According to a recent article in Yahoo News, unless treatment is discovered or a cure is found for a disorder called IRF2BPL, these young children will lose the ability to eat or drink, speak, and walk.

The four boys were healthy at birth but gradually began to stumble and lose some ability to speak. By the time they had reached kindergarten age, each child had begun using a wheelchair.

Currently, less than twenty cases of newly discovered IRF2BPL have been reported. The disease is named after the gene with which it is linked.

The Parents’ Burden

The boys’ parents were forthcoming about their everyday experiences with the disease. Each gave a straightforward account of how they are managing. Here we outline several events that led to a diagnosis for this very rare disease.

Eli Kadkhoda

If you were to visit with Eli and his mother, Sanam of West Los Angeles, you would see a normal boy. Yet Sanam can tell you that at the age of four her son Eli has started to lose muscle tone, balance, and has lost some of his ability to speak.

A year earlier, at the urging of Eli’s teacher, his parents took him to see Dr. John Graham, a geneticist at Cedars-Sinai. Despite outward appearances, Eli was a slow learner, and although he could walk, he never tried to run like other children.

However, once Eli was evaluated and placed under the care of a therapist, his speech improved and so did his gait. His parents eagerly accepted the doctor’s suggestion that Eli should be tested using whole-exome sequencing.

About a week after their meeting with Dr. Graham, Eli’s mother, Sanam, received a call from the geneticist with the results of Eli’s gene mapping which found IRF2BPL.

Sanam immediately searched the internet for the gene called IRF2BPL and found several posts on Facebook. The posts also had photos of Caleb, another child who was being tested. Sanam recognized similar traits in both boys.

The results of the sequencing came back as ‘De novo heterozygous on IRF2BPL’. The interpretation is that of a spontaneous but non-inherited mutation. There are two versions of the gene in each of Eli’s cells and a mutation was found on one of them.

Caleb MacKay

Caleb’s parents watched anxiously as their son began to lose his ability to walk unaided. Although his parents took him to many specialists, not one of them was able to stop the progression of Caleb’s disease. He eventually required a wheelchair. His parents saw to it that he had every possible diagnostic test, but the end result was always not what he had but what he did not have.

Even the strongest and most devoted parents have weaknesses when they are faced with a bleak future for their children. Caleb’s parents could see that his disease was taking hold. His mother, Cassidy, said that they had to confront the fact that his condition will continue to deteriorate. Every time they adapt to a setback another quickly follows. When they learned to accept the fact that Caleb will no longer be able to walk, they found that he could no longer sit independently.

Caleb was examined by a group of Duke University neurologists in May 2015 when he was four years old. He underwent a series of tests that found nothing.

Then the doctors recommended a new method called whole-exome sequencing, which identifies exons (proteins). Collectively, the exons are called the exome. This test is deemed to be most efficient as generally disease-causing mutations are found in this region of the DNA.

By the time the doctors received the results of the exome test, Caleb, who continued to see other specialists, was no longer able to sit upright without the aid of a harness.

Yet initially the geneticists at Duke announced that exome sequencing found nothing. It was not until Caleb was examined by physicians at the Undiagnosed Disease Network that Caleb was diagnosed with a mutation in his version of the IRF2BPL gene’s code.

Caleb’s Version of IRF2BPL

The NIH founded the Undiagnosed Disease Network (UDN) in 2015 with the goal of bringing research and clinical experts together from twelve sites throughout the nation. The UND intends to meet medical challenges through the use of advanced technologies. And yet of 1,100 cases brought to the UDN since its inception, a diagnosis was found for only one-third.

Duke University is a UDN site. In 2016, two physicians from Duke decided to present Caleb as a UDN candidate after he had been tested but had not received satisfactory results.

The MacKay family traveled to Durham, North Carolina in the latter part of 2016. The UDN paid all expenses including the cost of their traveling to Duke. By that time though, Caleb had to be fed by way of a gastrostomy tube. For one week Caleb underwent a battery of tests.

Analyzing the Exome

Working with the results of Caleb’s test in 2017, Duke’s biomathematician’s flagged a gene called IRF2BPL. It seemed that they found a mutation in Caleb’s version of the gene’s code.

The gene was then sent to GeneMatcher which is an international database. This, in turn, led the researchers to a French team that was able to match other patients who had the same symptoms and the same mutation

Six patients were identified (five boys and one girl). Two live in France, one lives in Arizona, a patient in Germany, and one in California. Caleb was the sixth patient. He lives in North Carolina. The majority were ten years old or younger. One patient was twenty years old. Another patient had died recently due to a seizure.

