For over 18 years, no one knew why Claudia Digregorio’s muscles were slowly betraying her.
For Laura Keenan, the mystery lasted even longer.
The two women, in their twenties and living in separate oceans, appeared to be perfectly healthy in infancy and childhood. In Italy, Digregorio began to fall around the age of 3. In San Diego, Keenan’s kindergarten teacher noticed that she mostly walked on toes.
In college, both were in wheelchairs and suffered from symptoms similar to those of middle-aged patients with amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease. The progression of ALS, the most common motor nerve disorder in adults, from the first symptom to death may take a few years. These girls progressed into infancy, puberty, high school and adulthood, their skills slowly diminishing.
Digregorio, 22, has been examined in almost every major hospital in his native Italy. Then by doctors from London and Holland. No one had an explanation for what was wrong.
For Keenan, 27, of San Diego, “the torture began” with repeated testing. He was diagnosed with cerebral palsy, followed by spinal atrophy. Neither matched his slowly declining physical condition.
Without the correct diagnosis, no one would be able to figure out how to help them.
Digregorio’s diagnostic mystery caught the attention of a police union, who traveled to the United States in 2015 to be examined by doctors at the National Institutes of Health. Pope Francis gave him a personal blessing before his departure.
The researchers, led by Dr Carsten Bönnemann, identified a genetic misspelling that they believed was causing his symptoms, but they couldn’t be sure. because it was in one person.
Two years later, trying to resolve his health problem, Keenan’s neurologist asked Bönnemann’s team to examine him. Like so many doctors before them, they took blood and skin samples.
Analysis of Keenan’s genes showed that she had a mutation similar to Digregorio’s in a gene called SPLTC1.
Finding another person with a similar mutation on the same gene as well as the same symptoms was the “smoking gun” that Bönnemann and his team were looking for. A worldwide search of the databases found nine younger people with similar symptoms and an SPLTC1 mutation in roughly the same location.
Four of them inherited the genetic error from a parent. In DiGregorio and Keenan, the mutation occurred on its own, shortly before or after conception.
Their condition still didn’t make sense.
Different mutations in this SPLTC1 gene were well known to researchers because they were initially found in six generations of a Pennsylvania family, who with age developed crippling loss of sensation in fingers, toes and skin. Why would a gene known to cause sensory neuropathy in some people trigger ALS in others?
Bönnemann and the team found the answer almost literally across the street.
Teresa Dunn had studied the SPLTC1 gene for years as a professor at Uniformed Services University, a branch of the federal government that sits across Highway 355 from her laboratory in Bethesda, Maryland.
The gene, she explained, is responsible for making a fat-like substance that provides structure to support nerve cells. The Pennsylvania family’s SPLTC1 genetic fluke caused their bodies to produce a toxic protein that damaged their nerve endings.
The Digregorio and Keenan mutations are found on another part of the gene and cause them to overproduce this normal fat-like substance, damaging the nerves and causing their slow decline in muscle control.
“For me, this is a defining moment” to establish all of these connections with a single responsible gene, said Bönnemann. “The power to really look in detail at even a single patient with a rare disease and not let go until the answer is found.”
Their findings may also offer clues to more common forms of ALS, one of the most feared diagnoses in medicine.
“The fact that a very rare disease provided insight into one of the more common illnesses is, I think, striking,” said Robert Brown, neurologist and researcher at the University of Massachusetts School of Medicine in Worcester, who discovered the SPLTC1 gene in 1998 and coincidentally spent his career trying to understand and treat ALS.
Keenan said the discovery gave him more hope for his own future. Her mother, Susan Small, was relieved to learn the identity of the gene. Her other three children do not have the mutation, so they are not carriers of the debilitating disease.
But the discovery didn’t change Keenan’s daily life, which revolves around wheelchairs, breathing apparatus and family support.
She rides an exercise bike every morning for an hour. Then she remains standing for an hour in a device her father designed to keep her upright. A self-proclaimed “Jesus monster,” Keenan studies the Bible. Her beloved chihuahua Lizzee recently passed away at the age of 16, but her chihuahua-Jack Russell mix named Beanie Baby accompanies her on her late-night outings.
“I have a wonderful life,” Keenan said. “Jesus Christ gives me the hope I need to be successful.”
Digregorio’s days are even more constrained by his illness.
Although her mind is intact, she cannot speak more than a word or two at a time. Her parents, Concetta and Gaetano, can understand her, but it is difficult for strangers.
Now that the diagnostic question has been resolved, the real challenge, the two families said, will be finding an effective treatment.
The therapy the Pennsylvania family tried, which triggers the production of the fatty substance, would be a disaster for Digregorio and Keenan. They’ll need a different approach to restore the substance to the proper levels, said Dr. Payam Mohassel, NIH clinical researcher and lead author of the team’s study. study published this year.
“Above all, we want therapy more than anything else,” said Concetta, DiGregorio’s mother. by a translator.
She is extremely grateful that although few people have the same mutation as her daughter, scientists are still working to find a solution.
“We have not been abandoned.”
Contact Karen Weintraub at [email protected]
Patient health and safety coverage at USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competition in Healthcare. The Masimo Foundation does not provide editorial contributions.
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