Simon Kunesh arrives at his physical therapy appointment hanging from his mother's neck, arms locked, swinging back and forth like a pendulum.
She's prying at his fingers, trying to put him down, but he stubbornly has retracted his long, spindly legs and flexed his feet to avoid touching the floor. When she succeeds in standing him up, Simon scuttles straight to a chair in the corner, pulls both arms in front of his chest like he's blocking a punch, buries his head in his shoulder, and whimpers.
They are 27 minutes late, but, still, he has to sit in the waiting room before he heads back to the gymnasium. This is the routine. And Simon doesn't like to deviate from the routine.
The Mesa boy's therapist wheedles and coos, and before long he's sitting cross-legged on a platform swing, chortling gleefully as she spins him in circles, singing:
Row, row, row your boat
Gently down the stream
If you see a crocodile
Don't forget to scream
Simon is 14 years old. He has sandy hair, a sprinkling of freckles, a goofy smile, and ears that look like stick-on accessories for a Mr. Potato Head toy. His head is small for his age — the result of brain damage sustained from frequent violent seizures — but it fits his bony frame. Although he's steadily grown taller year by year (defying the scoliosis that's slowly twisting his spine into a lopsided S), he hasn't gained a pound since 2007. He stands four feet and weighs 40 pounds.
With a cognitive capacity roughly equivalent to a toddler's, Simon displays symptoms of a number of fairly common ailments, including cerebral palsy and autism. After more than a decade of tests, however, his doctors have concluded that his condition appears to be something new — something that hasn't yet been recorded anywhere else in the world.
Simon's situation isn't unique. Thanks to rapid improvements in genetic testing, scientists are identifying more and more diseases every day.
Though these ailments always have existed, because each one affects fewer than 200,000 Americans, the chances that a child like Simon would get a diagnosis 10 years ago hovered at about 3 percent, says David Craig, deputy director of bioinformatics at the Phoenix-based Translational Genomic Research Institute (TGen). While parents of such children shuttled them from specialist to specialist searching for answers, the vast majority were either shoved into a diagnosis that didn't quite fit or remained medical mysteries.
Now, experts estimate that 30 million Americans have one of about 7,000 rare diseases, about 80 percent of which can be traced back to genetic mutations.
In a general clinical setting, the odds of finding the faulty gene have climbed to 10 percent, Craig says. Doctors at TGen's Center for Rare Childhood Disorders, one of the nation's most cutting-edge research institutions working on such problems, report a success rate of 40 percent.
For families like Simon's, just having an explanation for the symptoms brings some peace of mind. But research on rare diseases hasn't kept pace with advances in testing — so getting a diagnosis doesn't mean finding a treatment.
Simon's mother, Samantha Pacifico, describes the experience as "trading one uncertainty for another." She waited nearly 12 years to find out what was wrong with her son. Now, she's told, she must wait for scientists to find two other people with the same condition before the first study can commence.
It's statistically improbable that a child's genetic condition actually is one of a kind. Still, there may be only a few dozen cases in the world so the likelihood that everyone has been diagnosed is small. Even if doctors have pinpointed the genetic mutation in multiple patients, it's difficult to gather them because researchers haven't yet worked out a comprehensive way to share genetic information while also protecting patient privacy.
Some parents have found hope through organizations like TGen, which acts as a sort of matchmaking service between patients and the scientists interested in their rare gene mutations. Others, by sharing their stories repeatedly on Twitter and Reddit, have managed on their own to find other parents whose children have the same condition, build a community, and then advocate for research studies.
"I dream about meeting another child like Simon," Pacifico says. "I want to know what they can do and what they can't do. Are they tiny like him? Do they gain weight? Is their skin soft like his? Do they have long, thin, beautiful hands like he does?"
While she waits, she's taken to calling the mystery mutation in her son's genes "Simon's Syndrome."
A week after Simon was born on April 20, 2001, in Chicago, he started flinging his arms over his head repeatedly, then drawing his limbs in close, fists clenched, body tight, as if he were giving himself a hug.
