Rare variants and HLA haplotypes associated in patients with neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders (NMOSD) are rare, debilitating autoimmune diseases of the central nervous system. Many NMOSD patients have antibodies to Aquaporin-4 (AQP4). Prior studies show associations of NMOSD with individual Human Leukocyte Antigen (HLA) alleles and with mutations in the complement pathway and potassium channels. HLA allele associations with NMOSD are inconsistent between populations, suggesting complex relationships between the identified alleles and risk of disease. We used a retrospective case-control approach to identify contributing genetic variants in patients who met the diagnostic criteria for NMOSD and their unaffected family members. Potentially deleterious variants identified in NMOSD patients were compared to members of their families who do not have the disease and to existing databases of human genetic variation. HLA sequences from patients from Belgrade, Serbia, were compared to the frequency of HLA haplotypes in the general population in Belgrade. We analyzed exome sequencing on 40 NMOSD patients and identified rare inherited variants in the complement pathway and potassium channel genes. Haplotype analysis further detected two haplotypes, HLA-A*01, B*08, DRB1*03 and HLA-A*01, B*08, C*07, DRB1*03, DQB1*02, which were more prevalent in NMOSD patients than in unaffected individuals. In silico modeling indicates that HLA molecules within these haplotypes are predicted to bind AQP4 at several sites, potentially contributing to the development of autoimmunity. Our results point to possible autoimmune and neurodegenerative mechanisms that cause NMOSD, and can be used to investigate potential NMOSD drug targets.Published versio

Isolated Asymmetric Progressive Optic Neuropathy as a First Presentation of Charcot-Marie-Tooth Disease Type 2A

The differential diagnosis of optic neuropathy is broad and includes inflammatory, ischemic, nutritional, and hereditary etiologies. The most common hereditary optic neuropathies are autosomal dominant optic atrophy and mitochondrially inherited Leber optic neuropathy

Phase-Sensitive Inversion-Recovery MRI Improves Longitudinal Cortical Lesion Detection in Progressive MS.

Previous studies comparing phase sensitive inversion recovery (PSIR) to double inversion recovery (DIR) have demonstrated that use of PSIR improves cross-sectional in vivo detection of cortical lesions (CL) in multiple sclerosis. We studied the utility of PSIR in detection/characterization of accrual of CL over time in a 1-year longitudinal study in primary progressive multiple sclerosis (PPMS) compared to DIR. PSIR and DIR images were acquired with 3T magnetic resonance imaging (MRI) in 25 patients with PPMS and 19 healthy controls at baseline, and after 1 year in 20 patients with PPMS. CL were classified as intracortical, leucocortical or juxtacortical. Lesion counts and volumes were calculated for both time points from both sequences and compared. Correlations with measures of physical and cognitive disability were determined as well as new CL counts and volumes. Compared to DIR, PSIR led to detection of a higher number of CL involving a larger proportion of patients with PPMS both cross-sectionally (p = 0.006, 88%) and longitudinally (p = 0.007, 95%), and led to the reclassification of a third of CL seen on DIR at each time point. Interestingly, PSIR was more sensitive to new CL accumulation over time compared to DIR. PSIR is a promising technique to monitor cortical damage and disease progression in patients with PPMS over a short-term follow-up

The relationship between cortical lesions and periventricular NAWM abnormalities suggests a shared mechanism of injury in primary-progressive MS

In subjects with multiple sclerosis (MS), pathology is more frequent near the inner and outer surfaces of the brain. Here, we sought to explore if in subjects with primary progressive MS (PPMS) cortical lesion load is selectively associated with the severity of periventricular normal appearing white matter (NAWM) damage, as assessed with diffusion weighted imaging.To this aim, twenty-four subjects with PPMS and twenty healthy controls were included in the study. Using diffusion data, skeletonized mean diffusivity (MD) NAWM maps were computed excluding WM lesions and a 2mm-thick peri-lesional rim. The supra-tentorial voxels between 2 and 6mm of distance from the lateral ventricles were included in the periventricular NAWM mask while the voxels between 6 and 10mm from the lateral ventricles were included in the deep NAWM mask; mean MD values were then computed separately for these two masks. Lastly, cortical lesions were assessed on phase-sensitive inversion recovery (PSIR) images and cortical thickness was quantified on volumetric T1 images.Our main result was the observation in the PPMS group of a significant correlation between periventricular NAWM MD values and cortical lesion load, with a greater cortical lesion burden being associated with more abnormal periventricular NAWM MD. Conversely, there was no correlation between cortical lesion load and deep NAWM MD values or periventricular WM lesions.Our data thus suggest that a common – and relatively selective - factor plays a role in the development of both cortical lesion and periventricular NAWM abnormalities in PPMS. Keywords: Multiple sclerosis, MR

An HSV-based library screen identifies PP1α as a negative TRPV1 regulator with analgesic activity in models of pain

Transient receptor potential vanilloid 1 (TRPV1) is a pronociceptive cation channel involved in persistent inflammatory and neuropathic pain. Herpes simplex virus (HSV) vector expression of TRPV1 causes cell death in the presence of capsaicin, thereby completely blocking virus replication. Here we describe a selection system for negative regulators of TRPV1 based on rescue of virus replication. HSV-based coexpression of TRPV1 and a PC12 cell-derived cDNA library identified protein phosphatase 1α (PP1α) as a negative regulator of TRPV1, mimicking the activity of “poreless” (PL), a dominant-negative mutant of TRPV1. Vectors expressing PP1α or PL reduced thermal sensitivity following virus injection into rat footpads, but failed to reduce the nocifensive responses to menthol/icilin-activated cold pain or formalin, demonstrating that the activity identified in vitro is functional in vivo with a degree of specificity. This system should prove powerful for identifying other cellular factors that can inhibit ion channel activity

Retrospective analysis of new PSIR cortical lesions.

<p>Baseline and follow-up axial PSIR images of different patients with primary progressive MS demonstrating focal lesions in the cortical grey matter. Intracortical lesion that was too small to be counted at baseline (a, white arrow), but that enlarged and was counted on follow-up scan (b, white arrow). New LC lesion (d, white arrow) noted at follow-up but not at baseline (c).</p

Baseline and follow-up cortical lesion volumes and counts in patients with primary progressive multiple sclerosis.

<p>Baseline and follow-up cortical lesion volumes and counts in patients with primary progressive multiple sclerosis.</p

Significant baseline and follow-up correlations between CL counts and volumes and clinical variables (without correction for age and gender).

<p>Significant baseline and follow-up correlations between CL counts and volumes and clinical variables (without correction for age and gender).</p

Reclassification of new cortical lesions.

<p>Baseline and follow up axial DIR (a, b) of the brain of a patient with primary progressive multiple sclerosis (PPMS) demonstrating a new focal lesion in the cortical grey matter (white-arrows) at follow-up. Corresponding baseline and follow-up axial PSIR (c, d) of the same patient with PPMS demonstrating focal lesions in the cortical grey matter (white-arrows) at both baseline and follow-up.</p

Baseline and follow-up demographics and clinical characteristics of patients with primary progressive multiple sclerosis.

<p>Baseline and follow-up demographics and clinical characteristics of patients with primary progressive multiple sclerosis.</p