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Impact of multiple sclerosis risk loci in postinfectious neurological syndromes
Filippo Martinelli-Boneschi1, Riccardo Currò2, Silvia Santoro3
1Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Via Francesco Sforza 35, 20122 Milan, Italy; Neurology Unit and MS Centre, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.
Background:
The genetic component of multiple sclerosis (MS) is now set to 200 autosomal common variants. However, it is unclear how genetic knowledge be clinically used in the differential diagnosis between MS and other inflammatory conditions like adult-onset postinfectious neurological syndromes (PINS). The aim of this study was to investigate whether PINS and MS have a shared genetic background using an updated polygenic risk scores.
Methods:
Eighty-eight PINS patients have been consecutively recruited between 1996 and 2016 at Mondino Foundation of Pavia, diagnosed according to clinical, MRI and CSF findings and followed-up for several years. Patients were typed using Illumina array, and genotypes imputed using the 1000 Genomes Project reference panel. A weighted genetic risk score (wGRS) has been calculated based on autosomal MS risk loci derived from large-scale studies, and an HLA genetic burden (HLAGB) was also calculated on loci associated to MS.
Results:
PINS occurred as an episode of myelitis in 44% of patients, encephalomyelitis in 44%, and encephalitis in remaining cases, with an involvement of peripheral nervous system in 41% of patients. Mean age of onset was 50.1 years, and female:male ratio was 1.4. Patients were followed-up for a mean of 7.2 years, and at last visit 55% had a low disability grade (mRS 0-1). Disease was monophasic in 67% of patients, relapsing in 18% and chronic-progressive in 15%. The wGRS of PINS cases was comparable to 370 healthy controls, while significantly lower compared to 907 bout-onset MS (BOMS) cases (wGRS= 20.9 vs 21.2; p<0.0001). The difference was even larger for PINS with peripheral nervous system involvement (wGRS=20.6) vs BOMS.
Conclusion:
The distinction between MS and PINS is not easy to make in clinical practice. However, our study shows that the new set of MS risk alleles does not confer increased susceptibility to PINS. These data support the importance to discriminate these cases from MS with pathophysiological and therapeutic implications.
Insights
Genetic risk for multiple sclerosis (MS) does not increase susceptibility to postinfectious neurological syndromes (PINS). This finding helps differentiate PINS from MS, impacting diagnosis and treatment.
Area of Science:
- Neuroimmunology
- Genetics
- Neurology
Background:
- Multiple sclerosis (MS) has a known genetic component involving over 200 common variants.
- Clinical differentiation between MS and adult-onset postinfectious neurological syndromes (PINS) remains challenging.
- The utility of genetic information in distinguishing MS from PINS requires investigation.
Purpose of the Study:
- To determine if PINS and MS share a common genetic background.
- To assess the applicability of updated polygenic risk scores in differentiating these conditions.
Main Methods:
- Eighty-eight PINS patients were recruited and diagnosed using clinical, MRI, and CSF data.
- Genotyping was performed using Illumina arrays, with imputation against the 1000 Genomes Project panel.
- Weighted genetic risk scores (wGRS) and HLA genetic burden (HLAGB) were calculated based on known MS risk loci.
Main Results:
- PINS presentations included myelitis (44%), encephalomyelitis (44%), and encephalitis (12%), with 41% involving the peripheral nervous system.
- The mean age of onset was 50.1 years, with a female:male ratio of 1.4.
- PINS cases exhibited a wGRS comparable to healthy controls but significantly lower than bout-onset MS (BOMS) cases (20.9 vs 21.2, p<0.0001).
Conclusions:
- The genetic risk alleles associated with MS do not appear to confer increased susceptibility to PINS.
- These findings underscore the importance of distinguishing PINS from MS due to distinct pathophysiological mechanisms and therapeutic implications.
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