MONROVIA>> Looking into Marian McGlocklin’s big, bright blue eyes, she doesn’t seem to have a care in the world — just as any other 22-month-old shouldn’t.
But Marian’s mother, Sara McGlocklin, studies those eyes differently, scanning for a glimmer of hope.
Marian was diagnosed with a rare, uncurable and ultimately fatal, progressive genetic disorder — Neimann Pick Type C.
Even as her daughter’s sweet personality shines through, Sara McGlocklin can’t help but fear how this disease may drain the life right out of Marian.
“It’s hard to prepare for the future, if you don’t know what’s going to happen to her,” Sara McGlocklin.
Marian was small at birth. Her parents, Sara and Paul McGlocklin, never imagined her 5 pounds were a warning sign. Lots of babies are born small.
When Marian was around 6 months old, more symptoms appeared: Her development was slow; she had an enlarged spleen.
After more than a year of test after test, going from doctor to doctor, and with the McGlocklins’ continuing persistence for a diagnoses, genome sequencing in March led to the discovery of the Neimann Pick Type C gene mutation.
Marian’s 4-year-old big sister was also tested but cleared of the genetic disorder.
Despite the devastating news, the McGlocklins would soon find a reason to fight. After reaching out to other similarly affected families and learning about current developments in research, there was hope.
A Phase 3 trial of a treatment known as VTS-270 showed signs of slowing — although not reversing — the disease’s progression.
In learning about the drug, “I felt like I could breathe again,” Sara McGlocklin said .
They rushed to get Marian on the treatment plan with hopes of extending her life at least one or more years than she would have had without it. Now, researchers are looking to young patients like Marian to learn more about NPC and VTS-270 as a treatment.
Niemann Pick Type C-1
The types of NPC symptoms, including the timing of their onset, vary widely. Some can start before birth, while others appear in older children, even up to adulthood.
NPC causes progressive deterioration of the nervous system. It is caused by a defect in lipid transportation within the cell, interfering with the affected person’s ability to metabolize cholesterol. Large amounts of cholesterol accumulate within the liver, spleen and brain, which can lead to cell deterioration, then difficulty eating and breathing, and often seizures. The majority of people with early onset of NPC die by their late teens or 20s.
Some patients’ symptoms may be only neurological, others physiological, while others deal with both and a host of other symptoms and complications from the disease.
“It can present mostly as a coordination problem, or a thinking problem, and initially the patients don’t lose skills. They just gain them at a slower rate,” said Dr. Elizabeth Berry-Kravis, professor of pediatric neurology and biochemistry at Rush University Medical Center in Chicago.
“So, there are a lot of patients who are initially thought to have a developmental disability,” Berry-Kravis, a co-investigator for the VTS-270 trial, said. She has been treating NPC patients for years, including Marian when she first began the VTS-270 treatment.
Because of the variety of symptoms, a patient may not be properly diagnosed or misdiagnosed for years. It wasn’t until 1997 that scientists identified the gene responsible for causing NPC, thanks to the Ara Parseghian Medical Research Foundation, which funded early research. The foundation, named after the notable Notre Dame football coach, was started after three of Ara Parseghian’s grandchildren were diagnosed and ultimately succumbed to the disease.
Before the Parseghian Foundation, two labs were dedicated to NPC research. Now there are more than 20, and the foundation raises more than $2 million a year toward research.
Reaching a diagnosis is faster these days, Berry-Kravis said.
“Before you had to know that you wanted to diagnose for NPC. It would take four to six years, where the patient would have enough of the symptoms to know what to look for,” she said. “Now we have this genome sequencing, and then it comes back with the NPC gene, and the clinician no longer has to know what they’re looking for.”
Early diagnosis is especially important in young NPC patients, who have a limited time before the disease begins to debilitate their bodies. The earlier they can get treatment, the more effective it can be.
“If a patient is minimally affected earlier in their disease, they may do better than someone who has several symptoms already,” Berry-Kravis said. “You want to get it when the patient has almost no symptoms; but some don’t have them until they’re about 15.”
Cyclodextrins, compounds made up of sugar molecules, are the foundation for the treatment VTS-270, currently developed by Maryland-based VTesse.
The treatment seems to be the only hope for many NPC patients. Although the human trials for VTS-270 target ages 4 and up, the McGlocklins and some other parents of younger patients successfully petitioned to get the treatment through a compassionate use program.
Before approval for compassionate use at Children’s Hospital Los Angeles, Marian was flying out to Chicago to receive the treatment every other week.