Caleb’s mother, Cassidy, observed the similarities among the six children. They all began to develop normally. However, when they were between the ages of 30 months and until they were four years old, they began to regress in growth and speech and had other developmental delays. Yet their MRIs were normal.

At this juncture, three children have had to use feeding tubes, yet none of the children have significant issues with major organs such as kidneys, lungs, or heart. Several children were found to be at risk for seizures.

Manuel Martinez

Almost immediately after his appointment with Eli’s parents, Dr. Graham was asked to stop in and examine twenty-year-old Manuel because his doctor was unfamiliar with a recently discovered mutation on a gene called IRF2BPL.

The patient’s medical history sounded all too familiar to Dr. Graham. Manuel had a normal birth but was slow to crawl and walk. There were noticeable issues with his speech when Manuel was four years old. But now, at age twenty, he used a wheelchair and tube-fed.

Manuel’s mother had the burden of taking care of him during the day while she worked nights at a local market.

PART II   A Community of Proactive Parents

About Cognitive Testing

The search on the GeneMatcher allowed Caleb’s parents to be able to compare Caleb’s condition with others. It also put Cassidy on notice to be aware of the risk of seizures.

Caleb was the only child who had cognitive testing. The physicians used eye blinks or pointing to demonstrate his level of understanding. This was a help to the other families when they heard that his cognitive test results turned out to be near normal. It will enable them to have a better understanding of their own child’s comprehension.

Alex You

Alex was born in 2005. Although he was healthy at birth, he slowly began to show signs of missing growth milestones and had difficulties with his speech.

Caroline, his mother, often mentioned it to doctors who did not seem to be concerned. One doctor noted only a ‘global delay in development,’ but Caroline saw his symptoms increasing.

Caroline scheduled additional visits to specialists who recommended physical therapy. Yet Alex’s falls became more frequent. One fall required a visit to urgent care. The orthopedist who attended to Alex at urgent care jokingly commented after looking at his chart that Caroline should consider tying him to a chair. At that point, Caroline was convinced that the doctors had no idea how to treat Alex. His ability to eat had diminished to a point where he had to have a tube inserted called a gastrostomy tube.

Caroline had heard about genetic testing and decided to have Alex tested in 2012. The initial tests came back without a match to any disease. The parents continued their search for the cause of Alex’s symptoms.

In 2014 Caroline founded a family support group for undiagnosed rare diseases. Through this group, she became acquainted with Leo Enoue and his family.

Again, in 2015, Alex was tested by a neurologist in San Diego who ordered whole-exome sequencing but found nothing significant.

Leo Enoue

By the time Leo was 30 months old he was only able to say ‘papa’ and ‘mama’.  According to his mother, Yumi, Leo was able to walk and run, but his gait was off somewhat.

The Enoue’s family had been searching for a diagnosis for years. They flew back to their native Tokyo in 2012. Leo was examined at a prominent children’s hospital in Tokyo but was not given a diagnosis.

In 2017 the Enoues took Leo to a muscular dystrophy specialist in Los Angeles. Although he was unable to diagnose Leo’s disorder, he referred the Enoues to Dr. Nelson, the physician who consulted with Dr. Graham about Manuel. They decided to retest Leo.

Finally, after Leo’s second whole-exome sequencing the doctors found a mutation in IRF2BPL. The Enoues announced the findings at a meeting of their support group. When the Yius heard of Leo’s diagnosis they brought Alex to be tested. The test proved positive, and Alex was recognized as the fifth U.S. patient with a condition related to IRF2BPL.

Moving Forward

Although the children have continued to experience more symptoms, their parents continue to move forward.

Leo recently had surgery to remedy his constricted legs.

Caleb had to spend considerable time in the hospital the entire year. His family had to cancel their plans to take Caleb to Disney World for his birthday.

Alex has been coping with severe respiratory issues.

Eli appears to be in a holding pattern. His mother is aware that it is only temporary unless a curative drug is developed. The family is preparing to find a home that would be more convenient and would not require carrying Eli up a flight of stairs.

The parents have not given up. According to reports, Cassidy was able to keep a school open that Caleb loves. The school is designed to meet the needs of medically fragile children. Caleb attends every day with his service dog.

Other parents also plan to stay in touch through the support group.