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homocysteine problems in PD

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Hi John,

Yes, some years ago researchers found that long-time users of levodopa were at risk of elevated serum homocysteine, which is associated with risk for stroke, heart disease, depression, and cognitive impairment. Homocysteine is normally cleared from the blood by vitamins B6, folate, and B12.

 

I recommend everyone using levodopa ask their doctor to conduct a blood test for serum homocysteine, B12, folate, and B6. If homocysteine is elevated, then the levels of the B vitamins will determine which, or perhaps all, are deficient, and the doctor can then make recommendations as to supplementation.

 

I will separately post two articles dealing with homocysteine; I would read these, print out, and take them to your doctor for further discussion. Let me know if you have other questions.

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Hi John,

Yes, some years ago researchers found that long-time users of levodopa were at risk of elevated serum homocysteine, which is associated with risk for stroke, heart disease, depression, and cognitive impairment. Homocysteine is normally cleared from the blood by vitamins B6, folate, and B12.

 

I recommend everyone using levodopa ask their doctor to conduct a blood test for serum homocysteine, B12, folate, and B6. If homocysteine is elevated, then the levels of the B vitamins will determine which, or perhaps all, are deficient, and the doctor can then make recommendations as to supplementation.

 

I will separately post two articles dealing with homocysteine; I would read these, print out, and take them to your doctor for further discussion. Let me know if you have other questions.

Hi kathrynn,

My homocystein blood level came back as 17.2.My folate acid .b12,and mg were all in range.I did see some mention with myoclonus  but unsure.What are your thoughts on this?

thanks john

Edited by Kathrynne Holden, MS

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John, as your blood levels of B12 and folic acid were within normal limits, then your doctor should test for mutations in the “methylenetetrahydrofolate reductase (NAD(P)H)" gene, called MTHFR for short. This gene makes an enzyme is used in the process of converting the amino acid homocysteine to another amino acid, methionine. A mutation in this gene means that homocysteine is not properly converted, thus it can build up in the blood -- called hyperhomocysteinemia.

 

This is a genetic predisposition to elevated homocysteine, and there some indication that a mutation in the MTHFR gene may increase risk for PD as well. It is treated by diet and supplements, and your doctor can provide you with guidance in this regard. Here are two studies you can print out and take to your doctor for discussion:

 

(1)

J Neurol Sci. 2013 Dec 15;335(1-2):14-21. doi: 10.1016/j.jns.2013.09.006. Epub 2013 Sep 12.

Methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and susceptibility to Parkinson's disease: a meta-analysis.

Author information
  • 1Department of Epidemiology and Statistics, School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei, Anhui 230032, China.
Abstract
BACKGROUND:

The association between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and susceptibility to Parkinson's disease (PD) was controversial in previous studies. The present study was therefore designed to investigate a more reliable estimate.

METHODS:

15 studies were identified by a search of PubMed, EBMBASE, PDGENE, Elsevier, Springer Link, CBM (Chinese Biomedical Database), CNKI (Chinese National Knowledge Infrastructure), VIP (Chinese), and Wanfang (Chinese) databases, up to April 2013. Odds ratios (ORs) with corresponding 95% confidence interval (CI) were calculated using fixed effects model or random effects model. The subgroup analyses were made on the ethnicity.

RESULTS:

MTHFR C677T polymorphism had a significant association with susceptibility to PD in all genetic models (for T vs. C: OR=1.24, 95% CI=1.11-1.38; for TT+CT vs. CC: OR=1.27, 95% CI=1.10-1.46; for TT vs. CC: OR=1.56, 95% CI=1.22-1.98; for TT vs. CT+CC: OR=1.43, 95% CI=1.14-1.79). Subgroup analyses by ethnicity revealed that the association between the MTHFR C677T polymorphism and PD existed in Caucasian population and Asian population. However, no association was detected between the MTHFR A1298C polymorphism and PD.

CONCLUSIONS:

Results from this meta-analysis supported that the MTHFR C677T polymorphism was associated with an increased risk of PD. The MTHFR A1298C polymorphism may not increase the susceptibility to PD. Further studies are required to confirm our findings.

PMID: 24064257 [PubMed - indexed for MEDLINE]

 

 

------------------------------    

(2)

Neuromolecular Med. 2012 Mar;14(1):84-90. doi: 10.1007/s12017-012-8174-1. Epub 2012 Feb 22.

Coenzyme Q10, hyperhomocysteinemia and MTHFR C677T polymorphism in levodopa-treated Parkinson's disease patients.

