It started with a horrible, high-pitched wheezing, a sound unlike anything Laurian Scott and her husband, John, had ever heard, and it was coming from their 16-month-old daughter, Thisbe, as she gasped for air. After that Thanksgiving in 2005, that sound—a symptom of what the Scotts would later learn was a rare genetic defect—would become a familiar, terrifying part of their life.
From Normal to Nightmare
The Scotts had been married barely two years when Thisbe was born. She was Laurian's second daughter (she had an 11-year-old from her first marriage) and John's first. The pregnancy and delivery had been normal, as were Thisbe's first 16 months.
So nothing had prepared the Scotts for the ordeal they would soon experience. Thisbe's wheezing, also called "stridor," worsened throughout the week after Thanksgiving. At first, doctors thought the toddler had swallowed something that was interfering with her breathing, but when tests showed no signs of a blockage, they told the Scotts it was probably something viral.
By January 2006, however, Thisbe could no longer breathe on her own. Doctors suspected a neurologic cause, but had no idea what it was. To help her breathe, they inserted a tube through Thisbe's neck into her trachea and put her on a ventilator. The Scotts had to suction fluids from their daughter's lungs several times a day so she wouldn't develop pneumonia.
A Fatal Diagnosis
When the Scotts took Thisbe for a second opinion, the neurologist they consulted was also perplexed. After a visit to a third doctor, a pediatric neurologist, their daughter received a diagnosis of Brown-Vialetto-Van Laere syndrome (BVVLS), a rare genetic metabolic and neuromuscular disorder for which there was no treatment. Most children die within a few years of diagnosis. (See "BVVLS: The Basics" below.)
The words fell like a hammer on the couple. Laurian was five months pregnant.
By the time the Scotts' son, Noah, was born in May, Thisbe had lost all muscle control in her face and neck and could no longer walk, talk, or blink her eyes.
A Miracle Farm
On Thanksgiving 2006, exactly a year after her first symptoms appeared, Thisbe started suffocating on a plug of mucus. While the Scotts performed CPR and waited for the ambulance, they vowed that if Thisbe survived, John would sell his business in Phoenix, and they would buy a farm in Tennessee near both their families, where they felt Thisbe could have a better quality of life.
Thisbe recovered, and two weeks later, the Scotts found their farm.
The next few months were memorable, Laurian recalls. "We saw her come back to life," she says. Thisbe even seemed to improve a bit, going the occasional day without the ventilator. But in April 2007 she caught a virus, and no amount of oxygen helped. She died on April 30.
A Second Nightmare
Noah was nine months old when his sister died. A month after her death, his eyelid started to droop. "It sent us into craziness," Laurian remembers. Two months later, she heard the same hideous wheezing sound, the stridor that had started it all.
"It is inexplicable how it feels to hear that noise," says Laurian. "It's a kind of trauma and devastation you can't put into words." This time, however, she knew what Noah had and was determined to beat it.
She read about other treatments for neuromuscular diseases, including intravenous immunoglobulin (IVIG), which contains antibodies collected from the blood of healthy donors. It is often used to treat people who have autoimmune disorders like myasthenia gravis. The IVIG appeared to help initially, and Noah had five good months before he began deteriorating.
In a final attempt to find something to save her son, Laurian met with a hematologist. She recalls talking to the doctor while Noah sat on her lap. "He gave me the best advice I've ever received," she says. "He said, 'No one will help you until you find the gene.'"
Which is exactly what the Scotts set out to do.
The Hunt for the Gene
Within a few weeks of receiving the hematologist's advice, the Scotts created the Thisbe and Noah Scott Foundation (see "A Foundation for Families" below) and planned its first fundraiser.
Laurian also contacted every author of every published case study she could find on BVVLS to ask for help finding the gene. Within days, she heard from researchers in Great Britain and at the National Institutes of Health (NIH) in the United States. Working separately, the researchers sequenced tissue from at least 10 families affected by the disease, including the Scotts, to look for unique gene signatures.
Sadly, it was too late for Noah. His disease progressed, and he died on April 9, 2008, of respiratory distress, just a couple of weeks before the one-year anniversary of his sister's death.
The laboratories all found mutations or defects on the same gene within weeks of one another. The gene, SLC52A3, is a transporter that ferries riboflavin (vitamin B2) from the small intestine into the blood and into cells, where it helps break down fatty acids and produce energy for the metabolism. It is this malfunction that is responsible for the symptoms of the disease.
Since researchers discovered the mutation in 2010, they have identified defects in another gene, SLC52A2, that are associated with the disorder.
Time for Another Baby
When Laurian heard that researchers had found the defective gene, she realized she and John could have another child.
As testing had confirmed the role of the SLC52A3 gene in BVVLS, Laurian and John started pre-implantation in vitro treatments. Doctors harvested several of her eggs, fertilized them with John's sperm, and let them grow in the laboratory until they were a few cells large. They then tested the embryos for the defective gene; six of the 13 had the mutation. Doctors inserted three of the healthy embryos into Laurian's uterus.
Nine months later, she delivered twins, Hattie and Ovid. They are now healthy three-and-a-half-year-olds.
Treatment with a Vitamin
In 2010, Annet M. Bosch, MD, PhD, a pediatrician who specializes in metabolic disorders at the University of Amsterdam's Academic Medical Center, was having her own experience with BVVLS. It started with a six-month-old baby who suddenly stopped breathing while on vacation in Egypt with his parents. He was transferred home to Amsterdam on a ventilator, where Dr. Bosch and others tried to figure out what was wrong.
In the first weeks after he was admitted, Dr. Bosch found a clue: low levels of riboflavin. She thought the low levels might be related to his time in the Egyptian hospital, but started him on large oral doses of the vitamin anyway.
