Tuesday, September 02, 2014

Small Wonders

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TGen uses genome sequencing to unlock the mysteries of rare childhood disorders.

It was the best of times for 13-year-old Shelby Valint. Once unable to walk or talk, Shelby effortlessly bounced to the microphone at the opening ceremony for TGen’s Center for Rare Childhood Disorders (CRCD) on October 15, 2013. “It’s real hard to explain how much TGen has changed my life,” she said, thanking the researchers who freed her from the wheelchair she describes as “a prison.” TGen utilizes state-of-the-art gene-mapping technology to provide a diagnosis and treatment plan for youngsters stricken with profound illnesses. This process was literally a lifesaver for Shelby, who was born with a genetic disorder so rare it doesn’t have a name.

Three months after Shelby’s birth in 2000, her mother Renee noticed her daughter’s muscle tone degrading. Years of EEGs, brain scans and muscle biopsies followed, but doctors were unable to make a diagnosis. “They would do painful tests where they would zap her and see how fast the signal would travel to her brain and back to the muscle,” Valint recalls. “She screamed through the whole procedure.” The low point came in 2008, when Shelby had difficulty talking or swallowing and could only communicate via touch-screen computer.

After a Make-A-Wish-sponsored trip to Disney World in Florida that Valint describes as “bittersweet,” mother and daughter flew to Minnesota to consult with a team of world-class specialists at Rochester Methodist Hospital. One by one, they told Valint they were baffled. “That was the point I gave up,” she says. “There was nowhere else to go. There was no way it was going to be fixed or treated or even given a name.” For the next two years, Shelby was virtually motionless. Family members fed and dressed her, and she attended school in a power wheelchair.

But that chapter in the Valints’ lives was about to close, bookmarked by what the family considers a medical miracle. In late 2010, local neurologist Dr. Vinodh Narayanan provided Shelby’s blood sample to TGen, a nonprofit genomics research facility in Downtown Phoenix. Scientists inside TGen’s six-story, $46 million building had successfully sequenced the human genome – the “blueprint” for the complete genetic makeup of humans, containing 3 billion bits of information. By comparing an individual’s genetic code to the blueprint, scientists can see mutations or defects in genes that indicate the presence of – or a predisposition for – diseases and disorders.

TGen’s powerful computers, including the latest genetic analysis model from biotechnology company Illumina, decoded channeled slides of Shelby’s DNA into a “book” of genes, and then TGen’s team of physicians and geneticists pinpointed the letters in Shelby’s code that differed from reference samples. Geneticists Dr. David Craig and Dr. Matt Huentelman found a defect in the part of Shelby’s genome that regulates dopamine, a neurotransmitter important for motor control. “If you’ve ever had a lot of caffeine, you’ve stimulated dopamine,” Craig jokes. Narayanan suggested medication approved for treating Parkinson’s disease, which presents a similar dopamine defect. “Within a few weeks, she was getting stronger and holding up her head more. She got stronger and stronger,” Valint recalls. In March of 2011, Shelby walked into school for the first time in years. Her teachers nearly cried.

Three years later, a healthy Shelby attended the ribbon-cutting ceremony for TGen’s CRCD. Led by co-directors Craig and Huentelman, with Narayanan as Medical Director, the CRCD bridges the gap between research and clinical medicine. Two types of patients are currently being accepted for research studies: those who are undiagnosed despite extensive testing, and children who have rare conditions such as Rett Syndrome and Neurofibromatosis.  

The CRCD’s goal is to provide families with a diagnosis and treatment plan based on their genetic blueprint. Mom and dad’s genes are compared with the child’s (and any other affected siblings) to better identify the disease. As of this writing, TGen’s genome-mapping technology has been used to sequence more than 130 families. Among them are Newell and Becky Belnap, whose youngest son Seth was diagnosed with mitochondrial disease (see sidebar) in February 2010. Following a two-year quest to determine the cause of Seth’s movement problems and speech delay, he and siblings Sydney, Spencer and Sierra had their genomes sequenced. Seth was then prescribed a “mito cocktail” of vitamins and supplements and is currently talking and riding his bike like any other 7-year-old.  