Abstract

There is evidence that increased homocysteine (Hcy) levels might accelerate dopaminergic cell death in Parkinson's disease (PD) through neurotoxic effects. Homocysteine neurotoxicity mainly relies on redox state alterations. The present work was aimed at investigating the relationships between plasma Hcy concentrations and percent content of oxidized versus total Coenzyme Q10 (%CoQ10) in 60 PD patients and 82 healthy subjects. Both groups were screened for plasma levels of Hcy, vitamin B12, folate, %CoQ10 and C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism. The MTHFR TT677 mutated genotype was found more frequently in patients than in controls (p = 0.01). In a multivariate analysis, Hcy levels and %CoQ10 were associated with the case/control category (p < 0.0001), MTHFR genotype (p < 0.0001) and their interaction term (p = 0.0015), even after adjusting for age, sex, folate and vitamin B12. Patients carrying the TT677 genotype exhibited the highest values of Hcy and %CoQ10 (p < 0.0001). Structural equation modelling evidenced that the TT677 genotype and levodopa daily dose were independently and directly correlated with Hcy (p < 0.0001, and p = 0.003, respectively), which, in turn, showed a significant correlation (p < 0.0001) with the %CoQ10 in PD patients. Our results suggest that increased Hcy levels act as mediator of the systemic oxidative stress occurring in PD, and %CoQ10 determination might be regarded as a predictor of toxic Hcy effects.

PMID: 22354693 [PubMed - indexed for MEDLINE]

 

-----------------------------    

 

I hope this helps, John, and let me know if you have other questions.

Edited by Kathrynne Holden, MS
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After reading your contribution, Kathryn, I asked my PCP for a homocysteine test....she replied it was worthless. She is already treating me as a possible MI case, so the test would have no value.

 

Sigh....that is an example of the medical profession we deal with.

 

Thank you for your valuable assistance to our forum.

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Hi Kathrynne,

Thanks so much for finding this information.Ill keep you informed.

Thanks again

john

 

I'm hoping this will help, John. Please do keep us updated on your progress.

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After reading your contribution, Kathryn, I asked my PCP for a homocysteine test....she replied it was worthless. She is already treating me as a possible MI case, so the test would have no value.

 

Sigh....that is an example of the medical profession we deal with.

 

Thank you for your valuable assistance to our forum.

That is not accurate. If by chance your homocysteine is elevated, it may be treatable with B12 and folate, independently of treatment for MI. Ideally, though, she should also conduct a test for MTHFR (see my post to John, with two research studies on MTHFR's relationship to PD). I would print these all out, take them to her, and remind her that evidence-based medicine is practiced in this country. If she continues to refuse to conduct tests, then I would seek another physician. Let us know your progress.

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Hi Kathrynne,,

I did have a question about this hemocysteine  test.My test was non fasted and wondered if that could skew the results?

I unfortunately got a late season flu Saturday..Tamiflu states if exposed you can take itathalfthe dos.I got the shot in September and probably should have waitd.Im taking Tamiflu to help with it and it seems to have helped.I also noticed that we have to careful about cough meds.My fever has come down just left with a dry cough ,stuffed hed and body ache

best john

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I'm so sorry to hear you came down with the flu. I don't think waiting would have helped, though -- apparently the flu shot this year was only about 20% effective. Tamiflu usually helps, I hope it will speed up your recovery.

 

Regarding the test for homocysteine, your doctor should have mentioned to you whether you needed to be fasted or not, as that might skew the results. I would call the doctor's office and ask to speak to the nurse; relate your results, and ask if the non-fasted state is relevant in your case. Let us know the results.

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hi kathryn

just a updat,Two doctors gave me two drugs that i found out later conflict with my pd drugs.One was klonapin for my myoclonus .5 mg 2x daily,the other was a bo lordstan on top of my amodione bestalte.I was very unstable on these drugs always falling over,MY bp was 100/50 when taken in am at the hosptialand my jerks were aweful after the drug wore off.The eeg points to non epileptic myoclonus probaly spinal def not psychgenicim glad i got the eeg out of the way to prove I wasnt fakeing it ,lol Now how to treat it,The head nurse did say it looked like something was pricking my spine maybe it was the epidural afterall.

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John, it looks like you were given lorazepam and Klonopin; not everyone with PD does well on the benzodiazepines, and hypotension is a possible side effect. The hospital pharmacy probably checked your medications for interactions and side effects, and communicated that to the doctors. Again, I'm so glad you took the initiative and went to the hospital on your own instead of listening to your own doctors. Now you have some information that you didn't have before, and your doctors will be able to address that. Thanks for updating us, I will be hoping for better news in future!

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hi Kathrynne,

here is my med list as of now

5mg amlopine besylate

.5 clonazepam 2 daily

losartan 25 mg 1 daily

1.5 25/100 sinemet 4x

1 8mg reguip sr

My Bp is normal am 130/75 does comes up with myoclonus also white coat hbp is common with me

Ive stopped the clonazpam till i talk to my doc as it caused alot of instability don't need the walker to get around

The jerks have died down as my back pain is very minimal also now

 

Another good point is the eeg showed some very postive info in relation to the two hemispheres were operating together which allows more efficiency and a calmer emotional state

More should be said about the importance of EEG testing in PD,a proven early biomaker for PD

Thanks again for your support

john

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John, that's good and very positive news about the EEG, and I'm sure it was most welcome for you. Thank you for your comments, this kind of information benefits all the readers on the forum.

 

It does sound like your blood pressure is under good control; and it should not be surprising that it is elevated with myoclonus, I think that would be true for most everyone. Also, many people have "white coat hypertension." Also good news that the back pain and jerks are subsiding, I'm very happy for you.

