Girl’s floppy limbs lead to a surprising diagnosis
Chance meeting with researcher gets her into the right study
Elena Silva gripped her cellphone, struggling to convey a sense of urgency to her husband, Brian Woodward, whose response was drowned out by the background din of a suburban Maryland swimming pool on a steamy July afternoon.
"You have to bring the kids here — right now," Silva remembers insisting. She believed that the couple's long-running quest for a diagnosis of their daughter Gabriela, known as Gg (pro- nounced "Gigi"), then 7, hinged on the little girl's presence.
Woodward had taken Gg and her older brother Elian to the pool while Silva, hoping to meet researchers and network with knowledgeable parents, was attending a 2014 meeting at the Clinical Center, the research hospital on the grounds of the National Institutes of Health, a few miles from the family's home.
Silva, who had learned of the event only that morning, was mingling with participants when a parent-advocate asked, "Where's your daughter? Why isn't she here?"
When Silva replied that Gg was at the pool, the woman advised Silva to get the little girl to NIH — and fast. That way, one of the world- renowned researchers in attendance, preferably Carsten Bönnemann, chief of the neuromuscular and neuro-genetic disorders of childhood section at the National Institute of Neurological Disorders and Stroke, could meet her. Forty minutes later, still wearing their damp bathing suits, Gg, her father and her older brother appeared at the meeting. Silva introduced her daughter to Bönnemann.
Nearly 18 months later, Gg did receive a diagnosis, an occurrence that would have been far less likely without her mother's serendipitous encounter.
"I am still completely blown away by this coincidence," Silva said. "It turned out to be just the place I needed to be."
Within minutes of Gg's birth in April 2007, the obstetrician noted that she seemed to have low muscle tone in her arms.
When Gg was 6 months old, the pediatrician referred her to Maryland's early intervention program for children with developmental disabilities. A physical and occupational therapist made home visits and tested Gg; her gross motor development was clearly lagging.
In the meantime, it was clear that Gg's cognitive abilities were unaffected: She talked at a young age and was obviously bright. She continued physical and occupational therapy to try to strengthen her muscles. She crawled at age 2 and began walking by 3, much later than normal.
By 2013, doctors had largely decided that Gg probably had a form of myopathy, a disease affecting muscle tissue that has a wide variety of causes.
Some myopathies are caused by genetic mutations; others result from infections or for unknown reasons. Silva and Woodward had no idea what disorder Gg had, what caused it or how to treat it.
One increasingly likely possibility, based on the extensive testing Gg had undergone, was a congenital form of muscular dystrophy, or CMD. Congenital muscular dystrophy is present at birth or before age 2; the most pronounced symptom is floppiness or a lack of muscle tone.
In July 2014 as a result of her internet research, Silva stumbled upon the annual "Cure CMD" meeting, which was being held at NIH.
"Elena just showed up basically while we were milling around with the families," Bönnemann recalled. About 40 families from around the country were meeting with researchers as part of a study of congenital muscular dystrophy.
After hearing Silva's description of her daughter's case and meeting Gg, Bönnemann that day performed an exam that included an ultrasound of her leg muscles. It revealed clear structural abnormalities.
"In her case, there was only gross motor delay," said Bönnemann, who found Gg engaging and "a very smart little kid."
Silva was elated at what happened next.
"He said, 'I'd like to follow her,' " she recalled. "This was a breakthrough for us."
A muscle biopsy in February 2015 confirmed the presence of a muscle disease. The next step was whole exome sequencing of Gg and her parents — genetic screening that is among the most extensive available. The test uses a blood sample to perform a sophisticated analysis.
In the summer of 2015, the family took off on a longplanned year-long crosscountry road trip in an RV. In November 2015, while the family was at Lake Tahoe, Silva's cellphone rang.
A geneticist at NIH delivered the long-awaited news: Gg had inherited two different genetic mutations, one from each parent, affecting one of the body's largest genes, known as titin, or TTN. Gg had titin myopathy, one of a group of rare disorders first identified in Finland.
The TTN gene provides instructions for making a very large protein called titin, which is essential in muscle function — it allows muscles to stretch — and for proper cardiac function.
Titin myopathies can be dominant and result from a single gene or, as in Gg's case, recessive, occurring in someone who inherits two copies of an errant gene. A single gene means that a person is a carrier without obvious manifestations of the disease, as are Gg's parents and her brother, something they learned after they were screened.
To Silva, the news was portentous — and a relief. "It was a pretty big moment," she recalled. "I hung up the phone and went into the front room and told Gg what it was and that it came from me and Daddy. I think she was sort of relieved it was both of us."
So was Silva. "There's always a certain amount of guilt," she said, knowing that she passed on a gene, albeit unknowingly, that caused her daughter's condition. "But there's twice as much relief that it came from both of us."
Treatment of titin myopathy largely consists of managing the associated disorders, including preventing muscle contractures that further restrict movement and result from overly tight joints.