Environmental and genetic factors in pediatric inflammatory demyelinating diseases

Abstract

The onset of multiple sclerosis (MS) occurs in childhood in about 5% of all patients with MS. The disease in adults has a complex genetic and environmental inheritability. One of the main risk factors, also confirmed in pediatric MS, is HLA DRB1*1501. In addition to genetic factors, a large part of disease susceptibility in adults is conferred by environmental risk factors such as low vitamin D status, exposure to cigarette smoking, and remote Epstein-Barr virus (EBV) infection. In children, both exposure to cigarette smoking and prior EBV infection have been reported consistently as risk factors for MS. The role of vitamin D remains to be confirmed in this age category. Finally, although very likely critical in disease processes, few gene-environment interactions and epigenetic changes have been reported for adult and pediatric MS susceptibility. Of interest, some of the risk factors for MS have also been associated with disease course modification, such as low 25(OH) vitamin D serum levels in pediatric and adult MS. Age is also a clear disease modifier of clinical, CSF, and MRI phenotype in children with the disease. Finally, although much has yet to be unraveled regarding molecular processes at play in MS, there is a larger gap in our knowledge of genetic and environmental risk factors for pediatric neuromyelitis optica spectrum disorders and acute disseminated encephalomyelitis and only collaborative studies will answer those questions. Among pediatric acquired demyelinating disorders of the CNS, multiple sclerosis (MS), including clinically isolated syndromes (CIS), acute disseminated encephalomyelitis, and neuromyelitis optica (NMO) spectrum disorders are the most common. Due to its chronicity and proportionally higher incidence, substantial efforts have focused on understanding factors contributing to MS, although the study of risk factors for NMO is also accelerating. 1Despite the fact that several genetic and environmental risk factors have been consistently reported for adult MS, 2 underlying molecular processes at play remain largely unknown. The onset of MS in children, although representing only approximately 5% of all MS onsets, leads us to question whether the load of genetic factors and environmental exposures contributing to disease onset may in fact be higher than in adults who develop the disease. As such environmental risk factors should be easier to identify in younger patients and if disease processes at play overlap in all age groups, this information might be extended to adult-onset MS. It is unknown why disease onset is relatively rare in children vs adults. This could be in part due to developmental changes in the CNS or immune systems.Exposures to environmental risk factors for adult MS are believed to occur for the most part before age 15.2 As such, studying risk factors in pediatric MS during the putative window of disease susceptibility may considerably shorten the time between exposure action and time of

Paediatric multiple sclerosis: a new era in diagnosis and treatment

“…The association between neonatal levels of vitamin D and future risk of multiple sclerosis is controversial. 42 A Swedish population-based case-control study with 459 individuals with multiple sclerosis showed no association; however, the results may have been affected by degradation of 25-hydroxyvitamin D owing to high storage temperatures of dried blood spot samples. 43 Contrastingly, a similarly designed Danish case-control study that measured 25-hydroxyvitamin D levels on dried blood spot samples showed an association between low concentrations of neonatal vitamin D and increased risk of multiple sclerosis.…”

“…Low vitamin D status has been consistently associated with disease susceptibility in adult‐onset multiple sclerosis. The association between neonatal levels of vitamin D and future risk of multiple sclerosis is controversial . A Swedish population‐based case–control study with 459 individuals with multiple sclerosis showed no association; however, the results may have been affected by degradation of 25‐hydroxyvitamin D owing to high storage temperatures of dried blood spot samples .…”

Pediatric versus adult MS: similar or different?

“…With respect to adult MS, the pediatric form offers the unique possibility to better explore environmental factors associated to the risk of developing MS and relapses, as confounding factors occurring along the course of MS are less present [104]. Studies in children and adolescents have pointed out that an increased risk of MS is related to previous exposure to passive smoking [105], to Epstein-Barr virus (demonstrated by two independent studies [106,107]), and to BMI [108].…”

The Secret Lives of Human Herpes Virus 6 (HHV-6)

“…Perhaps it is because the process of brain development is more complete; myelination is now well established and "compacted" throughout the brain. This gives HHV-6, should it get "riled up" by any agent or event, an opportunity to create "plaques", the hallmark of MS [33], through withdrawal of lamellae by groups of neighboring, infected oligodendrocytes, leaving whitishlooking patches of demyelinated brain tissue here and there when the brain is examined by MRI or at autopsy. Plaques appear to be lacking in brains of autistic younger children.…”

“…Then came more specific, antibody-mediated stains such as glial fibrillary protein (GFAP) for astrocytes and myelin oligodendrocyte protein (MOG) for oligodendrocytes. The hallmark of MS is the classic plaque [33,[35][36][37], one of numerous, often extensive whitish regions in autopsy MS brain sections that stain strongly for GFAP, a marker for astrocytes, and poorly for myelin proteins, suggesting that this is a demyelinated area full of dead astrocytes, the so-called "glial scar". MS plaques also often contain evidence of inflammatory processes, such as of perivascular arrays of lymphocytes, and macrophages/microglia that stain for phagocytized myelin proteins.…”