Friday, August 24, 2018

Paroxysmal dyskinesia

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? [video at link]

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….

The pediatrician sent Kamiyah for an EEG and referred them to a pediatric neurologist.

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…

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…

 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…

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…

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…

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.

Courtesy of a colleague


  1. The fact that Kamiyah has a diagnosis makes her different from the five previous patients I have written about in this column. For those men and women, I invited the New York Times readership to help make a diagnosis. In Kamiyah’s case, my goal is different — and the crowd’s role is different, too. As her mom, Breteni, says, knowing the name of the gene mutation is only part of the overall picture. What Breteni now wants is for the global crowd to help her fit together the rest of the puzzle, to help give her a fuller understanding of what this information means for Kamiyah and her future.

    Kamiyah is not the only person to have this genetic abnormality. The medical literature has reported on 21 others with variations of the same gene. Because of the anonymity of case reports, we don’t know who those individuals are — or even where in the world they may live. Nor do we know anything about others who may have the same abnormality, whether diagnosed or not. I wrote to see if we could use the crowd to find a community for Kamiyah — others who have what she has, whom she can learn from and share with. Kamiyah’s mother once told me that it takes a village to raise any child. Her goal in telling Kamiyah’s story, and mine in writing it, is to find Kamiyah’s village.

    In that first story, I didn’t include the specific gene that was affected. I wanted to give people a chance to see what Kamiyah’s spells looked like. In that way, friends and relatives of those who have similar episodes wouldn’t be caught up in the numbers and letters that identify the gene but would rely on what they observed. And that’s been useful. Dozens wrote in with stories about their own children or people they knew who had similar symptoms. Now it’s time to reach out to those who know this gene by its proper name.

    Kamiyah has a mutation in the KCNMA1 gene. This is a gene that carries instructions to build a channel to let potassium in or out of a cell. This channel is found in the highest concentration in nerve tissue, mostly in the brain. Kamiyah’s version of the gene seems to cause these spells by affecting the way potassium moves in or out of the cell in a way that can transiently inhibit the brain’s normal control of the muscles of the body.

  2. Yeşil G, Aralaşmak A, Akyüz E, İçağasıoğlu D, Uygur Şahin T, Bayram Y. Expanding the Phenotype of Homozygous KCNMA1 Mutations; Dyskinesia, Epilepsy, Intellectual Disability, Cerebellar and Corticospinal Tract Atrophy. Balkan Med J. 2018 Jul 24;35(4):336-339.

    The KCNMA1 gene encodes the α-subunit of the large conductance, voltage, and calcium-sensitive potassium channel (BK channels) that plays a critical role in neuronal excitability. Heterozygous mutations in KCNMA1 were first illustrated in a large family with generalized epilepsy and paroxysmal nonkinesigenic dyskinesia. Recent research has established homozygous KCNMA1 mutations accountable for the phenotype of cerebellar atrophy, developmental delay, and seizures.

    Here, we report the case of a patient with a novel homozygous truncating mutation in KCNMA1 (p.Arg458Ter) presenting with both the loss- and gain-of-function phenotype with paroxysmal dyskinesia, epilepsy, intellectual delay, and corticospinal–cerebellar tract atrophy.

    This report extends the KNCMA1 mutation phenotype with a patient who carries a novel frameshift variant, presenting with both the gain- and loss-of-function phenotypes along with spinal tract involvement as a novel characteristic.