Caring for one child with a rare and unknown medical disorder is a challenge for parents and doctors. But when three additional children in the same family are found to have related health problems, all involved are faced with a medical quandary for which some answers have only recently been found through genetic research.
Newell and Becky Belnap learned their youngest son, Seth, 6, had a rare mitochondrial disease in 2010, when he was four. In 2012, they learned that their other children, Sydney, 18, Spencer, 15, and Sierra, 10, all had at least one copy of the recessive gene causing the disease, as well as related symptoms.
Newell says that while the news was devastating, the couple had faith that the doctors and researchers working on their case at the Translational Genomics Research Institute (TGen) in Phoenix would provide some answers.
The Belnaps along with children with rare or unknown disorders of 50 other families are the first patients of the Center for Rare Childhood Disorders (C4RCD), which opened in October at TGen.
The center is an extension of TGen’s mission to apply the research of genome sequencing to the medical needs of individuals, says Matthew Huentelman, an associate professor in the neurogenetics division at TGen and the co-director for the center. Rare childhood disorders that are not easily diagnosed are more likely to be caused by genetics, he says, because there are minimal environmental factors to consider as alternative causes.
Searching for answers
The Belnap family came to TGen at the recommendation of Vinodh Narayanan, a pediatric neurologist who also has had a practice and done research at Barrow Neurological Institute. Narayanan is medical director of the center and will continue his practice at a new clinic, operated by TGen, opening soon in central Phoenix.
“TGen gave us a gift finding the gene,” Newell says.
Though most patients and families do want treatment and a cure for disease, it turns out that knowledge and information are just as important.
Renee and Scott Valint spent more than 10 years seeking a diagnosis for their daughter Shelby’s condition. They traveled the country to see specialists who poked, probed, performed biopsies, but could not discover the cause of Shelby’s increasing muscle weakness and failure to grow and develop from infancy. The couple felt hopeless watching Shelby get weaker, not knowing what was causing her illness, Renee says.
Late in 2010, Shelby, her parents and three older sisters went on a Disney cruise hosted by the Make-a-Wish Foundation, which grants the wishes of children with life-threatening diseases.
During that same time period, Narayanan sent tissue samples from Shelby for genetic sequencing at TGen. Researchers targeted a gene that controls production of dopamine, a neurotransmitter that directs motor neurons in the brain. Without dopamine, skeletal muscles weaken and eventually muscles that control vital organs fail to work. The destruction of dopamine-producing cells in the brain is what leads to Parkinson’s disease. Narayanan and the Valints feared that Shelby’s inability to produce dopamine would further her decline and necessitate the use of a ventilator to keep her alive.
The discovery of her genetic disorder at TGen led Narayanan to treat her with medications used for Parkinson’s patients starting in December 2010.
Shelby got out of her wheelchair by herself for the first time in March 2011, after three months of drug therapies tailored to compensate for her rare genetic disorder.
Steven and Shannon Laffoon lost their son last July due to a genetic disorder that disrupts normal fat metabolism in cells. Wylder was three years old. He was diagnosed at seven months with Niemann-Pick Type A, affecting fewer than one in a million infants, Steven says.
The disease is characterized by an enlarged liver and spleen, as well as damage to the nervous system. It is caused by a recessive gene, so Wylder inherited a copy from both his parents. Though his genome was not sequenced at TGen, his diagnosis relied on knowledge gained in genetic research. And his parents say they believe the best chance for a cure is in the advances being made at TGen and the Center for Rare Childhood Disorders.
The Laffoons are active in their support of the center to honor their memory of Wylder.
“We’re glad it’s a local institution like TGen,” Steven says, having traveled across the country in search of medical treatment for his son, as the Valints did for Shelby.
Harnessing sequencing power
David Craig is a co-director of the center and has been a researcher in the neurogenomics division focusing on childhood disorders since 2003. He says the incidence of rare childhood disorders is higher than one might think.
“It’s in the realm of one in 200 (births), and if you want to include autism, it’s even higher,” he says, “because autism is enveloped by this group.”
Craig and Narayanan say that autism is a very broad diagnosis for several hundred disorders, mostly genetically caused. Children with autism often have other, more life-threatening physical problems.
While it is usually diagnosed psychiatrically, behavior is only one aspect of the medical issues they face. Changes to the diagnostic codes have caused greater numbers of autism diagnoses.
“They may have seizures, or GI (gastrointestinal) problems,” Craig says, “And our approach is to focus in on the individual differences and identify the best therapy for each individual.
“These disorders teach us a lot about how we are going to do individualized medicine down the road, in a way that allows us to learn on safe footing, knowing that in these cases there is really underlying genetics that dominates over environmental factors.
“Our road is going to involve research, but we’re actually getting the research to the clinic, and we’re seeing the early stages of success for individualized medicine,” Craig says.
