In 2007 I diagnosed a 74 year old woman with CF.
She had a positive sweat test and positive mutation with an intronic mutation as well.
I investigated this after she had bronchiectasis and no history of smoking. And a grandson with CF......... Why did I do the sweat test?
I needed to know if her bronchiectasis was due to CFTR mutations. Maybe she didn't need COPD treatment after all.
That same intellectual curiosity is found in a recent study in the NEJM. It turns out they are finding some patients who have Gaucher's also have Parkinson's Disease.
What's even more interesting is that Heterzygotes for Gaucher's are at increased risk of sporadic or familial Parkinson's disease. So one has to wonder, how many Parkinon's cases are due to GBA mutations.....
Well, this study aimed to elucidate that. First off, if the GBA mutations are higher than LRRK2, well, we my have another Ashkenazi Jewish disease.
What did these guys do?
5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel–Haenszel procedure used to estimate odds ratios across centers. Ok, a reasonable method.
Now what did they find?
This finding allows for confidence in reporting the Mantel–Haenszel combined odds ratios for N370S (odds ratio, 3.96; 95% confidence interval [CI], 2.60 to 6.02) and L444P (odds ratio, 6.73; 95% CI, 4.50 to 15.42). After correcting for outliers they can confidently report a Mantel–Haenszel odds ratio of 5.43 for GBA mutations, in patients versus controls Ok, so if you have either of these mutations, you are at a pretty high risk for Parkinson's Disease. Seriously. How many of the Parkinson's cases are due to this type of carrier mutation? Overall, when screening solely for N370S and L444P, one of these two mutations was found in 15% of Ashkenazi Jewish patients as compared with 3% of Ashkenazi Jewish controls and in 3% of non–Ashkenazi Jewish patients as compared with less than 1% of non–Ashkenazi Jewish controls That's a lot of cases.
Way more than the LRRK2 mutation Familial Autosomal Dominant disease that could be counseled by pedigree alone that Serge was so hepped up about.
But if you want a breakdown of LRRK2 versus GBA you can read about it here.
Of note, there are very few papers comparing both, but there is one that disproved my hypothesis that it is likely that the LRRK2's actually are GBA mutation carriers.... But 37 Families still gives me a little hope that Serge was focused on the WRONG gene...
Back to GBA mutation carriers, this like CF now has me asking "Does anyone in your family have a genetic disease like Gaucher's" when I see some PD history.
Which highlights a significant point, if Primary Care Doctors are supposed to perform family histories, then how in the hell are they supposed to know about this?
The answer: This NEJM article? Navigenics? Who? How?
Unfortunately, most Internists will look at the article and say "Meh, another one of those genetics articles I don't understand" Will giving each doctor a FREE Navigenics test break that attitude......doubtful.
The Sherpa Says: Geneticists need to do their job and teach other doctors, not serve on DTC genomics boards.
Sunday, October 25, 2009
Gluco...Wha? Parkinson's Disease and Glucocerebrosidase mutations.
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8 comments:
Ha, and if the DTC companies had no geneticists you would go ape $hit...
Trying to get a perfect genetic history from a patient always strikes me as a worthy goal but a daunting task; not only do families not always share this information but misdiagnoses & terminology changes over time. Plus persons with few blood relatives (or at least relatives with whom they are in contact)
In a few years, for many patients this will simply be secondary to a complete genome sequence. But, that data will certainly require computational sorting, as no M.D. is going to search through a few million variants on a routine basis.
@ Keith,
So let me get this straight.
1. The genome will be cheap enough to do on EVERYONE, in a "few years"
2. We will know what the hell all/any of the shit in the genome means in a "few years"
3. The computational engines required to assess risks based on the "Genome" will be available in a "few years"
4. You need a "perfect" history to figure out someone is at risk for heart disease or diabetes
5. You have taken up smoking hashish.
Is this correct?
-Steve
@Anonymous,
Correct. Ape $h!t, but what part of me blogging was not going Ape $h!t?
True, the LRRK2 p.G2019S mutation accounts for a small percentage of Parkinson's cases. However, low frequency alleles within LRRK2 especially a specific signature of low frequency alleles are common among cases, and much less common in the general population. If you want to compare LRRK2 to other genes, this needs to be considered.
Steve:
Let's tease apart your two objections to my comment
Cost: you can buy a human genome today for $50K from Illumina; a human exome for about @25K from Knome. Complete Genomics claims they can get lower today but only if you order in bulk. These are the real costs today -- too expensive for wide-scale use but certainly something a desperate patient might consider -- or any very wealthy patient.
Illumina is projecting getting the raw cost to around $10K by early next year & perhaps something on the order of $5K late next year; I think SOLiD claims similar. Polonator crew thinks they can get their cost to $1K. While this set is all projections, they are plausible given that they will involve driving existing technologies along well mapped paths (higher densities, more automation). For a few $K, a lot of patients who aren't so desperate might consider this (or have serious challenges getting a medical history, such as a closed adoption or uncertain paternity in their ancestry), and perhaps even payers.
Then there are the not-yet-available technologies such as nanopores and PacBio and such. Right now I count all of them as wild cards, though PacBio is apparently in customer hands now. Given the amount being invested in this area, I see it as possible but not guaranteed that one of these will hit and drive a genome sequence to the $100-500 level, which is where a lot of diagnostics are.
Okay, then there is the interpretation problem. There are already tools out there to figure out the simple stuff (SNP-o-matic). Which do you think will be easier as new discoveries are made at an ever-increasing pace?
1) Continue to develop, update & validate automated tools
2) Continually retrain the entire medical community
Various sources I have read (e.g. "Better" by Gawande) have lamented that history-taking is uneven between who is practicing & subject to the whole range of human biases & issues. Taking a good history should never go away, but it will always be fraught with trouble. I think I have a pretty good handle on my family's history, but still am faced with terminology issues. For example, an ancestor died of leukemia -- I'd love to know which type, but at that time in medical history (a) there were only 2-3 types and (b) this wasn't considered information to pass on to the family.
Ask yourself very honestly, would you have tested your elderly female patient for CF if she did not have an affected grandson? What fraction of internists would have? Clearly she is an interesting & atypical case; presumably one of her CF alleles is very mild as simply her age places her in an unusual spot for a CF patient. How many other cases of genetic diseases go unrecognized due to incomplete family histories?
There are many ways to control chronic pain, and one of them is through anxiolytics, which are medicines that have obtained a better result than other drugs such as naproxen, aspirin, ibuprofen, medications that relieve pain but are not effective for these chronic cases, as these pains are more like a back pain that the world is one of the most common causes of absenteeism in findrxonline as indicated in your article on back pain and chronic pain, and opioid medications are as Vicodin, Lorcet, Meperidine to soothe the pain caused by this disease and we must be very careful
The health system must help people with chronic illness and much suffering to get the right medicines to counteract the pain they suffer, it is necessary that health reforms are established quickly to benefit people if needed.
Since these drugs for chronic pain such as Vicodin, Lortab, Hydrocodone, Oxycodone, are opioids narcotics are not available for high prices that companies put these drugs, we hope that the reform actually helps these people.
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