To a trained eye, the chromosome chart (karyotype) above has 4 irregularities, circled in red. Theyre chromosome pairs of uneven size.
The chromosomes represent genetic material missing or extra, but also a beautiful girl. Her father contacted me after he read my recent post about a friends child with a rare mutation in a single gene, a more typical driver of so-called diagnostic odysseys. Did I have any insight on treatments for his daughter? Hed send her lab reports.
The notations were in Hebrew, but the universal language of chromosome charts spoke clearly to me. The chromosome pairs are size-ordered, its members matching, but pairs 9, 14, 15, and 16 look like tall and short dance partners. This was something more profound than a single gene glitch, or even a missing or extra chromosome.
Shattered and Scattered
Aviya has an exceedingly rare condition called chromothripsis, which is Greek for shattered colored bodies. Breaks that sever both strands of the DNA double helix riddle one or more chromosomes. Lost pieces may have been ejected and glommed onto other chromosomes at or before fertilization, creating the karyotype that veers from the neat, normal, 23-pair organization.
Chromothripsis is best studied in cancer cells, where the genome is shot to smithereens, but only a few dozen people in the world are known to have it in all their cells. When the medical team at Schneider Childrens Medical Center in Israel discovered the childs condition, they told the parents that only 30 cases had been reported in the medical literature. Ever.
For some of the cases, researchers deduced how chromosomes broke long ago, in developing eggs. Since human eggs sit in an ovary for dozens of years before they mature at the moment of fertilization, enough time elapsed for natural DNA repair to fix some of the breaks and fill in small deletions.
In the few cases of fetuses surviving chromothripsis, enough of the genome must have been knit back together, even if in the wrong places, to sustain development and life. Sperm mature much too quickly, over a few months, to heal themselves in this way.
So a person with chromothripsis is about as rare as rare can be. Each case is unique, for the genomes of no two people that come apart in this highly unusual manner are stitched back together in exactly the same way.
The Diagnostic Odyssey
Aviya is now just past her second birthday and is beginning to walk, although she doesnt yet talk. Her symptoms unfolded early and rapidly, about 3 months after her birth in May 2017.
She started throwing up multiple times a day and regardless of how much or what she ate, breast milk or formula, she would not gain weight. She wasnt reaching developmental milestones. The physical therapist noted her hypotonia (low muscle tone, or floppiness), her dad recalled. Her weight steadily dropped, as the vomiting worsened.
Hospital stays followed. Tests and scans ruled out intestinal malrotation, while neurological tests and abdominal ultrasounds were normal too. Doctors inserted a nasogastric tube, for nutrition.
At 7 months old, Aviya started at the failure-to-thrive clinic at Schneiders, where she had tests and evaluations for physical therapy (PT) and occupational therapy (OT). She also met with an eating specialist.
Everyone poked and prodded and measured and checked. She had blood tests, gave stool samples, had CT scans, MRI images, and drank stuff for x-rays through the GI tract, Yosef said. The doctors initially suspected malrotation of the intestines behind the vomiting, but that didnt hold up. They didnt find any evidence or suspicion of anything amiss based on symptoms only, he added. Heart, brain, blood, all looked ok.
The next step: probing genetics. A chromosomal microarray test (CMA; for small deletions and insertions) and a karyotype revealed the four unusual chromosomes, deemed a complex chromosomal rearrangement. Tests for selected single-gene conditions, like Beckwith-Wiedemann syndrome, were negative.
Further analysis led to the chromothripsis explanation. Because the parents CMA tests and karyotypes were normal, their daughter hadnt inherited her unusual chromosomes they originated in her, likely an ultra rare event in a lone developing egg, followed by spectacular natural healing.
But deducing chromosomal origins and even contemplating whether a gene therapy might be possible for a situation so complex took a backseat to addressing Aviyas daily challenges. First, she had to be able to eat.
Focusing on Symptoms
Vomiting send Aviya to the hospital regularly. For 9 months she received supplemental feedings through a nasogastric tube, and the frequency of episodes slowed as she slowly gained weight. When the gaining once again slowed, and days-long bouts of vomiting led to more hospitalizations, doctors performed a procedure called PEG (for percutaneous endoscopic gastrostomy). A tube through the abdominal wall into her stomach now delivered nutrients. That was done on March 5th, 2019.