 

I do think you would do well to discuss drug interactions with the prescribing doctors. Here are the results of an interaction check, showing several interactions of moderate significance:

 

  • Major Moderate Minor Food
Interactions between your selected drugs
interaction-2-big.png clonazepam ↔ levodopa

Applies to: clonazepam, Sinemet (carbidopa / levodopa)

ClonazePAM can decrease the effects of levodopa in some people. You may need a dose adjustment or more frequent monitoring by your doctor to safely use both medications. Contact your doctor if your Parkinson symptoms worsen. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

 

interaction-2-big.png levodopa ↔ amlodipine

Applies to: Sinemet (carbidopa / levodopa), amlodipine

Levodopa and amLODIPine may have additive effects in lowering your blood pressure. You may experience headache, dizziness, lightheadedness, fainting, and/or changes in pulse or heart rate. These side effects are most likely to be seen at the beginning of treatment, following a dose increase, or when treatment is restarted after an interruption. Let your doctor know if you develop these symptoms and they do not go away after a few days or they become troublesome. Avoid driving or operating hazardous machinery until you know how the medications affect you, and use caution when getting up from a sitting or lying position. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

 

interaction-2-big.png clonazepam ↔ losartan

Applies to: clonazepam, losartan

Losartan and clonazePAM may have additive effects in lowering your blood pressure. You may experience headache, dizziness, lightheadedness, fainting, and/or changes in pulse or heart rate. These side effects are most likely to be seen at the beginning of treatment, following a dose increase, or when treatment is restarted after an interruption. Let your doctor know if you develop these symptoms and they do not go away after a few days or they become troublesome. Avoid driving or operating hazardous machinery until you know how the medications affect you, and use caution when getting up from a sitting or lying position. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

 

interaction-2-big.png levodopa ↔ losartan

Applies to: Sinemet (carbidopa / levodopa), losartan

Levodopa and losartan may have additive effects in lowering your blood pressure. You may experience headache, dizziness, lightheadedness, fainting, and/or changes in pulse or heart rate. These side effects are most likely to be seen at the beginning of treatment, following a dose increase, or when treatment is restarted after an interruption. Let your doctor know if you develop these symptoms and they do not go away after a few days or they become troublesome. Avoid driving or operating hazardous machinery until you know how the medications affect you, and use caution when getting up from a sitting or lying position. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

 

interaction-2-big.png clonazepam ↔ ropinirole

Applies to: clonazepam, Requip (ropinirole)

Using clonazePAM together with rOPINIRole may increase side effects such as dizziness, drowsiness, and difficulty concentrating. Some people may also experience some impairment in thinking and judgment. You should avoid or limit the use of alcohol while being treated with these medications. Avoid driving or operating hazardous machinery until you know how the medications affect you. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

 

No other interactions were found between your selected drugs.
Note: this does not necessarily mean no interactions exist. ALWAYS consult with your doctor or pharmacist.

Other drugs that your selected drugs interact with Interactions between your selected drugs and food
interaction-2-big.png levodopa ↔ food

Applies to: Sinemet (carbidopa / levodopa)

You may experience reduced effectiveness of levodopa in the presence of foodsicon1.png or enteral (tube) feedings with a high protein content. This may make the symptoms of Parkinson's disease worse. Talk with your doctor or nutrition counselor about the best foods to eat while you are taking this medication. Contact your doctor if your condition changes. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

Switch to professional interaction data

interaction-2-big.png losartan ↔ food

Applies to: losartan

If you are taking losartan you should avoid potassium-containing salt substitutes or over-the-counter potassium supplements without first talking to your doctor. This can cause high levels of potassium in your blood. High levels of potassium can cause weakness, irregular heartbeat, confusion, tingling of the extremities, or feelings of heaviness in the legs. Call your doctor at once if you have any of these symptoms. In some patients grapefruits and grapefruit juice may decrease the efficacy of losartan. Grapefruits and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interacticon1.png.

Switch to professional interaction data

interaction-1-big.png

 

Drug Interaction Classification

The classifications below are a guideline only. The relevance of a particular drug interaction to a specific patient is difficult to determine using this tool alone given the large number of variables that may apply.

Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit. Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances. Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.

Do not stop taking any medications without consulting your healthcare provider.

Disclaimer: Every effort has been made to ensure that the information provided by Multum is accurate, up-to-date and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This material does not endorse drugs, diagnose patients, or recommend therapy. Multum's information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill, knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective, or appropriate for any given patient. Multum Information Services, Inc. does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. Copyright 2000-2015 Multum Information Services, Inc. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse, or pharmacist.

-------------------------------------------------

 

Again, thank you for updating us, we all learn from each other. I hope we'll keep hearing from you.

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Hi Kathrynne,

 

Thanks so much for taking the time to do all this.I'm seeing my primary today and will give her your information.

best

john 

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You're welcome, John, and hoping for good news at your doctor's today.

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Hi Katheryn,

While I was in the hosptial I mentioned your interest with homocystein but didnt get very far with the staff.They only saw the problem with heart issues and didn't test me .My primary also dismissed the idea One thing i"m so glad you mentioned is the problems we have with drugs like clonazepam.I know some here take it but for me it has been a disaster.It Makes the jerks stronger and the walking is the worst.But I'm finding strategies on how to live with whatever this is.

