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Rare Disease Day 2023: Isla’s Story and NGLY1 Deficiency

The road to naming an unusual collection of unfolding symptoms is called the “diagnostic odyssey” for good reason: the journey takes, on average, nearly 5 years.

Worldwide, about 400 million people have one of the 10,000 or so recognized rare diseases, or one in ten people, according to Global Genes. About half are children, and 95 percent of the conditions do not have FDA-approved treatments.

In the US, 25 to 30 million people have a rare disease. Ten-year-old Isla Richman is one of them. She has NGLY1 deficiency. Her family shared their story with me in recognition of Rare Disease Day 2023, the last day of February.

The ability to quickly sequence an exome – the smidgeon of a genome that encodes proteins – has sped diagnosis of ultrarare conditions for many families. But even that level of scrutiny can miss mutations, like passing by a tiny town along a major highway. Isla’s two recessive mutations are hidden in an intron, a gene part once called “junk.” Her gene variants are the most intriguing I’ve ever encountered.

Isla’s mom Molly Hero contacted me recently while reading my book The Forever Fix: Gene Therapy and the Boy who Saved It, now a decade old. She shared the path to finding the cause of her daughter’s odd symptoms.

In NGLY1 deficiency, a missing enzyme hampers the ability to trim sugars from misfolded proteins, part of a cell’s routine dismantling of debris. Just over 100 people have been diagnosed with the condition, most of them children; the oldest is 41.

About 80 percent of rare conditions with a genetic component are de novo (mutation originating in the affected individual) and the rest are inherited (mutation from one parent if dominant, from two if recessive). Both origins are due to mutation, a change in DNA from the most common form of a gene, called wild type. Some rare conditions arise from non-genetic events during development.

Diagnostic Odysseys

Naming an extremely rare set of symptoms can follow several trajectories.

Some families look for symptoms because relatives have or had an inherited condition, and know which tests to request. For other families, the possibility of a genetic condition comes as an unwelcome surprise following routine newborn screening, which detects telltale metabolic glitches for dozens of conditions. DNA tests confirm genetic conditions, creating “patients-in-waiting” if symptoms haven’t yet appeared.

Later, other tests may help narrow a diagnosis after a trio of broad conditions appears: developmental delay, intellectual disability, and ataxia (impaired balance and coordination). Panels of genetic tests may find rare neuromuscular or metabolic conditions. But even single-gene tests can miss diagnoses if they detect only the more prevalent mutations. A gene’s DNA sequence can vary in many ways.

When a constellation of symptoms doesn’t seem to fit any diagnostic patterns, or they fit but single-gene tests are negative, the search intensifies – if the individual can access health care and find practitioners familiar with the nuances of genetic disease, or who can make appropriate referrals.

Fortunately, even people who seem to be the only ones in the world with their symptoms have options.

The Undiagnosed Diseases Network (UDN) and “n-of-1” Clinical Trials

The UDN is “a nationwide network of clinicians and researchers who use both basic and clinical research to uncover the underlying disease mechanisms associated with these conditions.” The NIH’s Common Fund began the program in 2013 and expanded it in 2018. It has since identified dozens of syndromes.

Another approach is an “n-of-1” clinical trial developed to treat a specific individual, based on the mutation. That’s been happening for years, but didn’t attract media attention until a rebranding in late 2021, when the NIH unveiled its Bespoke Gene Therapy Consortium. “Bespoke” means “made for a particular user.” That caught on with the news media in a way that the nerdy “n-of-1” never did.

Isla’s Symptoms

Isla was born on June 6, 2012, four weeks early and weighing less than 4 pounds. She came home from the NICU 20 days later, small but healthy.

“The next few months were a blur. Isla cried a lot, but she grew and started smiling in September,” Molly recalled. Twice the scared parents took Isla to the ER when she choked and become lethargic, but tests turned up nothing amiss.

Another clue was a rare contraction of neck muscles that twists the head to one side, a condition called torticollis that may be inherited. When Isla was diagnosed with it at around 6 months, physical therapy followed. By the fourth session, the PT “had concerns” about walking ability, Molly recalled. Next came referral to a neurologist.

