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Just 21 People Are Known to Have This Rare Genetic Condition. Can You Help Us Find More?

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Wednesday, September 12, 2018

This is the sixth of the 10 patients I will present here in The New York Times Magazine as part of our collaboration with Netflix, seeking your help. Usually I ask for assistance in making a diagnosis, but this time we are asking for something a little different. Below is the story of a little girl named Kamiyah. She's 6 years old now. But around the time she turned 1, she began to have strange spells, which can be seen in the video below. As I explain in the story, she now has a diagnosis. But she is the first child to receive a diagnosis of this genetic abnormality from the National Institutes of Health's Undiagnosed Diseases Network. We are looking for others with the same kind of spells. If you recognize Kamiyah's symptoms — if you have seen this in someone you know or if this child reminds you of a patient you haven't been able to find a diagnosis for — please let us know.

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The toddler zipped across the room on her hands and knees. She had only recently started crawling and clearly loved the sense of speed and independence that her newfound mobility gave her. Go, baby, go, her mother called out encouragingly. Suddenly the child stopped; her head dipped toward the floor. Her arms bent, lowering her upper body to the floor. Kamiyah? Her mother called out. Baby? She hurried toward where her daughter knelt, head on the floor, eyes closed. But before she got there, the child's eyes popped open; she lifted her head, straightened her arms and immediately raced across the floor, as if nothing had happened.

What was that? the young mother asked her husband. Is that normal? The baby, their first, now seemed fine. Maybe it was O.K., the father suggested. Then it happened again, and again. A total of 10, maybe 20 times in the hours she played on the floor. The mother had never seen anything like it before. Neither had the father. Maybe this was just something that babies did? She had an appointment with her pediatrician in Sioux Falls, S.D., in a couple of weeks. She could ask him then.

After that day, the little girl's mother began to see the strange spells all the time. Sometimes it was so quick that it was almost as if she imagined it. Her beautiful daughter's eyes would flutter shut, and she would seem to be asleep — but just for a second or two. Then her eyes would open and she would be back in the room, back with them, as if she had never been away. Was is something that just started? Or was it that they had never really noticed it until she was moving. The baby had some developmental delay — they had been told that — but was this part of whatever it was that caused her delay?

The strangest part of these little spells was that she was most likely to have them when she was happy. That first time, the delight in her own speed had been so clear on the little girl's face. Other times, she would be smiling, even laughing, when suddenly she would draw her arms close to her body stiffly. Then she would blink, once, twice, and her eyes would close. Sometimes you could hear her breathing change, becoming raspy and slowed, before she drew her arms in and her eyelids fell. If she was sitting up, her head would drift forward until her chin was resting on her chest. And then her torso would take up the movement, sinking forward, almost in slow motion. Sometimes her mother would catch her before her forehead made contact with the floor, but often enough before she even got close, the child would wake up and sit back up as if the past 10 to 15 seconds had never happened.

Help Dr. Lisa Sanders find patients with similar symptoms.

First Suspect: the Ear
The mother brought it up at their next appointment. The doctor, a young-looking guy with an eager smile, listened as she described Kamiyah's strange episodes. It looked as if she was a little dizzy, the mom suggested, as if she were putting her head down to let the dizzy spell pass. The doctor thought a moment. Maybe she has an earache, he offered.

He looked in her ears. She'd had several ear infections that spring. And, sure enough, though the ear canal wasn't red, he could see fluid behind the ear drum. He prescribed a few days of ear drops. That should take care of it, he said. Mom was hopeful, but the medication didn't make a difference. Kamiyah had dozens of these little spells every day, before, during and after she took the medication.

Second Suspect: Seizures
If they didn't improve when the infection was treated, maybe these were seizures, the doctor suggested when mother and child returned. Did she seem a little slow after these little spells, as if she was confused? Not even a little, the mom insisted. She just kept doing whatever she was doing before the blanked-out episode. There was no change at all. And now that she was crawling, these spells weren't just odd, they were terrifying. They happened dozens, sometimes hundreds, of times a day. They had carpeted all the floors she normally moved on, but how in the world could they protect her once she started to walk? The pediatrician sent Kamiyah for an EEG and referred them to a pediatric neurologist. (You can see the notes from those first two visits here. )

When the day of the appointment with the neurologist finally came, the child's mother brought all Kamiyah's favorite toys. She knew that if she could make her laugh, she would trigger one of these spells and the doctor could see what was happening. The neurologist did see. It looked to her like an absence seizure, a type of epilepsy usually seen in children and characterized by brief episodes of a loss of awareness, without a loss of consciousness.