The vomiting finally ceased and Aviya has reached the 10th percentile in body weight, up from inexorably losing. Shes also catching up on gross motor skills and reaching developmental milestones. And shes intelligent. She understands basically everything you tell her, for the level of a 2-year-old, Yosef said. Thats pretty amazing considering the number of unusual chromosomes and how many genes affect brain function.
But boosting nutrition isnt the only intervention helping Aviya to overcome whatever limits her chromosomes have set. Yosef credits her overall improvement to the excellent care shes been receiving at a special education day care program near their home on the West Bank. Shes been attending since November, and she gets PT, OT, speech therapy, and does specialized exercises tailored to her abilities. Aviya also returns to the failure-to-thrive clinic every other month, down from once a week.
Instead of Fixing Genes, Address Symptoms
When parents become sucked down the rabbit hole of rare diseases, they quickly learn about biotech approaches: enzyme therapies, stem cells, antisense oligonucleotides, gene therapy, and even gene editing. Its overwhelming. Some of the parents DNA Science has featured rapidly became nearly as expert as some of the scientists developing new treatments (see Celebrating the Moms of Gene Therapy).
Would exome sequencing shed any more light on the situation, or it would just lead to more questions that no one has the answers to? Yosef asked me. Exome sequencing, which reveals the information in the part of the genome that encodes protein, might actually provide too much information, noting too many missing genes to consider treatments for all of them. But it might reveal which proteins Aviya cant make, and maybe that could lead to something.
The TMI issue also affects the utility of a gene therapy for chromothripsis: too many targets.
Specific mutations in single genes cause the conditions for which gene therapy has been FDA approved Luxturnato treat a form of inherited blindnessand Zolgensmato treat spinal muscular atrophy (SMA). The cost of gene therapy for now is prohibitive, although the manufacturers help with patient access. Zolgensma recently made headlines for its $2.1 million price tagand Luxturna for both eyes is about $850,000. The gene therapies, though, are intended to be one-and-done, or at least just in need of a booster. And the alternatives, in these two frontrunners, are blindness or death.
Given the cost of gene therapy and its restriction to genetic disruptions far simpler than the chaos of Aviyas chromosomes, its great that standard therapies are having an effect.
Shes been improving by leaps and bounds in everything, from how much she eats to what shes willing to try to her understanding of everything. Shes just so much better, since the PEG and beginning the special ed day care. She eats more, theres more variety to her food choices, and shes willing to try anything, Yosef said.
He knows that no research team or company is going to pursue a treatment for a sample size of one. What were doing is the best we can do. Its working, so if it aint broke dont fix it. If we find something else to do, then for sure well do it, but in the meantime, were doing the best that we figured out for now. Well see what the future holds.
So Ill end with a shout-out to the supportive therapies that help so many. Even after a sophisticated gene therapy that takes years, if not decades, to take to a clinical trial, supportive therapies are critical to maximizing any effect, on a daily basis. Perhaps no one knows that better than Lori Sames, whose daughter Hannah had gene therapy for giant axonal neuropathy in 2016. (See After Gene Therapy: Hannahs Journey Continues).
PT is incredibly important! When Hannah was a toddler and developed low muscle tone, our first sign something was wrong prior to her diagnosis, her first physical therapist emphasized how important it was to let her do everything. Do not pick her up and put her in her car seat. Open the door of the minivan and let her crawl in and hoist herself up into the car seat. Let her walk. If shes tired and asks to be carried for a bit, carry her for a bit. Keep her as active as you can for as long as you can.
Hannahs PT continues today. While standing, she does squats, leaning back as if shes sitting but powering back through to a stand before she touches the seat. Were trying to keep her hips and quads and hamstrings strong. We have her stand twice an hour and shes in the EasyStand device at least an hour a day. This is critically important for her internal organs and bone density, Lori recently told me.
Aviya is a wonderful, spirited child.
Shes a fun-loving, constantly happy kid, even though she has spent more time in the hospital then most people I know. Even while she was hospitalized she would always smile at the doctors and nurses and play with the other kids, with as much energy as she had. She loves taking things out of and putting them into bags or boxes. She loves hugging dolls and pretending to feed them. She loves playing outside with plants and watching ants going back and forth. She loves to be part of everything and to crawl around the house, and loves when people talk or sing to her and she talks and sings back, said her father.
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