I want to again personaly thank you for all your help with enlightening us.

best,

john

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"There is evidence that increased homocysteine (Hcy) levels might accelerate dopaminergic cell death in Parkinson's disease (PD) through neurotoxic effects. "  

 

I have PD, diagnosed at 45, now 49.  Just learned I have this mutation through a functional doctor.  But can supplements & diet help?  And  taking levodopa can make it worse?  Am I understanding this right?   I will see the doctor again soon, I'm sure she will provide guidance but I didn't know until a few hours ago this might make the PD progress faster.  

 

No one wants to have the fast progressing PD.  

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Hi Katheryn,

While I was in the hosptial I mentioned your interest with homocystein but didnt get very far with the staff.They only saw the problem with heart issues and didn't test me .My primary also dismissed the idea One thing i"m so glad you mentioned is the problems we have with drugs like clonazepam.I know some here take it but for me it has been a disaster.It Makes the jerks stronger and the walking is the worst.But I'm finding strategies on how to live with whatever this is.

I want to again personaly thank you for all your help with enlightening us.

best,

john

 

John, we're here to help whenever we can -- which isn't always, unfortunately. But definitely the more we know what meds you take the more information it gives us to get a bigger picture. I do wish physicians would take homocysteine vs depression, etc., more seriously, especially for those with PD. I would keep asking -- the squeaky wheel gets the grease.

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"There is evidence that increased homocysteine (Hcy) levels might accelerate dopaminergic cell death in Parkinson's disease (PD) through neurotoxic effects. "  

 

I have PD, diagnosed at 45, now 49.  Just learned I have this mutation through a functional doctor.  But can supplements & diet help?  And  taking levodopa can make it worse?  Am I understanding this right?   I will see the doctor again soon, I'm sure she will provide guidance but I didn't know until a few hours ago this might make the PD progress faster.  

 

No one wants to have the fast progressing PD.  

 

Hi Kaydee, take heart. Genetics is not my focus, but I have colleagues who do practice in this area. My understanding from them is that whether one is heterozygous or homozygous for the MTHFR mutation, it does not necessarily mean that there will be an increase in homocysteine, just that there appears to be an increased risk.

 

Have you been tested for serum homocysteine levels? If not, that would be my advice at this point. If your homocysteine is within normal limits, no worries. If elevated, your functional doctor will no doubt choose methylated forms of B vitamins for you, to control homocysteine.

 

I will say, though, that this is still a relatively new area, and not one in which most of us have experience. I would print out all the information you can find, and ask your doctor for a clear interpretation. Here are some I have compiled:

 

Select item 259098721.
Folia Neuropathol. 2015;53(1):24-8.
Association of the rs1801133 variant in the MTHFR gene and sporadic Parkinson's disease.
Abstract

The MTHFR gene has been reported as a susceptibility locus for sporadic Parkinson's disease (sPD). The functional variant rs1801133 has been linked to hyperhomocysteinemia and dopaminergic cell death. Among different populations, Mexican-Mestizos (most present-day Mexicans) have the highest frequency of this variant. Therefore, we sought to determine a possible association of rs1801133 with SPD. In total, 356 individuals were included: 140 patients with PD, diagnosed according to the Queen Square Brain Bank criteria, and 216 neurologically healthy controls. Genotyping was performed using TaqMan probes for rs1801133 and real-time PCR. Logistic regression analysis with adjustment for smoking and gender was used to test for an association between genotype and SPD. The CC genotype was associated with SPD; exp() = 2.06; 95% CI: 1.101-3.873, p = 0.024. No association with age at onset, cognitive impairment or gender was found in our study group. Our data suggest an important role of MTHFR gene variants in SPD.

PMID: 25909872 [PubMed - in process]  
 
  •  
Select item 255644162.
Neurol Sci. 2015 Jan 7. [Epub ahead of print]
Association of MTHFR C677T with total homocysteine plasma levels and susceptibility to Parkinson's disease: a meta-analysis.
Abstract

The C677T single-nucleotide polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR) may elevate homocysteine (Hcy) levels and increase the risk of Parkinson's disease (PD); however, results are conflicting. Our aim was to resolve contradictions in the literature and to determine whether MTHFR C677T has a significant role in regulating Hcy levels and/or is a significant risk factor for PD. MEDLINE, EMBASE, the Cochrane Library, China Biological Medicine Database and Google Scholar were searched until May 2014. Strict selection and exclusion criteria were determined, and odds ratios (ORs)/weighted mean differences (WMDs) with 95 % confidence intervals (CIs) were used to assess the strength of associations. Statistical analyses were performed using STATA 12.0. Fifteen studies that together assessed 2690 PD cases and 8465 controls were included. Meta-analysis showed that no significant difference in the distribution of MTHFR C677T between PD cases and controls was found. While stratifying for ethnicity, significant association was revealed in Europeans (T vs. C, OR = 1.17, 95 % CIs 1.04-1.31) but not in Asians. Significant association between the T allele and increased Hcy levels was found in PD cases and controls; Hcy levels were higher in PD cases and controls carrying the MTHFR T677 allele than in non-carriers (TT vs. CC, PD WMD = 6.50, 95 % CIs 6.20-6.80; controls WMD = 4.52, 95 % CIs 4.24-4.80). Other within-group comparisons showed similar results. This meta-analysis suggests that MTHFR C667T may confer PD susceptibility in Europeans. The T allele may be an independent risk factor for elevated Hcy levels in PD patients.

