Genomics Overcomes One Tiny Mutation That Was Slowly Trying to Kill a Wheelchair Bound Child Who Fac

(Photo courtesy of TGEN and its Center for Rare Childhood Disorders. Shelby Valint is the child in the center of the picture).

The power of genomics can be especially stunning when applied to children. The lesson for me was highlighted last week during a meeting at TGEN, which is the Translational Genomics Research Institute. Broadly speaking, TGEN is perhaps the foremost US-based translational genomic sequencing powerhouse, and is located in Phoenix. TGEN includes a group of researchers focusing the power of genomics on children through the Center for Rare Childhood Disorders.

The meeting included mention of "the story of Shelby Valint, a 12-year-old Phoenix girl who was wheelchair-bound for nearly a decade due to a rare disease of unknown cause. She had difficulty walking, talking, holding her head up, swallowing, and even breathing… but the key word in that description of Shelby is "had". Scientists at the non-profit Arizona research institute TGen sequenced Shelby’s genome; something they couldn’t have done in a reasonable amount of time or cost just five years ago. By sifting through the unique alterations in her data they were able to provide clues to the genetic basis of her rare disorder and empower her physician to prescribe a medicine based on this new information that resulted in changes to Shelby that were nothing short of a miracle. Today, she can talk and walk, even run, and is a 7th-Grade honors student. "

What did TGEN do? Thanks to her smart and determined doctor (Dr. Vinodh Narayanan), Shelby became the first patient for TGEN’s Center for Rare Childhood Disorders, and they put their analytic power to work for Shelby. They found a mutation in Shelby’s DDC gene. As explained by the NIH: "The DDC gene provides instructions for making the aromatic l-amino acid decarboxylase (AADC) enzyme, which is important in the brain and nervous system. This enzyme takes part in the pathway that produces dopamine and serotonin, which are chemical messengers that transmit signals between nerve cells (neurotransmitters)." With the defective gene identified, an existing drug was put to work to transform Shelby’s life.

The following summary is taken from a Phoenix newspaper article in the Arizona Republic, written by Ken Alltucker:

"TGen mapped Shelby’s genome twice. The first found no significant abnormalities. But a more powerful scan revealed what appeared to be an anomaly in a gene called DDC.

That, combined with information from the earlier spinal tap, led Narayanan to believe the genetic anomaly blocked her ability to synthesize dopamine.

Renee wanted results. The doctor had already treated Shelby with L-Dopa, which had too many side effects.

"I was skeptical," Renee said. "I couldn’t see just giving her a pill, turning around and seeing her walk."

Narayanan prescribed a different dopamine treatment, bromocriptine, often used to treat Parkinson’s disease. Shelby started the pills at the end of the year.

Within two weeks, Renee said, she could notice slight changes. Shelby could hold her head up. Sit upright in her wheelchair. Speak more clearly.

Three months after she started taking the drugs, Shelby took her mother’s hand. They stepped outside and walked down the sidewalk.

Renee took out her cellphone and called her mother Marilyn Greiner. "Your granddaughter is walking up and down the street right now," she said. And Shelby’s grandmother cried."

How bad were things for Shelby before TGEN and her doctor found the genetic flaw? Set out below are key quotes from Mr. Alltucker’s news article telling Shelby’s story.

"For Shelby, most days were spent lying on the couch. Renee would carry Shelby in her arms, bathe her and chop up her food into tiny pieces. She could not swallow liquids without risk of choking, so the family mixed a thickening ingredient with her drinks

At school, she was a fixture in her motorized wheelchair. Shelby’s elementary school held fundraisers and events such as a "Skate for Shelby" day and a wheelchair race among teachers and students.

But, in 2009, the family and her doctor considered putting her in a hospital with a feeding tube so she could regain her strength.

"Day by day, I didn’t know if she was going to make it," Renee said.

"Even in her first few years, Shelby endured struggles some never face. At 6 months old, she had trouble holding up her head. Her limbs were lifeless.

"She felt limp in my arms," said Renee Valint, Shelby’s mother. "She felt like a rag doll.

Shelby’s symptoms seemed to worsen in 2008. She began to have trouble swallowing food, and she was down to 37 pounds.

As her childhood progressed, Shelby was subjected to needles, biopsies, scans and other medical tests. Each sought to rule out a disease or condition. Each left Renee and her husband, Scott, frustrated over the lack of a clear diagnosis.

Renee and Scott watched their second-born daughter grow weaker. She would try to walk along furniture, but she would often fall down.

She was bright, her thoughts were clear, but she was trapped in a body that betrayed her."

YouTube includes a growing number of videos presenting aspects of Shelby’s transition to a normal life. This video provides a longer version of the story with some expert commentary. This video presents Shelby and her mom explaining the story in short form. Perhaps best of all is this video showing Shelby dancing at her school.

Watching Shelby Valint dance is a great way to really internalize the reality that we truly are at the dawn of precision medicine. In other words, diagnosis and treatment based onincredibly advanced and meaningful analysis of the conditions present in one particular person. Yes, of course, there is much more to learn, but molecular biology is light years ahead of where it was just five or ten years ago. Much more will be learned, and personalized medicine will transform more lives, and will transform disease analysis and treatment (not to mention litigation involving diseases).

#Science

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About Kirk

Since becoming a lawyer in 1983, Kirk’s over 30 years of practice have focused on advising a wide range of corporations, associations, and individuals (as both plaintiffs and defendants) on both tort and commercial law issues centered around “mass torts.”

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