Narayanan says traditional medicine has based diagnosis and treatment on symptoms, sometimes getting stuck on the name of a disease, and with symptoms lumped together.
“We could only look at the diseases as if looking at the earth from outer space, a blue ball,” Narayanan says.
Craig says that prior to 2006 or 2007, the technology to find the individual or genetic causes of disorders was not very accessible.
“Next generation” genome sequencing technology became available at that time, he says.
Even now, “the ability to sequence a genome is powerful, but it’s a fairly big challenge to interpret it,” Craig says.
This April was the 10th anniversary of the first human genome sequencing. It was a product of the Human Genome Project, a multi- lateral, international effort that took 13 years and $3 billion.
“There are three billion letters or codes in a single human genome,” Huentelman says, “so that’s $1 per letter.”
This year is also the 60th anniversary of scientists James Watson and Francis Crick describing the double-helix structure of DNA, the genetic code for all life forms.
Today, using next-generation genome sequencing machines and technology, TGen can sequence an individual’s genome in 27 hours at a cost of about $10,000. Exome sequencing, which only looks at genes known to provide codes for protein synthesis, is more commonly used in genetic diagnosis, Narayanan says, and it costs about $7,000.
Huentelman says that faster technology and lower cost make it possible to have more genomes to study and increase knowledge and accuracy of the data produced by researchers.
For individuals, the decision to have genetic testing needs to be weighed, Craig says.
“You always want to think about whether the genetic testing is helpful and constructive,” Craig says. If testing indicates a gene related to a disease, but no treatment is available, “That’s not helpful,” he says.
“We are a product of genes and environment, we respond differently to different treatments, we are fundamentally different,” Craig says.
These differences in genes and the response to treatments is the basis for individualized or precision medicine, Craig says. Genetic testing and research allows doctors to treat patients at the molecular level, targeting the specific causes of a disease for them.
“We don’t understand every part of our genome. There are 4 million differences between each person,” Craig says, “And we only understand those things that are within genes, and that’s about 1 percent.”
With the help of genome sequencing, Craig says that 40 percent to 50 percent of rare disorder cases are diagnosed now, as compared with perhaps 10 percent previously.
Some disorders still have no treatment or cure, he says.
Answers — even when it’s too late
“Some cases, like Shelby’s, have treatments, some have paths that will help them get better, and then there are cases that are really tough and we don’t have treatments,” Craig says, “We’ve found that all of those paths are really important for the family because it allows them to manage – and not question – ‘Is there anything more I could have done?’”
Craig says one mother, whose son died before his third birthday, was surprisingly appreciative of getting a diagnosis for her child even though it was after he died. She told Craig she was glad to know the cause of her son’s disease and thought if she’d known sooner, she would have spent more time just being with him, including feeding him marshmallows whenever he wanted, instead of pursuing medical answers.
“This story is hard, but if you don’t have an answer, it’s harder,” Craig says.
One benefit of a diagnosis is being able to communicate with other parents and families facing similar health problems for information and support, Craig says.
Narayanan says that personalized medicine promotes understanding of specific gene and cell interactions.
Rare disorders and diseases also offer an opportunity for fast-track drug development, Craig says.
Translational Drug Development (TD2), a division of TGen, creates drug therapies for cancers and other diseases that target each patient’s cellular and molecular processes in the disease. The U.S. Food and Drug Administration allows this fast-track drug development for rare and individual cases. The benefit to medical knowledge and the drug companies is the opportunity to observe a direct cause and effect between the drug and a specific, known gene function. Craig says the development of statins to control cholesterol came from this approach.
Narayanan says that Becky and Newell Belnap both have the same mutation on the gene that causes mitochondrial disease, which affects Seth and Sydney because they inherited both copies. Spencer and Sierra each have one copy, and while Sierra has shown no symptoms, Spencer has developed some muscle weakness and experiences migraine headaches, as do his parents and some siblings. Narayanan says these differences are due to phenotype variations, but not enough is known to predict or completely understand the variation in symptoms experienced by the Belnaps.
The best treatment he can offer them is called a “mito cocktail,” for its intended target of mitochondrial processes in the body’s cells. It is a combination of vitamins and supplements, including folic acid that has helped Seth in particular.
The Laffoons now have the knowledge of the recessive, but deadly gene they each carry in their genome. They say the experience of having Wylder in their lives, even for just three years, encourages them to have another child. This time, they are able to use their knowledge and medical technology to select egg and sperm that are free of the problem gene, even before conception.
Narayanan says the analytical tools and research staff at TGen are speeding up and improving the diagnosis and treatment of rare disorders and all of the individual variances in known diseases.
“Though not quite mainstream, and still done in a research environment, there’s no question it’s completely changed medicine.”
For children and parents of the Center for Rare Childhood Disorders, information gives hope and some peace of mind.
As Steven Laffoon says, “An answer alone is critical.”