At first, Pacifico thought it was just the moro, or startle, reflex, an instinctive self-protection mechanism usually triggered in infants by loud noises, sudden movements, or a feeling of falling, such as being lowered into a bassinet without proper support. As Simon screamed, she would joke, "He's going to be really high-strung like his dad!"
Pacifico, a petite brunette with wide-set eyes and a normally sunny temperament, quickly got nervous. Simon was her second son and, she says, "There was something off." Simon stayed stiff, limbs contorted, just a little too long. His chest turned bright red, and his eyes bulged unnaturally. Three times she called the nurse, who assured her: "Babies do strange things."
At 5 weeks old while staying with family in Kenosha, Wisconsin, Simon had a full-out grand mal seizure. His heart rate dropped, his breathing slowed, his torso trembled, and his limbs jerked rhythmically in and out. When it was finished, the infant barely had time to cry before another began. Pacifico rushed to the hospital and ran into the emergency room, wailing, "Help my baby! Help my baby!"
“I dream about meeting another child like Simon,” Pacifico says. “I want to know what they can do and what they can’t do?”
Simon stayed at a local hospital for three days, having one seizure after another, until doctors decided to life-flight him to the larger Wisconsin Children's Hospital in Milwaukee, where he spent 32 days. Each seizure seemed more violent than the last. His face was so puffy and swollen that he could barley open his eyes. His skin, covered in sores, turned brown, as if he'd been sunning himself on the beach rather than sleeping in the intensive care unit.
When Pacifico, now divorced, overheard a group of student doctors whispering about "infantile spasms," she angrily shushed them. It sounded like nothing, and there clearly was something very wrong with her baby. A quick Google search, though, revealed the horrifying reality: infantile spasms are one of the severest forms of epilepsy and often lead to developmental disabilities — or death.
Once doctors determined that Simon was having infantile spasms, they taught Pacifico how to inject adrenocorticotropic hormone into his tiny thigh twice a day. (Mom was hysterical, but after a few pokes, Simon didn't even flinch.) Except for an occasional grand mal, the seizures slowed. He wasn't out of the woods, though. Infantile spasms are just a symptom of an underlying condition. To form an optimal treatment plan, doctors had to determine what caused the seizures.
Simon had CAT scans, MRIs, X-rays, muscle biopsies, skin biopsies, and blood test after blood test. Every time, Pacifico says, the results came back the same: healthy, normal boy.
Meanwhile, the quiet spaces between grand mal seizures got shorter and shorter until Simon's brain was short-circuiting between 30 and 70 times a day.
Was it Angelman syndrome?
Diagnosis: Healthy, normal boy.
Simon refused to eat. When Pacifico tried to give him a bottle, his mouth hung open. He spit baby food right out. Pacifico took him to feeding therapy, where specialists rubbed his mouth with nubby brushes in an attempt to desensitize it, but, still, for years he refused to eat anything but sour cream. Pacifico purchased it by the gallon and stealthily mixed in spinach soufflé and peanut butter to improve the nutritional content.
Was it cerebral atherosclerosis?
Diagnosis: Healthy, normal boy.
Pacifico worried constantly: "Did I do something to cause this?" When she got pregnant with her third child, she was petrified that she would be born with the same condition. Would her children need to worry about passing this — whatever it was — on to their children?
Was it celiac disease?
Diagnosis: Healthy, normal boy.
None of the treatments traditionally prescribed for seizures like Simon's — not even a strict high-fat diet — made any difference. So when Pacifico's doctor approached her about putting Simon on an experimental drug that never before had been administered to humans, she jumped at the opportunity.
With tears in her eyes, Pacifico now recalls, "We always swore we'd never do a drug study. We'd never use our child as a lab rat. But, by that point, we were so desperate we'd try anything."
After one dose of the anti-epileptic Keppra, Simon slept through the night for the first time in months. Thanks, in part, to the experiment, the drug now is FDA approved.
