Author Affiliations: Neurology Section, Veterans Affairs North Texas Health Care System, Medical Service, Dallas (Dr Stüve); Department of Neurology, University of Texas Southwestern Medical Center at Dallas (Drs Stüve and Lambracht-Washington); Department of Neurology, University of California, San Francisco (Dr Wang); Department of Neurology, Ruhr University Bochum, Germany (Dr Chan); Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Germany (Drs Hemmer and Cepok); Department of Neurology, Georg August University Göttingen, Göttingen, Germany (Dr Nessler); Department of Neurology, Johannes Gutenberg University Mainz, Mainz, Germany (Dr Zipp); Department of Neurology, University of Virginia, Charlottesville (Dr Goldman); Department of Neurology, Inflammatory Disorders of the Nervous System and Neurooncology, University of Münster, Münster, Germany (Dr Meuth); Institute for Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany (Dr Korth).
This article was corrected | View correction
Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system. Approximately 10% to 20% of patients with MS are diagnosed with primary progressive MS (PPMS), defined as a disease course with gradual accumulation of disability without any clinical attacks or remission from onset.1 Primary progressive MS is considered by many to have more neurodegenerative characteristics than other MS phenotypes. In addition, and perhaps supportive of the notion that PPMS has a degenerative rather than an inflammatory pathogenesis, are that (1) immune therapies are ineffective, (2) the age at onset is typically around 40 years and thus significantly later than that of relapsing-remitting MS,2- 5 and (3) that there appears to be no sex predilection.3
The endogenous cellular prion protein (PrPc) is an α-helical glycophosphatidylinositol-anchored sialoglycoprotein. The PrPc protein is highly expressed in neurons, lymphoid cells, and myeloid cells. A single-nucleotide polymorphism (SNP) at codon 129 of the PrP gene (Prnp), which is located on chromosome 20p12, has been shown to have a significant effect on the clinical course of numerous nonprion neurodegenerative disorders of the central nervous system including Alzheimer disease, Down syndrome, and Wilson disease.6- 10 In all of these disorders, methionine/valine heterozygosity is associated with less severe clinical disease. Finally, the Prnp 129 SNP also appears to have a negative effect on long-term memory in adult and senescent healthy individuals.11- 13 The mechanisms by which the Prnp SNP 129 alters central nervous system function remain to be elucidated.
Given that PPMS is considered a neurodegenerative disorder, we hypothesized in this study that Prnp SNP 129 has an effect on susceptibility to this distinct MS phenotype.
To determine whether the Prnp 129 M/V SNP plays a role in PPMS susceptibility, we assessed the genotypes of 498 patients with PPMS and 600 healthy controls. Appropriate institutional review boards had approved all studies, and informed consent was obtained from all participants. Genotypes were generated by a TaqMan allelic discrimination assay on an ABI7900HT genotyping platform, using the Assay-by-Design service from Applied Biosystems (Foster City, California).
The female to male ratio among patients with PPMS was 1:1. No deviations from Hardy-Weinberg equilibrium were observed for genotypes in the patients (Table). There was no statistically significant difference in frequency of Prnp 129 genotypes between patients with PPMS and controls (P = .14) (Table). There was also no difference in allelic frequency distributions between the 498 patients with PPMS and 979 patients with relapsing-remitting MS (P = .23) (Table). No difference in allelic transmission was observed in either subgroup.
While the results of this association analysis do not suggest the role of an SNP in Prnp 129 in PPMS susceptibility, our study was almost certainly underpowered to conclusively eliminate this mutation as a susceptibility factor. Our negative results may also be consistent with recent pathological studies that suggested a strong association between inflammation and neurodegeneration in progressive MS.14 Therefore, in contrast to other typical neurodegenerative disorders, the pathology of progressive MS may be consistent with that of an inflammatory disease rather than degenerative disease in some patients.
We were unable to study the role of Prnp 129 on the disease course of PPMS, as clinical and neuroimaging information was only available on a very small subset of patients. As larger patient databases are being developed, we will be able to study the effect of this SNP on clinical and paraclinical in patients with this disorder.
Correspondence: Dr Stüve, Neurology Section, Veterans Affairs North Texas Health Care System, Medical Service, 4500 S Lancaster Rd, Dallas, TX 75216 (firstname.lastname@example.org).
Financial Disclosure: None reported.
Funding/Support: This study was supported by a Merit Review, Department of Veterans Affairs (Dr Stüve).
Additional Contributions: The authors wish to thank the individuals who participated in this study. In addition, the authors would like to thank Holly Smith for her support, and Jorge Oksenberg, PhD, from the University of California, San Francisco, for his tremendous assistance in designing the study, helping with all technical aspects of the study, and preparing the manuscript. The authors would also like to thank the Accelerated Cure Project for Multiple Sclerosis for making available samples for the project.
This article was corrected on February 14, 2011.
Thank you for submitting a comment on this article. It will be reviewed by JAMA Neurology editors. You will be notified when your comment has been published. Comments should not exceed 500 words of text and 10 references.
Do not submit personal medical questions or information that could identify a specific patient, questions about a particular case, or general inquiries to an author. Only content that has not been published, posted, or submitted elsewhere should be submitted. By submitting this Comment, you and any coauthors transfer copyright to the journal if your Comment is posted.
* = Required Field
Disclosure of Any Conflicts of Interest*
Indicate all relevant conflicts of interest of each author below, including all relevant financial interests, activities, and relationships within the past 3 years including, but not limited to, employment, affiliation, grants or funding, consultancies, honoraria or payment, speakers’ bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. If all authors have none, check "No potential conflicts or relevant financial interests" in the box below. Please also indicate any funding received in support of this work. The information will be posted with your response.
Some tools below are only available to our subscribers or users with an online account.
Download citation file:
Web of Science® Times Cited: 1
Customize your page view by dragging & repositioning the boxes below.
Users' Guides to the Medical Literature
How Serious Is the Risk of Bias?
Users' Guides to the Medical Literature
All results at
Enter your username and email address. We'll send you a link to reset your password.
Enter your username and email address. We'll send instructions on how to reset your password to the email address we have on record.
Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.