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News & Press: University News

VTCRI destination for those with CASK mutation

Monday, February 13, 2017  
Posted by: Caron Trumbo
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Audrey Alves is 2-year-old from California with a great big challenge. There’s a gulf of several inches between where she’s sitting on the floor of a Roanoke hotel room and a bin of shiny beads. Three weeks ago, Audrey probably wouldn’t have cared about the beads, but if she did, she would have had no way to reach them. She would, at most, have cried and flopped over. Now, she squeals with delight, moves her hands together to sign “more,” and then, with much encouragement from her therapist, plants them firmly on the ground, lifts her bottom so she’s on all fours and tries to crawl.

Audrey has a rare gene mutation that resulted in her brain failing to grow the way it should. She has microcephaly, which means a small head and brain, and she has little control over her muscles. Her challenge is to overcome the medical opinion delivered to her parents along with her diagnosis: She’ll never walk, she’ll never talk, and a whole lot of other nevers.
 
But what did Audrey’s doctors know? Her mom, Rachel Alves, soon discovered that specialists in Sacramento were unfamiliar with the CASK mutation. The disease has been diagnosed in only about 100 children worldwide. So Alves turned to the internet and found one place that knows about CASK mutation: the Virginia Tech Carilion Research Institute. She found a small, but determined, network intent on kicking CASK. Konark Mukherjee, perhaps the only neuroscientist in the world studying the CASK gene at its molecular level, created a website, caskmutation.org, as a way to connect with families and to discover whether what he’s learning from mice is applicable to children. And if it helps children with a CASK mutation, could it help all children with microcephaly, regardless of the cause?
 
Families told him the only thing that seemed to help was a lot of therapy, so Mukherjee turned to his colleague Stephanie DeLuca. She runs the institute’s Neuromotor Research Clinic and brings in several children each month, mostly with cerebral palsy, for intensive bursts of therapy. DeLuca said she wasn’t sure whether she could develop a therapy for children with CASK mutation because the condition is so rare, but there was only one way to find out. “We literally said let’s bring a child in and see if we can get positive results.” They are taking a bench-to-bedside approach to research that, while not as rare as a CASK mutation, is a unique model. “We are trying to bridge the gap between bench science and clinical science that many places can’t do simply because they don’t have the same similar researchers from both lines in the same facility,” DeLuca said. Ordinarily, Murkherjee would work in the lab and develop protocols, and someone at another institution would try them out with patients. The results would eventually funnel back to his lab to refine, and the cycle would repeat until an effective therapy was developed. At VTCRI, he’s able to partner with DeLuca and both of  them can make adjustments at a quicker pace.
 
DeLuca said she sent off a grant application seeking funds to cover the travel and living expenses for the families of 36 children with microcephaly to come to Roanoke during the next few years. The Alveses had to pay their own way, and as a one-income family, Audrey’s dad, Matthew, had to stay behind to work. Her nana, Patti Hutton, came along to help with Audrey’s round-the-clock care. Finding an effective therapy for microcephaly is becoming more urgent. The term, which means small brain, worked its way into the lexicon last year when the mosquito-borne Zika virus began to spread in the Western Hemisphere. Though the virus appears to have a mild effect on healthy adults, that isn’t the case for developing fetuses. Pregnant women who are infected with Zika are at risk of delivering a baby with microcephaly, in which the brain does not develop and grow as it should. Zika is just one cause of microcephaly. Sometimes the cause is not known, and the condition can vary in severity.
 
Audrey Alves, the first child of Rachel and Matthew Alves, arrived on Jan. 16, 2015, following an uneventful pregnancy. It wasn’t clear at first that she was ill. “When she was born, they were concerned with her small head size, but they didn’t classify it as microcephaly yet. They just said to watch if milestones weren’t met,” Alves said. Audrey didn’t roll over, sit up, pull herself up, rock back and forth or begin to help feed and dress herself. She was a tiny baby. Full-term, Audrey weighed in at 5 pounds 9 ounces and was slow to grow. Alves found it difficult to nurse as she wasn’t producing enough milk. She knows now that Audrey’s low muscle tone prevented her from suckling properly. At 6 months, Alves knew her daughter wasn’t developing as she should. Audrey’s right hand remained clenched like a newborn’s. She couldn’t sit and she was missing all the infant milestones. At 9 months, Audrey’s pediatrician sent her to neurology for an MRI.

