Rare Disease Day 2019: Roan’s Story
For 2019’s Rare Disease Day, DNA Science honors those who have fragile X syndrome (FXS). It isn’t among the rarest of the rare, yet when health care providers can’t assemble the diagnostic puzzle pieces that parents are practically yelling at them, the statistics don’t matter and the diagnostic odyssey lengthens. Because fragile X is an “expanding repeat” disorder, it lies beneath the radar of standard chromosome and single-gene tests.
The Orphan Drug Act of 1983 in the US defined a rare disease as affecting fewer than 200,000 people. “Orphan” initially referred to pharma’s disinterest in developing drugs with minuscule markets, but was deemed non-PC and became “rare” somewhere along the way. In the European Union, the definition is fewer than 1 in 2,000 people, which is pretty close to the US number. The disinterest in seeking treatments for ultrarare conditions has evolved into doing so, but with sky-high price tags.
A few weeks ago I heard from Desiree Moffitt, who uses my human genetics textbook to teach an online course. She kindly offered to share her family’s story about life with a child who has fragile X syndrome. “Usually the face of disability is a very happy, quirky family. While we are happy and also quirky, our story isn’t as fun,” she emailed me. First, some background on fragile X.
Where Are the Clinical Trials?
When I looked into the status of developing new treatments for this not-so-rare disorder, I was stunned that all I could find were a few preclinical studies (mice and cells) from the FRAXA Research Foundation and 74 entries at Clinicaltrials.gov. Type in “sickle cell disease” and 636 entries appear; Parkinson’s 2,229. So fragile X is still an orphan, it seems.
Most clinical trials for FXS repurpose existing drugs: riluzole (ALS), sertraline (depression), metformin (diabetes), donepezil (Alzheimer’s), acamprosate (alcoholism), minocycline (antibiotic), and lovastatin (high cholesterol), and a few experimental drugs borrowed from ADHD, anxiety, Rett syndrome, and seizures. A promising drug, AFO056, didn’t make it past phase 3. CBD of course is on the list.
There’s a glaring lack of innovation, unless I’m missing something.
No gene therapy, like for blindness, Crigler-Najjar syndrome, “butterfly-children” with epidermolysis bullosa, Sanfilippo syndrome, giant axonal neuropathy, or myotubular myopathy.
No CRISPR gene editing, like is being considered for Huntington’s disease, Prader-Willi syndrome, and sickle cell disease.
No antisense oligonucleotides (like for spinal muscular atrophy).
No exon skipping (like for Duchenne muscular dystrophy).
No protein therapy (like for boys missing hair, teeth, and sweat glands due to hypohidrotic ectodermal dysplasia, and for those with PKU).
And these links are just for my posts on these technologies.
An Expanding Triplet Repeat
Fragile X syndrome affects one in every 2,000 males and one in every 6,000-8,000 females, so it is on the cusp of rarity. FXS is the most common inherited form of intellectual disability. As the #1 single gene cause of autism, FXS accounts for 3 percent of cases, and about a third of people with FXS are on the spectrum.
The first inklings of FXS in the 1940s partly explained the preponderance of males among those with intellectual disability (then called mental retardation). Geneticists attributed it to the X chromosome, the second of which in females is presumably protective. A girl or woman with fragile X typically has mild symptoms.
In 1969 a clue emerged. Two affected brothers and their mother each had an X chromosome with a constricted tip. When the cells were cultured in medium lacking folic acid, this part of the X seemed to dangle by a thin thread and was prone to breaking—hence, the name.
FXS starts early, with brain differences on MRI scans apparent by age 2. By young adulthood, the face lengthens, with a pronounced jaw and protruding ears. Testicles are oversized. Learning disabilities, repetitive speech, hyperactivity, shyness, social anxiety, a short attention span, language delays, and temper outbursts are also part of the clinical spectrum.
The inheritance pattern is complicated. FXS should be transmitted like any X-linked trait, from carrier mother to affected son. One-fifth of males who inherit the fragile chromosome don’t develop symptoms. But because they pass the chromosome to all of their daughters—half of whom have some mental impairment—they’re called “transmitting males.” His grandchildren may inherit fragile X syndrome, even if he’s unaffected.
Another mystery is that maternal grandfathers of affected boys may develop the tremors, balance problems, cognitive or psychiatric difficulties of FXTAS, for fragile X–associated tremor/ataxia syndrome. Hold that thought …
Normally the fragile X area includes 29 or 30 repeats of the DNA sequence CGG, in a gene called the fragile X mental retardation gene (FMR1). But in people who have the fragile chromosome, the gene balloons to 2,000 CGG repeats – a classic expanding triplet repeat mutation. But there’s a middle ground. Transmitting males and females with mild symptoms or who have affected sons may have a “premutation” of 55 to 200 repeats, which may cause mild symptoms, such as tremors and poor balance. About a fifth of women with the premutation have infertility due to ovarian failure.
