Ep. 63 | The Broken Sequence

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One morning in 2015, a scientist sat at his computer feeling a growing sense of confusion.

He was looking over the DNA samples of two little boys, brothers with a mystifying illness that had left their parents frantic with worry.

The boy's pediatrician had already ruled out a virus or bacteria or any other infection.

That left only one possibility.

Something was wrong with their genes.

And the pediatrician was counting on this scientist to figure it out.

It had taken the scientist two months to compile his data, as he painstakingly pulled apart billions of tiny pieces of the boy's DNA.

But now that it was all done, the scientist realized he had found nothing.

Everything looked totally fine.

Nothing was broken, nothing was missing, nothing looked strange.

Disappointed, the scientist sent his finding to the boy's doctor, apologizing for not discovering anything helpful in their DNA.

He knew that something was seriously wrong with both brothers.

Yet, genetically, they seemed like two perfectly healthy little boys.

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Follow Lawless Planet on the Wondry app or wherever you get your podcasts.

From Balin Studios and Wondry, I'm Mr.

Balin, and this is Mr.

Balin's Medical Mysteries, where every week we will explore a new, baffling mystery originating from the one place we all can't escape, our own bodies.

So if you like today's story, please invite the follow button to a big fun costume party, but don't tell them that it's actually not a costume party, it's a funeral.

This episode is called The Broken Sequence.

On an April morning in 2012, Newlyweds Nikki and Danny Miller sat on the floor of their living room playing with their six-month-old son, Carson.

Carson lay on his back on the rug, smiling his toothless smile, his chubby little legs kicking in the air.

Nikki had a stuffed animal that she kept lowering over Carson's face, then pulling it back when he reached for it.

The boy went into a fit of giggles every time, and Danny's heart swelled with love as he watched.

Danny was 42 and Nikki was 40, so when they got married last year, they weren't even sure they could have kids.

To Danny, Carson was a little miracle with his soft blonde hair and bright blue eyes.

Danny never took a single second for granted, even though his energetic baby really wore him out.

Danny leaned over Carson and made silly faces until the baby turned red from laughter.

Then Nikki waved the stuffed animal again, and their baby swiped at it.

But Carson's arm was stiff and awkward.

Danny had noticed over the past few weeks that Carson's movements were somewhat awkward.

At first, Danny had assumed it was just his son getting used to his own body.

It was sort of cute.

But But over the last couple of days, Danny had noticed something else that was unusual about Carson's coordination.

It took a lot of work for his son to roll over onto his stomach.

Danny and Nikki had been reading a ton of baby books, so they knew that by month six, he should be able to roll onto his stomach, then onto his back again.

But even when Danny or Nikki helped, their son still struggled to roll.

Danny knew that as a first-time parent, he could sometimes be alarmist.

So he tried his best not to fixate on his son's delayed motor skills.

But just to be safe, he decided to schedule an appointment with his son's pediatrician.

When they saw that pediatrician, he'd recommended they speak with someone else, a specialist, who might be better equipped to give them answers.

A week later, Danny sat beside Nikki in a doctor's office, watching the behavioral specialist examine their son.

The specialist was kind and had a calming demeanor, and he listened intently while Danny explained explained their concerns about Carson.

And he never made Danny feel like he was an over-anxious new parent.

Eventually, the specialist's examination of Carson turned into a little game of peekaboo.

And once Carson was giggling, the specialist turned to Nikki and Danny and said that he was not too concerned.

He reassured them that babies develop at different rates, and it seemed like Carson was just taking his sweet time.

Danny nodded and squeezed his wife's shoulder as she exhaled with relief.

Danny wished he felt the same way, but he didn't.

Instead, he was left with this nagging feeling that there might be something more to Carson's problems than just him taking his sweet time.

That night, as Nikki put Carson to bed, Danny began poking around on the internet, researching developmental delays in children.

He learned about a disruption in muscle movement called spasticity, which seemed to describe the jerky way that Carson moved his arms.

Danny also read about a condition called hypotonia that could account for Carson's lack of muscle tone.

He wondered if that was why Carson still couldn't roll over on his own.

And yet, Danny didn't really know what to do with this information.

They'd seen a specialist who presumably would have known all about these conditions in babies, and he didn't seem concerned.

So Danny closed his laptop, deciding he would just be patient.

