Further expansion and confirmation of phenotype in rare loss of YWHAE gene distinct from Miller-Dieker syndrome.

Deletion of 17p13.3 has varying degrees of severity on brain development based on precise location and size of the deletion. The most severe phenotype is Miller-Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death. Haploinsufficiency of PAFAH1B1 is responsible for the characteristic lissencephaly in MDS. The precise role of YWHAE haploinsufficiency in MDS is unclear. Case reports are beginning to elucidate the phenotypes of individuals with 17p13.3 deletions that have deletion of YWHAE but do not include deletion of PAFAH1B1. Through our clinical genetics practice, we identified four individuals with 17p13.3 deletion that include YWHAE but not PAFAH1B1. These patients have a similar phenotype of dysmorphic facial features, developmental delay, and leukoencephalopathy. In a review of the literature, we identified 19 patients with 17p13.3 microdeletion sparing PAFAH1B1 but deleting YWHAE. Haploinsufficiency of YWHAE is associated with brain abnormalities including cystic changes. These individuals have high frequency of epilepsy, intellectual disability, and dysmorphic facial features including prominent forehead, epicanthal folds, and broad nasal root. We conclude that deletion of 17p13.3 excluding PAFAH1B1 but including YWHAE is associated with a consistent phenotype and should be considered a distinct condition from MDS.

Altered white matter connectivity in children with congenital heart disease with single ventricle physiology.

Children born with congenital heart disease (CHD) have seen a dramatic decrease in mortality thanks to surgical innovations. However, there are numerous risk factors associated with CHD that can disrupt neurodevelopment. Recent studies have found that psychological deficits and structural brain abnormalities persist into adulthood. The goal of the current study was to investigate white matter connectivity in early school-age children (6-11 years), born with complex cyanotic CHD (single ventricle physiology), who have undergone Fontan palliation, compared to a group of heart-healthy, typically developing controls (TPC). Additionally, we investigated associations between white matter tract connectivity and measures on a comprehensive neuropsychological battery within each group. Our results suggest CHD patients exhibit widespread decreases in white matter connectivity, and the extent of these decreases is related to performance in several cognitive domains. Analysis of network topology showed that hub distribution was more extensive and bilateral in the TPC group. Our results are consistent with previous studies suggesting perinatal ischemia leads to white matter lesions and delayed maturation.

Clinical, Neuroimaging, and Electrographic Predictors of Phenobarbital Failure in Newborns With Hypoxic Ischemic Encephalopathy and Seizures.

BACKGROUND: Many neonates with hypoxic ischemic encephalopathy and seizures do not respond to the first line antiepileptic drug, phenobarbital. Little is known about what factors are associated with its failure. OBJECTIVE: To examine factors associated with failure of phenobarbital therapy in neonates with hypoxic ischemic encephalopathy and seizures. DESIGN/METHODS: A single-center retrospective review of 50 term (>35 weeks) neonates with hypoxic ischemic encephalopathy and seizures treated with phenobarbital as the first-line antiepileptic. Neonates were classified into either responders (n = 30) or nonresponders (n = 20). Nonresponse was defined as continued seizures after maximum dosing of phenobarbital or an additional antiepileptic. Subjects with acceptable magnetic resonance imaging (MRI) scans obtained within 2 weeks of birth were included in the study and rated using an MRI injury scoring system. Charts were reviewed for demographic, clinical, and laboratory variables. Resuscitation and seizure scores were also calculated. Electroencephalographic (EEG) background activity was reviewed in 2 different time epochs (12-24 hours and 24-36 hours of life) and graded as per ACNS guidelines. RESULTS: There were no significant group differences in demographic, clinical, and laboratory variables except nonresponders, who had higher mean seizure score (P = .01) and significantly more injury on MRI scan for white matter (P = .004), parenchymal cortex (P = .027), and watershed (P = .009) regions. Neonates with moderately abnormal or severely abnormal background EEG responded poorly to phenobarbital. CONCLUSION: In the presence of above factors, one can anticipate that additional antiepileptic medication may be needed. These data also support that larger studies should be done to look prospectively at using alternative agents first line in patients with severe injury.

CNTNAP1-Related Congenital Hypomyelinating Neuropathy.

BACKGROUND: Congenital hypomyelinating neuropathy is a rare form of hereditary peripheral neuropathy characterized by nonprogressive weakness, areflexia, hypotonia, severely reduced nerve conduction velocities, and hypomyelination. Mutations in contactin-associated protein 1 (CNTNAP1) were recently described as a cause of congenital hypomyelinating neuropathy. CNTNAP1-associated congenital hypomyelinating neuropathy is characterized by severe hypotonia, multiple distal joint contractures, and high mortality in the first few months of life. METHODS: Whole-exome sequencing was performed in two siblings with congenital hypotonia. Detailed phenotyping data were compared with previously reported cases. RESULTS: A novel, heterozygous compound mutation of CNTNAP1 was identified in both siblings. We also reviewed 17 patients harboring 10 distinct mutations from previously published studies. All patients presented with severe hypotonia, respiratory distress, and multiple cranial nerve palsies at birth. Six of 19 patients survived beyond infancy and required chronic mechanical ventilation. Seizures were common in the surviving patients. CONCLUSIONS: These findings suggest that CNTNAP1-related congenital hypomyelinating neuropathy is a distinct form of hereditary neuropathy that affects both the central and peripheral nervous systems with no clear phenotype-genotype correlation. Our findings also indicate that arthrogryposis multiplex congenita and early lethality are not universal outcomes for patients with congenital hypomyelinating neuropathy.