“Cerebral palsy kept being mentioned, yet hesitantly, like the doctors weren’t quite sure but needed to check a box. I did a lot of research. CP has widely varying presentations, but no story I read sounded quite like our daughter. What else could it be?” Molly wondered.

Meanwhile, developmental milestones were lagging.

When Isla was 3, a pediatric neurologist noted “underdeveloped white matter” on an MRI scan. “As we were preparing to leave, the chief neurologist casually mentioned ‘genetic disorder,’ and I heard ‘Rett Syndrome.’ She recommended we seek genetic testing.”

NGLY1 deficiency is often initially thought to be Rett syndrome, passed on the X chromosome, or a mitochondrial disorder. Testing eliminated both.

Somewhere along the odyssey, a clinician had mentioned exome sequencing, “as an afterthought,” Molly recalled. Sequencing the protein-encoding part of the genome can provide a genetic diagnosis. At the time, 2016, it cost $16,000.

The exome findings, returned months later, were disappointing: no name had emerged for Isla’s symptoms. But her exome information would be stored in the database, in case a matching gene variant popped up in someone else.

“I tried to settle into the CP diagnosis. I joined some Facebook groups and connected with other CP parents,” Molly remembered. But while she and Isla’s dad Chris were starting to accept the interim diagnosis, they became more aware of their daughter’s oddities: Tiny feet. Dry eyes. Chronic constipation. Elevated liver enzymes. Long eyelashes. Speech delay. Needing a lot of sleep.

In retrospect, the growing list of observations echoed clinical descriptions of NGLY1 deficiency, which also includes spasms, quivers and shakes, seizures, rapid jerks and slow writing movements, fractures, a curved spine, loose joints and dislocations. Perhaps most telling were the very small feet.

When Isla was 7, a friend Molly had met at the NAPA Center in LA, where Isla spends three weeks twice a year for intensive physical, occupational, and speech therapy, mentioned that her son had been diagnosed with an ultra-rare genetic disorder thanks to the Undiagnosed Disease Network. Over the next few months, Molly gathered medical records and documentation and applied to the UDN.

Then COVID happened. Priorities shifted and Isla’s progress slowed. (See Rare Disease Families Cope with COVID). Isla eventually got COVID, but it was just a few days of coughing.

At age 9, Isla had her first seizure.

“I got that dreaded call from the teacher. The following day, at the exact same time, it happened again, and once more a week later. All three incidents were the same – spacing out, looking in one direction, stiff arms, unable to be roused, then, after about 3 minutes, she was back, tired but present,” Molly recalled.

An Answer: Diagnosis and Unusual Mutations

In January 2022, everything changed. Molly got a phone call from the geneticist they’d seen at Stanford, who had a colleague, Maura Ruzhnikov, MD, who worked for the UDN and had a few questions about Isla.

Molly was thrilled. “Dr. Ruzhnikov told me that Isla’s case had been accepted for review by the UDN, and, she had a suspicion of a possible diagnosis!”

Isla would need a urine test that had been refined since she’d last had it in 2016. Would they agree to repeat that test? Of course!

The urine test showed a high amount of a chemical that builds up in NGLY1 deficiency. Was that her diagnosis? If so, why hadn’t exome sequencing revealed her mutations? Perhaps they were hiding in almost-plain sight.

Rebecca J. Levy, MD, PhD and Child Neurologist and Geneticist at Stanford Medicine Children’s Health had recently published a natural history study of NGLY1 deficiency with Dr. Ruzhnikov and colleagues, which chronicles symptoms. They suspected that Isla’s mutations might lie within an intron, a section of a gene that is removed before the messenger RNA is translated into protein. “An intron is a gene part that may regulate transcription of the neighboring exons into RNA but is not translated into the encoded protein, which in NGLY1 deficiency is the enzyme N-glycanase,” Dr. Levy explained. The enzyme trims sugars off proteins during cellular housekeeping.

The next step: a close look at the parent’s DNA. If the mutations hadn’t shown up in exome sequencing, which looks only at the protein-encoding exons, then they must be in the introns. Isla’s parents should each have one – carriers because they are healthy. Isla has two.