Carson was only six months old.

and Danny told himself that Carson would just grow into his body over the next few months.

Nine months later, in early 2013, Danny sat on the floor with Nikki, their backs against the living room sofa.

Wooden blocks and storybooks were strewn all around them.

Nikki's hands were resting on her very pregnant stomach.

They were both very excited to be having a second child.

Carson, who was now almost 16 months old, was sitting in Danny's lap as Danny flipped through a pack of animal flashcards.

He encouraged Carson to say the names of each animal or to at least make the animal noises.

But while Carson reached out a shaky hand to pet the animal cards, he didn't say any of their names or imitate the sounds they made.

Carson still wasn't talking, which was highly unusual for a kid his age.

And Carson had other developmental delays, too.

He couldn't sit upright on his own or crawl either.

Eager to find something his child could do well, Danny put the flashcards away and reached for the wooden block set.

Maybe Carson was more of a builder.

Danny Danny sat his son next to the blocks, and right away, Carson grabbed a blue square in his tiny fist.

Carson started moving the block to add it to the little pyramid his dad was building, but then Carson's hand shook uncontrollably and he dropped it.

Danny jumped up and scooped Carson into his arms.

He was quite accustomed to Carson's poor motor skills, but he'd never seen his son's hand tremble like that before.

He held Carson, waiting to see if he could feel any more shaking, but Carson seemed okay.

Danny gave gave Nikki a wary look and told her maybe it was time to take Carson back to the doctor.

And Nikki nodded and said she was thinking the same thing.

A few days later, Carson's pediatrician ordered an MRI to see if there was a physical problem that would explain Carson's developmental delays.

But when the MRI came back, it was normal.

That's when Danny told the pediatrician about the alarming conditions he had found online.

He talked about spasticity and hypotonia and a few other rabbit holes he'd fallen into.

And to Danny's surprise, the pediatrician thought he might actually be onto something and referred them back to that specialist.

Now, Danny and Nikki sat in the behavioral specialist's office for the second time as he looked over Carson's file and ran some of the same little tests that he'd used to examine Carson's motor skills the first time.

But this time, the specialist agreed with Danny and Nikki.

Carson's development was definitely falling behind, behind, and the doctor believed that the little boy might have a condition that would account for some of these developmental delays.

In his opinion, Carson's delays were due to cerebral palsy, which is a group of conditions that affect movement and posture, sometimes severely.

It's caused by damage to or abnormal development of the brain.

Danny nodded and squeezed his wife's hand.

He'd come across cerebral palsy several times when he was Googling Carson's symptoms, so Danny had known known that this diagnosis could be a possibility, but it was still hard to hear it aloud.

Cerebral palsy is not curable, which meant that Carson would never grow out of his developmental delays.

Carson would have a lifelong disability.

The specialist assured Danny and Nikki that therapy could help Carson manage the cerebral palsy and suggested that they begin physical and occupational therapy right away.

Together, these therapies would help with his motor skills and cognitive development.

Danny began calling therapists the next day, trying to find the perfect fit for Carson.

However, he had to put the search on hold for a week when Nikki went into labor.

And in mid-January 2013, Carson's little brother, Chase, was born.

Nearly a year later, toward the end of 2013, Danny pushed Carson in a stroller up a steep hill in San Francisco, where he and Nikki were vacationing.

Danny's legs were burning, but Carson was enjoying enjoying the feel of the steep incline so much that Danny forced himself to keep on moving.

Besides, he was following Nikki, who trudged ahead, carrying little Chase in a sling.

And if she wasn't complaining, neither would he.

At this point, Chase was 10 months old and Carson was almost three, and neither boy could walk yet.

Now, this made sense for Chase, who was still a bit young to be on his feet.

But for Carson, it was definitely concerning.

And they had to push him in a stroller whenever whenever they went anywhere, which made carting him up and down the steep hills of San Francisco extremely tiring.

Intellectually, Carson seemed to be just fine.

He was curious, always looking around and giggling, trying to grab at things that sparked his curiosity.

But even after a year of therapy, he still couldn't sit upright on his own very well, let alone crawl or walk.

His little brother Chase also struggled to sit upright, which worried Danny.

He'd been noticing that Chase was experiencing a lot of the same developmental delays that Carson struggled with.