She ordered an EEG to look for seizure activity. It was completely normal. Thinking that they had missed the episodes, she ordered a longer EEG and then a video EEG. None showed any seizure activity in the brain. A CT scan was also normal. Despite the normal EEGs, the neurologist continued to think that what she was seeing in her office and on the videos were most likely some type of seizure. She prescribed an anti-seizure medication called Keppra, but Kamiyah's parents weren't ready to drug their child. Instead they sought a second opinion from a pediatric neurosurgeon in nearby Omaha. That doctor agreed with the first neurologist: Despite the normal EEG, it was still possible that these were seizures. They would get an M.R.I., but if it was normal, she still should try the medication. (You can see the letter from the second neurologist here, along with the M.R.I. report.)

Perhaps an Inherited Disorder?
They started the little girl on Keppra. Nothing. The seizures kept coming, and the medicine made the child sleepy. They tried a second drug, which seemed to make the spells a little less frequent, but she still had them. What about sending her to the Mayo Clinic in Rochester, Minn., the first neurologist suggested. They would try anything, the parents told him. So when Kamiyah was 2 years old, she and her mother went to the Mayo Clinic. The pediatric neurologist there saw several of Kamiyah's spells. Her first thought was also that these were some sort of seizures, and she ordered still another EEG with video monitoring. Other possibilities on her list was some sort of movement disorder — either a type of dystonia, a transient stiffening of the muscles, or dyskinesia, a loss of voluntary muscle control.

When Kamiyah's mother revealed that Kamiyah's grandmother has narcolepsy, the possibility that the child had inherited that disorder was raised. Narcolepsy is a rare disorder that causes excessive daytime sleepiness and can induce something called a sleep attack, where sleep can come on suddenly, often at inappropriate times. In addition, most of those with narcolepsy experience something known as cataplexy — sudden transient muscle weakness episodes often caused by strong, usually positive, emotions. The fact that Kamiyah had most of her episodes of weakness when she was happy was suggestive of cataplexy. But her mother dismissed the questions of daytime sleepiness — she was a very active child — and the sleep studies weren't consistent with a diagnosis of narcolepsy. None of the other tests were revealing either, so Kamiyah and her mother left the Mayo Clinic the same way they had come, without a diagnosis. (You can see the admission note and sleep doctor note here.)

The Referral of Last Resort
The following year, Kamiyah's neurologist suggested that the child be referred to the National Institutes of Health's Undiagnosed Diseases Network. This is a program developed by three branches of the N.I.H. — the National Human Genome Research Institute, the Genetic and Rare Diseases office of the National Center for Advancing Translational Sciences and the N.I.H. Clinical Center — to help provide a diagnosis for patients with mysterious symptoms who have remained without one even after a thorough evaluation. The application process is rigorous, requiring medical records from all the physicians who have seen the patient and results of all the studies done. Even so, the program accepts only a fraction of those who apply.

Kamiyah's mother recognized the challenge. She described for me her understanding of what the N.I.H. was looking for: "You had to be sick enough to go, rare enough to be appealing and well enough to not die before you got there. That's a hard boat to rock. We're really, really sick, but we're not dying. Please take us."

They sent in their application, and then they waited. The response took months, but finally the letter came that said that Kamiyah was one of the few, one of the chosen. And so, in January 2016, she and her mother traveled to Bethesda, Md., for an evaluation at what Kamiyah's mother knew was the diagnostic center of last resort — the Undiagnosed Diseases Network.

When mother and child arrived at the N.I.H., they were given a schedule of the dozens of tests to be performed and specialists Kamiyah would see over the next five days. She would be evaluated by a team including a neurologist, a dermatologist, an ophthalmologist, an immunologist and a specialist in rehabilitation medicine. She would have studies done on just about every part of her body — her skin, her heart, her blood, her brain.

At the end of the five days, the child and her mother met with the team so that the available results could be explained. The experts still didn't have a diagnosis, but they were hopeful. It could be that the child actually did have some kind of seizure disorder, one that couldn't be picked up on EEG. They were also testing the child again for narcolepsy. And finally, it was possible that genetic testing might reveal the cause of these strange spells. But, they reminded Kamiyah's mother, most of those who came to the U.D.N. did not get a diagnosis.

