Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia.

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated de novo mutation (p.Cys188Trp) in the GABAA receptor Cl- channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na+ and Ca+ channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca2+ channel Cav3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.

Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.

Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.

Tubular approach to minimally invasive microdiscectomy for pediatric lumbar disc herniation.

OBJECTIVE Lumbar disc herniation (LDH) in the pediatric population is rare and exhibits unique characteristics compared with adult LDH. There are limited data regarding the safety and efficacy of minimally invasive surgery (MIS) using tubular retractors in pediatric patients with LDH. Here, the outcomes of MIS tubular microdiscectomy for the treatment of pediatric LDH are evaluated. METHODS Twelve consecutive pediatric patients with LDH were treated with MIS tubular microdiscectomy at the authors' institution between July 2011 and October 2015. Data were gathered from retrospective chart review and from mail or electronic questionnaires. The Macnab criteria and the Oswestry Disability Index (ODI) were used for outcome measurements. RESULTS The mean age at surgery was 17 ± 1.6 years (range 13-19 years). Seven patients were female (58%). Prior to surgical intervention, 100% of patients underwent conservative treatment, and 50% had epidural steroid injections. Preoperative low-back and leg pain, positive straight leg raise, and myotomal leg weakness were noted in 100%, 83%, and 67% of patients, respectively. The median duration of symptoms prior to surgery was 9 months (range 1-36 months). The LDH level was L5-S1 in 75% of patients and L4-5 in 25%. The mean ± SD operative time was 90 ± 21 minutes, the estimated blood loss was ≤ 25 ml in 92% of patients (maximum 50 ml), and no intraoperative or postoperative complications were noted at 30 days. The median hospital length of stay was 1 day (range 0-3 days). The median follow-up duration was 2.2 years (range 0-5.8 years). One patient experienced reherniation at 18 months after the initial operation and required a second same-level MIS tubular microdiscectomy to achieve resolution of symptoms. Of the 11 patients seen for follow-up, 10 patients (91%) reported excellent or good satisfaction according to the Macnab criteria at the last follow-up. Only 1 patient reported a fair level of satisfaction by using the same criteria. Seven patients completed an ODI evaluation at the last follow-up. For these 7 patients, the mean ODI low-back pain score was 19.7% (SEM 2.8%). CONCLUSIONS To the authors' knowledge, this is the longest outcomes study and the largest series of pediatric patients with LDH who were treated with MIS microdiscectomy using tubular retractors. These data suggest that MIS tubular microdiscectomy is safe and efficacious for pediatric LDH. Larger prospective cohort studies with longer follow-up are needed to better evaluate the long-term efficacy of MIS tubular microdiscectomy versus other open and MIS techniques for the treatment of pediatric LDH.