But Danny tried not to focus on that today.

They'd spent the morning at Golden Gate Park, then they had taken a trolley ride through town.

Danny had loved the way the boys laughed themselves silly on the trolley as it coasted down some of the steeper hills.

And so now, after lunch, Danny and Nikki were taking the boys to another park to play.

They walked through the gates of a playground and set Carson and Chase into a big red sandbox.

Nikki sat behind Carson, helping him sit upright, while while Danny handed Chase a little plastic shovel.

Chase reached out with a jerky arm and grabbed the shovel, but just as his fingers wrapped around it, his hand shook.

He lost his grip and dropped it.

Danny realized that Chase had a tremor in his hand, just like his older brother Carson.

Danny's mind started racing.

He wondered if Chase might have cerebral palsy too.

Except, that didn't make any sense.

Danny had read once that statistically, the odds of siblings each having cerebral palsy were one in a million.

And yet, the more he thought about it, the more it seemed like Chase was developing the same delays as his older brother.

Danny thought hard for a second.

If both his boys had the same condition, then again, based on statistics, they probably did not have cerebral palsy, which meant that Carson may have been misdiagnosed.

And if that was the case, well, Danny and Nikki were back at square one.

Only worse.

Now they were searching for a diagnosis for both of their children.

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Two years later, in late 2015, Danny and Nikki still felt like they didn't actually know what was wrong with their sons.

Over the past two years, they had brought Carson and Chase to specialist after specialist.

And most of them agreed that whatever the boys had, it was not cerebral palsy.

It was likely genetic.

But none of the specialists had been able to pinpoint what exactly was causing the boys' symptoms.

Carson and Chase had been tested for a staggering array of diseases.

Rare metabolic disorders like phenyl ketonoria and Tay-Sachs, which damage the body's ability to process nutrients and enzymes.

They had been tested for abnormalities in their chromosomes, as well as genetic disorders like fragile X syndrome and degenerative disorders like Friedrich's ataxia that attacks the nervous system.

So far, the voice tested negative for all of them.

But that only encouraged Danny to spend more time researching on his own, looking for some kind of answer.

Danny and Nikki had even discussed whether or not it was maybe something they'd done.

Like, had Nikki taken the right prenatal vitamins?

Or had they unknowingly exposed the boys to some kind of environmental toxin or something?

They didn't know, but Danny hated the idea that they were now blaming themselves for their boys' mysterious condition.

Danny knew they could not keep living like this.

He had to find answers soon.

A few months later, Danny was at home playing with his boys.

Chase was now two years old and Carson was four.

Both boys had grown into happy kids with matching blue eyes and pale yellow hair.

Carson had grown out of his baby fat and looked like a handsome little boy.

He still couldn't walk, but he could sit up by himself and had recently started crawling.

This morning, Danny put both boys on the carpet in the living room.

Then he dangled a Christmas ornament in front of Carson, who was sitting upright watching the ornament catch the sunlight and sparkle.

Danny hoped Carson would reach out and grab the ornament.

This was something he had been working on in physical therapy.

But today, the boy just reached clumsily toward the little figurine, touching it with his palm, but seemingly unable to close his hand around it.

Eventually, when he continued not being able to grab the ornament, Carson started to get visibly upset, until Danny finally set the ornament in his lap.

and told his son it was a good try.

But Danny was worried.

Only a week earlier, Carson could actually grab hold of an object, but now he couldn't.

It was like he was going backward.

That afternoon, Danny called the boy's pediatrician to try to make an appointment.

And that's when the pediatrician suggested that it was time to do a specialized type of testing called gene sequencing.

It can detect missing or broken base pairs among the billions of pieces of the boy's DNA.

The doctor thought they should do this as soon as possible.

Gene sequencing is an involved procedure, and it can take two or three months months to get the test results back.

Danny sighed at the doctor's recommendation.

It felt like he spent his entire life waiting around for test results that always disappointed.

After all this time, they still didn't know what was wrong with Carson and Chase, making it impossible to treat the boys or even know their limitations.

Danny worried that his son's quality of life suffered because the doctors could not figure out what condition they actually had.

Still, Danny agreed to do the genetic sequencing and hid his frustration from the doctor.

And when he hung up the phone, Danny grabbed his computer and took up his usual place on the couch, diving back into his own research.