A Maddening Wait
At the end of the meeting, Kamiyah's mom told me, they told her that the work they did to try to make a diagnosis took time but that they would be in touch with her. They told her that it could be months before they had an answer — if they had an answer. "It was like: 'We're sorry. We don't have any answers right now. Hopefully we'll call you in six months or, you know, 10 years,'" she told me, laughing. "And off we went on our merry way." But then she added: "At that point, I knew that I had done absolutely 100 percent everything humanly possible. I had now gone to the end of the Earth." As a patient at the U.D.N., she said, they tell you that "you're offering what you have in hopes of helping somebody else in the future. That was a really tough pill to swallow, because let's be honest, I'm a selfish mom. I want them to save my kid, too." (You can see the admission and discharge notes from the N.I.H. here.)

And so mother and child returned to South Dakota, hopeful, but trying to remain realistic. Kamiyah's mother waited, and waited, for an answer, but none came. She had practically given up when she finally heard from the U.D.N. just six weeks ago. The email said they had an answer for Kamiyah, now 6 years old. The whole team wanted to be there to discuss the results. When would she be available the following week? The young mother almost exploded. When she recovered herself, she emailed back, How about now? I mean, I've waited more than two years, and you call me with an answer that I have to wait another week for? The team couldn't get together before then, the reply said.

It was one of the longest weeks of her life.

A Diagnosis. But Then What?
Finally, the call came. It was good to hear the voices of the doctors she and Kamiyah had gotten to know during their trip to Bethesda. Dr. Cynthia Tifft, the pediatric geneticist who led the team, broke the news. Kamiyah had a genetic defect that was causing these strange spells. It was not something she inherited from either of her parents but was what is called a de novo, or new, mutation. This particular mutation caused a slowdown of one of the mechanisms controlling activity in the brain and spinal cord, and that, in turn, caused her episodes of slowing down, or what the U.D.N. team called paroxysmal dyskinesia.

There are a number of types of paroxysmal dyskinesia, triggered by a variety of problems. Although many of those with this kind of rare disorder experienced unexpected movement, Kamiyah's mutation actually causes a suppression of movement leading to her transient episodes of weakness. And while Kamiyah was the first to receive this diagnosis at the U.D.N., a handful of patients around the world were known to have the same abnormality. Most of these young people had, in additional to the paroxysmal dyskinesia, some combination of seizure disorder, intellectual disability or developmental delay.

So Kamiyah was something of an outlier, even here. They were certain that Kamiyah did not have a seizure disorder or intellectual disability, and Tifft thought that much, perhaps all of Kamiyah's very mild developmental delay was caused by these frequent episodes of dyskinesia, which stole developmental time from her. Treating these episodes — probably with some type of anti-seizure medication — so that they became less frequent, could allow Kamiyah to catch up to her normal developmental age. She doesn't have epileptiform seizures, but those medicines can affect brain activity, and that's what she needs — a medication that can affect her brain in a way that lets it work more normally.

Which seizure medication? Kamiyah's mother wanted to know. The answer was, We can't tell you. While science is still learning about how this gene works — knowledge that may someday help doctors choose the best type of medicine for Kamiyah — it still isn't clear which medicine or combination of medicines will be most effective. You'll have to work with a neurologist to figure that out. The mother had heard that Gillette Hospital in Minneapolis had expertise in dealing with children with complex medical problems. Would they refer Kamiyah there? They would.

And then the call was over. And mother and child were left to try to understand what this new information might mean for Kamiyah. Kamiyah's mother has hope, and a few ideas. "Maybe we're not the only ones," she started. "What if there's something somewhere that somebody tried that I haven't found? Because I am only one person, and as far as I reach and as hard as I try, it takes a village to raise a kid. Now, I'm looking for that village."

And that's where you may be able to help. There have been 21 patients with this exact genetic abnormality published in the scientific literature. But there are probably many more than that here in the real world. Does your child, nephew, granddaughter, patient have a disorder that looks like Kamiyah's? Let us know. If possible, send us a video, with the patient's consent, naturally. Let's help Kamiyah and her mother build their village and, with luck, find a treatment that works well for Kamiyah.

Click here to submit a case like this (form at the bottom of the page).

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Author: LISA SANDERS, M.D.
Source: The New York Times
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