eyes, knowing there is nothing they can do to stop it. The majority of children die by age 20 (and many before age 10), according to the National Niemann-Pick Disease Foundation (NNPDF).
As the family left the hospital with little hope and only a prescription for an antidepressant (to treat the cataplexy), Gavin cried out, “My legs are hurting.” “That’s the last thing he ever said,” reveals Lopez.
Since then, Gavin has stopped using the bathroom on his own and communicates only with a moan. He has “lost touch with the world,” says Lopez. “The doctors told us, ‘there is nothing you can do but give him a good life.’”
But that’s a tough pill to swallow for any mother. Lopez decided that she would have to become the expert for her child, who is afflicted with a disease that strikes approximately 500 children and adults worldwide. Through her own due diligence, she discovered that the drug Zavesca (Miglustat) has been approved in the European Union as the first promising treatment of NPC. But the pills are expensive (roughly $200 each). She pushed for Gavin to access the drug “off label,” [meaning that the drug was approved for a different disease but doctors can prescribe it to treat something else] so the cost would be covered by insurance. Quickly, his eye contact and strength improved.
“Many of the children and adults that have access to Zavesca are now at least ‘holding their own’ against NPC,” asserted Barb Vorpahl, chairman of the NNPDF, in her presentation to the FDA this past January. Without the FDA’s approval, getting the expensive drug would be “insurmountable for most families.”
Patterson, who was a co-investigator in the clinical studies of Zavesca, notes that it was difficult to achieve a statistical significance in the research because there are so few patients to test. However, the findings showed that the drug could extend life 20-25 percent in lab mice.
‘You’ve got to be kidding me’
Desperate for answers, Lopez also reached out to a team of active parents who are not taking “no treatment” for an answer. One of the moms Lopez contacted is Chris Hempel, a Reno, Nevada, mom of 6-year-old identical twin girls named Addi and Cassi.
Like the Lopezes, it took Chris and her husband Hugh a grueling 18 months to claim an NPC diagnosis for their daughters. And, when they did, the advice was similar to what the Lopezes heard: “Sorry, there is nothing we can do.”
“I thought, ‘you’ve got to be kidding me,’” recalls Chris Hempel. The former technology PR executive immediately began looking into medicinal alternatives. “You are in a trap. You find out quickly that there is not going to be a new drug for you, so you start doing the research,” asserts Hempel. “I figured a vitamin has to be better than nothing.”
Hempel also turned to online medical journals (once only available to physicians) and started studying the effects of different supplements. When scans revealed that her daughters suffered from brain inflammation, she gave them ibuprofen and “optimized” curcumin, based on research she found that this component of the Indian spice turmeric improved the disease in mice.
“It comes down to common sense. I try something and watch them,” she avows. “I can’t wait around … or they will be dead.”
Shockingly, there is little support for rare diseases. According to the National Institutes of Health (NIH), approximately 7,000 different rare diseases exist today, with countless others waiting to be identified by researchers. Of those rare diseases, 75 percent affect children (22.5 million in the United States).
Unfortunately, pharmaceutical companies have only developed treatments for 200 rare diseases. Why? Because for a disease like NPC, with such a low prevalence, there is a lack of financial incentives to pharmaceutical and biotech companies, according to a 2009 study by H.E. Heemstra, et al., entitled “Translation of rare disease research into orphan drug development: disease matters,” published in Drug Discovery Today.
It takes approximately $802 million and 10 to 15 years to bring a drug to market, reports Dr. John Kelly, senior vice president for scientific and regulatory affairs, at Pharmaceutical Research and Manufacturers of America (PhRMA).
“It’s unlikely that a drug company will get behind a drug” for such limited use. “They are not charities; they have to make a profit for shareholders,” says Waber.
Congress is stepping in by providing $24 million a year for the next five years to start the Therapeutics for Rare and Neglected Diseases program (TRND) at the NIH. Hempel acknowledges that this is a step in the right direction; the initiative will jump start the development of treatments and stimulate research collaboration with academic scientists. “The problem is we need billions,” Hempel insists.
‘Seek treatments today … cures tomorrow’
With no potential treatment other than Zavesca in the pipeline, the Hempels knew they needed to do something … and fast. “This is an absolute nightmare … No parent should be faced with getting a diagnosis of Niemann-Pick Type C and then enter into a totally dysfunctional medical and drug development system on top of it,” declares Hempel. So, they asked themselves, “What resources do we need … to solve this problem?”
Chris and Hugh, former Netscape executives, turned to a Silicon Valley healthcare company called CollabRx that builds and operates virtual biotechs for foundations and patients who urgently seek treatments and cures for their diseases. Together with three other NPC family foundations, the Addi and Cassi Fund supports SOAR-NPC (Support of Accelerated Research for Niemann-Pick Type C disease), a cutting edge research collaborative between four leading NPC researchers and universities, including Washington University in St. Louis, Oxford University in England, Mt. Sinai School of Medicine and Albert Einstein College of Medicine.