Early in 2016, Danny had just gotten home from work when the phone rang.

It was the specialist who'd conducted Chase and Carson's genetic sequencing.

Danny held his breath.

They'd been waiting for these results for three very stressful months.

During that time, both boys continued to go downhill.

Chase stopped crawling, something he'd actually begun to get fairly good at, and Carson still was not walking.

By this point, he should not only have been walking, but maybe even running.

He should also have been in preschool by this point, making friends with kids his own age.

Instead, he was stranded on the living room floor, unable to carry himself from room to room.

But the specialist call did not give Danny any relief.

Danny was told that the long-awaited sequencing results didn't show any genetic damage that would explain his son's symptoms.

On paper, at least, the boys seemed genetically perfect.

Danny felt hopeless.

He asked the doctor, like, what is he and his wife supposed to do now?

The doctor advised Danny that the best thing he could do was just check back in in a year.

They might have better testing by then, and maybe then they could find some answers.

Then they hung up, leaving Danny wanting to scream in frustration.

It was beginning to feel like Carson and Chase were the only two people on the planet with this mysterious condition.

The next day was a Saturday.

Danny wanted to spend an easy morning with his family, but he knew he had a mission.

Right after breakfast, he moved his laptop to the living room and spent the entire day combing through articles and medical journals.

10 hours later, At the bottom of one of his research papers, he saw something.

A mention of a group called the Undiagnosed Diseases Network.

Curious, Danny followed the ad to the network's homepage.

The UDN was run by the National Institutes of Health, and its goal was to provide answers to patients affected by mysterious medical conditions.

UDN promised to take on the most challenging medical cases like a last resort for families with nowhere else to go.

To Danny, that sounded exactly like his family's situation.

He called to his wife and then brought his laptop into the kitchen to tell her what he'd found.

She immediately asked, you know, would they take the boy's case?

Danny said there was only one way to find out, and he opened up an application to the program.

Almost a year later, in January of 2017, Dr.

Jonathan Bernstein walked out of his office at the Undiagnosed Diseases Network Clinic.

He made his way down the hallway and to an examination room where his newest patients were waiting.

Danny and Nikki Miller had applied to the UDN clinic for help help in the spring of 2016, and they were finally accepted into the program in the fall.

But before they could come into the clinic for their first appointment, Dr.

Bernstein had ordered an even more ambitious form of genetic testing called whole genome sequencing.

And not just for the two boys, Dr.

Bernstein wanted the testing for the entire family.

Whole genome sequencing decodes a person's entire gene sequence, almost like breaking down the entire instruction manual to an individual person.

It's the gold standard for genetic testing because it reveals every single gene, not just a portion of them.

Dr.

Bernstein hoped that if he could see the entire family's genetic sequence, he'd be able to spot what was going on with the boys.

Now, three months later, the testing still was not done, but Dr.

Bernstein wanted to meet his new patients in person.

He walked into the exam room, and immediately saw that Chase and Carson had regressed significantly since their parents first applied to the program last spring.

Both Carson and Chase were strapped into their wheelchairs to keep them from slumping to the side.

Dr.

Bernstein suspected that neither of the boys could sit up on their own.

And yet, both boys seemed to perk up when Dr.

Bernstein entered the room.

He said hello, and both boys gave Dr.

Bernstein big smiles.

It was clear to Dr.

Bernstein that the boys were aware of what was going on around them.

They just weren't able to verbalize.

Nikki and Danny both stood to greet Dr.

Bernstein and shake shake his hand.

Then Nikki explained that over the past year, Chase and Carson had both lost almost all of their motor skills.

Chase was three years old now, and Carson was five, but neither boy could walk or talk.

Danny chimed in, adding that at this point, they also needed assistance just to eat and drink.

Dr.

Bernstein began giving Carson and Chase routine physical examinations.

As he did, he warned the Millers that it would still be a little while before their whole genome sequencing results were back from the lab.

But when they were done, he'd have detailed genetic information for both parents and children that told the story of the entire family.

But even then, he warned, Nikki and Danny would need to be patient.

It could take nearly a year for Dr.

Bernstein's team to make a diagnosis.

Still, Dr.

Bernstein promised that if anyone was going to find an answer, it would be this clinic.

