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Cover story: Facing the unthinkable

The Nye family helped scientists discover a new disease. Now they're on a mission to find a treatment.

Kim Nye helps son, Colton, 4, into his shoes while daughter Maggie, 7, looks on. (Photo by Michelle Le/The Almanac.)

Kim and Zach Nye had the storybook Peninsula life.

She grew up in Portola Valley attending Ormondale and Corte Madera, he in Menlo Park, where he attended Oak Knoll and Hillview Middle School. They met in high school at Menlo School, where they took Latin together, but didn't start dating until they were both undergraduates at Princeton.

After college they got married and moved to England, where Zach studied finance at the London Business School and Kim studied law, literature and history in Greek and Latin at Oxford.

While pursuing their graduate studies, the Nyes had their first daughter, Tessa.

Within hours after she was born, their lives took a sudden turn.

Tessa began having hundreds of seizures a day.

From that point, the family began a journey that would lead them to help discover a new genetic disorder and create a foundation to research a treatment.

Looking for answers

It was "heartbreaking to have this child who kept trying to die on us for no apparent reason," Ms. Nye said. In her first two years, the young family took dozens of ambulance trips to the hospital and consulted with about two dozen of the world's top neurologists, searching to understand what might be wrong, she said.

Tessa's condition stumped all the doctors, but each told the Nyes that the condition was not inherited.

So the family decided they would have other children. They felt it would help Tessa to have a strong family network, Ms. Nye said. Daughters two and three, Lily and Maggie, were born, and both developed without complication.

Within hours of the birth of their fourth child, a boy named Colton, however, the Nyes again knew something was wrong.

The dreams for their child that parents typically have – planning for future sports games and college tours, for instance – were dashed when they recognized the same symptoms in Colton they'd seen in Tessa. That knowledge came with an acceptance that, in Ms. Nye's words, "our son would probably never talk or live independently."

"The prognosis was not good, despite initial appearances," she said. "It was just beyond devastating to me and my husband."

By then, the Nyes had returned to the Peninsula – after England, they lived for several years in southern California while Mr. Nye pursued a Ph.D. in finance – and Tessa had begun to work with pediatric neurologist Dr. Brenda Porter at Lucile Packard Children's Hospital.

Capitalizing on the knowledge developed from learning what medications helped to stabilize Tessa's seizures, Dr. Porter quickly put the newborn Colton on a medication regimen that seems to have given him more stability and fewer seizures in his first few years than his older sister.

Now that the family knew there was a strong chance the condition was inherited, they again sought the help of researchers to pinpoint what might be causing the seizures and neurological problems.

Having two kids in the family with the disorder made hunting through the genome to find the problem easier. Working with Dr. Matthew Bainbridge at Baylor University, they ultimately tracked down the problem to a mutation in a gene called SLC13A5. Parallel research in France with other subjects matched Dr. Bainbridge's findings.

They found that the disease occurs only if a child inherits two copies of the defective gene. Both Kim and Zach had one defective copy of the gene, and it turns out that Tessa and Colton inherited both deficient copies.

SLC13A5 is a gene that typically codes for a protein that forms what's called a sodium citrate co-transporter. When operating properly, the transporter regulates the levels of citrate – a key molecule needed for cells to make energy – that can enter a cell. The deficient copies of the gene that Tessa and Colton inherited make it so that very little citrate enters their cells. It's still not known why this causes seizures and other neurological problems, and whether the problem has to do with too little citrate inside, or too much citrate outside the cells, said Dr. Porter.

Other symptoms associated with SLC13A5 deficiency are delays in expressive language skills, low muscle tone or a lack of muscle control, episodes of body stiffening or weakness, weak tooth enamel, mildly elevated citrate levels in the blood, and a brain MRI that appears normal or has subtle changes in white matter.

Seeking a treatment

After completing an unsuccessful clinical trial across the country in search of an effective treatment, the Nyes decided to help create a more formal hub to centralize the growing community of people who had been identified with citrate transporter disorder.

They gathered a board of researchers, doctors and family and created the TESS Research Foundation, which stands for Treatments for Epilepsy and Symptoms of SLC13A5. The name's resemblance to their daughter's is kismet, Ms. Nye said. The foundation was approved formally in April 2015 as a nonprofit, has since completed its first cycle of awarding research grants. So far, a total of $300,000 has been awarded to three research projects, and more research proposals were received than could be funded. Much of the funding raised for the first round of research came from donation requests solicited from people on their Christmas card list, Ms. Nye said.

According to Dr. Porter, who works with many families who have children with epilepsy, "This is one of the few situations where I've had a family go ahead and (decide) they were going to be the ones to figure out how to help their own kids."

She credits Ms. Nye for helping to expand the foundation rapidly. "It has gone amazingly fast compared to the other foundations I work with," she said.

The foundation has helped create strong research results from a shoestring budget but, Dr. Porter noted, for research to continue toward something like a clinical trial, major partnerships and funding will be needed, perhaps with the NIH, or biotech or pharmaceutical firms.

It's also not known yet how many people have this condition. The foundation has so far helped to identify almost 50 cases around the world. One priority of the foundation that Ms. Nye has been focused on has been to encourage genetic testing agencies to include tests for SLC13A5 abnormalities with other tests that screen for epilepsy. While this particular genetic disorder is rare, Dr. Porter said, the hope is that studying it "may fundamentally tell us something about how seizures occur with abnormalities in citrates."

Moving forward

While the Nyes work with the foundation to raise funds to do research for their kids, they've also got to deal with the day-to-day effort of raising four children, two of whom require a lot of extra help. Mr. Nye works as a vice president and financial economist at Stanford Consulting Group and Ms. Nye works at home and with the foundation.

The area provides lots of supportive resources for her family, she said. Sure, when they walk as a family to the grocery store, she said, they tend to draw lingering stares. But that generally results in people being extra nice to them. Her only complaint is when other moms, during hectic school drop-offs, nab handicapped parking spots they don't need.

Special education programs work on speech and occupational therapy and help Tessa and Colton make progress. Colton goes to equine therapy that helps with some of his mobility problems. Inclusive spaces, like the Magical Bridge Playground in Palo Alto, also are good for her family.

"It doesn't have to all look different," to accommodate kids who have disabilities, she said. Schools help by providing opportunities for groups of kids with mixed abilities to play together, and allowing Tessa's younger sisters to visit her during recess.

Ms. Nye runs a mixed-age, mixed-ability Girl Scouts troop that the sisters participate in together.

Extended family in the area also provides support. Cousins, aunts and siblings living in nearby towns "always show up and guarantee a good time," she said.

Now, Tessa, 13, Lily, 10, Maggie, 7, and Colton, 4, can all go play outside in the backyard together, although not without effort.

"It ends up being a simpler life," Ms. Nye said. "Complicated, but simpler."

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For more information, go to tessresearch.org or contact Ms. Nye at kim@tessfoundation.org.

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