But even with Illumina’s recent announcement of a new lower-cost DNA sequencer, gene mapping doesn’t come cheap. The sequencing that helped Seth and Shelby costs around $9,000 per family – and isn’t always covered by medical insurance. Luckily, TGen’s pint-sized patients receive free sequencing thanks to private funding and charity events like the P.F. Chang’s Rock ‘n’ Roll Marathon, which raised $60,000 for the Center in January 2014.

“It would have been a lot easier for me if I had an early diagnosis,” says Jennifer Smestad, 21, who appeared at the marathon on behalf of TGen’s Center for Rare Childhood Disorders as part of her Miss Arizona duties. As a young child, Smestad suffered years of social anxiety, facial spasms and an obsessive-compulsive disorder that caused her to repeat simple tasks such as walking down a flight of stairs. She was diagnosed at age 10 with Tourette’s Syndrome, a neurological condition characterized by motor and vocal tics. She successfully controlled her disease with a combination of therapy, medication and acupuncture. Though the CRCD isn’t studying Tourette’s, Smestad understands how getting a diagnosis can alter the course of a child’s life for the better. “I changed my attitude and I notice a difference in how I feel,” Smestad says. “I’m living proof that things can get better.”

Renee Valint feels the same way about her daughter. Now gearing up for high school, Shelby is a vibrant, introspective child who loves science and pop band One Direction. “Without TGen, I know for a fact she wouldn’t be here right now,” Valint says. “They’re going to help a lot of people.” Three years after Shelby’s recovery, mother and daughter still worry their story won’t have a happy ending. Shelby is likely to develop a tolerance to her medications in the future, making it necessary to continually increase the dosage.

For now, Valint is elated to watch her daughter run, ride horses and boogie on the back patio of their north Phoenix home. “I want to inspire people,” Shelby says. “And maybe be famous.” With each child diagnosed and treated at TGen’s Center for Rare Childhood Disorders, researchers learn more about neurological conditions and the genetic misfires that cause them. “Shelby is teaching us,” Craig says. “If we figure out why she does well, we can help someone else with this.” When that day comes, Shelby hopes her disorder will finally be given a name: Shelby Syndrome.

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DNA Detectives
As of February 2014, TGen’s Center for Rare Childhood Disorders had sequenced the DNA of 134 families, with 60 more in process. “We don’t see successes every day. We only get to a diagnosis about half of the time,” says geneticist Dr. David Craig. The other 50 percent of families are left still seeking answers to their child’s mystery illness. Craig’s hope is that diagnosis will become easier as more cases are studied.

Here are a few of the unusual childhood conditions TGen has mapped:
 
Leigh’s Disease - 1 in 40,000
A neurometabolic disorder affecting the central nervous system, Leigh’s generally appears in infants two and younger.
Symptoms: Diarrhea and vomiting, muscle weakness, declining mental and motor function.
Treatment: According to the National Institute of Neurological Disorders and Stroke, some cases of Leigh’s have been managed with dietary changes or Vitamin B1 and thiamine supplements.
Info: umdf.org/leighsdisease
    
Alpers’ Disease - 1 in 100,000
Alpers’ is caused by a mutation in the POLG gene that helps the body make a particular protein. Those born with the disease often go years before exhibiting symptoms.
Symptoms: Hypoglycemia, liver damage, seizures, blindness.
Treatment: Seizures can be treated with medication, though many sufferers die within a decade.
Info: ninds.nih.gov/disorders/alpersdisease/alpersdisease.htm

Mitochondrial disease - 1 in 3,000
Characterized by failures in the mitochondria, specialized cell compartments that help create energy.
Symptoms: Muscle weakness, developmental delay, diabetes, seizures, respiratory problems, heart disease.
Treatment: Tailored to the individual; can include dietary change, physical therapy or anticonvulsant drugs.
Info: umdf.org

Pontocerebellar Hypoplasia
Babies born with Pontocerebellar Hypoplasia have brains that fail to form properly. The six known forms are inherited, with each parent carrying the mutated gene. According to The National Institutes of Health, the disorder is so rare, its rate of occurrence is unknown.   
Symptoms: Weak muscles, spasms, vision loss, delayed development and microcephaly (small head size).
Info: ghr.nlm.nih.gov/condition/pontocerebellar-hypoplasia

 

 

 

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