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Tuesday, April 04, 2017

Diagnosing a Rare, New Childhood Genetic Anomaly

"Nobody could give us a diagnosis, so he was passed from one specialist to another over the years and various people did various tests."
"He[her infant son] showed signs of so many different diseases.They tested him for Crohn's disease, ulcerative colitis; it turned out not to be either."
"Daniel was over the moon to get a diagnosis. When they found out what was wrong, it was a real relief. In his mind, it's all about the cure. Now that there's a diagnosis, there's now going to be a cure."
"While we have never let his illness define him, and he remains a very positive and energetic boy, it was always on the back of his mind."
Christina Arulrajah, Toronto
Daniel suffered a stroke at four weeks old. (Christina Arulrajah)

"All the doctors thought that he must have a genetic cause to his disease."
"ARPC1B, we know, plays a very important role in the immune system and how different cells int he body -- mostly found in the blood -- work."
"Sometimes it's surprising that one defect causes such widespread different types of disease in one patient, but this one mutation explains all the problems Daniel had."
"It [identifying the genetic mutation] gave us enough evidence to know that this was a brand-new disease that hadn't been described before."
"If you do a bone-m,arrow transplant or you replace his immune system, this should cure him of his disease."
Dr. Aleixo Muise, gastroenterologist, Hospital for Sick Children, Toronto

Daniel Nevins-Selvadurai's painful symptoms baffled doctors at Toronto's Hospital for Sick Children for years.
Daniel Nevins-Selvadurai's painful symptoms baffled doctors at Toronto's Hospital for Sick Children for years. (Hospital for Sick Children)

Bad enough to realize that a child has serious and puzzling symptoms of things going dreadfully awry with his body imperilling the state of his health and possibly his very existence. At the ripe old age of three, little Daniel Nevins-Seivadurai had blood in his stool, which might have been a harbinger of inflammatory bowel disease he could have inherited. Yet when specialists performed tests related to all the genetic mutations the condition was linked with as causatives, they all were returned negative.

At four weeks of age, Daniel had symptoms of an illness that his mother took to be influenza. He was rushed to Sick Children's Hospital in Toronto where examining doctors informed his mother that her baby had suffered a stroke. The baby recovered fully but he also became a frequent visitor to SickKids as a patient with a weak immune system and a rising roster of painful symptoms such as stomach problems, blood in his stool, and rashes and infections resulting in sepsis.

And as the child grew older the symptoms bedevilling his parents and the doctors examining him were more diverse in character with the added development of unusual rashes and the appearance of lumps in his legs that were painful. He also had an abnormally high white cell count, along with low platelets in his blood. Clearly pointing doctors in the direction of a problem they were unable to identify, with his immune system.

The specialists who were engage in attempting to discover the source of Daniel's problem represented those whose expertise was in blood disorders, cancer, rheumatology, immunology and gastroenterology, yet none was able to establish the cause and origins of the little boy's mysterious illness. The very fact that the symptoms were so wide-ranging puzzled specialists while the one thing they all appeared to agree on was that the source must have a genetic component.

Coincidentally, in 2014, a research team of which Dr. Muise was the head, engaged a project meant to explore the genetic basis of IBD (Irritable Bowel Disease) with the use of an advanced technology to study the DNA of selected patients -- and Daniel's genome happened to be included among those under investigation, with the use of a technique known as whole-exome sequencing.

Daniel's genome tests revealed a mutation as yet unknown to medical science. The defect appeared in a gene known as ARPC1B, known to produce a protein required by the body's cells to change shape, move, divide and perform other vital bodily functions. And Daniel's ARPC1B gene expressed none of this critical protein. Two other patients, related to one another but not to Daniel, also were discovered to have a mutation leaving them with very little ARPC1B protein. And over time another 20 children globally have also been identified with this same genetic mutation.

The discovery of this entirely new disease appearing in children, as a rare genetic mutation was published in the journal Nature Communications. Daniel's doctors feel confident that a bone-marrow transplant will succeed in giving him entirely new blood cells -- immune cells included -- that will not include the genetic mutation. Leading to a search for an appropriate donor for the now-ten-year-old little boy.

The difference between a normal platelet and the platelet of someone with Daniel's protein deficiency. (Hospital for Sick Children)
His mother has hopes that should a successful bone-marrow transplant take place, all the medications that Daniel has been taking in the treatment of his various symptoms over the past seven years, can cease. The steroids he has taken over long courses have affected normal growth patterns for the little boy.

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