The Scientist Magazine: A Rare Chance

http://www.the-scientist.com/article/display/57100/

Print Issue:  Volume 24 | Issue 2 | Page 18

By Alison McCook

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A rare chance

Over the course of 5 days last summer, an army of researchers and clinicians examined, poked, and prodded 1-year-old Hannah Ostrea at the National Institutes of Health (NIH). Experts in neurology, rehabilitation medicine, physical therapy, speech pathology, and anesthesiology gave the little girl an EEG, a test of her heart’s electrical activity (EKG), an MRI, a CT scan, X-rays, and a throat exam (laryngoscopy). All this testing was meant not only to help Hannah but in the hope that her rare disease could reveal something about another condition that affects 1 million Americans: Parkinson’s.

Hannah has Gaucher’s disease, and within hours of her birth, it was obvious something was wrong. Looking past her thick head of dark hair, and the fact that she could down an entire bottle of formula in 5 minutes, clinicians quickly saw that her spleen was massive, and her platelet counts were rock bottom. Her liver was expanding—in a few months it looked like she had a volleyball in her stomach. These are the classic signs of Gaucher’s, a rare, recessive genetic disorder in which the body does not produce enough of a lysosomal enzyme that breaks down the fatty substance glucocerebroside, causing it to glob up in cells of the liver, spleen, and other organs—including, sometimes, the brain.

But researchers have never seen the combination of mutations Hannah carries, so doctors couldn’t determine if she had the Type 2 or Type 3 form. Children with Type 2 typically die before their third birthdays, while those with Type 3 can live much longer. “They [wouldn’t] give us a prognosis,” Hannah’s mom, Carrie Ostrea, says. “They came out and said that to us. Which is fine by me.”Hannah has many classic Gaucher’s symptoms, such as developmental delays, and the inability to easily shift her eyes from side to side or up and down. But she also has some puzzling symptoms. For one, she only blinks once every 30 minutes or so—“you’ll have a staring contest with her,” Ostrea laughs. This is not a symptom of Gaucher’s disease, but it is a symptom of Parkinson’s.

Indeed, in recent years, researchers have been noting more and more crossover between the two diseases, and the hope is that insights into one will reveal secrets of the other.

In an October issue of the New England Journal of Medicine, Ellen Sidransky at the NIH and her colleagues found that Parkinson’s patients were five times more likely to carry a mutation in the gene associated with Gaucher’s disease. Furthermore, Parkinson’s patients with the mutation in the Gaucher’s gene tended to develop Parkinson’s earlier, and were more likely to have family members with Parkinson’s (N Engl J Med, 361:1651–61, 2009). It’s unknown how many people have signs of both diseases, Sidransky notes, but it’s “clearly dozens and dozens.”

Still, Parkinson’s and Gaucher’s are more different than they are alike. One comes from a deficiency of the lysosomal enzyme that breaks down glucocerebroside, the other likely from a deficiency of dopamine, and it’s largely unclear why the two diseases are linked, says Sidransky. Perhaps the lysosome plays a role in Parkinson’s; the protein misfolding that underlies Parkinson’s may be aggravated by mutations in the Gaucher’s gene.

Gaucher’s itself is an interesting model for trying to understand single-gene diseases, Sidransky adds. She and her colleagues like to invite patients with rare presentations of a disease to the NIH to study them and hopefully learn something about an entirely different condition. “I’ve always been convinced that focusing on one thing and becoming an expert helps you see connections” between that one question you’re investigating and other unanswered—perhaps even more significant—questions.

The NIH visits can be long, but Hannah held up fairly well, her mother says. She didn’t like waking up from the EEG and being tied down, and didn’t like the heart ultrasound, but the neuro-ophthalmologist got her to laugh hysterically by turning his video camera around so she could look at herself. “She just thought that was the funniest thing in the world,” Ostrea says.

The Parkinson’s Disease – Gaucher Disease link

What we have known for a few months has finally started hitting the mainstream media now as well as some other medical sites.  There are just a few….

Question is, now how can we capitalize on this and get the Parkinson’s community to start paying attention to our Gaucher kids?

Gaucher disease linked to Parkinson’s – Los Angeles Times
Mutant Gene Raises Risk of Parkinson’s (WebMD)
Glucocerebrosidase Mutations in Parkinson’s Disease  New England Journal of Medicine (subscription)
Study Conclusively Ties Rare Disease Gene To Parkinson’s – Medical News Today

Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: A biological link between Gaucher disease and parkinsonism

http://www.ncbi.nlm.nih.gov/pubmed/19576930?dopt=Abstract

The Parkinson’s Institute, 675 Almanor Ave., Sunnyvale, CA 94085, USA.

