TORONTO - Canadian researchers have used the power of genomics to identify the cause of a rare Parkinson's-like disease in children of one extended family and come up with a treatment to help reverse its effects.
It's believed to be the first time a new disease has been discovered, its cause figured out and a treatment successfully determined in such a short time, in this case about two years.
The eight children — five boys and three girls born to four sets of parents in a large Saudi Arabian family — were born with symptoms similar to those experienced by adults with Parkinson's disease, said principal researcher Dr. Berge Minassian, a neurologist at Toronto's Hospital for Sick Children.
"They're very interesting, they're like little babies with Parkinson's disease," said Minassian, explaining that the children exhibited typical symptoms of the neurological disorder, including tremors, problems executing movements, and the flat facial expression known as a "masked face."
"Those kids are like that. They cry, but you don't see them cry," he said.
Dr. Reem Alkhater, a pediatric neurology resident at the hospital, has been travelling back and forth between Toronto and Saudi Arabia as part of the research team's investigations into the familial disorder.
The children are part of an unidentified family of Bedouin ancestry living in a western Saudi city whose members had intermarried through several generations. Known as consanguineous marriages, the offspring of such unions have a one in four chance of inheriting mutated genes if they are carried by both parents.
"When you have consanguinity, then you end up with problems where you get the bad copy from each side because the two sides are related," said Minassian. "In this case, consanguinity played a role in these children being sick and having this autosomal recessive disease."
Using genomic sequencing, the Toronto scientists pinpointed a common mutated gene among the children, known as SLC18A2. (The genome is all the genetic material in a person or any other organism.)
The gene, which is involved in the production of the brain chemicals dopamine and serotonin, had a single genetic-letter misprint, which dramatically reduced its function and produced the Parkinson's-like disorder, he said.
Based on the symptoms, doctors treated one 16-year-old girl and three of her affected younger siblings with L-dopa, a drug that boosts dopamine in the brain. Classic Parkinson's is caused by diminished levels of the neurotransmitter, and L-dopa is one of the standard treatments.
"It made them worse, so we quickly stopped," he said.
The researchers then determined that despite the mutation, the children's bodies were making enough dopamine — it just wasn't getting "packaged" properly and delivered where it needed to go in the brain. In fact, in that state, it was toxic to brain cells.
The children were then treated with another standard drug called a dopamine agonist. "These are newer compounds that bypass the whole packaging thing and go directly to the dopamine receptors (on the surface of cells)," Minassian said.
"Now we are providing dopamine where it belongs without the need of packaging and so it made the patients better," he said.
Within days of starting the drug, the children began improving, although those who were older did not do as well as the younger kids, say the researchers, who detail their work in Wednesday's issue of the New England Journal of Medicine.
"If we treated them very young, they responded almost completely," Minassian said.
"It was magical. These kids, it's like one day they're frozen and cannot move and they're just either sitting or lying, depending on their age, and as soon as we treated them, they get up and start running.
"And then they were so excited to walk and run, they wouldn't stop. So we had to put helmets on them because they were falling all over the place."
It's been almost three years since the children began receiving the drug, which they must take for life. Their symptoms continue to improve with minimal side-effects, primarily slight overactivity and weight loss, the authors report.
Their work is a good example of personalized medicine — medical care that is tailored to an individual's genetic profile, said Dr. Sylvia Stockler, head of the division of biochemical diseases at B.C. Children's Hospital.
"It's really a great article, so congratulations to the team in Sick Kids that they had such a successful story to report," she said of the study.
"It's really great work because we have so many children with unexplained, severe neurological handicaps and intellectual disability, where we just do not know where it comes from," Stockler said Wednesday from Vancouver.
Even knowing that such rare diseases must have a genetic basis — and having high-tech genomic-sequencing equipment to investigate — doesn't mean it's easy to narrow down the search for a faulty gene or a series of faulty genes, she said.
