Tuesday, August 8, 2017

Titin myopathy

“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 (pronounced “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. Once a year, specialized neurology researchers and families affected by a constellation of rare neuromuscular disorders get together, a confab that is both supportive and aimed at furthering research…

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 neurogenetic disorders of childhood section at the National Institute of Neurological Disorders and Stroke, could meet her. If Bönnemann took an interest in her case, Gg might be accepted into a study and could receive a diagnosis, something that had so far proved maddeningly elusive…

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. A second doctor checked the newborn and told her parents she was “a little floppy” but that there was no cause for concern.

The couple noticed that Gg was far less active than Elian, three years older, had been. In her mother’s words, she seemed “weak and floppy and small.” Gg had difficulty holding her head up. When placed on her stomach, she couldn’t push up using her arms, something most infants accomplish at around 2 months. Her legs seemed to dangle helplessly.

“She was like a noodle,” recalled her mother, a policy director at New America, a Washington think tank…

“Everything kept coming back negative,” Silva recalled, “which is wonderful and not wonderful. You just want to know.”

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…

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. Some forms are progressive and may be accompanied by cognitive disabilities.

Gg was enrolled in a study of undiagnosed neuromuscular diseases that Bönnemann was overseeing. Her parents hoped researchers would be able to make a definitive diagnosis.

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.
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. (Silva said that she and her husband are unaware of any Finnish ancestry and that no one in their families has muscular dystrophy.)

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…

Some titin mutations have also been linked to certain forms of cardiomyopathy, a common disease that affects the heart’s ability to pump blood and can lead to heart failure.

Bönnemann, co-author of a 2014 study, said scientists don’t yet understand “why some kids have heart disease and some don’t.” Gg shows no sign of cardiac involvement. “Hopefully this will be quite stable over the years,” he said…

Because Gg’s disease is so rare and recently identified, Bönnemann said, it is not known how common it is, although he noted a recent “explosion” in the identification of titin-related disorders. In the past three years or so, NIH has seen 20 newly identified titin myopathy patients. Silva said the titin myopathy Facebook group to which she belongs has only about a dozen members.

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.


Courtesy of a colleague

See also:  http://childnervoussystem.blogspot.com/2015/12/a-new-titinopathy.html

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