PMID: 25564416 [PubMed - as supplied by publisher]  
 
  •  
Select item 246942313.
Curr Drug Metab. 2014 Feb;15(2):129-81.
Genomic and pharmacogenomic biomarkers of Parkinson's disease.
Abstract

The relative role of genetic and environmental factors in the pathogenesis of Parkinson's disease (PD) has been the matter of investigation and debate, especially in the last 30 years. The possible interaction between genetic and environmental factors led to a great number of association studies between single nucleotide polymorphisms (SNPs) of many candidate genes and PD risk. In this study we summarized and critically reviewed the results of studies published on this issue, with especial reference to those reported in the last 5 years. Many studies provided conflicting findings and, when positive associations were identified, associations were weak. Polymorphisms related with activation or detoxification of drugs and xenobiotics, such as CYP1A1, CYP1A2, CYP19A1, CYP1B1, CYP2C9, CYP2C19, CYP2E1, CYP2D6, NAT2, GSTM1, GSTM3, GSTO1, GSTP1, PON1, PON2, ABCB1 and ADH genes have not been demonstrated convincingly a definitive association with the risk of developing PD. Nor did polymorphisms in genes related to dopamine or serotonin DRD, DAT, TH, DDC, DBH, MAO, COMT, SLC6A4, MTR, MTHFR, oxidative stress NOQ1, NOQ2, mEPHX, HFE, GPX, CAT, mnSOD, HFE, HO-1, HO-2, NFE2L2, KEAP1, inflammatory processes, ILs, TNF, ACT, NOS, HNMT, ABP1, HRHs, trophic and growth factors BDNF, FGF, or mitochondrial metabolism and function. In addition we analyzed other putative relations and genes associated with monogenic familial PD.Taking together the results of candidate gene association studies and genome wide association studies, only some SNPs of the MAPT, SNCA, HLA and GBA genes seem to be the most likely associated with PD risk.

PMID: 24694231 [PubMed - indexed for MEDLINE]  
 
  •  
Select item 246861884.
Neurosci Lett. 2014 May 7;568:1-5. doi: 10.1016/j.neulet.2014.03.044. Epub 2014 Mar 28.
Association of seven functional polymorphisms of one-carbon metabolic pathway with total plasma homocysteine levels and susceptibility to Parkinson's disease among South Indians.
Abstract

This study from South India was performed to ascertain the impact of seven functional polymorphisms of one-carbon metabolic pathway on total plasma homocysteine levels and susceptibility to PD. A total of 151 cases of Parkinson's disease and 416 healthy controls were analyzed for fasting plasma homocysteine levels by reverse phase HPLC. PCR-RFLP approaches were used to analyze glutamate carboxypeptidase II (GCPII) 1561 C>T, reduced folate carrier 1 (RFC1) 80 G>A, cytosolic serine hydroxymethyl transferase (cSHMT) 1420 C>T, methylene tetrahydrofolate reductase (MTHFR) 677 C>T, methionine synthase (MTR) 2756 A>G and methionine synthase reductase (MTRR) 66 A>G polymorphisms. PCR-AFLP was used for the analysis of thymidylate synthase (TYMS) 5'-UTR 28bp tandem repeat. PD cases exhibited elevated plasma homocysteine levels compared to controls (men: 28.8 ± 6.9 vs. 16.4 ± 8.8 μmol/L; women: 25.4 ± 5.3 vs. 11.2 ± 5.1μmol/L). Homocysteine levels showed positive correlation with male gender (r=0.39, p<0.0001) and MTRR 66 A>G (r=0.31, p<0.0001) whereas an inverse correlation was observed with cSHMT 1420 C>T polymorphism. MTRR 66 A>G polymorphism showed independent risk for PD (OR: 3.42, 95% CI: 2.35-4.98) whereas cSHMT 1420 C>T conferred protection against PD (OR: 0.11, 95% CI: 0.07-0.17). Multifactor dimensionality reduction analysis showed synergistic interactions between MTHFR 677 C>T and MTRR 66 A>G, whereas cSHMT 1420 C>T exhibited counteracting interactions in altering susceptibility to PD. To conclude, PD cases exhibited hyperhomocysteinemia and MTRR 66 A>G and cSHMT 1420 C>T gene variants were shown to modulate PD risk by altering the homocysteine levels.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

KEYWORDS:

Homocysteine; One-carbon metabolism; Parkinsondisease; Polymorphism

PMID: 24686188 [PubMed - indexed for MEDLINE]  
 
