Genetics of multiple sclerosis

Dans une démarche qui vise à uniformiser les procédures d’allogreffe et d’autogreffe de cellules souches hématopoïétiques, la Société francophone de greffe de moelle et thérapie cellulaire (SFGM-TC) a organisé les huitièmes ateliers d’harmonisation des pratiques en allogreffe de cellules souches hématopoïétiques en septembre 2017 à Lille. Dans le contexte de cet atelier, il a été développé et mis à jour les indications et le suivi des autogreffes de cellules souches hématopoïétiques dans la sclérose en plaques sous l’égide de la SFGM-TC et de la Société francophone de la sclérose en plaques.

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 8th allogeneic hematopoietic stem cell transplantation clinical practices harmonization workshop series in September 2017 in Lille, France. In this article we give the indications of autologous stem cell transplantation in multiple sclerosis as well as recommendations regarding post-transplant follow-up of patients under the hospice of the SFGM-TC and the Francophone Society of Multiple Sclerosis.

As with other autoimmune diseases, susceptibility to multiple sclerosis (MS) is believed to result from the complex interaction of a number of genes, each with modest effect. Several genome-wide screens have implicated the nitric oxide synthase 2A gene (NOS2A), which encodes the inducible form of nitric oxide synthase, as being potentially associated with MS. To determine whether genetic variants within this gene may constitute a risk factor for causing MS, we investigated 13 single nucleotide polymorphisms in the NOS2A gene, in a case–control group of 214 Italian patients with MS and 121 controls. All these single nucleotide polymorphisms (SNPs) were analyzed using the SNPlex™ Genotyping System (Applied Biosystems). Data were analyzed using Genemapper 4.0 and Haploview 4.1. No significant association between cases and controls (P > 0.05) was observed for the alleles of the SNPs. Defining the haplotype blocks also failed to detect any associated haplotypes. Our results suggest that polymorphic variation within the NOS2A gene does not influence the susceptibility to MS in patients of Italian origin.

This case report describes a rare presentation of multiple sclerosis (MS) that was initially diagnosed as a peripheral nerve lesion in the emergency department.

A 30-year-old woman presented to a chiropractic teaching clinic with a complaint of a sudden right foot drop. Magnetic resonance imaging of the brain revealed a large mass in the left parietal lobe with additional white matter lesions. The mass and smaller lesions were consistent with a rare presentation of demyelinating disease, tumefactive MS.

The patient was referred to a neurologist for further evaluation and treatment. Her short-term clinical course was punctuated by recurrent myospasms and neurologic deficits.

Tumefactive MS may mimic the clinical and magnetic resonance imaging characteristics of glioma or a cerebral abscess. The clinical presentation, pathophysiology, differential diagnosis, role of diagnostic imaging, and treatment options of MS are described. This case report illustrates that the timely diagnosis and optimal treatment of MS require recognition of its varied, sometimes atypical, and often nonspecific clinical and imaging manifestations.

Multiple sclerosis (MS) is the most frequent autoimmune, inflammatory disease of the central nervous system. It is believed to be a multifactorial and multigenic disease. Despite numerous efforts to find a locus with hypothesis-free whole genome screens, no repeatable locus other than HLA could be found. Genomic screens use polymerase chain reaction (PCR) based methods to find a difference between patients and controls. This method is insensitive to differences other than disparities in the DNA sequence. The negative results of these efforts suggest that other mechanisms may be involved in MS pathophysiology. Epigenetics denotes all heritable mechanisms which result in a transcriptional difference without a change in the DNA sequence. In the last decade, there have been several findings implying the significance of epigenetic modifications as causal factors for multifactorial diseases like MS. Epigenetic factors might be affecting MS induction and clinical severity by modulating such diverse biological processes as X chromosome inactivation, viral infections, myelin protein production and Th1 type immune response differentiation.

The gene encoding the inducible form of Nitric Oxide Synthase (NOS2A) has been considered with interest in the evaluation of the genetic predisposition to Multiple Sclerosis (MS). The aim of the present study was to address the possible contribution of two microsatellites repeats of the NOS2A promoter region – (CCTTT)_n and (AAAT)_n – to MS susceptibility.

One hundred and thirteen Italian patients with clinically definite RRMS and 237 age and sex matched healthy controls from Calabria (South Italy) were studied. The distribution analysis of the markers frequencies showed that the (CCTTT)₁₄ allele was found in 11.5% of the RRMS patients and in 25.3% of the healthy subjects, with a statistically significant difference (χ² = 8.843, p = 0.003). This data seems to confer a significant protection against MS (OR = 0.348; 95% CI = 0.174 – 0.693, corrected for age and gender).

No association with MS susceptibility was observed for the bi-allelic (AAAT)_n microsatellite.

In conclusion, we found that the NOS2A (CCTTT)₁₄ allele was detected more frequently in the control group than in the RRMS patients, thus confirming the scientific interest on this marker.

Though independent findings suggest roles for the allergic arm of the immune system and myelin-reactive antibodies in MS, myelin-reactive IgE has not been investigated. We have developed a radioimmunoassay that measures reactive IgE, IgG and IgA against short (5–6-mers) myelin protein-derived peptides bearing little to no sequence identity with other human proteins, and which might therefore be targets of a CNS-specific autoimmune attack. Here we show that, irrespective of clinical subtype, MS patients' sera are characterized by a higher frequency of measurable IgE against the peptides. Moreover, in controls with measurable IgE reactive against test peptides, IgG or IgA reactive with the same peptide epitopes is almost always present in vastly greater quantities, whereas in MS subjects peptide-reactive IgA or IgG is often undetectable. The sensitivity of the full assay, when considering overall positive a serum sample that has detectable autoreactive IgE without other competing Igs, is 69% (S.E.: 5%), with a specificity of 87% (S.E.: 9%). We speculate that IgE reactive against CNS target antigens may have both diagnostic and pathogenic significance, particularly if other peptide-specific, potentially blocking Igs are absent.