Stockler's own team has been trying, so far unsuccessfully, to pin down the genetic cause of similar rare neurological diseases in children that share some of the symptoms seen in the Saudi kids.
"We will probably go back and look right away into that gene," she said of SLC18A2.
"We have quite a list of patients where we think there might have been a new gene defect and this definitely will help us also in looking at the right spot in the genome of those patients."
Minassian said the team is "very excited" about helping the children and the speed at which they were able to pin down the cause of their disease. He attributes their success to new technology that allows scientists to sequence chunks of DNA much faster than in the past.
"So many diseases are either completely genetic or have big contributions from genetic mutations," he said. "And now we have technologies that get us directly to the causes by whole-genome sequencing.
"And so it's quite striking what can be done these days. A project like this would have taken 20 years, just a few years ago. But now it can all be done very quickly."
Here are 21 other rare diseases that you can help spread awareness on.
This disease, which according to the NIH is most often caused by a begnin tumor in the pituitary gland, results in an excess of GH, or growth hormone. This causes sufferers to grow abnormally large, not just in terms of height, weight but also organ size. It results in complications like delayed puberty, increased sweating, and secretion of breast milk.
Characterized as an eating disorder, Pica causes people to eat what the National Organization for Rare Disorders describes as "non-nutritive" things. That umbrella term can include (but isn't limited to) dirt, clay, paper, and paint. Interestingly, it's not unusual for young kids to experience transient pica as a kind of phase, and pregnant women are also known to develop temporary pica cravings. The cause? Unknown. But in order to be diagnosed with full-blown Pica, a person's symptoms must last for more than a month.
MSUD, which is passed down through families, is a life-threatening metabolic disorder passed down through families that stems from the body's inability to process certain amino acids, leading to a build-up of them in the body. According to the NIH, symptoms usually surface in early infancy and can include vomiting, lack of energy, seizures, and developmental delays. MSUD takes its name from another symptom -- the urine in affected infants smells like caramel or maple syrup.
Situs Inversus is a congential condition in which internal organs of stomach and chest lie in mirror image of their normal body position -- something many sufferers aren't aware of until they seek medical help for an unrelated problem. People with Situs Inversus typically wear some form of identification to help doctors in the case of a medical emergency.
Trigger thumb, or trigger finger as it's sometimes known, causes a person's finger or thumb to get caught in a locked position. According to the Mayo Clinic, it can then stay stuck or straighten with a painful "snap." The cause? It depends. Trigger Thumb is the result of a narrowing of the sheath around the tendon in the problem figure, but that can be caused by a lot of things, including any activity that requires people to grip things frequently. Trigger Thumb is also more frequent in women.
Once the disease of sailors and pirates, scurvy does still exist in the United States, though predominantly in older, malnourished adults. It usually stems from a Vitamin C deficiency, which can result in gum disease, skin leisons, and swelling of the joints.
This progressive genetic disorder causes sufferers to store excess copper in tissues, including the brain and liver. Though the Mayo Clinic says that the body depends on copper in order to use iron and sugar, too much of it in the body can have real consequences. Which is why sufferers of Wilson's Disease are prone to liver failure.
According to researchers at the University of Texas at Dallas, this speech disorder causes people to experience a sudden shift in their accents and though it is known to be caused by things like brain trauma, conversion disorder, or multiple sclerosis, an exact reason behind the syndrome is unknown. Sufferers of FAS dramatically shift their speech in terms of timing and intonation, which often causes them to sound foreign, but they remain totally comprehensible. Documented accent shifts include from American English to British and from British to French.
People who suffer from this acquired neurological disorder experience repeated, often painful, muscle spasms as well as muscular rigidity and stiffness. According to the National Organization of Rare Diseases, spasms can occur at random or they can be caused by something as seemingly benign as light physical contact or an unexpected noise. The cause of Stiff Person Syndrome isn't yet known, but symptoms can be stabilized with medication. Left untreated, however, a person can lose the ability to walk.
