Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease

Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease

Juliane Neumann1,2, Jose Bras3,4,*, Emma Deas1,*, Sean S. O’Sullivan1, Laura Parkkinen1, Robin H. Lachmann1, Abi Li1, Janice Holton1, Rita Guerreiro3,4, Reema Paudel1, Badmavady Segarane1, Andrew Singleton3, Andrew Lees1, John Hardy1, Henry Houlden1, Tamas Revesz1 and Nicholas W. Wood1

1 Department of Molecular Neuroscience, Institute of Neurology, University College London, London, and Reta Lila Weston Institute, Institute of Neurology, London, UK 2 International Graduate Program Medical Neurosciences, Charité University Hospital, Berlin, Germany 3 Molecular Genetics Unit, Laboratory of Neurogeneticso, National Institutes on Aging, National Institutes of Health, Bethesda, Maryland, USA 4 Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

Correspondence to: Nicholas W. Wood, Institute of Neurology, Queen Square House, Queen Square, WC1N 3BG London, UK E-mail:

Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher’s disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher’s disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson’s disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson’s disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson’s disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12–12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant {alpha}-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5–6, and had McKeith’s limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson’s disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson’s disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson’s disease and suggest that to date, this is the most common genetic factor identified for the disease.

 Key Words: Parkinson’s disease; GBA; Gaucher’s disease; neuropathology

 Abbreviations: AC, amygdaloid complex; BFB, basal forebrain; DMV, dorsal motor nucleus of vagus; GBA, glucocerebrosidase; HRC, human random control; LC, locus ceruleus; NBM, nucleus basalis of Meynert; SN, substantia nigra

Impaired IL-10 transcription and release in animal models of Gaucher disease macrophages

Kacher Y, Futerman AH.

Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.

A number of studies have shown altered cytokine levels in serum from Gaucher disease patients, including changes in levels of the anti-inflammatory cytokine, interleukin-10 (IL-10). However, the source of IL-10, or the mechanisms leading to changes in IL-10 serum levels are not known. We now show that mouse macrophages treated with an active site-directed inhibitor of glucocerebrosidase, or macrophages from a mouse model of Gaucher disease, the L444P mouse, release significantly less IL-10 than their untreated counterparts, but that TNFalpha release is unaffected. These changes are due to reduced transcription of IL-10 mRNA in macrophages. The reduction in IL-10 secretion observed in animal models of Gaucher disease macrophages may be of relevance to explain the increase in inflammation that is often observed in Gaucher disease.

Publication Types:

PMID: 19380242 [PubMed – in process] Kacher Y, Futerman AH.

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

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.

However, numerous studies have linked pathogenic mutations within GBA with increased susceptibility to Parkinson’s disease. In perhaps the most definitive work to date [Mitsui J et al. (2009) Arch Neurol 66(5):571-6], researchers resequenced the GBA gene in over 500 cases of Parkinson’s disease and matched controls; whilst only 2 of the control subjects had any of the pathogenic mutations associated with Gaucher disease, 50 of the cases were heterozygous for one of 11 mutations in the gene. Having one of these mutations therefore confers a substantial and significant increased risk of developing Parkinson’s disease of nearly 30-fold (OR = 28.0, 95% confidence intervals 7.3-238.3), though individual mutations may be associated with various lower risks [Gan-Or Z et al. (2008) Neurology 70(24):2277-83]. In addition, patients with mutations in GBA were significantly younger at the age of onset of Parkinson’s disease than those without. In contrast, there was no statistically significant association between non-pathogenic mutations in GBA and Parkinson’s disease.
Comment: This research is important for three different reasons. First, by combining numerous pathogenic mutations in the GBA gene in a relatively large study, the work unifies various earlier and smaller studies linking the gene with Parkinson’s disease.
Second, it highlights a general paradigm shift from the common disease-common variant hypothesis within human genetics, which underlies the recent plethora of genome-wide association (GWA) studies, to the common disease-rare variant hypothesis. If the majority of genetic risk for common diseases is actually located in rare variants, not common polymorphisms, conducting resequencing analysis of specific susceptibility genes is the logical next step in the hunt for the genetic basis for all common diseases. Adopting such a strategy could therefore be substantially more fruitful than conducting ever larger GWA studies.
Third, and perhaps most significantly, the work raises serious ethical concerns over carrier screening for Gaucher disease, particularly within the Ashkenazi Jewish population (see previous news). According to the National Gaucher Foundation, the carrier status may be as high as 1 in 15 amongst Jewish people of Eastern European ancestry (and 1 in 100 amongst the general population). The current policy of the UK National Screening Committee is that carrier testing for Gaucher disease should not be offered, as it is treatable and can be relatively mild. However, those who are considering getting tested privately prior to becoming pregnant may now want to think again; a relative risk of ~30 is one of the largest genetic risks known, and may even have predictive ability (though further research is needed here). As Parkinson’s disease has a UK population prevalence of around 1% in the over 65’s (based on data from the Parkinson’s Disease Society), such information could potentially have enormous personal and societal consequences. Additionally, authorities face an even greater challenge – should people who have already had carrier testing be informed of the associated risk of Parkinson’s disease, or not?
Such ethical conundrums are only likely to increase as more and more genetic susceptibilities are discovered that have relevance to multiple diseases. To date, this has been a relatively small problem, as most of the susceptibilities discovered through GWA studies have been associated with extremely low risks (OR<2) and have very limited predictive ability. However, if the common disease-rare variant hypothesis is correct, we can expect significantly more issues of this nature to surface over the coming years. Policymakers and clinicians will need to bear this in mind when forming national guidance regarding genetic testing and screening.

