A Case of Beta-Propeller Protein-Associated Neurodegeneration With a Unique Truncating Variant in the WDR45 Gene and Uncommon Clinical and Radiologic Findings.

Beta-propeller protein-associated neurodegeneration (BPAN), a subtype of neurodegeneration with brain iron accumulation, is caused by variants in the WDR45 gene. In this paper, we describe a patient with an atypical presentation of BPAN whose whole exome sequencing revealed a previously unattested truncating variant in the WDR45 gene (c.830+3G>C/p.Leu278Ter), the pathogenicity of which was verified by RNA transcriptomics. A number of uncommon neuroanatomic and clinical findings in our patient are discussed, expanding the phenotype associated with BPAN. This unique case challenges existing genotype-phenotype correlations and highlights the role of X chromosome skewing in shaping the clinical spectrum of BPAN.

Morning blue light treatment improves sleep complaints, symptom severity, and retention of fear extinction memory in post-traumatic stress disorder.

Disrupted sleep is a major feature in numerous clinical disorders and is related to decrements in affective memory processing. The prevalence of sleep disruption in post-traumatic stress disorder (PTSD) is suggested to be a key feature that exacerbates the impaired ability to recall extinction memories during experimental fear conditioning. We hypothesized that an intervention employing blue-wavelength light therapy (BLT) to regulate sleep and stabilize circadian rhythms in patients with PTSD (i.e., via regulated morning exposure) would be associated with PTSD symptom improvement, decreased sleep-related complaints, as well as improved consolidation and retention of extinction memories relative to a fear conditioning/extinction paradigm. Eighty-two individuals with PTSD underwent a well-validated fear conditioning/extinction protocol with subsequent assignment to receive morning BLUE (BLT) or placebo AMBER (ALT) light therapy daily for 30-min over 6-weeks. Participants returned after the intervention for post-treatment extinction recall, comprised of exposure to the previously conditioned stimuli, with the difference in skin conductance response between the "extinguished" and the "never-extinguished" stimuli at follow-up. Participants also viewed previously conditioned stimuli in a novel context during a functional magnetic resonance imaging (fMRI) scan. BLUE light therapy was associated with improvements relative to correlated decreases between PTSD symptoms and sleep-related complaints. Participants receiving BLT also sustained retention of the extinction memory, while those in the placebo amber light treatment group showed impairment, characterized by the restoration of the extinguished fear response after 6-weeks. Participants in the ALT also demonstrated greater reactivity in the left insula when viewing the previously extinguished fear-conditioned stimuli in a novel context. Daily BLUE-wavelength morning light exposure was associated with greater retention of extinction learning in patients with PTSD when compared to ALT, as supported by both autonomic and neurobiological reactivity. We speculate that improved sleep facilitated by a stabilized circadian rhythm, after fear-learning, led to greater consolidation of the fear extinction memory, decreased PTSD symptom presentation, and associated decreases in sleep-related complaints. Prominent exposure treatments for PTSD incorporate principles of fear extinction, and our findings suggest that blue light treatment may facilitate treatment gains by promoting the consolidation of extinction memories via improved sleep.

On the development of a neoantigen vaccine for the prevention of Lynch Syndrome.

Lynch Syndrome (LS) is an autosomal dominant genetic condition that causes a high risk of colorectal cancer. The hallmark of LS is genetic instability as a result of mismatch repair (MMR) deficiency, particularly in repetitive low complexity regions called microsatellites (MS). MLH1-/- mice deficient in MMR are prone to developing tumors in the colon, upon oral administration of dextran sodium sulfate (DSS), at a rate of more than 70%. Using this LS mouse model, we found a novel tumor neo-antigen from a deletion mutation of the coding MS in the SENP6 gene that prevented tumorigenesis or hindered tumor growth rate in immunized mice. This was accomplished via high throughput exome sequencing of DSS-induced colorectal tumors in the MLH1-/- mice and predicting the most highly immunogenic mutant gene products processed and presented as antigens in C57BL/6 MHC-I molecules. Throughout our study, we were able to prove the validity of the vaccine by analyzing the colorectal tumors in immunized DSS-treated mice using either our epitope, called Sp6D1, or an unrelated peptide as a negative control. Tumors developed in this context were found to be antigenic and Sp6D1-specific CD8+ tumor infiltrating lymphocytes were detected by flow cytometry and cytotoxic T lymphocytes (CTL) killing assays. Additionally, immunohistochemistry showed that tumor-adjacent tertiary lymphoid organs were a potentially significant source of CD8+ lymphocytes. Altogether, our results indicate that there may be a protective effect to patients carrying LS mutations through the induction of a peptide-specific CTL response from the use of neoepitope vaccination.