Last year, the families raised more than $1 million collectively and are funneling the money into specific NPC research projects (with an emphasis on novel ways to approach the small population of affected individuals and short term trials).
Through their organization, they hired a doctor with a neuroscience background to stay abreast of current research. The focus, says Hempel, is on the already approved 3,000 plus FDA drugs that could be used off-label and repurposed for the needs of an NPC patient. In addition, SOAR-NPC is testing over-the-counter supplements that can be applied today to help affected children.
Until researchers discover a way to replace or repair the defective gene, the goal is to arrest the variable progression of the disease. “We must seek treatments today and cures tomorrow,” says Hempel.
When they learned that prominent researchers were eyeing the viability of a nontoxic sugar compound called cyclodextrin, Hempel (along with the help of their hired physician and her children’s doctor) began the laborious process of filing a compassionate use investigational new drug (IND) application with the FDA. Notably, cyclodextrin, and its potential to impact NPC by removing cholesterol from cells, is currently being studied on lab mice at Dallas’ UT Southwestern Medical Center by Dr. John Dietschy and Nobel Laureates Drs. Michael Brown and Joseph Goldstein (whose findings in the underlying mechanisms of cholesterol metabolism led to the development of statin drugs, cholesterol-lowering compounds used by 16 million Americans today).
Though the research has yet to yield conclusive results, “I’m not going to wait five years for a clinical trial,” Hempel asserts. “I don’t want treatments in one or two years. I want them today.” The girls’ treatment, which began last year, is the first and only of its kind in the United States, and is currently being monitored by the FDA.
Patterson, who is sympathetic to parents’ desires to do whatever it takes to save their child, adds that from a scientific perspective, it will be difficult to measure the success of cyclodextrin on the Hempel twins (due to a lack of controls).
Hempel, however, has seen the evidence firsthand with improved strength, awareness and mood, as well as a reduction in the size of the twins’ lysosomes. Hempel admits that their decision might seem radical to some, but the couple is so certain of the drug’s efficacy, that they plan to file a new IND in April to alter the treatment protocol from the bloodstream to the brain.
Although rare, NPC has generated enormous interest by scientists. Every person carries an NPC gene on chromosome 18—it’s critical to human health because it regulates cholesterol metabolism at the cellular level. However, when both parents carry a defect on the NPC gene, the chances of having a baby with a mutation is one in four. In fact, researchers are paying close attention to NPC because it could offer clues into the treatment of Alzheimer’s and Parkinson’s disease, as well as other cholesterol-related diseases.
Both families have been thrown into a world of the unknown—a world that is filled with the red tape of insurance companies, social services, special needs at school and medical research. It’s also an unthinkable world of wheelchairs, seizures and decisions about breathing tubes.
The Hempels cope with “an army” of people, including divorced grandparents living under the couple’s roof to help out with carpool and insurance claims (“a full-time job,” says Hempel). The twins, who have lost their ability to speak but can still walk and recognize their parents, “do not understand they are sick,” as the family keeps life as normal as possible.
Lopez, who works part-time and attends school full-time (she is studying to become a scientific researcher to help find a cure for NPC), continues to press for solutions for Gavin, while admitting, “We know in our hearts what’s going to happen. We’ve accepted it, but we’re going to do something about it.” She grows quiet before revealing that it can be a challenge to take care of both kids (Ethan is not affected by NPC) and also work on her marriage.
With mounting medical bills (even with insurance coverage), the family turned to a social worker, who helped get Gavin on Medicaid. She and Fernando have also discussed palliative care options with Waber. “We worry about keeping him alive and comfortable for as long as possible in case there is a cure,” she explains.
Recently, the Lopezs entered Gavin, who attends a special needs program in public school, into an NIH Clinical Center study in Washington, D.C. The study aims to learn more about NPC and, so far, it’s revealed promising biomarkers that have helped spearhead further research, says Nicole Yanjanin, a pediatric nurse practitioner, who works with children and families affected by NPC at the Program in Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development at NIH.
Back in Texas, Lopez also started a nonprofit organization called Huggles ’N Kisses. She is in the process of lobbying for “Gavin’s Law” which would require early screening for NPC via a simple blood test in babies who suffer from prolonged jaundice (an early symptom in about 50 percent of NPC cases, says Patterson).
The families were heartened to see rare diseases garnering the attention of Hollywood. Earlier this year, a movie called Extraordinary Measures (starring actors Brendan Frazier and Harrison Ford), highlighted the real-life efforts of John and Aileen Crowley to find a researcher who might help find a cure for their two children’s rare genetic disorder (Pompe Disease).
“I hope this movie is a wake-up call to the NIH, FDA, Congress and other government agencies,” implores Hempel. “Like the Crowleys, we are not going to sit around and wait for our kids to die. But every day it is a battle with hurdle after hurdle to cross to make the slightest progress.”
For moms bonded together under such rare circumstances, one thing is common: their willingness to do whatever it takes to give their own, and other NPC children, a future.
“We just want our baby back,” murmurs Lopez.