Common antibiotic shows promise to lessen effects of Fragile X, autism

From the Los Angeles Times:

Slouched sideways at his desk in the front row of class, a sneakered foot jittering distractedly, Chase Brown (pictured) could be any 14-year-old in academic captivity.

As the discussion turns to the American history of slavery, the teacher draws Chase back from his apparent reverie. A classmate has said that Abraham Lincoln freed the slaves. Does Chase agree or disagree?

Chase locks eyes with his teacher. "I agree," he says emphatically.

It is a moment of triumph for Chase, one of an estimated 90,000 in the U.S. who live with an inherited form of intellectual disability known as fragile X syndrome. Only a year ago, he would have fled the classroom, thrown something at the teacher or stayed mute. Last year, he tested below first-grade level in all academic domains.

Impulsive, distracted and quick to boil over, he seemed incapable of learning.

This year, he can sit in a classroom for half an hour before needing a "sensory break": a walk around the parking lot to clear his overstimulated brain. He is reading at a fourth-grade level, following class discussions, looking teachers squarely in the eyes and answering questions.

On a surprising drug — a workhorse antibiotic used since the 1960s to treat acne, skin infections, strep throat and chlamydia — Chase is learning.

Minocycline, the medication Chase has been taking for almost eight months, is one of several drugs that might correct — even reverse — many of the brain perturbations of fragile X and several other developmental disorders, including autism.

The medications are still far from proven: Large-scale trials may take several years to complete. But if they live up to their promise without dangerous side effects, they could accomplish what no medication has been able to: cure a genetically based intellectual disability.

Last year, Chase was among the first 50 children and adults with fragile X to take the drug as an experimental treatment. Since then, said his mother, Heather Brown (pictured), he has changed in ways she hadn't thought possible.

He has developed the ability to chat: share details of his day, make thoughtful observations and inquiries, and respond with apparent understanding, even empathy.

His explosions of kicking, hitting and object hurling, and the terrible remorse that followed, have vanished.

It's not sedation: She saw that before when Chase cycled through a list of powerful antipsychotic medications. He seems instead to be learning new ways to behave.

"It's life-changing, it really is," said Brown, who lives in Mission Viejo with Chase and his stepfather. "I was, like, 'Minocycline? They use that for acne.'"

The condition that Chase was born with is caused by an abnormal elongation of a portion of DNA on the X chromosome. It is the most common inherited intellectual disability worldwide, affecting about 1 in 4,000 babies. It causes some cases of autism. Depending on the extent of the error, a child with fragile X can range from nonverbal to having communications skills that are mildly impaired. Epilepsy is common. Short-term memory deficits and very short attention spans can short-circuit academic progress.

It can seem like a train wreck of conditions — autism, attention deficit, bipolar disorder, anxiety and more — rolled into a single kid.

Yet now there's some genuine muscle pulling on the hope side of the equation, thanks to a confluence of parental activism, advances in brain science and luck.

"People haven't thought about what it would be like to reverse intellectual disability or mental retardation," says Dr. Randi Hagerman, medical director of UC Davis' MIND Institute, who ran the minocycline study in which Chase was enrolled. "We now think it may be possible."

It's a goal as controversial as it is ambitious. For decades, activists and parents championed inclusion for those with what was until recently called "mental retardation" (the preferred term now is "intellectual disability" or "developmental disability").

Somewhere along the way, many came to reject the idea that a "cure" was needed, or desirable. To suggest that intellectual disability is an illness crying out for a fix devalues and stigmatizes these children, they contended.

Advances in biomedical research have already begun putting that conviction to the test for families of those with Down syndrome.

In 2009, researchers at Stanford University School of Medicine and Packard Children's Hospital announced "a ray of hope" for those born with the condition. Working with mice bred to have the equivalent genetic error, they identified a faulty brain mechanism that disrupts the laying down of certain memories and, in turn, learning.

They also found that a readily available drug cocktail that boosts the brain chemical norepinephrine could compensate for the problem, enabling the mice to learn normally. With early use, the scientists suggested, such a drug might put a child born with Down syndrome on a normal cognitive trajectory.

Not all parents hailed this "ray of hope." Reacting to the news on a blog called Contrarian, Jenn Power, a Canadian mother of twin boys with Down syndrome, echoed the views of many who have been active in promoting the rights of those with intellectual disabilities.

"They do not need a needle in their brain to make them more functional, to help them find their car keys," she wrote. "What they need is a society that values what they have to offer."

After physicians recognized in Chase the classic profile of a fragile X child five years ago, he was treated with psychiatric medications, with limited results.

When puberty set in, his anxiety, aggression and repetitive behaviors escalated dramatically — along with his size and strength.

Heather Brown, a 38-year-old office manager for an electric contracting company, worried for his safety — and sometimes her own.

"I was dealing with hitting and kicking and throwing stuff," she said.

By then, she and her ex-husband, Chris, who lives in Carlsbad, had met UC Davis' Hagerman, who urged them to consider participation in her minocycline study. It went on to show that 70% of those with fragile X responded with significant improvement in language, behavior and cognitive function.

Minocycline's effectiveness in these early trials appears to be due to its suppression of a protein called MMP-9, which is overproduced in fragile X brains, derailing normal neural development. The antibiotic also tamps down inflammation in the brain. Both effects, amazingly, are incidental to the drug's antibiotic powers.

The drug's principal side effect in the studies is a graying of the teeth. A small number of patients developed blood signs suggestive of autoimmune inflammation, albeit with no associated symptoms.

Beyond minocycline, early trials are underway for three medications that inhibit a second protein that is overactive in fragile X brains and for a fourth drug, arbaclofen, that acts on yet another brain chemical. Arbaclofen appears from early drug-trial results to reduce the hyperactivity and hypersensitivity that are hallmarks of fragile X, and may help children with autism unrelated to fragile X.

Mark Bear, a neuroscientist at MIT's Picower Institute, says there's universal agreement that such drugs should produce the most dramatic changes in young children. But conducting early trials on very young children raises ethical and safety concerns, so they will focus on adults with fragile X for now.

Though this may limit the findings, "we have our fingers crossed that we'll still see substantial benefit," Bear said.

Many of the drugs considered promising for fragile X also have excited interest as treatments for a wider range of neurological conditions — stroke, spinal cord injury, multiple sclerosis, autism and Alzheimer's disease — a fact that will probably speed their path to market.

Chase, in the meantime, will continue to take minocycline, now prescribed off-label by Hagerman because the trial in which he participated is over.

"I'm sure people thought he might be a lost cause," his mother said of his situation before his treatment began. "I did wonder myself."

She said she didn't know what to make of today's talk of potential "cures." But now she sees a future in which her son might navigate the adult world — complete high school, have a job, an apartment, a girlfriend — with just a little help from family and social services.

"I'm definitely thinking differently," she said. "He's on a good path."