The major language pathways such as superior longitudinal fasciculus (SLF) pathways have been outlined by experimental and diffusion tensor imaging (DTI) studies. The SLF I and some of the superior ...parietal lobule connections of the SLF pathways have not been depicted by prior DTI studies due to the lack of imaging sensitivity and adequate spatial resolution. In the current study, the trajectory of the SLF fibers has been delineated on five healthy human subjects using diffusion tensor tractography on a 3.0-T scanner at high spatial resolution. We also demonstrate for the first time the trajectory and connectivity of the SLF fibers in relation to other language pathways as well as the superior parietal lobule connections of the language circuit using high spatial resolution DTI in the healthy adult human brain.
The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation ...types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.
Lymphocytic meningoradiculitis (Bannwarth syndrome) is a rare manifestation of Lyme neuroborreliosis in children. It is the most common clinical manifestation of early Lyme neuroborreliosis in adults ...in European countries where the disease is endemic but is rare in children. We report an imported case of Bannwarth syndrome in a pediatric patient and review the literature for other pediatric cases reported.
Background New intraparenchymal brain injury on magnetic resonance imaging is observed in 36% to 73% of neonates after cardiac surgery with cardiopulmonary bypass. Brain immaturity in this population ...is common. We performed brain magnetic resonance imaging before and after neonatal cardiac surgery, using a high-flow cardiopulmonary bypass protocol, hypothesizing that brain injury on magnetic resonance imaging would be associated with brain immaturity. Methods Cardiopulmonary bypass protocol included 150 mL · kg−1 · min−1 flows, pH stat management, hematocrit > 30%, and high-flow antegrade cerebral perfusion. Regional brain oxygen saturation was monitored, with a treatment protocol for regional brain oxygen saturation < 50%. Brain magnetic resonance imaging, consisting of T1-, T2-, and diffusion-weighted imaging, and magnetic resonance spectroscopy were performed preoperatively, 7 days postoperatively, and at age 3 to 6 months. Results Twenty-four of 67 patients (36%) had new postoperative white matter injury, infarction, or hemorrhage, and 16% had new white matter injury. Associations with preoperative brain injury included low brain maturity score ( P = .002). Postoperative white matter injury was associated with single-ventricle diagnosis ( P = .02), preoperative white matter injury ( P < .001), and low brain maturity score ( P = .05). Low brain maturity score was also associated with more severe postoperative brain injury ( P = .01). Forty-five patients had a third scan, with a 27% incidence of new minor lesions, but 58% of previous lesions had partially or completely resolved. Conclusions We observed a significant incidence of both pre- and postoperative magnetic resonance imaging abnormality and an association with brain immaturity. Many lesions resolved in the first 6 months after surgery. Timing of delivery and surgery with bypass could affect the risk of brain injury.
The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI).
To ...characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD.
This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives.
Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data.
Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (-22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies.
The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.
Expectations for outcomes after the neonatal arterial switch operation (ASO) continue to change. This cohort study describes neurodevelopmental outcomes at age 12 months after neonatal ASO, and ...analyzes both modifiable and nonmodifiable factors for association with adverse outcomes.
Patients who underwent an ASO (n=30) were enrolled in a prospective outcome study, with comprehensive clinical data collection during the first 12 months of life. Brain magnetic resonance imaging was done preoperatively and 7 days postoperatively, and the Bayley Scales of Infant Development III was performed at age 12 months.
Ten of 30 patients (33%) had preoperative magnetic resonance imaging injury; 13 of 30 patients (43%) had new postoperative magnetic resonance imaging injury. Twenty patients (67%) had Bayley Scales of Infant Development III: Cognitive Composite standard score mean was 104.8±15.0, Language Composite standard score median was 90.0 (25th to 75th percentile, 83 to 94), and Motor Composite standard score mean was 92.3±14.2. Best subsets multivariable analysis found associations between lower preoperative and intraoperative cerebral oxygen saturation, preoperative magnetic resonance imaging brain injury, total bypass time, and total midazolam dose and lower Bayley Scales of Infant Development III scores at age 12 months.
At 12 months after ASO, neurodevelopmental outcome means were within normal population ranges. The new associations reported in this study between potentially modifiable perioperative factors and outcomes require investigations in larger patient cohorts. Beyond survival, which was 100% in this cohort, factors influencing quality of life including neurodevelopmental outcomes should be routinely investigated in studies of ASO patients.
Although mild traumatic brain injury (mTBI) is now recognized as a major health issue, there have been relatively few studies of its acute effects. Previous studies of mTBI assessed at 1 week or less ...post-injury have produced inconsistent results, spanning reports of no ill effects to findings of robust dysfunction. These gross disparities reflect study differences such as the criteria for mTBI diagnosis and selection of comparison groups. In consideration of these issues, this study investigated outcome in the first 96 hours after injury in adolescents and adults ages 12-30 years with mTBI (n=73) compared with orthopedically injured (OI, n=65) and typically developing controls (TDC, n=40). The mTBI group reported significantly greater general psychological distress, post-concussion symptom severity, and post-traumatic stress severity than OI (all p<0.0001) and TDC (all p<0.0001); the OI and TDC groups responded similarly on these variables. There was a significant Group × Age interaction on the Total score (p<0.009), and the Cognitive (p=0.01) and Somatic (p<0.032) subscales of the Rivermead Post Concussion Symptoms Questionnaire where increasing symptom severity was associated with increasing age in the mTBI group. On neuropsychological assessment, the mTBI group performed significantly more poorly compared with OI for Verbal Selective Reminding Test (delayed recall, p=0.0003) and Symbol-Digit Modalities Test (SDMT written p=0.03; oral, p=0.001). The TDC group more robustly outperformed the mTBI group on these measures and also on the Brief Visuospatial Memory Test (delayed recall, p<0.04), Letter Fluency (p<0.02), and Category Switching (p<0.04). The TDC group outperformed the OI group on SDMT and Letter Fluency. These findings are consistent with previous reports of acute deficits in episodic memory and processing speed acutely after mTBI. Notably, however, these data also demonstrate the challenges of comparison group selection because differences were also found between the TDC and OI groups.
The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological ...membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.
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