The FMR1 gene encodes a protein that, when too bulky, blocks other proteins that are crucial for brain neuron function. But facts and figures can’t adequately describe what it’s like to raise a child with a rare disease. A parent can.
“Roan was born in November of 2012 and diagnosed with FXS at 8 months. He has very typical features, such as large ears and almond-shaped eyes, but he’s also beautiful,” said Desiree.
Roan had a few troubles from the beginning. He couldn’t suck and at two weeks he started screaming, for hours. “Within 2 months he was diagnosed as failure-to-thrive after falling completely off the growth chart. We struggled as parents to keep it together,” Desiree recalled.
The doctors noticed a few oddities: large ears, a single palm crease, a dimple at the bottom of his spine. When Roan was three months old, a pediatrician finally ordered a chromosome check. It was normal – without removing the folic acid, the telltale fragile X wouldn’t show up.
“By this time, Roan had been hospitalized twice for failure-to-thrive, dehydration, and constant screaming. We tried every reflux medication known and finally got approved for Nexium, which did work, but didn’t quiet the screaming,” Desiree said.
In the summer of 2013 Desiree and her husband Jacob found a pediatrician at the University of North Carolina who referred the family to a geneticist, but with an appointment 6 months out. “Roan was 7 months old and had missed his first milestone, sitting up. I was struggling so much with him I hadn’t even noticed.”
Desiree started digging into the family history, beginning with her stepmother. Was there anyone with a genetic condition that she knew of?
Clue #1: “My father’s brother was born in the 1950s but died in the 1970s of a seizure. His ears were normal-sized and his eyes looked typical. I’d been told that his condition was due to a virus, but I began to examine my uncle more closely.”
Clue #2: Her stepmother mentioned a distant relative who had a child with a condition called fragile X. “I’d heard of it, but didn’t know anything about it. I read as much as I could and then built a pedigree back to my great-grandparents. And everything started to make sense,” Desiree remembered.
Clue #3: Desiree’s father had FXTAS. He’d been in the military for 28 years and retired about a decade before Desiree began unearthing the family history in 2013. He’d recently started a job driving for FedEx but had problems. “He backed into a mailbox and then a tractor. After reading as much as I had about fragile X, I knew my father had FXTAS. He participated in a research study with Dr. Randi Hagerman and it’s been confirmed.”
When that third puzzle piece dropped, Desiree called Roan’s pediatrician and asked for a FXS test for her son – but the doctor said to wait months for the meeting with the geneticist. “By two weeks I was beside myself so I contacted her again, and she agreed after I started crying on the phone while explaining everything I had found. She ordered the test.”
Parents of children with rare diseases never forget where they were when they got the bad news. Jacob and Desiree were walking in a pasture with their son in a backpack carrier when her phone rang at about 5:30.
“I was surprised to hear our pediatrician outside of business hours. She said she wouldn’t normally deliver results over the phone, but we were a unique case and she felt comfortable because I fully understood what we were looking at,” Desiree said.
Roan had tested positive for FXS. “I don’t remember the rest of the call. I remember falling to my knees. What you imagined your life would look like, what you imagine your child’s life looking like, dies. It crumbles.”
The therapies began: OT, PT, speech therapy, and feeding therapy because he wouldn’t eat. The parents tried one anti-anxiety med after another.
By 3 Roan was diagnosed with autism. He found comfort from walks in the woods, seeming to soak in the sounds of the crinkling leaves and the vivid colors and smells.
At 4, Roan became aggressive.
Then he began attacking his now-16-month-old twin sisters when they were 5 months old, and lashing out at his parents. (Prenatal diagnosis is available for those who know of a family history). Desiree, who works from home and cares for the kids while Jacob goes to work, couldn’t handle it. But their family, along with 12,000 others in North Carolina, is waitlisted for the Innovations Waiver to receive Medicaid services that they need for Roan to remain at home. This NPR report tells of their plight.
Finally when they could no longer control his behavior, the couple took Roan to the ER, and he was hospitalized for a few days to adjust his meds. Then respite plans for the distraught parents to figure things out fell through. So the boy now lives at a psychiatric residential treatment facility in South Carolina, where he receives medication and behavioral intervention.
While Roan’s future is uncertain, his parents’ devotion is unwavering. Said Desiree, “We love Roan intensely. He will always be our most vulnerable child.”
Fragile X Syndrome Facebook group
Thank you for such a wonderful post, Dr. Lewis!! This means a lot to our family and the fragile x community!
Please do all you can to assist theses families – this is heartbreaking stuff. I would be more than willing to assist with processing research data.