  •  
Select item 245329855.
Curr Genomics. 2013 Dec;14(8):534-42. doi: 10.2174/1389202914666131210210559.
Homocysteine Level and Mechanisms of Injury in Parkinson's Disease as Related to MTHFR, MTR, and MTHFD1 Genes Polymorphisms and L-Dopa Treatment.
Abstract

An elevated concentration of total homocysteine (tHcy) in plasma and cerebrospinal fluid is considered to be a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). Homocysteine (Hcy) levels are influenced by folate concentrations and numerous genetic factors through the folate cycle, however, their role in the pathogenesis of PD remains controversial. Hcy exerts a neurotoxic action and may participate in the mechanisms of neurodegeneration, such as excitotoxicity, oxidative stress, calcium accumulation, and apoptosis. Elevated Hcy levels can lead to prooxidative activity, most probably through direct interaction with N-methyl-D-aspartate (NMDA) receptors and sensitization of dopaminergic neurons to age-related dysfunction and death. Several studies have shown that higher concentration of Hcy in PD is related to long-term administration of levodopa (L-dopa). An elevation of plasma tHcy levels can also reflect deficiencies of cofactors in remethylation of Hcy to methionine (Met) (folates and vitamin B12) and in its transsulfuration to cysteine (Cys) (vitamin B6). It is believed that the increase in the concentration of Hcy in PD can affect genetic polymorphisms of the folate metabolic pathway genes, such as MTHFR (C677T, A1298C and G1793A), MTR (A2756G), and MTHFD1 (G1958A), whose frequencies tend to increase in PD patients, as well as the reduced concentration of B vitamins. In PD, increased levels of Hcy may lead to dementia, depression and progression of the disease.

KEYWORDS:

Biothiols, PD.; MTHFD1 polymorphism; MTHFR; MTR

PMID: 24532985 [PubMed]   PMCID: PMC3924248  Free PMC Article
 
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Select item 240642576.
J Neurol Sci. 2013 Dec 15;335(1-2):14-21. doi: 10.1016/j.jns.2013.09.006. Epub 2013 Sep 12.
Methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and susceptibility to Parkinson's disease: a meta-analysis.
Abstract
BACKGROUND:

The association between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and susceptibility to Parkinson's disease (PD) was controversial in previous studies. The present study was therefore designed to investigate a more reliable estimate.

METHODS:

15 studies were identified by a search of PubMed, EBMBASE, PDGENE, Elsevier, Springer Link, CBM (Chinese Biomedical Database), CNKI (Chinese National Knowledge Infrastructure), VIP (Chinese), and Wanfang (Chinese) databases, up to April 2013. Odds ratios (ORs) with corresponding 95% confidence interval (CI) were calculated using fixed effects model or random effects model. The subgroup analyses were made on the ethnicity.

RESULTS:

MTHFR C677T polymorphism had a significant association with susceptibility to PD in all genetic models (for T vs. C: OR=1.24, 95% CI=1.11-1.38; for TT+CT vs. CC: OR=1.27, 95% CI=1.10-1.46; for TT vs. CC: OR=1.56, 95% CI=1.22-1.98; for TT vs. CT+CC: OR=1.43, 95% CI=1.14-1.79). Subgroup analyses by ethnicity revealed that the association between the MTHFR C677T polymorphism and PD existed in Caucasian population and Asian population. However, no association was detected between the MTHFR A1298C polymorphism and PD.

CONCLUSIONS:

Results from this meta-analysis supported that the MTHFR C677T polymorphism was associated with an increased risk of PD. The MTHFR A1298C polymorphism may not increase the susceptibility to PD. Further studies are required to confirm our findings.

© 2013.

KEYWORDS:

Homocysteine; MTHFR; Meta-analysis; Methylenetetrahydrofolate reductase; Parkinson's disease; Polymorphism

PMID: 24064257 [PubMed - indexed for MEDLINE]  
 
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Select item 240524517.
Neurol Sci. 2014 Jan;35(1):73-7. doi: 10.1007/s10072-013-1545-z. Epub 2013 Sep 20.
The MTHFR C677T polymorphism modifies age at onset in Parkinson's disease.
Abstract

Hyperhomocysteinemia is a risk factor for Parkinson's disease (PD) and may result from genetic mutations or/and environmental factors. 5,10-methylenetetrahydrofolate reductase (MTHFR) is a folate-dependent enzyme that catalyzed remethylation of homocysteine (Hcy) and the MTHFR C677T polymorphism makes the MTHFR enzyme thermolabile causing hyperhomocysteinemia. In this study we analyzed whether two functional polymorphisms of MTHFR gene, A1298C and C677T, affect age of onset in PD. We enrolled 120 patients with sporadic PD. Patients were divided into three groups based on MTHFR C677T polymorphisms: (a) homozygotes wild type (CC) (B) heterozygotes (CT) and © homozygotes carriers of mutation (TT). MTHFR SNPs were analyzed using High-Resolution Melt analysis and ANOVA was performed to assess whether polymorphisms of MTHFR gene could influence age of onset. The MTHFR A1298C polymorphism had no effect on PD age at onset (p = 1.0) while there was a significant association with MTHFR C677T (p = 0.019 Bonferroni-adjusted post hoc) showing an earlier onset in CC as compared with TT. (p = 0.024). No differences were found for vascular load assessed with magnetic resonance imaging, pharmacological therapy and cognitive state for two MTHFR SNPs. Our results suggest a possible association of MTHFR C677T with age at onset of PD and may have important implications regarding the role of MTHFR.

