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A Family's 19-Year Question Is Solved by Exome Sequences
When her daughter Amanda was about 10 months old, Samantha Anastasia noticed her development regressing. The baby’s posture slumped, and her new skills—sitting up, rolling over, babbling, playing with toys—diminished and then disappeared.
“She could move, it wasn’t like paralysis, but she couldn’t control her movements enough for them to be purposeful,” Anastasia says. Although Amanda never learned to talk, her parents felt certain she understood them. They searched, unsuccessfully, for a diagnosis.
In the meantime, they had two sons. Nicholas, developed normally. But Daniel, more than five years younger than Amanda, followed the same pattern she did at roughly the same age. “The doctors were just stumped, so you shift your focus onto meeting their needs,” Anastasia says.
It would take 19 years to get an explanation. Anastasia applied to the National Institutes of Health’s Undiagnosed Diseases Program (UDP) about two years ago, when Amanda was 18 and Daniel was 12.
Within five years of its May 2008 launch, the UDP, which has an emphasis on unraveling genetic disorders, received 2,500 applications from patients with mysterious medical conditions, and accepted just 575 of them. With two siblings sharing similar histories, the Anastasias’ condition appeared likely genetic, says Camilo Toro, a UDP neurologist who handled their case.
The family of five traveled from their home in New Jersey to the NIH campus in Bethesda, Md., for a week packed with meetings with specialists and tests from nerve conduction studies to cognitive
abilities. Then they returned home and waited.
In the absence of a clear answer, Toro and colleagues decided to sequence the exomes, or protein coding regions of the genome, from all five family members. They looked within the sequences for likely culprit variations.
“For the Anastasias, it was very clear,” Toro says. “Once we saw the results on this particular gene, everything just fell into place.”
The gene was a variant of RNASEH2B, which is associated with a rare disorder known as Aicardi-Goutieres syndrome. Both Amanda and Daniel carried two copies of the variant, while each parent carried one copy.
The mutation causes an immune response that ravages the brain with inflammation early in life before receding. But the Anastasias were unusual. Although the inflammation took away almost all of Amanda and Daniel’s motor control, it did not leave behind the typical calcium deposits and damage in their brains’ white matter. As a result, the Anastasias do not suffer from the severe mental impairment often associated with AGS. What’s more, when the illness was acute, the children did not exhibit the typical fever, rashes, and signs of inflammation, according to Toro.
In November 2012, almost a year after their first visit, the UDP called the Anastasias back down to Maryland for their results, where Toro explained the finding.
“I started to cry, it was so overwhelming to know,” Samantha says.
She and her husband, Daniel, had developed rudimentary means of communicating with Amanda, and then with her younger brother, by following the gaze of their eyes. Later, they adopted a system that harnessed the children’s ability to move their heads, one movement they retained, to allow them to use a computer to communicate or a laser pointer to spell out words.
Using these techniques, Amanda asked if she would one day be able to walk or talk; the answer was no. After the acute phase, which struck both Anastasia children as babies, has passed, there is no treatment for AGS, Toro says. Daniel wanted to know if his own children would have the disorder.
Samantha says both children adjusted well to the news. “They have always lived with this, it has never been any different, but now they have a name for it,” she says. “I don’t think much changed for their way of thinking about themselves.”
The diagnosis, perhaps, held more significance for their mother. “To me it kind of says 'everything is going to be OK, you have done the right things.' There wasn’t a treatment that we missed that could have changed things for them," she says. "But it sets us on a new path. Now that we have a name there is more certainty with this path.”
Wynne Parry is a journalist based in New York. She is a regular contributor to LiveScience.com, and her work has appeared in The New York Times, Scientific American, Discover Magazine and the New York Post.
“She could move, it wasn’t like paralysis, but she couldn’t control her movements enough for them to be purposeful,” Anastasia says. Although Amanda never learned to talk, her parents felt certain she understood them. They searched, unsuccessfully, for a diagnosis.
In the meantime, they had two sons. Nicholas, developed normally. But Daniel, more than five years younger than Amanda, followed the same pattern she did at roughly the same age. “The doctors were just stumped, so you shift your focus onto meeting their needs,” Anastasia says.
It would take 19 years to get an explanation. Anastasia applied to the National Institutes of Health’s Undiagnosed Diseases Program (UDP) about two years ago, when Amanda was 18 and Daniel was 12.
Within five years of its May 2008 launch, the UDP, which has an emphasis on unraveling genetic disorders, received 2,500 applications from patients with mysterious medical conditions, and accepted just 575 of them. With two siblings sharing similar histories, the Anastasias’ condition appeared likely genetic, says Camilo Toro, a UDP neurologist who handled their case.
The family of five traveled from their home in New Jersey to the NIH campus in Bethesda, Md., for a week packed with meetings with specialists and tests from nerve conduction studies to cognitive
abilities. Then they returned home and waited.
In the absence of a clear answer, Toro and colleagues decided to sequence the exomes, or protein coding regions of the genome, from all five family members. They looked within the sequences for likely culprit variations.
“For the Anastasias, it was very clear,” Toro says. “Once we saw the results on this particular gene, everything just fell into place.”
The gene was a variant of RNASEH2B, which is associated with a rare disorder known as Aicardi-Goutieres syndrome. Both Amanda and Daniel carried two copies of the variant, while each parent carried one copy.
The mutation causes an immune response that ravages the brain with inflammation early in life before receding. But the Anastasias were unusual. Although the inflammation took away almost all of Amanda and Daniel’s motor control, it did not leave behind the typical calcium deposits and damage in their brains’ white matter. As a result, the Anastasias do not suffer from the severe mental impairment often associated with AGS. What’s more, when the illness was acute, the children did not exhibit the typical fever, rashes, and signs of inflammation, according to Toro.
In November 2012, almost a year after their first visit, the UDP called the Anastasias back down to Maryland for their results, where Toro explained the finding.
“I started to cry, it was so overwhelming to know,” Samantha says.
She and her husband, Daniel, had developed rudimentary means of communicating with Amanda, and then with her younger brother, by following the gaze of their eyes. Later, they adopted a system that harnessed the children’s ability to move their heads, one movement they retained, to allow them to use a computer to communicate or a laser pointer to spell out words.
Using these techniques, Amanda asked if she would one day be able to walk or talk; the answer was no. After the acute phase, which struck both Anastasia children as babies, has passed, there is no treatment for AGS, Toro says. Daniel wanted to know if his own children would have the disorder.
Samantha says both children adjusted well to the news. “They have always lived with this, it has never been any different, but now they have a name for it,” she says. “I don’t think much changed for their way of thinking about themselves.”
The diagnosis, perhaps, held more significance for their mother. “To me it kind of says 'everything is going to be OK, you have done the right things.' There wasn’t a treatment that we missed that could have changed things for them," she says. "But it sets us on a new path. Now that we have a name there is more certainty with this path.”
Wynne Parry is a journalist based in New York. She is a regular contributor to LiveScience.com, and her work has appeared in The New York Times, Scientific American, Discover Magazine and the New York Post.
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