One in a million

The disease began early for Tyler Clegg.

After a few years of normal development, he began having difficulty swallowing, chewing, eating and keeping food down and he had difficulty moving. Those deficits developed into defined musculature—too defined. It wasn’t normal. He had a hard time moving his legs or arms in a meaningful way and couldn’t learn to walk.

Then the screaming began. Sometimes the spells would last for days. His mother, Jillian, remembers carrying him around the house through the long marches of the night, unsure of what she could do. And in the end, there was nothing she could do. For nine years, there was no answer.

At first, it seemed like Tyler had a mutant disease. Although she consulted her doctor in Pittsburgh, no one could identify what was happening to her son. She resigned herself to never knowing what was wrong with him, praying that when she got to heaven, God would tell her what was wrong with Tyler. Jillian and her husband had another child who seemed to be normal. But then, in 2008, she had twins, Luke and Aiden.

“I knew instantly that Luke had the condition,” Jillian wrote on her website, Hope 4 Tyler and Luke. “Once Luke began progressing the same as Tyler had, the doctors knew.”

Soon, Luke began the screaming fits. He progressed along the same path as Tyler, but with more frequent screaming fits. The Cleggs and their specialist physicians knew that the disease had to be genetic, but there was no definite modus operandi for the condition. It escaped their primary care physician, who became an expert at faxing the two boys’ records to and fro across the healthcare system, desperately searching for a foothold on a diagnosis.

Then, in 2010, the Cleggs were accepted into the National Institutes of Health’s Undiagnosed Diseases Program. Their pediatrician had suggested they apply on a long shot that their case might be accepted. The program receives thousands of applications every year, so the chances were slim, but they were the one case selected and went to the NIH’s facility in Washington, D.C. in June for a week. In that week, the scientists conducted hundreds of tests, MRIs, blood

The NIH called her with a final diagnosis. It’s called Med23 genetic defect, she heard over the phone. It also known as autosomal recessive nonsyndromic mental retardation-18. It is recessive and both parents have to carry it, with a 25 percent chance of passing it to their children. Tyler and Luke are the only two known patients in the U.S., although several members of a family in Algeria were diagnosed with the disease a few years ago.

Although Jillian was flooded with gratitude once she had a diagnosis for the disease plaguing her children, it was the beginning of a long silence. More than a year passed before someone else contacted her about potential treatments for the condition.

Tyler and Luke in therapy. Original image from the Pediatric Brain Foundation, courtesy of Jillian Clegg.
Tyler and Luke in therapy. Original image from the Pediatric Brain Foundation, courtesy of Jillian Clegg.

Tyler and Luke have one of more than 7,000 diseases defined as rare. Theirs is more rare than most, but many suffer from a common issue—there is such a small patient population that they are hard to research. Even when they are researched, pharmaceutical companies may not see a benefit in developing a medication to treat the condition. And even if they do, it is likely to be extremely expensive because of the cost of bringing a drug to market: More than $1 billion in most cases.

The National Organization for Rare Disorders, a nonprofit that advocates for rare condition research, keeps a number of disease-specific funds for research. Although there are dozens of studies and clinical trials focusing on rare diseases, there are not nearly enough to cover the wide variety of disease discovered. One family, the Talaricos, took the idea of funding their own research and ran with it.

Gaby Talarico got her diagnosis in 2006. Plagued by seizures, a type of yeast infection called candidiasis — known as thrush when it infects the mouth and throat — and muscle weakeness, she has a rare genetic disorder called autoimmune polyglandular syndrome type 1, or APS Type 1. She is one of approximately 200 people in the U.S. to be diagnosed with the disorder. Her parents, Todd and Heather, found little research and few resources to help them, so they took off running and founded their own nonprofit advocacy foundation in March 2014. They have so far raised $400,000 to fund three research studies and plan to hold their first symposium on the diseases in Toronto in June.

The gene affected in Gaby’s case is the AIRE gene, located on chromosome 21, which regulates the immune system. It controls the cells on the inner part of the thymus. When there is a mutation, it attacks those cells, causing hypoparathyroidism, which is a hallmark of APS Type 1.

The structure of the AIRE protein. Original image from Wikimedia commons.
The structure of the AIRE protein. Original image from Wikimedia commons.

The mutation of genes seems monstrous, but it literally happens all the time. There are two kinds of gene mutation: hereditary and somatic. Hereditary gene mutations, naturally, are inherited —they begin when the egg and sperm cells meet and exchange information. If one parent’s cell has a misspelling among the adenine, cytosine, thymine and guanine nucleobases, it has a chance of being transmitted across the child’s cells.

The most important part of human evolution has just occurred. Now, most of those mutations will go unnoticed. However, one genetic change may cause something so simple as skin tone to darken slightly. That exposes the person to more sunlight, potentially with the negative effects of ultraviolet radiation from the sun striking their skin. Or, they may be more likely to die younger because of lack of healthcare access based on racial profiling.

But the slow exchange of DNA information changes humans over time, for better or for worse. The worse ones are beginning to draw our attention much more.

“Advances in precision medicine have already led to powerful new discoveries and several new treatments that are tailored to specific characteristics of individuals, such as a person’s genetic makeup, or the genetic profile of an individual’s tumor,” read the White House statement on the Precision Medicine Initiative. “This is leading to a transformation in the way we can treat diseases such as cancer.  Patients with breast, lung, and colorectal cancers, as well as melanomas and leukemias, for instance, routinely undergo molecular testing as part of patient care, enabling physicians to select treatments that improve chances of survival and reduce exposure to adverse effects.”

Soon, Americans nationwide will have access to genomic medicine. The 2015 – 2016 fiscal budget includes $215 million for the initiative, $70 million of which will go to the National Cancer Institute and $130 of which will go to establishing a national registry for genomic information to compare and contrast details. This is a huge boon for healthcare — hundreds of Americans’ genomes have already been sequenced in the 12 years since the Human Genome Project was completed.

A diagram of point mutation, which shows where some of the chemicals of genetics are exchanged and altered. Original image from the National Human Genome Research Project.
A diagram of point mutation, which shows where some of the chemicals of genetics are exchanged and altered. Original image from the National Human Genome Research Project.

For people like Tyler and Luke, those answers cannot come soon enough. Although their diagnosis is final, there is still no treatment. They may have some success with drug trials and treating the diseases symptomatically — antacids for stomach troubles, muscle relaxers for the spasms and sedatives for the screaming — but without definitive research into the condition, there will be no way to treat the systemic disease itself.

However, it raises an ethical question as well. How much can we know about ourselves, and at what time, before it becomes a danger to our behavior?

For example, would you like to know if you’re going to develop cancer in fourteen years based on your genetics? Even if you want to know, does your insurance agency? The massive amounts of information available to us will change the way we approach medicine and possibly even our lives. It will be up to people to determine how much we want to know about ourselves moving forward. The healthcare industry is increasingly using predictive analytics and massive data crunching methods to improve care and reduce costs, so medical professionals will use the data available to them. What is up to us is how we use it and how deep into the weave of our bodies that we look.


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