According to the National Organization of Rare Diseases, about 10 percent of people with carcinoid tumors -- which the Mayo Clinic says are slow growing tumors that produce excess serotonin and usually appear in the gastrointestinal tract or lungs -- get this syndrome. It occurs only in patients whose tumors have metastasized to the liver. The symptoms? Wheezing, hotness, and extreme facial blushing.
Children and adults afflicted with CVS experience recurrent episodes of severe vomiting, which can last for days, followed by sudden periods of no vomiting. While kids are likely to experience more frequent attacks, adults's often last longer. To date, the cause of CVS is unknown.
This obscure, genetic skin disorder does exactly what its name implies: causes sufferers to experience constant shedding of their skin. (In some patients, peeling is limited to the feet and hands.) Along with that, sufferers often feel itching and redness -- symptoms that can appear from birth or develop later in life. Although the exact cause is unknown, a mutation in the TGM5 gene has been identified in many sufferers.
This is a blanket designation for several rare platelet abnormalities, most of which lead to mild or moderate bleeding disorders. According to the NIH, the problem stems having limited granules -- the parts of platelets that, among other things, store ADP -- the energy released when a molecular bond is broken. That reduction in storage space inhibits the platelets' ability to secrete ADP in a speedy fashion, which is thought to be what causes the bleeding. Classic symptoms of a Platelet Storage Pool Deficiency are nosebleeds, excessive bruising, and profuse bleeding in surgery.·
Only nine people in the United States are known to have this disease, which was just given a name in a recent study in the New England Journal of Medicine. ACDC, or arterial calcification due to CD73 deficiency, results in calcium build-ups in the arteries below the waist of sufferers and in the joints of their hands and feet. According to the NIH, the breakthrough discovery found that the disease is related to a variant in the NT5E gene.3
This condition, which typically occurs after an extremely stressful emotional event, causes a person to experience sudden blindness or paralysis that can't be otherwise explained. People with mental illlnesses are at particularly high risk and psychological treatment can help lessen the symptoms.·
Ochronosis results in black or blue external tissues, often the ear cartilage or eye, though it can occur throughout the body. It affects people who suffer from certain metabolic disorders, but it can also be caused by exposure, though scientists aren't exactly sure to what. Not just a cosmetic issue, the affected areas can become brittle and degenerate over time.
This condition, which is caused by genetic mutations in the so-called ACADVL gene, keeps people from converting certain fats to energy. According to the NIH, the deficiency often presents during infancy in symptoms including low blood sugar, weakness, and lethargy.
As the name suggests, Hairy Tongue is a condition in which the tongue develops a black, hairy texture. According to the Mayo Clinic, the disease is "harmless" and is caused by an overgrowth of bacteria in the mouth, which can be treated with antibiotics. The NIH reports that hairy Tongue can also present as brown, yellow, or green discoloration. ·
This obscure, inherited disorder presents at birth and causes infants to grimace when, in fact, they are attempting to smile. The disorder also includes an extreme urinary abnormality: an obstruction that interrupts the connection between nerve signals in the spinal cord and bladder, leading to incontinence. Though treatment does exist in the form of antibiotics and bladder re-education, some patients can develop renal failure in their teens and 20's, which can be life-threatening.
This syndrome, caused by a particular calcified ligament or elongated bone, frequently causes sufferers to feel that something is stuck in their throat. (Scientists don't know the reason behind said elongation/calcification.) Other symptoms can include ear and throat pain as well as difficulty swallowing. According to the NIH, it can be treated surgically or non-surgically with steroid injections and other anti-inflammatories.
According to the Mayo Clinic, only around 130 cases of this devastating genetic disorder have been documented since it was discovered in 1886. Affected babies normally appear normal at birth, but within 12 months begin to have symptoms like hair loss and wrinkles. According to the Mayo Clinic, progeria is caused by a genetic mutation, but not one that's passed down through families; it's a chance event that affects only one egg or sperm. The average life expectancy for sufferers is 13.