Faculty Bibliography

Background/UNASSIGNED:The Global Multiple System Atrophy Registry (GLOMSAR) was established in 2013. It is an online patient-reported contact registry open and free that relies on self-reported diagnosis by the patient or caregiver. Objectives/UNASSIGNED:To report the demographics of patients enrolled in GLOMSAR and the results of an ancillary online symptom questionnaire. Methods/UNASSIGNED:Patients enrolled in GLOMSAR were invited to complete a custom-designed online questionnaire about disease onset and symptom prevalence. Results/UNASSIGNED:At the time of writing, there were 1083 participants in GLOMSAR, of which 33% (365) completed the questionnaire. The onset and frequency of most symptoms was similar to those reported in the literature in physician-reported studies. Some were understudied or not typically associated with multiple system atrophy (MSA), including reduced female sexual sensation (55%), forgetfulness (60%), pseudobulbar affect (37%), olfactory changes (36%), and visual hallucinations (21%). Conclusions/UNASSIGNED:Patient-reported studies and ancillary online questionnaires are valid, underused research tools useful to advance our knowledge on understudied MSA features and highlight the patients' voice.

Dejerine-Sottas syndrome (DSS) is the earlier onset, more severe form of Charcot-Marie-Tooth (CMT) disease with heterogenous neurologic manifestations in addition to the peripheral neuropathy depending not only on the underlying causative gene but also the specific mutation. The Trembler mutation is an uncommon missense mutation in the PMP22 gene, the most commonly mutated gene responsible for CMT. We report two cases of DSS in a mother and son with the Trembler mutation, with associated findings of hearing loss and cognitive impairment. The mother had developmental gait abnormalities and became wheelchair bound in adolescence. She displayed impairment on cognitive and audiologic testing. Her son had similar developmental gait abnormalities and became wheelchair bound at age 19. Cognitive function showed an earlier decline in the son as compared to his mother. This report extends the clinical spectrum of the Trembler mutation in humans to include associated hearing loss with cognitive impairment.

In response to concerns about the declaration of death by neurologic criteria, the Uniform Law Commission created a drafting committee to update the Uniform Determination of Death Act (UDDA) in the Fall of 2021. One of the key questions for the committee to address was the following: Should the revised UDDA address objections to the use of neurologic criteria to declare death? This article (1) provides historical background and survey results that demonstrate the need to address this question; (2) summarizes the ethical principles that support and oppose accommodation of objections to the use of neurologic criteria to declare death; (3) reviews accommodation in other areas of medicine and law; (4) discusses existing legal and hospital guidance on management of these objections; (5) examines perspectives of stakeholder medical societies and expert health care professionals, lawyers, ethicists, and philosophers on whether the revised UDDA should address these objections; (6) identifies some questions for the drafting committee to consider when deciding whether the revised UDDA should address objections to the use of neurologic criteria to declare death; and (7) summarizes the potential downstream effects of the drafting committee's decision.

OBJECTIVE:To compare "hybrid immunity" (prior COVID-19 infection plus vaccination) and post-vaccination immunity to SARS CoV-2 in MS patients on different disease-modifying therapies (DMTs) and to assess the impact of vaccine product and race/ethnicity on post-vaccination immune responses. METHODS:Consecutive MS patients from NYU MS Care Center (New York, NY), aged 18-60, who completed primary COVID-19 vaccination series ≥6 weeks previously were evaluated for SARS CoV-2-specific antibody responses with electro-chemiluminescence and multiepitope bead-based immunoassays and, in a subset, live virus immunofluorescence-based microneutralization assay. SARS CoV-2-specific cellular responses were assessed with cellular stimulation TruCulture IFNγ and IL-2 assay and, in a subset, with IFNγ and IL-2 ELISpot assays. Multivariate analyses examined associations between immunologic responses and prior COVID-19 infection while controlling for age, sex, DMT at vaccination, time-to-vaccine, and vaccine product. RESULTS:Between 6/01/2021 and 11/11/2021, 370 MS patients were recruited (mean age 40.6 years; 76% female; 53% non-White; 22% with prior infection; common DMT classes: ocrelizumab 40%; natalizumab 15%, sphingosine-1-phosphate receptor modulators 13%; and no DMT 8%). Vaccine-to-collection time was 18.7 (±7.7) weeks and 95% of patients received mRNA vaccines. In multivariate analyses, patients with laboratory-confirmed prior COVID-19 infection had significantly increased antibody and cellular post-vaccination responses compared to those without prior infection. Vaccine product and DMT class were independent predictors of antibody and cellular responses, while race/ethnicity was not. INTERPRETATION/CONCLUSIONS:Prior COVID-19 infection is associated with enhanced antibody and cellular post-vaccine responses independent of DMT class and vaccine type. There were no differences in immune responses across race/ethnic groups.

