High-Throughput Sequencing of mGluR Signaling Pathway Genes Reveals Enrichment of Rare Variants in Autism

Identification of common molecular pathways affected by genetic variation in autism is important for understanding disease pathogenesis and devising effective therapies. Here, we test the hypothesis that rare genetic variation in the metabotropic glutamate-receptor (mGluR) signaling pathway contributes to autism susceptibility. Single-nucleotide variants in genes encoding components of the mGluR signaling pathway were identified by high-throughput multiplex sequencing of pooled samples from 290 non-syndromic autism cases and 300 ethnically matched controls on two independent next-generation platforms. This analysis revealed significant enrichment of rare functional variants in the mGluR pathway in autism cases. Higher burdens of rare, potentially deleterious variants were identified in autism cases for three pathway genes previously implicated in syndromic autism spectrum disorder, TSC1, TSC2, and SHANK3, suggesting that genetic variation in these genes also contributes to risk for non-syndromic autism. In addition, our analysis identified HOMER1, which encodes a postsynaptic density-localized scaffolding protein that interacts with Shank3 to regulate mGluR activity, as a novel autism-risk gene. Rare, potentially deleterious HOMER1 variants identified uniquely in the autism population affected functionally important protein regions or regulatory sequences and co-segregated closely with autism among children of affected families. We also identified rare ASD-associated coding variants predicted to have damaging effects on components of the Ras/MAPK cascade. Collectively, these findings suggest that altered signaling downstream of mGluRs contributes to the pathogenesis of non-syndromic autism

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Neuro-Ophthalmic Signs and Symptoms of Closed Head Injury Patients

We receive 60 Consecutive patients presenting to the Kresge Eye Institute over the past 6 years with various eye complaints and a history of closed head injury. Causes of closed head injury included 41 motor vehicle accidents, 10 falls, 3 assaults, and various objects striking the head including a television, mop, box, rug, door and crane. 33 patients had already acquired the assistance of a lawyer upon entering the Kresge Eye Institute

Neuro-Ophthalmic Morbidity and Mortality of Retrobulbar Needle Block Anesthesia

Of 3215 consecutive retrobulbar needle blocks given at our Eye Institute as anesthesia for various ophthalmic procedures, neuro-ophthalmic complications resulted in 1 brainstem block with seizure, 2 inferior rectus compartment syndromes resulting in permanent vertical diplopia, 2 temporary inferior rectus muscle pareses both resolving in one week of the block being given, 3 cases of permanent dilated pupil from presumed ciliary body injury, and 5 retrobulbar hemorrhages with one compressive optic neuropathy

Evolution of Anesthetic Techniques for Optic Nerve Sheath Decompression

We have performed over 531 ONSD's from May 1992 to December 1996 on our neuro-ophthaJmic surgical service. Indications were PTC (72%), CRVO (8.4%), NAION (8.1%) (prior to moratorium), cryptococcal meningitis (5%), and other optic neuropathies (6.4%). During this period 57% of optic nerve sheath decompressions were performed utilizing local anesthesia and 43% were performed under general anesthesia

Rochalimaea Neuroretinitis and Retinal Vasculitis

Since the recent association of cat-scratch disease (CSD) with the bacteria Rochalimaea henselae, the spectrum of illness associated with CSD has been widening. We describe the previously unreported finding of retinal arterial occlusions in two patients with neuroretinitis due to CSD

Traumatic Optic Neuropathy among Patients Suffering Traumatic Retrobulbar Hemorrhages

We retrospectively analyzed 16 cases of traumatic optic neuropathy occurring among 86 patients suffering traumatic retrobulbar hemorrhages over the past 9 years. Traumatic optic neuropathy was diagnosed by continued optic nerve compromise with decreased vision after adequate orbital decompression had been achieved by lateral canthotomy and cantholysis decreasing intraocular pressure from a mean of 62.3 to a mean of 24.6

Management of Traumatic Orbital Hemorrhages with Visual Loss

A review of a consecutive series of traumatic orbital hemorrhages presenting to a major inner city trauma center is given. A comprehensive approach to the management of traumatic orbital hemorrhages is outlined. An algorithm including diagnostic and therapeutic modalities is presented