Exome sequencing and the management of neurometabolic disorders” , download article here

The metabolic evaluation of the child with an intellectual developmental disorder: Diagnostic algorithm for identification of treatable causes and new digital resource, download article here.

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Eight-year old Luke belongs to a very select group of children. Diagnosed at the age of 5 with alpha-mannosidosis—possibly one of the rarest genetic diseases in the world— he received the only available treatment just five months later. The decision to have their child undergo an invasive and risky bone marrow transplant (BMT), without hard scientific evidence for success in alpha-mannosidosis, was one of the toughest decisions Robin and Kevin Chaplin have ever made. But it turned out to be a great one because today, 2.5 years after his BMT, Luke, followed by the TIDE team on a regular basis, continues to improve intellectually and physically.
Alpha-mannosidosis is an extremely rare, inherited lysosomal storage disorder, characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual disability. It affects approximately 1 in 500,000 children. Finding information on the disease is a daunting task for parents, as Robin and Kevin Chaplin can testify. But having the diagnosis established in Luke proved equally challenging, precisely because it is such a rare disease.

READ LUKE'S FULL STORY HERE




The Long Journey to Diagnosis
At 3.5 years of age, Luke was found to suffer hearing loss, and that, his parents initially believed, was the cause of his grumpiness and developmental delays. However, his hearing loss prompted further testing: a CT scan revealed that his skull was very thick, and results from eye tests suggested something impinging on his optic nerve. Eventually, after many more investigations, the Chaplin’s pediatrician referred Luke to the Department of Medical Genetics at BCCH; they waited over a year, at which point Luke had already turned 5.
“We saw Dr. Patel in Medical Genetics,” Kevin Chaplin said. “He thought there were three possibilities, and ordered the tests accordingly. After about 5 months the results came back positive for one disease—a result that was surprising and suggestive of a certain type of lysosome storage disease. Dr. Patel did a confirmatory blood test; Luke was then five and a half,” Kevin said. They finally had a diagnosis.

Hearing the News
Finding out Luke suffered alpha-mannosidosis seemed like a mixed blessing. “It was such bad news,” Kevin said. It was good to know that it was something, but it is such a terrible disease. It turns out Luke is missing an enzyme – so his body can’t break down sugar. The sugar builds up in the cells and over time the cells are destroyed and it ends up destroying his body and his brain and he dies early,” Kevin explains. In severe cases children with this disease die as infants, in milder cases they have a shortened life. “It was devastating news, to be told that our son will be going through this.

Robin remembers how strange it felt to hear the news. “It almost didn’t seem real, in some ways, because the disease is so rare. But we didn’t have time to dwell on that,” she said. Instead, they started investigating treatment.

Researching Treatment
“We were told that bone marrow transplants have been tried to correct or stop the progression of alpha-mannosidosis,” Kevin said. Dr. Patel referred the Chaplins to the BMT team at BCCH.

But when the Chaplins began investigating BMT as treatment for their son’s disease, they could not have been prepared for the results. “We were told there was only one other recorded case in Canada,” Kevin said.

“So we searched actively for all the other families in the world – about 10-20 in number– and we got in touch with them via a non-profit organization that had connected these families. We found the families that had undergone a BMT as well as those who hadn’t. We researched the difference between children who had and hadn’t undergone a BMT,” he explained.
They discovered that the longest post-transplant follow-up of a child receiving a BMT for alpha-mannosidosis was 6 years. “That wasn’t much time to see what would happen over the long term,” Kevin said. “However, you could clearly see what happened in older adults who hadn’t undergone the BMT. It seemed relatively clear there was benefit,” he said.

After Luke underwent the BMT, which was expertly managed by the transplant team at BCCH, the Chaplins met Dr. Clara van Karnebeek. “We heard about TIDE at the Rare Disease Picnic,” Robin said.

Today, Robin wonders whether the TIDE screening protocol would have reduced the time to Luke’s diagnosis, had it been in place when he went to BCCH for his initial hearing tests. Developed by Drs Stockler and van Karnebeek, the TIDE protocol is now applied to all children referred with developmental delays or intellectual disability (ID) to BCCH. “There was a two-year gap between getting the hearing aids and the diagnosis for alpha-mannosidosis,” Robin said “All that time the disease was progressing.”

Today, Robin wonders whether the TIDE screening protocol would have reduced the time to Luke’s diagnosis, had it been in place when he went to BCCH for his initial hearing tests. “There was a two-year gap between getting the hearing aids and the diagnosis for alpha-mannosidosis,” Robin said “All that time the disease was progressing.”

The answer is yes, absolutely. ‘Time is Brain’ is the slogan that summarizes TIDE’s major goal: to avoid unnecessary diagnostic delay, time during which the brain can be damaged. By performing routine blood and urine tests in all children with ID, as well as low-threshold individual investigations for genetic conditions such as alpha-mannosidosis, the TIDE protocol shortens the time to diagnosis of treatable diseases. Facilitated by the Treatable-ID App, routine testing and an increased awareness, TIDE also speeds up referrals and the initiation of treatment. “I think the protocol is a very useful tool,” Robin said.

Sharing the Knowledge & Facing the Future
Today, with the love and support of his family and the help of TIDE, Luke is doing well. “We probably go to the TIDE clinic at least once a month, for tests,” Robin said. “Luke needs to have his vision screened, his hearing tested, they monitor his heart, and enzyme levels in his blood as a result of the BMT. And he has an orthopedic doctor who sees him for gait analysis. It’s as if he has a specialist for every body part – because the illness affects every body part of his body. Dr. van Karnebeek has been very helpful in coordinating this.”
As a result of their journey with alpha-mannosidosis and as demonstration of their resourcefulness and giving nature, the Chaplins have set up a website about Luke, the illness and his treatment experience and outcome. At the time of our interview in July 2012, Kevin Chaplin said that they had at least 4 families contact them in the past 2 years wanting more information for their children. Two of those families have had BMTs and the other two were looking for donors. Luke’s website can be seen at: http://lukechaplin.wordpress.com/
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