De novo and biallelic DEAF1 variants cause a phenotypic spectrum.

PURPOSE: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. METHODS: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. RESULTS: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). CONCLUSION: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

Craniocervivcal Spinal Dural Arteriovenous Fistula Ligation via a Modified Suboccipital Craniectomy and C1 Laminectomy: Operative Video.

Dural arteriovenous fistulas (dAVFs) are vascular malformations of the central nervous system that feature an arteriovenous shunt fed by dural arteries and can be intracranial or spinal.1-3 Spinal dAVFs are classically found at the nerve root sleeve.3 The arterial supply can often be predicted by the fistula location, whereas the symptomatology and risk of hemorrhage is determined by the venous drainage pattern.1-3 Craniocervical fistulas, a subset of dAVFs, may arise in association with the anterior condylar venous confluence or more dorsally in association with the transdural segment of the vertebral artery.1-3 This latter type of fistula typically has spinal venous drainage and may present with myelopathy from spinal cord venous congestion. We present a 61-year-old man who presented with a 2-week history of neck pain and paraparesis. Magnetic resonance imaging of the cervical spine revealed diffuse T2 hyperintensity of the cord from the pons to the level of the T1 vertebra. A computed tomography angiogram showed a possible dAVF at the craniocervical junction on the left. Because of the unclear nature of the patient's spinal cord lesion, a cerebral angiogram was performed. It confirmed a dAVF associated with the transdural segment of the left vertebral artery, with small dural feeders from the left vertebral artery and venous drainage into the anterior spinal vein. The patient underwent a modified suboccipital craniectomy and C1 laminectomy for dAVF ligation (Video 1). He was extubated postoperatively and discharged to a rehabilitation unit with improvement in lower extremity strength.

SARS CoV-2 mRNA vaccination exposes latent HIV to Nef-specific CD8+ T-cells.

Efforts to cure HIV have focused on reactivating latent proviruses to enable elimination by CD8+ cytotoxic T-cells. Clinical studies of latency reversing agents (LRA) in antiretroviral therapy (ART)-treated individuals have shown increases in HIV transcription, but without reductions in virologic measures, or evidence that HIV-specific CD8+ T-cells were productively engaged. Here, we show that the SARS-CoV-2 mRNA vaccine BNT162b2 activates the RIG-I/TLR - TNF - NFκb axis, resulting in transcription of HIV proviruses with minimal perturbations of T-cell activation and host transcription. T-cells specific for the early gene-product HIV-Nef uniquely increased in frequency and acquired effector function (granzyme-B) in ART-treated individuals following SARS-CoV-2 mRNA vaccination. These parameters of CD8+ T-cell induction correlated with significant decreases in cell-associated HIV mRNA, suggesting killing or suppression of cells transcribing HIV. Thus, we report the observation of an intervention-induced reduction in a measure of HIV persistence, accompanied by precise immune correlates, in ART-suppressed individuals. However, we did not observe significant depletions of intact proviruses, underscoring challenges to achieving (or measuring) HIV reservoir reductions. Overall, our results support prioritizing the measurement of granzyme-B-producing Nef-specific responses in latency reversal studies and add impetus to developing HIV-targeted mRNA therapeutic vaccines that leverage built-in LRA activity.