Tortured by the drive to do something — anything — to help their children, many parents in Samantha Pacifico's situation find themselves suddenly taking risks they never would have imagined while reading What to Expect When You're Expecting and dreaming about their babies' futures.
When Stephanie Rankin had, like Pacifico, exhausted all FDA-approved options for her son Beorn's pediatric seizures, she started taking road trips to Mexico on the advice of her neurologist to snag an anti-convulsant called Sabril. The family drove 240 miles from their home in Mesa, parked their minivan on the U.S. side of the border, and walked into Los Algodones, where they went from pharmacy to pharmacy until they had collected a 90-day supply.
U.S. officials had outlawed the drug because it was shown to cause vision impairment in some children — but now-10-year-old Beorn already was blind.
"I still hope Beorn will regain his vision someday," she says seated in her living room. "But I felt like I was being asked to choose between his life and his sight. Obviously, I was going to choose his life."
Just a few feet away, Beorn, whose developmental development is on par with a 3- to 6-month-old baby, is stretched out on a full-size mattress squeezed between a couch and a love seat. He has thick eyebrows like his father and smooth, olive skin. There's an ever-so-slight shadow of a mustache forming on his upper lip. He's just finishing a bottle of a special high-fat, low-carbohydrate formula designed to help control his seizures. He has low muscle tone so he struggles to control his limbs, but Rankin has taught him to pin the bottle to his chest with his forearms to stabilize it. When he's satisfied, he lets it roll to the side, and his eyes flutter closed.
His mother scoots up next to him and pulls him into her lap.
"Buuuuuuuba," she says softly in a sing-song voice, stroking his thick, dark hair and kissing the top of his head. "Buuuuuba. No napping yet. The therapist is on her way."
She pulls out a board book of ABCs, takes Beorn's hand in hers, and runs it over the textured letters.
"Bubba," she says, "do you want to read a story?"
Beorn already is in dreamland.
Beorn appeared to be healthy until, at a well-baby checkup at 4 months old, a doctor noticed his eyes weren't tracking. Although Beorn's eyes were perfectly constructed, the images they were capturing weren't registering in his brain. At first, there was talk of seeing-eye dogs and schools for the blind. The ideas soon were abandoned, though, when Beorn started missing developmental milestones: He wasn't grasping, he wasn't rolling over, he wasn't sitting, crawling, walking, speaking.
"He wasn't doing anything," Rankin says.
Seizures soon became such a routine part of daily life that Rankin only took Beorn to the emergency room if he stopped breathing (which still was pretty often).
Once, Rankin recalls, Beorn had a grand mal seizure while she was out to dinner with visiting relatives. She calmly cooed and stroked his cheek to comfort him while his body convulsed and his face turned blue. Nervously, she counted his breaths until the seizure passed. No one at the table knew anything was awry; they simply thought Rankin was playing with her child.
All Beorn's tests, like Simon's, suggested that nothing was wrong.
Pacifico went to four specialists, moving from Wisconsin to California to Arizona with no luck. It was her pediatrician who, during a social call, recommended that she look into getting Simon's genetic code analyzed. Simon was nearly 12 years old.
Meanwhile, doctors were so stumped trying to figure out what was ailing Beorn that, at one point, his mother was invited to a neurology conference, where she plunked her child on a conference table while about 30 experts gathered around to brainstorm possible diagnoses.
When her neurologist brought up the idea of genetic sequencing near Beorn's 9th birthday, she was burnt out, nearly out of hope. But she trusted him.
"Absolutely," she agreed. "If you recommend it."
DNA, recognized in 1944 as the blueprint for life, is composed of four chemical building blocks called bases: adenine, guanine, cytosine, and thymine. In humans, the bases bond — adenine with thymine and guanine with cytosine — to create about 3 billion pairs.
The color of a person's hair and eyes, whether they are a thrill-seeker or a homebody, their risk for obesity and breast cancer are determined by the order in which the base pairs are strung together into roughly 30,000 genes.
In 1970, researchers at Cornell University were the first to put forth a method for deciphering the lineup of base pairs. In 1995, the Institute for Genomic Research, a nonprofit in Rockville, Maryland, published the first complete genome of a free-living organism, the bacterium Haemophilus influenzae.