PMID: 24052451 [PubMed - indexed for MEDLINE]  
 
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Select item 239166228.
Gene. 2013 Nov 15;531(1):78-83. doi: 10.1016/j.gene.2013.07.034. Epub 2013 Aug 3.
Meta-analysis supports association of a functional SNP (rs1801133) in the MTHFR gene with Parkinson's disease.
Abstract

The MTHFR is a candidate risk gene for Parkinson's disease (PD), and a functional SNP (rs1801133) in the coding region of this gene has been investigated for the associations with the illness extensively among worldwide populations, but overall the results were inconsistent. Here, to assess the relationship between rs1801133 and risk of PD in general populations, we conducted a systematic meta-analysis by combining all available case-control samples in European and Asian populations, with a total of 1820 PD cases and 7530 healthy controls, and the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for rs1801133 and PD were calculated using the Mantel-Haenszel method with a fixed-effect model. Overall, rs1801133 was significantly associated with the risk of PD (allelic model, pooled OR=1.212 for T allele, 95% CI=1.097-1.340, p-value=0.0002). When stratifying for ethnicity, significant association was also observed in European (allelic model, pooled OR=1.187 for T allele, 95% CI=1.058-1.332, p-value=0.004) and Asian samples (allelic model, pooled OR=1.293 for T allele, 95% CI=1.058-1.580, p-value=0.012) respectively. In addition, rs1801133 was also significantly associated with MTHFR mRNA expression in both CEU (European, p-value=0.0149) and CHB (Chinese, p-value=0.0178) HapMap populations. Collectively, our meta-analysis suggests that rs1801133 is significantly associated with susceptibility to PD in European and Asian populations, and MTHFR is likely an authentic risk gene for PD.

© 2013 Elsevier B.V. All rights reserved.

KEYWORDS:

ACMSD; AD; Alzheimer's disease; CI; Functional polymorphism; GBA; GWAS; MAPT; MCCC1; MTHFR; Meta-analysis; OR; PD; Parkinson's disease; SNCA; SNP; STK39; SYT11; aminocarboxymuconate semialdehyde decarboxylase; confidence interval; genome-wide association study; glucosidase beta acid; mRNA expression; methylcrotonoyl-CoA carboxylase 1 (alpha); methylenetetrahydrofolate reductase; microtubule-associated protein tau; odds ratio; rs1801133; serine threonine kinase 39; single nucleotide polymorphism; synaptotagmin XI; synuclein alpha

PMID: 23916622 [PubMed - indexed for MEDLINE]   -----------------------   I realize this is confusing, and I have only a narrow understanding of genetics so cannot interpret. But your doctor should be able to clarify, and to assess your needs. Please let us know how you are doing, I do care very much.
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Thank you Kathrynne, yesterday I sent my primary care a link to your topic, and she has already responded and requested blood work for iron and homocysteine as my functional doctor requested.  It was very quick.  She did say keep in mind that homocysteine is a non specific test?  What does that mean? 

 

I just read that it can increase with age also, especially around menopause.  Oh, that may be why the functional doctor requested hormone levels testing as well.  Which my PCP suggested I need to ask my OB/GYN to test for.  I'm 49, and think I may be starting perimenopause.

 

On reading about folate & B12 defienciency, symptoms are subtle.  But one of them listed is dizziness, which I've been having sporadic issues with for 3 years now.

 

The dizziness issue has been one of my most annoying symptoms.  Would be good to understand better some of this.  I'd pretty much given up with my doctors on figuring out the cause.   

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There are a number of gene polymorphisms, and it appears that most are unrelated to elevated homocysteine. I think your PCP meant that elevated homocysteine could be due to a number of unrelated causes; and as you are perimenopausal, that in and of itself could raise homocysteine levels. I'm sure that is why your other doctor has requested hormone levels.

 

You are doing all the right things -- seeking doctors who will work with you, seeking information that will help them as well (not all doctors are aware of the many complexities in PD because most do not see many patients with PD). With good tests, I am pretty sure your doctors will be able to make a good assessment of your condition and needs. As for dizziness, while B vitamin deficiency is plausible, I would not worry about that prior to tests results, as there are dozens of other possible causes, most of which are benign. I am very happy that your doctors now are working with you to assess your condition correctly; that is vital in determining your needs. Please do continue to keep us updated on this very important issue.

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Hi Kathrynne,

Thank you for the Rx interactions... I certainly wish I had done my homework 7 years ago regarding the Benzo's.

I'm not sure how Clonazepam got by me until you mentioned it last fall suppressing ones appetite, then Music Man posted a study on them from Canada.

I did some more research and couldn't' believe my Neuro hadn't informed me of the long term dangers of Clonazepam or any benzo, or why he even rx it NIGHTLY for leg tremors, muscle spasms. These rx shouldn't be used beyond 4 weeks, as one may become addicted and then to have them cause what they were rx for!