Sure enough, Molly has a mutation near where an intron is removed from the N-glycanase gene as the RNA is processed into the final form that encodes the enzyme. But NGLY1 is recessive. Wouldn’t Chris have a mutation too? That hadn’t turned up, so they needed to delve deep into the territory of the intron instead of just sequencing its tips, a short-cut.

Dr. Levy summarized the complex challenge:

“Isla’s symptoms matched NGLY1 deficiency, and when a biochemical marker was discovered for it, she indeed had the enzyme deficiency. These pieces of evidence made us dig deeper to see if there was a second gene variant. Lo and behold a second variant was on her other copy of the gene, so deep into the intron that it isn’t a part of standard testing or reporting.”

The sequestered gene variant came from Chris.

A Unicorn Among Zebras

Isla Richman is highly unusual, genetically speaking. Mutations in introns are rare, mutations in their interiors rarer still (perhaps because we don’t always look). And so the famous phrase given to fledgling medical students – when you hear hoofbeats, think horses not zebras – might replace zebras with unicorns.

The genotype created when Isla’s genome formed rendered her cells unable to make the critical enzyme. NGLY1 deficiency was first reported in 2012. It is, in the language of biochemistry, a “congenital disorder of deglycosylation,” which means impairment of removing sugars.

It had taken a technological tour de force to get to the bottom of the symptoms.

“This was a case where DNA sequencing, clinical phenotyping, biochemical testing, and RNA sequencing combined to uncover the diagnosis. Fitting together pieces of the puzzle like this to give an answer to a family is one of the most rewarding parts of my job!” Dr. Levy said.

Now Molly and Chris belong to a much smaller Facebook group than when they thought Isla had a generalized form of cerebral palsy. “We are part of the NGLY1 ‘family,’ following email threads and FB group posts, which is wonderful,” Molly said.

Sharing with other parents has made sense of minor manifestations too, such as very strong preferences. “Isla’s favorite book is Eric Carle’s ‘Brown Bear, Brown Bear, What do you See?’ and she never gets tired of it. Fifty-minute speech therapy sessions relied on this book and little else!” Molly recalled.

Even though Isla has significant cognitive delays, “she also has glimmers of surprising intelligence. When we drive around San Jose and even Los Angeles, she knows where we’re going. If I take a different route, she vocalizes her protest,” Molly said.

And since age 4 Isla has loved riding horses weekly at the National Center for Equine Facilitated Therapy near her home. The hippotherapy helps her motor skills, and perhaps more importantly, makes her happy.

“She’s so little, her feet only fit in the stirrups starting about a year ago. Some typical kids ride horses as a sport, a hobby. Isla does it for therapy, but I talk about her love of horses, ‘horseback riding.’ We look for ways in which our special kids are similar to their peers,” Molly said.

With a name finally put to her symptoms, Isla can participate in future studies, including treatment trials, Dr. Levy said.

The NGLY1 community is awaiting news about a gene therapy trial that may launch this year, which is why Molly was reading my book. Experiments in a rat model show halting of disease progression and improvements in cognition and motor skills with the therapy.

“Isla’s neurologist seems skeptical, ‘keep your expectations low.’ We will, but even a slowing of progression would be huge. My eyes tear as I imagine hearing Isla’s voice saying real words,” Molly said.

In the rare disease community, patient-originated non-profits are critical for catalyzing and supporting clinical trials, and only about half of rare diseases have such organizations, according to Global Genes. The organizations share resources, experience, knowledge, and contacts. For NGLY1 deficiency, that’s the Grace Science Foundation.

“Our mission is to cure NGLY1 deficiency, by pioneering approaches that are faster, less expensive, and more collaborative. The innovations we develop will be used to treat and cure other diseases,” said Ryan Dant, director of patient advocacy. A gene therapy clinical trial won’t come soon enough – four of the older individuals with NGLY1 have died in the past month, of respiratory or hospital-related complications, Molly said.

Today Isla is a happy and joyful girl, her mother said, and is learning to use an augmentative and alternative communication device for communication. And she loves her horses …

To donate, please visit the Grace Science Foundation website.

  1. Excellent article which helps us, as grandparents of a child with NGLY-1 deficiency, better understand the disorder and how to describe it. We can’t adequately express our appreciation for everything Grace Science is doing to find treatments for this devastating condition.

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