Baby J, you will never be forgotten…

Baby J.  He wasn’t even 7 months old.  I emailed with his mom a few weeks ago shortly after he was diagnosed.  Now he is gone.   He had Gaucher’s type 2.  My heart is breaking for his parents, as it just happened so quickly.

I’ve been sitting here with Hannah leaning against me, watching the Wiggles, thanking whoever would listen that she is still here with me.  Thirty minutes, I have been trying to write this post, and in between my tears for J’s family and for Hannah, I just have a hard time putting my feelings into words. 

Being in the rare disease community, we have seen other children lose their battles and their lives to these diseases.  But this is the first time that I knew that Joseph was alive and fighting, and now he is gone.   Does that make any sense?  I don’t make any sense.

This has completely shaken me, literally.   I’m not naive…I see the progression of this disease in Hannah, and now with J…argh!   I don’t even know what to say.   I can’t seem to think of anything else right now.  I don’t know what to do.

Sly Syndrome: Delivering Medicine To Fight Rare Genetic Disorder

ScienceDaily (July 27, 2007) — The scientist who discovered “Sly Syndrome” nearly four decades ago and a team of colleagues at Saint Louis University are a step closer to finding an approach to treat the rare genetic disease. Sly Syndrome causes bone defects, mental retardation, vision and hearing problems, heart disease and premature death.

They found that a potentially life-saving enzyme can be induced to cross the blood-brain barrier, a structure which protects the brain from foreign substances, if it is given with the hormone epinephrine.

Ever since William S. Sly, M.D., chairman of the department of biochemistry and molecular biology at Saint Louis University, discovered the rare genetic disease in 1969, he and his colleagues have conducted research to learn more about how to treat it.

He says their recent findings have significance beyond treating the extremely rare disease that bears his name.

“There are at most 100 living cases of Sly Syndrome. Nonetheless, this disease is a model for all the diseases in this group, some of which are much more common,” Sly says.

“Lysosomal storage diseases affect 1 in 7,000 live births, and 90 percent of those with the diseases have brain involvement. What we find with Sly Syndrome has some importance for all those diseases as well. It is potentially a big finding and an important first step.”

The discovery potentially points to a new way to get big molecules, such as certain medications, across the blood-brain barrier. It is reported in the Proceedings of the National Academy of Sciences online early edition the week of July 16.

SLU researchers found that the right amount of epinephrine probably works by stimulating transport by vesicles — blister-like wrappers that carry substances across the blood-brain barrier – so that the enzyme missing in patients who have Sly Syndrome can get into the brain.

Those who have Sly Syndrome lack the enzyme called beta-glucuronidase. Without this enzyme, protein-sugar molecules accumulate in the brain and other organs in the body. By replacing the missing enzyme, doctors believe they can treat the genetic disease.

The problem, though, was slipping the enzyme past the blood-brain barrier to where it needs to do its work.

“This is a disease that is simply made for testing drug delivery vehicles. If you can get the enzyme into the brain, the vehicle that delivered it could work to deliver other chemicals, too,” says William A. Banks, M.D., professor of geriatrics and pharmacological and physiological sciences at Saint Louis University, and a leading researcher on the blood-brain barrier.

Sly Syndrome, which occurs in fewer than one in 100,000 births, is a progressive disorder that ranges in severity from mild to deadly. It is among a group of genetic diseases call mucopolysaccharidoses.

“Some children who have this group of diseases are doomed to an early death because they don’t make a certain enzyme,” Banks says.

Enzyme replacement therapy — or putting the missing enzyme into the bodies of those who have Sly Syndrome — holds promise in treating the physical problems of the disease.

“In the case of Sly Syndrome, the missing enzyme is more than 1,000 larger than a sugar molecule and so huge it can’t get across the blood-brain barrier, which prevents it from reaching the brain.”

Scientists used a mouse model to figure out how to get the enzyme into the brain. They knew that injections of the missing enzyme into the brains of baby mice reached their target, but similar injections into mature mice did not. As the mice grew older, the transporter that brought the enzyme past the protective blood-brain barrier was lost.

“We found that the right amount of epinephrine allowed the enzyme to pass into the brain of older mice, which means we reinduced the way to get the enzyme where it is needed,” Banks says.

Epinephrine is a drug that treats cardiac arrest and is given to open the airways of asthma patients who have difficulty breathing. Discovering epinephrine as the transportation key to unlock the blood-brain barrier for the missing enzyme was “a shot in the dark,” Banks says.

 “High doses of epinephrine can destroy the blood brain barrier and let everything into the brain, which is toxic,” Banks says. “We tested three things. One didn’t work at all. One worked partially and epinephrine worked incredibly well.”

The finding changes how scientists look at getting medications through the blood-brain barrier, he says, and could have implications for treating other diseases such as Alzheimer’s disease and obesity.

Instead of viewing the blood-brain barrier as an obstacle to fight, researchers should consider it something to finesse, using its special features to help in drug delivery, Banks adds.

“The field has approached the problem as if you have a Volkswagen that can get across the street and you put your cargo on it so the cargo can get there too. We’ve found that trying to transport the cargo changes the Volkswagen and the Volkswagen can no longer get across.”

The research was funded by the National Institutes of Health, The Sanfilippo Syndrome Medical Research Foundation and VA Merit Review.

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 DISEASECheck 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!