A growing body of experimental and clinical literature indicates an association between Gaucher disease and parkinsonism, raising the possibility that convergent mechanisms may contribute to neurodegeneration in these disorders. The aim of this study was to determine whether there is a relationship between alpha-synuclein (alpha-syn), a key protein in Parkinson’s disease pathogenesis, and abnormalities in glucocerebroside (GC) catabolism that lead to the development of Gaucher disease. We inhibited glucocerebrosidase (GCase) with conduritol B epoxide (CBE) in neuroblastoma cells and mice to test whether a biological link exists between GCase activity and alpha-syn. After CBE exposure, enhanced alpha-syn protein was detected in differentiated cells challenged with CBE as compared to vehicle, with no change in alpha-syn mRNA. In the mouse model, after one injection of CBE, elevated nigral alpha-syn levels were also detected. Analyses by Western blot and confocal microscopy revealed that normal alpha-syn distribution was perturbed after CBE exposure with its accumulation apparent within nigral cell bodies as well as astroglia. These findings raise the possibility that alpha-syn may contribute to the cascade of events that promote neuronal dysfunction in Gaucher disease and are the first to implicate this protein as a plausible biological intersection between Gaucher disease and parkinsonism using a pharmacological model.

PMID: 19576930 [PubMed - as supplied by publisher]

Mutations for Gaucher disease linked to high risk of Parkinson’s disease

http://www.phgfoundation.org/news/4676/

What’s the connection between Gaucher disease, a rare single gene disorder of metabolism that appears during childhood, and Parkinson’s disease, a common multifactorial disorder of the nervous system that occurs late in life? The answer lies in just a single gene (glucocerebrosidase or GBA), which encodes an enzyme required for lipid metabolism and storage within the lysosome. Numerous pathogenic mutations in this gene have been characterised, which result in Gaucher disease if present in both copies of the gene; these recessive mutations are generally assumed to be relatively harmless to the carrier.

Meeting with a Parkinson’s Neurologist

Dr. William Ondo, Associate Director of the Parkinson Disease Center at Baylor, Houston

About a month ago, I sent an email to the Baylor Department of Neurology’s Parkinson’s group asking if I could meet with one of their clinicians to have Hannah’s symptoms evaluated.  I explained that Hannah has neuronopathic Gaucher’s disease, and I wanted to talk with someone regarding the possible commonalities between the two diseases.

Yesterday afternoon, I got a phone call from the scheduler for this department saying that Dr. William Ondo, Associate Director of the Parkinson Disease Center and Movement Disorders Clinic is willing to consult with us and evaluate Hannah!   Because she is a patient at Texas Children’s Hospital (Baylor’s pediatric hospital), all of her records and patient information was already accessible to him.

We meet with him in early July, right before we leave for NIH.  The timing for this appointment is actually perfect, even though it is about 5 or 6 weeks away because it gives me more time to learn more about the disease processes of Gauchers and Parkinson’s.

Hannah’s lack of blinking reflex

When we went to see Hannah’s ENT doctor a week or so ago, we were in the elevator on the way down, and one of the doctors going down said “Hey, your daughter doesn’t blink.”   He didn’t say it in a concerned way, just more like he found it somewhat amusing that she kept her eyes wide open the entire way down. 

So I had experimented with her for the rest of the afternoon.  Sure enough, she can go for over 10+ minutes without blinking.  I got tired of watching at that point!  She isn’t having a seizure or anything, as she just goes about her day when this happens, playing with toys, drinking a bottle, taking a walk, etc.  She has no problems interacting and has no changes in her personality when this happens.  We also have no idea when this started because we had never noticed it before!

She will close her eyes if you touch her eyelash, and when she gets tired she will close her eyes (most of the way) to sleep. 

So we shared this at our pediatrician visit, and he was just amazed at this symptom.   So we now give her eye drops a couple of times a day to make sure her eyes are lubricated.

This is where it gets very interesting…

I asked Dr. Sidransky at the NIH about this new symptom, and her response was “That is very interesting and not typical of the eye movements in type 3 GD. It will be interesting to see what our neuro ophthalmologist thinks!”