Danny nodded, and Nikki told Dr.

Bernstein that they were used to waiting.

Finally, in February of 2018, a full two years after Danny first reached out to the Undiagnosed Disease Network, Dr.

Bernstein called the Millers to say he had figured out what was wrong with Carson and Chase.

They were suffering from one of the rarest diseases in the entire world.

And the fact that both boys had the same condition was the result of almost unimaginably bad luck.

Carson and Chase did in fact have a genetic defect, but one so tiny, no other genetic testing revealed any problem.

Their condition was caused by a malfunction in a single gene out of the 20,000 genes needed to make a person.

The defect was so hard to detect that Dr.

Bernstein's team could only find it by looking at all 3 billion DNA-based pairs that are the building blocks for genes.

And remarkably, both Chase and Carson had inherited the same defect.

The whole genome sequencing revealed that the boy's parents, Nikki and Danny, carried an incredibly rare genetic mutation.

It's almost inconceivable that two people with this mutation would meet and have kids, and rarer still, that they would pass the mutation on to both of their kids.

In both Carson and Chase's DNA, a small section of a gene called the MECR gene was broken, and this caused a catastrophic problem.

Because the MECR gene is what allows our cells to generate the energy they need to function.

If the MECR gene is broken, the cells cannot function properly.

Dr.

Bernstein explained that the cells most affected by a broken MECR gene are the cells at the base of the brain, which is the area responsible for movement.

That's why the boys couldn't crawl or walk or move around.

It's why they suffered so many developmental delays and had a lack of basic physical abilities.

This condition called mitochondrial enoil-CoA reductase protein-associated neurodegeneration, or meepan syndrome, is so rare that Carson and Chase were only the eighth and ninth patients in the world to be diagnosed with it.

Danny and Nikki were relieved that doctors had finally given them a diagnosis for their kids, but it was accompanied by grim news.

Dr.

Bernstein told them that there was no recognized treatment for Mepan and no proven way to help the boys regain their motor skills.

But that's when Danny Miller took over.

Once he received the diagnosis, Danny went back to his research, this time looking for a way to manage Meepan syndrome.

And he quickly learned that patients with Meepan syndrome lack something called lipoic acid in their cells.

Lipoic acid is crucial to generating power inside cells, and without it, the brain runs out of energy.

At first, Danny thought that overcoming this deficiency would mean expensive treatments and therapies.

But after looking into it more, he was amazed to find that he could actually buy lipoic acid supplements for only $16 a bottle online.

He ordered the supplements for Carson and Chase, and after a few months of taking them, it seemed like the boys' motor function had stopped deteriorating.

In fact, when Danny and Nikki took the boys to the neurologist, he told them that Carson and Chase were even showing some signs of improvement.

Unfortunately, though, there is no way to fully restore their physical abilities, at least at this time.

Carson and Chase still rely on wheelchairs to get around, and they both rely on computers to communicate.

However, thanks to their parents' dedication, their condition seems to have stabilized.

And hopefully in the future, there will be a better treatment plan or even a cure.

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Bollins Medical Mysteries on the Wondery app, Amazon Music, or wherever you get your podcasts.

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Ballin's Medical Mysteries early and ad-free right now by joining Wondery Plus in the Wondery app, Apple Podcasts, or Spotify, or by listening on Amazon Music with your Prime membership.

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From Balin Studios and Wondery, this is Mr.

Bollin's Medical Mysteries, hosted by me, Mr.

Balin.

A quick note about our stories.

They are all inspired by true events, but we sometimes use pseudonyms to protect the people involved.

And a reminder, the content in this episode is not intended to be a substitute for professional medical advice, diagnosis, or treatment.

This episode was written by Aaron Lan.

Our editor is Heather Dundas.

Sound design is by Matthew Cilelli.

Our senior managing producer is Nick Ryan.

and our coordinating producer is Taylor Sniffin.

Our senior producer is Alex Benedon.

Our associate producers and researchers are Sarah Bytak and Taja Pelaconda.

Fact-checking was done by Sheila Patterson.

For Ballin Studios, our head of production is Zach Levitt.

Script editing by Scott Allen and Evan Allen.

Our coordinating producer is Samantha Collins.

Production support by Avery Siegel.

Executive producers are myself, Mr.

Ballin, and also Nick Witters.

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