By 2001, as part of the Human Genome Project, an international collaboration between numerous universities and laboratories in the United States, the United Kingdom, France, Germany, Japan, and China, scientists successfully had sequenced a human genome.
At the time, Francis Collins, a geneticist who played an influential role in the Human Genome Project, prophesied that the human genome, a "shop manual with an incredibly detailed blueprint for building every human cell," would become "a transformative textbook of medicine, with insights that will give healthcare providers immense new powers to treat, prevent, and cure disease."
“Nobody is putting limits on my child,” Rankin says. “I don’t know what Beorn is capable of so there’s always this lingering hope that’s he’s capable of more.”
His vision has yet to be realized — but progress has been rapid. The first human genome took 15 years and $3 billion to produce. Now, for about $200, people can swab some saliva, mail it to a lab, and, in six to eight weeks, get an analysis of about a million base pairs, revealing genetic predisposition toward a number of ailments ranging from male pattern baldness to stomach cancer. For a few thousand dollars, they can get all 3 billion base pairs mapped out in a matter of weeks.
TGen's David Craig compares the upgrade in sequencing technology to "going from a cassette tape to an mp3."
Previously, genetic test results were produced as a series of colored bands on film, called a chromatogram, that required specialized training to interpret. The process was so laborious and costly that clinicians only could realistically analyze segments of the genome. Next-generation sequencing, on the other hand, produces digital results that are easier to read and, therefore, search.
"It's turned the field on its head," Craig says. "It's the equivalent of walking into a library and knowing exactly where every single book is. Suddenly we're searching with Google instead of the Dewey Decimal System."
Still, even with the price drops, many patients can't afford to pay out of pocket to have their child's complete genome sequenced, he says. Within the past year, some private insurance companies have begun to embrace the procedure. However, because of overwhelming medical costs, the majority of children with rare disorders rely on state-funded, long-term medical insurance, which does not cover the test.
Both Simon and Beorn fell into that coverage gap.
Because Pacifico couldn't afford to pay to have Simon's complete genome sequenced, she opted to get an older test called a chromosomal microarray, which analyzes just snippets of the genetic code. Luckily, Simon's unique mutation, a deletion on Chromosome 4, was located on a segment of genes included in the test (doctors still maintain that Pacifico would benefit from next-generation sequencing of Simon's genome).
When Beorn had a microarray test in 2008, however, no abnormalities showed up. Stephanie initially thought her son, too, would have to forgo next-generation sequencing. She can't work because Beorn needs 24-hour care, and her husband's job as a network engineer barely covers the cost of medication.
"We thought about fundraising," she says. "But I was already so overwhelmed just taking care of my kid, I couldn't even stomach the thought."
She was elated to learn that Dr. Vinodh Narayanan, the neurologist she was seeing free of charge through a state-run clinic, also was medical director of TGen's Center for Rare Childhood Disorders. Dr. Narayanan, a teddy bear of a man with twinkling eyes, helped her snag Beorn a spot on one of the institute's research studies and secure a scholarship to cover the cost.
To arrive at Beorn's diagnosis in July 2015, Dr. Narayanan and his team at TGen first compared his genome to his mother's, his father's, and a growing database of thousands of anonymous strangers to find abnormalities.
Tracing a disorder back to a gene is more complicated than simply identifying a mutated gene, however. More than a decade after completion of the first human genome, scientists still are in the early stages of figuring out which genes do what, and Dr. Narayanan estimates that the process probably will last decades more. While a gene mutation may look ominous, it simply might express itself as a particularly long index finger — and have nothing to do with disease.
By combing through scientific literature to discover which of Beorn's mutations were located on genes with known neurological functions and which previously had been connected to human disease, the TGen team was able to narrow down the suspects to one: a gene called DNM1, which is vital to transmitting signals between brain neurons.
Before he told Rankin what he had found, Dr. Narayanan put up his hands in warning.