The boy slowly improved, although he remained hospitalized and on a ventilator. After a few weeks of supplementation, Dr. Bosch stopped the riboflavin. When the baby's riboflavin levels immediately dropped, she restarted oral doses of the vitamin. A year and a half after he was admitted, unable to move or breathe on his own, the toddler left the hospital, still needing ventilation but walking like any other 24-month-old. He is now a normal five-year-old, with no long-term effects.
His sister was born two years later. When she was three months old, she began exhibiting the same symptoms as her brother. Dr. Bosch started her on riboflavin, and she recovered fully within days. That's when Dr. Bosch knew there had to be a gene involved. Independently of the ongoing work of the UK and US groups, her laboratory identified the same defective gene—the one that transports riboflavin to the small intestine. She published the finding in 2012 in the Journal of Inherited Metabolic Disorders.
In fact, riboflavin's correlation with BVVLS led to a change in the disorder's name: "riboflavin transporter deficiency."
Raising Awareness
Today, Dr. Bosch's protocol for using riboflavin in children with BVVLS is posted on Riboflavin Transporter Deficiency, International. Dr. Bosch has also made it her mission to get the word out about riboflavin, sending emails to every clinician who has ever published anything on BVVLS.
As with many rare disorders, however, the small number of patients makes it difficult to conduct large-scale, randomized, placebo-controlled studies to test the therapy. Thus, the only available evidence to support the effectiveness of riboflavin comes from case reports on the children who received it. There is also no information on its long-term effectiveness, notes Dr. Bosch.
"My major aim is to create awareness for physicians so that if it even crosses their mind that this might be BVVLS, they start a patient on riboflavin until they are sure that the patient does not have it," she says. Because riboflavin is water-soluble, meaning the body gets rid of any excess in the urine, "it cannot do harm and it can be lifesaving."
"There's no reason not to use it," agrees Bruce H. Cohen, MD, the interim director of the NeuroDevelopmental Science Center at Akron Children's Hospital in Ohio, a Fellow of the American Academy of Neurology (FAAN), and a member of the Neurology Now editorial advisory board.
He often uses the vitamin for children with similar diseases, so when he began treating a child in 2009 with what other doctors suspected was a mitochondrial disease, he started the patient on riboflavin. Genetic testing eventually led to a diagnosis of BVVLS. Today, the girl is stable, says Dr. Cohen. Her sister, who also has BVVLS and is being treated with riboflavin, still has numerous problems, however.
Nowadays it's much easier to do genetic testing, thanks to improved technology and lower costs, says Dr. Cohen. Indeed, until 2007, there were few laboratories that could test for rare disorders, much less perform non-targeted genetic testing. Previously, doctors had to diagnose BVVLS based on the patient's symptoms.
Today, Laurian finds herself wishing Dr. Bosch had been Thisbe's and Noah's doctor.
Dr. Cohen understands Laurian's regrets. But rare diseases like BVVLS are notoriously difficult to diagnose, he says. Even with genetic testing, a diagnosis is confirmed only about 25 percent of the time.
Brown-Vialetto-Van Laere Syndrome: The Basics
Brown-Vialetto-Van Laere syndrome (BVVLS), named for the physicians and researchers who first identified it, is an extremely rare genetic metabolic and neuromuscular disorder marked by loss of nerve function, breathing problems, muscle weakness, and deafness. It was initially considered to be an infantile form of amyotrophic lateral sclerosis since both involve severe, progressive muscle weakness.
Before 2010, the condition was diagnosed based on symptoms alone. Today, however, doctors can use DNA testing to confirm its presence, says Bruce H. Cohen, MD, the interim director of the NeuroDevelopmental Science Center at Akron Children's Hospital in Ohio, a Fellow of the American Academy of Neurology (FAAN), and a member of the Neurology Now editorial advisory board.
The disease appears in children, sometimes just weeks after birth. Others are not diagnosed until they are school-aged or even in adolescence. The most common symptoms in younger children are severe muscle weakness and breathing difficulties; without treatment with riboflavin, most die within a year. In older children, the most common symptoms include deafness and progressive muscle weakness in the face and jaw. Without treatment, older children with the syndrome typically die within a few years of diagnosis.
Fewer than 100 cases of BVVLS have been identified in the scientific literature, although more likely exist.
Despite progress, many questions remain, says Annet M. Bosch, MD, PhD, a pediatrician for metabolic disorders at the University of Amsterdam's Academic Medical Center. For instance, no one knows for sure whether riboflavin supplementation is effective long-term, or if it works in every patient.
Researchers are also trying to identify the specific parts of the defective genes that contribute to the disease. However, due to the rare nature of the disease, it is unlikely that children would be routinely screened for the genetic mutations unless they had a sibling with the disease.
A Foundation for Families
The Thisbe and Noah Scott Foundation focuses on all pediatric neurologic diseases, including BVVLS.
The Thisbe and Noah Scott Foundation was established to promote research, awareness, and support for children and families affected by pediatric neuromuscular diseases. It is currently funding the work of Kevin Eggan, PhD, a professor of stem cell and regenerative biology at Harvard University, who has created an animal model and a cell model of the disease, which can be used to find other treatments and, possibly, a cure.
The Foundation also hopes to create welcome centers in neuromuscular clinics of hospitals that would provide information on these diseases, as well as activities to educate patients. It also teamed with the Gwendolyn Strong Foundation to bring iPads to children with neuromuscular diseases who are in desperate need of communication devices.
In 2014, the Child Neurology Foundation presented the Scotts with its first national parental advocacy award, naming the honor The John and Laurian Scott Hero of Promise Award.