“They were expecting to find a brain abnormality, and they didn’t. That is why we were sent to genetics,” Alves said. “They told us basically they had ruled out everything and there’s a such a small chance they’d find anything with genetics, but it was the next protocol.” During the six-week wait for the genetic test results, the Alveses became reconciled to not knowing why their daughter was so small and developmentally delayed. Then the doctor called and told them Audrey has a defect on her CASK gene. She’s one of only 100 or so children in the world with this diagnosis, though most likely many other children’s microcephaly was caused by this mutation — they just haven’t had genetic testing. The gene is located on the X chromosome. Since boys have but one X chromosome, if this gene is defective, they die at birth or shortly after. Girls generally will have microcephaly and low muscle tone and are at risk of being deaf, blind and having heart and kidney problems. They can survive with the mutation. Mukherjee and DeLuca believe they also can thrive.
 
Every day for three weeks, therapist Dory Wallace spent four hours with Audrey helping her learn to use and control certain muscles. Audrey learned how to take bigger bites of food and eat from a fork. She can move from sitting to a crawling position and back to sitting without flopping over. She can pick up small toys and release them with both hands. Her right hand is no longer clenched in a fist. She delights in toys of different shapes and textures, which bothered her when she first arrived. Most of all, she’s beginning to talk through hand signs. “I know the motor skills are exciting, but the communication is huge,” DeLuca said. “What we know that often happens with older children is the communication and social interaction is delayed. So it’s exciting to help her start early, and she can build on those skills.” DeLuca said evidence suggests Audrey will keep the skills she’s gained and can build on them, depending on the type of therapy she gets at home. From the time of her diagnosis, Audrey began to receive one hour of therapy five days a week through California’s early intervention program. One day she has feeding therapy, another day speech, another physical therapy and so on. In Roanoke, she had all of it for hours each day. “The amount of therapy we are getting in three weeks is what we get in a year,” Alves said. DeLuca said from what she’s seen in more than 30 years of working with children with cerebral palsy and now microcephaly, the traditional delivery of therapy does not work. “We are simply diluting therapies too much when we give it for an hour a week,” she said.


She credits her colleague Sharon Ramey with a descriptive analogy. Suppose you had to treat 10 children with an ear infection that requires a 10-day course of antibiotics, but you had enough for only one child. Would you give 10 children one dose or one child 10 doses and then figure out how to get 10 more doses to treat the next child? DeLuca said she’s hoping to secure a grant to treat 36 more children with microcephaly with intensive bursts of therapy. The bursts are similar to teaching a child the ABCs by buying ABC bedsheets, hanging the alphabet on the wall, putting magnets on the refrigerator and singing the song over and over until the child gets it. Then it’s a matter of reinforcing and building on the skill. As she watched Audrey sign for “more” toys, DeLuca said she was encouraged by how much the little girl has progressed in three weeks and by the fact that she is now developing skills to communicate. Similar improvements were seen in the other two children with CASK mutations who came to Roanoke.
 
“I don’t have specific evidence it will be applicable to all children with microcephaly, but I don’t have specific evidence that it won’t,” she said. “If I have seen anything work for all children with motor disorders, it has been intensive therapy bursts.” Mukherjee said he sees the same in the lab with his mouse model. He’s planning next to pull in another colleague, Stephen LaConte, a pioneer in functional MRI, which allows scientists to watch the brain as it works and interacts. Through this, they might be able to peek inside a child’s brain and see what occurs on the inside. The changes in Audrey in three weeks were dramatic, her mom said. She’s beginning to move and she’s beginning to communicate, and Rachel Alves believes her daughter is capable of so much more.


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