So far, she has been the youngest to start the treatment, which is given through the spinal cord. Her body is elevated head down for a time to help the treatment reach the brain. For now, the treatment has to be given every two weeks, indefinitely.
“We’ll be seeing (Marian) periodically, every 6 months or a year, to see her developments,” Berry-Kravis said. “What we’re interested in is her developmental projections, mapping what her development does, seeing if she catches up developmentally where she’s supposed to be.”
The McGlocklins said they have seen a marked improvement in Marian’s progress since beginning the treatment. She is bearing more weight on her legs, and learning to walk, a big step in her development, even at this stage in her infancy.
“She always seemed tired. Now she wants to play more,” Sara McGlocklin said. “We see more of her personality coming through.”
Marian even threw a bit of a tantrum once — something Sara McGlocklin said she and her husband cheered because it showed their daughter had enough strength to show defiance.
The trial ends early next year and will then2 be presented to the Federal Drug Administration for approval.
Berry-Kravis said hopefully the trial data will prove it is effective enough for FDA approval, and can help Marian and other patients continue the treatment. Hopefully the approval will also mean, the families can get help to cover the treatment costs.
“We’re trying to show there is a little bit better outcome,” she said. “The real thing that we need to know is whether the drug works over the long-term.”
The hope for NPC families is a cure, of course, but a hopeful treatment is a step in the right direction. And knowing the strength of the almighty dollar, families like the McGlocklins know the importance of funding the critical research that will help find a cure.
The McGlocklins started a GoFundMe page soon after learning Marian’s diagnosis, and a blog, with the idea of spreading awareness of NPC and helping to fund research.
“(The research for a cure for NPC) is moving faster than some diseases, but it never moves fast enough for the families who are dealing with this disease,” Berry-Kravis said.
Sara McGlocklin’s ultimate goal, after clinching FDA approval and Marian’s continued progress, will be to push for newborn screening, she said. Earlier screening will hopefully mean more children diagnosed earlier, avoiding misdiagnosis and earlier intervention.
The Chans of Diamond Bar
Even in utero, Galya Chan, was always behind her twin brother Ezra. Caris and Brian Chan’s twins were born premature in 2012. But while Ezra eventually was growing on schedule, Galya struggled to catch up developmentally. Like Marian, complications were more clear by the time she was 6 months old.
After several misdiagnoses and complicated surgeries, the Chans learned Galya’s had NPC when she was 13 months old. But it would be about six months more before she began the VTS-270 treatment through compassionate use at Children’s Hospital Orange County in 2014.
“It was crazy because I didn’t have time to think. Because it was fatal, I sprang into action,” Brian Chan said. “Within a split second, all the hopes you have for your child, those are all gone.”
Though Galya ended up getting cerebral palsy because of a complication during a biopsy surgery, Brian Chan said he did notice improvements right away.
VTS-270 “has been a lifesaver. She’s able to sit up; physically she’s strong, which you don’t see with other NPC children,” he said.
Galya does need a feeding tube and is not able to walk on her own. She goes through physical therapy, just as Marian, who also does speech therapy.
One of the side effects of the treatment is hearing loss, which is also a symptom of NPC. So far, Galya has not had any indication of side effects, while Marian recently began to show ultra high frequency hearing loss, but doctors cannot contribute that to the treatment or the disease.
Brian Chan, an entrepreneur with a software company, created another company, Galya Tech, to focus on gene therapy, “because we think that would fix the root of the problem.”
The Chans’ three other children, including Galya’s twin brother, were tested and shown to be carriers, meaning they can pass on the disease to their children but they will not get symptoms.
Hope for a future
Sara McGlocklin always wanted to have three children, and despite the 25 percent chance another child will also have NPC, she said she hopes to one day continue to fulfill that dream.
But for now, the McGlocklins want to focus on their daughters; trying to have a normal life between treatments and therapy; and being advocates for Marian and NPC.
“I still feel worried. It can be a little depressing,” said Sara McGlocklin, who oscillates between feeling hopeful and being a realist.
“I see a door opening, and it’s wonderful,” she said of the treatment’s trial. “We know this is not going to be a cure. The proof (of the treatment working) will be in Marian.”
Brian Chan said he has two kinds of hopes, short and long term.
“For my short-term hope, getting the gene therapy, but I realize that may not be in time for Galya,” he said.
For his ultimate, long-term hope, he leans strongly on his faith.
“When I look at my other healthy kids, they’re going to die one day, too, and my hope is that they will ultimately rise again,” Brian Chan said. “So, my hope is that I will see her again in heaven and I will dance with her.”