PURPOSE/OBJECTIVE:Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants. METHODS:We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments. RESULTS:We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity. CONCLUSION/CONCLUSIONS:Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping.

Loss of Paneth cells and their antimicrobial granules compromises the intestinal epithelial barrier and is associated with Crohn's disease, a major type of inflammatory bowel disease^1-7. Non-classical lymphoid cells, broadly referred to as intraepithelial lymphocytes (IELs), intercalate the intestinal epithelium^8,9. This anatomical position has implicated them as first-line defenders in resistance to infections, but their role in inflammatory disease pathogenesis requires clarification. The identification of mediators that coordinate crosstalk between specific IEL and epithelial subsets could provide insight into intestinal barrier mechanisms in health and disease. Here we show that the subset of IELs that express γ and δ T cell receptor subunits (γδ IELs) promotes the viability of Paneth cells deficient in the Crohn's disease susceptibility gene ATG16L1. Using an ex vivo lymphocyte-epithelium co-culture system, we identified apoptosis inhibitor 5 (API5) as a Paneth cell-protective factor secreted by γδ IELs. In the Atg16l1-mutant mouse model, viral infection induced a loss of Paneth cells and enhanced susceptibility to intestinal injury by inhibiting the secretion of API5 from γδ IELs. Therapeutic administration of recombinant API5 protected Paneth cells in vivo in mice and ex vivo in human organoids with the ATG16L1 risk allele. Thus, we identify API5 as a protective γδ IEL effector that masks genetic susceptibility to Paneth cell death.

Introduction: Treatment of pediatric MS is challenging as most disease-modifying therapies (DMT) lack efficacy data in children, including switching from first-line platform DMT. Objectives/Aims: To assess real-world effectiveness of switching DMT in patients initially treated with platform injectable DMT on disease activity in pediatric MS and CIS.
Method(s): This is a cohort study of children with MS/CIS at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with platform injectable (interferon-beta, glatiramer acetate) and switched to the other class of injectable, oral (dimethyl fumarate, fingolimod, teriflunomide) or infusion (natalizumab, rituximab, ocrelizumab, alemtuzumab) DMT. Relapse rate after switch to platform injectable, oral or infusion DMT was modeled with negative binomial regression, adjusted for pre-identified confounders (age at onset, disease duration, sex, race/ethnicity, body mass index, first event severity and localization, baseline annualized relapse rate (ARR), MRI new T2 lesions, MRI gadolinium-enhancing lesions, EDSS).
Result(s): 212 children switched DMT before 18 years (67% female, 95% MS). Of these, 93 switched from injectable to injectable, 76 injectable to oral and 43 injectable to infusion. Compared to switching to another injectable, switchers to oral or infusion were older at onset (injectable 12.3 years vs oral 13.5, infusion 14.2) and switch date (injectable 14.6 years vs oral 16, infusion 15.7), and switchers to infusion were more likely to have new enhancing lesions prior to switch (injectable 45% vs oral 28%, infusion 67%). Other baseline characteristics were not significantly different between groups. In adjusted analysis, compared to switchers from injectable to injectable (ARR 0.59, 95%CI 0.28-1.26), relapse rates were lower for switchers from injectable to oral (ARR 0.22, 95%CI 0.10-0.48; rate ratio 0.38, 95%CI 0.21-0.69) and injectable to infusion (ARR 0.15, 95%CI 0.06-0.35; rate ratio 0.25, 95%CI 0.11-0.53) (p < 0.001). The adjusted number needed to treat to prevent 1 relapse with oral over injectable was 2.70 and infusion over injectable was 2.22.
Conclusion(s): Switching from platform injectable to oral or infusion as opposed to another injectable DMT led to better disease activity control of pediatric MS. Long-term safety data for oral and infusion DMTs are required