"Don't get too excited," he said.
At that point, the mutation had been noted in only five other people (and one lab mouse) in the world. Scientists don't know why the gene mutation would cause Beorn's symptoms. They don't know how long Beorn might live or how his disease might progress. There are no known treatments.
As Rankin relates the story, an occupational therapist arrives.
She pauses to lift Beorn into his wheelchair. She snaps a Plexiglas tray over his lap. Using plastic clips, she secures an iPad in front of him. With the help of Beorn's therapist, Rankin has built a personalized game to help him practice both controlling his arms to select something on the screen and understanding cause and effect.
In Rankin's voice, the iPad enthusiastically squawks: "Touch to play patty cake!"
Rankin and the therapist, standing behind Beorn, ask, "Do you want to play patty cake? Touch the screen if you want to play patty cake."
When Beorn does nothing, the iPad moves on: "Touch for sensory bin!"
This time, Beorn flails his arms a bit and swipes the corner of the screen. Rankin isn't sure it was purposeful, but she wants to reinforce the connection anyway — so she rushes to give him a small drum.
He smiles a little, eyes lolling to the side, as he bangs his hands haphazardly across it. Patta-pat-pat. Patta-pat-pat-pat. Pat. Pat. Pat. Pat.
The first time Rankin sat down with an occupational therapist, he asked her what goals she'd like to work toward. After careful consideration, she told him she wanted two things:
1) For Beorn to learn to sit up on his own.
2) For Beorn to learn to give her a hug.
After a decade of therapy, though, Beorn has made excruciatingly little progress. Although she's spent hours cradling his back while he practiced engaging his abdominal muscles and pulling himself into an upright position, still he struggles even to hold up his head on his own.
In a way, Rankin muses, watching the therapist work with Beorn, the fact that Beorn's diagnosis didn't come with a prognosis is comforting.
"Nobody is putting limits on my child," she says. "I don't know what Beorn is capable of so there's always this lingering hope that's he's capable of more."
In an immediate sense, for parents whose children do not have a well-studied disorder, not much changes after doctors identify a faulty gene.
Samantha Pacifico went online, hoping to find parent support groups and forums full of ideas about therapies. She found instead only a few academic papers, which made her head spin.
"It makes me feel better to know because, for the first time, we're making progress," Rankin says. "But, at the same time, it's kind of a letdown because you're still kind of alone."
The only thing Rankin knows about the others who share Beorn's genetic mutation, she says, is, "Well, they're people."
From the other room, her husband calls: "One of them is a rat!"
"A mouse!" Rankin corrects him with a laugh, putting her hands on her hips and feigning indignation. "Give the little guy some respect."
Some parents find comfort in joining support groups for more common ailments.
Candice Miguel, a first-time mom whose 3-year-old daughter has been racked with seizures since birth, relies heavily on an online group of parents whose children have Rett syndrome, a neurological disorder that affects a child's ability to speak, walk, eat, and even breathe easily.
Her daughter, Alexandria, initially was diagnosed with Rett syndrome, but through genetic sequencing, she recently learned the girl actually had a mutation of the little-studied gene GNAO1.
"I can't find anyone with Alexandria's problem," she says, so she regularly turns to the group for advice about dealing with the day-to-day challenges of raising a special-needs child.
"It's all so overwhelming," she says. "I couldn't do it on my own."
Some parents, though, desperate to connect, blast messages on Twitter hashtagged with the name of their gene, hoping someone who knows someone with the same condition as their child's may stumble upon it.
The TGen team hasn’t found Beorn a miracle treatment — but in the months since his diagnosis, they’ve located five more cases of people with DNM1 mutation.
"Are there any families out there with a #DNM1 diagnosis? #Epilepsy #Seizures #Genetics #Dynamin," asked an IT consultant in Canberra, Australia.
Some parents blog about their children, hoping someone somewhere whose child shares the condition may read it.