I expressed this concern to my Neuro and MDS, both said, your only taking .05mg 1x nightly....

 

Well, that little .05mg of Clonazepam made these last 5 months the most challenging physically, mentally and emotionally of my life!

You remember me telling you of my GERD, sinnitus, numerous staff infections, cellulitis, UTI, respiratory issues, palpitations, rashes, random pains throughout my body, severe full body non PD tremors, red spots all over my body, neck pain, arms chest tightness,

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Sorry... Continued, I hit the post by mistake.

Flu like symptoms, numbness in my feet, arms hands, fevers, incontinence , breast swelling and secreting, sores in my mouth, gum inflammation and blurry vision, couldn't concentrate....

 

I know, your thinking what? No way... Well, yes this has been going on since mid December. All due to CLONEZEPAM withdrawal.

 

Yes, my flooring that had flamaldehyde just added to this nightmare.

I started tapering the Clonazepam on Nov. 16, I planned a 3 month taper. Well a month later all the above started happening.

My docs initially said the chest tightness was probably due to the taper, so go back up a 1/4 of a pill until, you feel better. So, I would have a few good days, re-start the taper and a few days later a new symptom would occur. Everyone was stumped because blood work was fine, pulse, BP was higher than my normal low, but not dangerous. Neither doc's or Gastro, Optomistrist, dentists, I went to another hospital looking for answers as new symptoms came and went. A trip to ER, they did a stress test on my heart, due to the chest pain etc.. Two doc's told me I needed to see a Rhumatologists.

After my final crumb of the Benzo, I had 4 good days, then BAM. I was hit with every thing above at once, the same flu like I'll feeling I had back in Dec when it all started, that's when the light came on. This had to be withdrawal, but Doc's said no, no way...

I did more research, www.benzo.org.uk. Benzobuddies.org and between the two sites I found the answers. None of my docs supported this, my PCP kept telling me I'm having anxiety about my health and I need to see a psychiatrist, As they can rx.... I was opposed to this...so I sought out a addiction physician. And BINGO, I have been in withdrawal starting back to December to present. And I probably had been in TOLERANCE WITHDRAWAL for a few years prior, due to the long term use, even when one is on a regular dose. My brain was asking for more, but thank goodness I never took more. I knew it wasn't helping at night with leg tremors, I had been complaint of this for a few years. I was told to take another half or whole pill ,but I didn't. Anyway, withdrawal usually last 4-8 weeks following the last dose. I am at week 4.5. The doc thinks I've been through the worst, yah... and I should reach the COMFORT LEVEL. Means, not having anxiety, which I had never had.. Hello PCP, it's the worst initial w/d symptom, comfort level means not having any w/d that causes intolerable discomfort. This is my 3 consecutive week out of work, I had to take 2 weeks back in Feb as well. I have two good days then I am hit again with w d sx. Not as severe, but there, and unpredictable. I've had two super days, appetite has returned, sinuses are clearing on their own, I can sneeze now. I can taste and feel hot foods better. Benzos suppress, desensitize our brain. I know they can be very helpful in short term use and for seizures. I just don't understand why these SILENT ADDICTIVE DRUGS are rx'd beyond their benefit. Withdrawal from these is more difficult then heroin and cocaine, because withdrawal can last months, years in some. And, the worst symptom is INSOMNIA. I was awake for 51 hours without any sleep, then it has been just two hours, then awake for many before another 1-2. That is why many people just go back on these. I have a routine now of chamomile tea, lavender bath, deep breathing, music, had reflexology today, hopefully I will sleep some. For a small dose, what a powerful one because I was one it way too long...

Before people that are taking them get upset with me and my situation. To each his own, this is my experience, take what information you want or don't want. They are a great RESCUE RX. used only a couple times a week. Thanks

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Karen, this is absolutely devastating, there are no words that can possibly express how sorry and how sad I'm feeling after reading your post. I have indeed known people who did not tolerate benzodiazepines, and I always try to make some mention of this when a member includes them in a post. But your story is the most horrific I've ever heard. You are braver than anyone I know, to persist in seeking a solution, in spite of all your doctors' insistence to the contrary and denial that it could have been Clonazepam. Such a struggle deserves a medal. To finally locate an addiction physician, and then to put yourself through the nightmare of withdrawal, insomnia, pain -- you are indescribably brave, indeed heroic. I think it is insupportable that doctors so freely prescribe medications, no matter how small the amount, without doing the research on possible side effects -- and then to insist that one's suffering isn't due to the medication, you need to see a psychiatrist! No, there are no words to express my feelings at this moment.

 

I do, though, want to thank you for the time and effort it has taken you to write out and post this invaluable message. It is quite true that some people do very well on the benzodiazepines; but not all are so fortunate, and doctors are not always willing to blame the medication, but rather the patient. And I hope with all my heart, that others will read it and take heed.

 

I am more than grateful for your post, and please do continue to keep us informed of your progress. You are in my thoughts and prayers for a successful return to health, you most certainly deserve it.

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