I did some research into this, and you know what disease lack of blinking is a symptom of?   PARKINSON’S DISEASE!  Check it out, 1st on this list from MedicinePlus Encyclopedia/NIH.  You can NOT tell me that these two diseases do not have a definite commonality of some sort in their disease process!  

Hannah, who has a never-before-seen genetic mutation of neuronopathic Gaucher’s disease, has developed a symptom that is not a symptom of her Gaucher’s disease but IS a symptom of Parkinson’s disease, the very same disease that last week a 10-year-study and a second study solidifed the genetic link between the two diseases. 

There is a VERY STRONG connection here!!   Something that DESERVES to be looked at!  Hannah and the other GD23 children truly MAY hold a key to understanding Parkinson’s disease, yet we can’t seem to get them to notice! 

10-year-study solidifies strong link between Gaucher’s Disease and Parkinson’s Disease

Today is an INCREDIBLE day in the world of Gaucher’s Disease!  Two very important studies came out in the past day or two that have not only proven the strong link between Parkinson’s Disease and Gaucher’s Disease, but they will also open the eyes of many Parkinson researchers and biopharmaceuticals towards Gaucher’s Disease!  

Is GD23 similar to a “childhood Parkinson’s Disease?”  Now that this genetic link between PD and GD is here, it is time for researchers to realize that researching the babies of Gaucher’s disease with the neuronopathic type is critical to understanding Parkinson’s disease.  Gaucher’s Diseases types 2 and 3 share so many of the same symptoms as Parkinson’s disease such as supranuclear gaze palsy, balance problems, fine and gross motor problems, fatigue, and swallowing problems.  It cannot be just a coincidence that these two disease share so many of the same symptoms!

It is time to reach out to organizations such as the Michael J Fox foundation, the National Parkinson foundation, and the Parkinson Disease Foundation and say “Hey, our kids may hold the key to understanding your disease!”  

Not only that, but the pharmaceutical companies that make Parkinson’s medications such as Sinemet, Stalevo, Parcopa, Cogentin, Artane, Eldepryl, Zelepar, and Azilect need to be looked at more closely to see if there is something within those medications that can be reformulated and used to possibly help our gaucher kids!

Association between Mutations in the Lysosomal Protein Glucocerebrosidase and Parkinsonism
A body of work has emerged over the past decade demonstrating a relationship between mutations in glucocerebrosidase gene (GBA), the gene implicated in Gaucher disease (GD), and the development of parkinsonism. Several different lines of research support this relationship. First, patients with GD who are homozygous for mutations in GBA have a higher than expected propensity to develop Parkinson’s disease (PD). Furthermore, carriers of GBA mutations, particularly family members of patients with GD, have displayed an increased rate of parkinsonism. Subsequently, investigators from centers around the world screened cohorts of patients with parkinsonism for GBA mutations and found that overall, subjects with PD, as well as other Lewy body disorders, have at least a fivefold increase in the number of carriers of GBA mutations as compared to age-matched controls. In addition, neuropathologic studies of subjects with parkinsonism carrying GBA mutations demonstrate Lewy bodies, depletion of neurons of the substantia nigra, and involvement of hippocampal layers CA2-4. Although the basis for this association has yet to be elucidated, evidence continues to support the role of GBA as a PD risk factor across different centers, synucleinopathies, and ethnicities. Further studies of the association between GD and parkinsonism will stimulate new insights into the pathophysiology of the two disorders and will prove crucial for both genetic counseling of patients and family members and the design of relevant therapeutic strategies for specific patients with parkinsonism. © 2009 Movement Disorder Society

Researchers believe they have found genetic cause for Parkinson’s disease
A team led by Shoji Tsuji of the University of Tokyo, and Tatsushi Toda of Kobe University discovered that those with a mutation in a gene called GBA are 28 times more likely to contract Parkinson’s disease. They now hope to use their finding to explain exactly how the disease is caused, and develop a treatment.

There are an estimated 150,000 cases of Parkinson’s disease in Japan. In 90 percent of the cases, however, they are the only members of the family to contract the condition, and the genetic component of the disease has never been identified.  However, the team noticed that the GBA gene, which is responsible for causing an unusual condition called Gaucher’s disease, also showed a mutation in those with Parkinson’s disease. They examined 534 Parkinson’s patients and 544 healthy people, and found that 9.4 percent of those with the mutation suffered from the disease, and just 0.4 percent did not. They also discovered that those with the GBA mutation contracted the disease around six years earlier than those without.

“It’s the first time that a risk factor has been this clearly identified,” said Tsuji.

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