After Salt Lake City computer scientist Matt Might wrote a blog post about his son's NGLY1 mutation in 2014, he was able to gather enough people with the same ailment to launch an experiment. The piece, provocatively titled "Hunting down my son's killer," was all over Twitter a half-hour after he posted it. By the end of the day, it was the top story on Reddit. A week later, it reached a geneticist in Turkey who had just sequenced genomes for two patients with NGLY1.
Other parents have had luck using several new websites designed to help people with rare diseases connect.
Ellen Macnamara, a genetic counselor in the National Institutes of Health undiagnosed disease program, calls them "dating sites for genetics." It works pretty much the same way, she says, except instead of creating a profile highlighting love for deep conversation and long walks on the beach, users list a child's genetic variant and detail the frequency and severity of his or her symptoms.
"In the medicine world, we worry a lot about privacy and confidentiality, but for many parents in the rare and undiagnosed disease community, that is low on the list of priorities," Macnamara says. "They are going to share anything and everything with the public."
Even if researchers manage to gather enough cases to launch a study, challenges remain. Typically, because of a combination of poor funding for rare-disease research and bureaucracy, it can take years for new discoveries to trickle down from the lab to the patient.
In an attempt to address the problem, TGen acts as a liaison between parents and researchers, scouring the latest scientific journals for new information, then pushing to have clients included in new studies.
Dr. Narayanan took a skin biopsy from Beorn and put it on ice. So, as soon as he finds a specialist in DNM1, he can send it over. If a scientist rolls out a potentially helpful therapy, Dr. Narayanan says, "It's straight from the lab to the clinic."
Meanwhile, Dr. Narayanan is in the process of writing a case study on Beorn to submit to a scientific journal. Another TGen researcher is trying to create a zebrafish model of his mutation.
Sometimes, using the model, the team comes up with treatment ideas.
Dr. Naraynan, for example, discovered that Shelby Valint, a whip-smart 15-year-old whose physical development had deteriorated to the point that she struggled to walk, talk, and swallow food, had a mutation on a gene known as DDC. After learning DDC codes for an enzyme critical for the production of dopamine, a brain chemical that regulates movement, muscle control, and balance, he decided to prescribe the Phoenix resident a pair of drugs usually used to treat another neurological disorder associated with insufficient dopamine: Parkinson's disease. Within weeks of starting treatment, Shelby had ditched her wheelchair.
The TGen team hasn't found Beorn a miracle treatment — but in the months since his diagnosis, they've located five more cases of people with DNM1 mutation.
When Simon finishes his physical therapy session, Pacifico tousles his hair and asks, "Do you want to eat?"
His face lights up. "Eat!" he exclaims.
There's a Paradise Bakery across the parking lot. Simon jumps and skips beside his mother, making a zigzag pattern.
Pacifico orders a salad for herself and a bowl of potato soup for him. The boy is so excited that he grins from ear to ear and flaps his arms like a chicken.
As soon as they're seated, he takes a big bite of a roll, then quickly spits it out.
His mother laughs.
"You don't like bread, remember?" she says.
She dumps a package of oyster crackers into his soup. He dips in his spoon. His face barely pokes up above the big bowl.
For now, the future remains an enigma for her son.
"Tomorrow he could be in the hospital with a new kind of seizure," Pacifico says. "He could go into liver failure from the medications. He could leave us . . ." Her voice trails off, and she dabs at her eyes with a napkin.
She tries not to spend too much time worrying.
She'll just have to take life day to day.
She'll wake Simon up. He'll put his pillow over his head, annoyed. She'll make him his favorite breakfast (eggs, cheese, and an avocado) and send him off to catch the bus that takes him to his special-education classes.
In the evenings, they'll take walks together, counting all the flags in the neighborhood. (Flags are one of Simon's favorites.) They'll watch home videos of Simon swimming over and over until Pacifico thinks she'll go mad. Simon will dance around singing, "Shoes! Shoes! Shoes!" when he's happy. And Pacifico will keep hoping that maybe, just maybe, doctors will figure out how to treat him.
"I just have to have faith that he's exactly who he is supposed to be," she says. "We just love him exactly the way he is."