Imaging neuroinflammation in Alzheimer's disease with radiolabeled arachidonic acid and PET.

UNLABELLED: Incorporation coefficients (K*) of arachidonic acid (AA) in the brain are increased in a rat model of neuroinflammation, as are other markers of AA metabolism. Data also indicate that neuroinflammation contributes to Alzheimer's disease (AD). On the basis of these observations, K* for AA was hypothesized to be elevated in patients with AD. METHODS: A total of 8 patients with AD with an average (+/-SD) Mini-Mental State Examination score of 14.7+/-8.4 (mean age, 71.7+/-11.2 y) and 9 controls with a normal Mini-Mental State Examination score (mean age, 68.7+/-5.6 y) were studied. Each subject received a (15)O-water PET scan of regional cerebral blood flow, followed after 15 min by a 1-(11)C-AA scan of regional K* for AA. RESULTS: In the patients with AD, compared with control subjects, global gray matter K* for AA (corrected or uncorrected for the partial-volume error [PVE]) was significantly elevated, whereas only PVE-uncorrected global cerebral blood flow was reduced significantly (P<0.05). A false-discovery-rate procedure indicated that PVE-corrected K* for AA was increased in 78 of 90 identified hemispheric gray matter regions. PVE-corrected regional cerebral blood flow, although decreased in 12 regions at P<0.01 by an unpaired t test, did not survive the false-discovery-rate procedure. The surviving K* increments were widespread in the neocortex but were absent in caudate, pallidum, and thalamic regions. CONCLUSION: These preliminary results show that K* for AA is widely elevated in the AD brain, particularly in regions reported to have high densities of senile (neuritic) plaques with activated microglia. To the extent that the elevations represent upregulated AA metabolism associated with neuroinflammation, PET with 1-(11)C-AA could be used to examine neuroinflammation in patients with AD and other brain diseases.

Spatial and frequency differences of neuromagnetic activities between the perception of open- and closed-class words.

The present study investigated the spatial and frequency differences of neuromagnetic activities between the perception of open- and closed-class words by using a 275-channel whole head magnetoencephalography (MEG) system. Two groups of words, 110 open-class and 110 closed-class, were presented visually and auditorily simultaneously. The data of 12 healthy subjects were analyzed with synthetic aperture magnetometry (SAM) which can identify the frequency-dependent volumetric distribution of evoked magnetic fields (EMFs). Both vocabulary classes elicited spectral power changes in the left inferior frontal gyrus (Broca's area) and left posterior-superior temporal gyrus (Wernicke's area) within 70-120 Hz. However, the open-class words elicited event-related desynchronization (ERD) while the closed-class words elicited event-related synchronization (ERS) in the two areas within 70-120 Hz. In addition, the open-class words also elicited ERS in the right inferior frontal gyrus, right middle frontal gyrus and right inferior parietal lobe within 1-8 Hz, but the closed-class words only elicited ERD in the right inferior frontal gyrus within 1-8 Hz. Furthermore, there were ERD in the right posterior-superior temporal gyrus within 120-200 Hz for the open-class words, but not for the closed-class words. These results indicate that open- and closed-class words are processed differently in the brain, not only in the anatomical substrates, but also in the frequency range of neuromagnetic activity.

Outcome of Isolated Absent Septum Pellucidum Diagnosed by Fetal Magnetic Resonance Imaging (MRI) Scan.

Improved fetal imaging has resulted in increased diagnosis of isolated absent septum pellucidum without other intracranial abnormalities. There is little literature regarding outcomes for these fetuses. This study hypothesized the majority of infants diagnosed by fetal magnetic resonance imaging (MRI) with isolated absent septum pellucidum would retain this diagnosis postnatally. Specifically, in the absence of postnatal endocrine or ophthalmologic abnormalities, postnatal imaging would find no additional related findings, and fetuses would be at low risk for developmental delay. Two of 8 subjects met postnatal criteria for septo-optic dysplasia; remaining subjects had normal postnatal endocrine and ophthalmologic evaluations and no significant related findings on postnatal MRI. One subject without septo-optic dysplasia had delays on developmental screening; all others had normal screening (range of follow-up 8-72 months). Our study questions the necessity of postnatal imaging for prenatally diagnosed isolated absent septum pellucidum. Majority of fetuses with isolated absent septum pellucidum retained this diagnosis postnatally.

Conventional MRI scan and DTI imaging show more severe brain injury in neonates with hypoxic-ischemic encephalopathy and seizures.

BACKGROUND: Neonates with hypoxic-ischemic encephalopathy (HIE) and seizures have poorer outcome for undetermined reasons. AIMS: Our aim was to determine if brain imaging was more abnormal in neonates with HIE and electrographically confirmed seizures and whether this was impacted by seizure burden. STUDY DESIGN: Single center retrospective review. SUBJECTS: Forty-eight term neonates with HIE (with and without seizures) underwent MRI brain scans before age 14 days between the years 2008 and 2013. OUTCOME MEASURES: Images were rated using a MRI injury score and fractional anisotropy (FA) values were extracted from diffusion tensor imaging (DTI). RESULTS: The seizure group (n = 25) had significantly more injury within white matter, basal ganglia, posterior limb of internal capsule, and watershed areas compared to the group without seizures (n = 23). The severity of injury in all measured areas increased with increasing seizure severity. The seizure group also had lower FA values in posterior limb of the internal capsule and the splenium of corpus callosum. CONCLUSIONS: Neonates with HIE and seizures had more brain injury that occurred in areas typically affected by HIE and was greater with higher seizure burden. Seizures may be a marker of more severe brain injury or seizures themselves may amplify brain damage from HIE.

Coenzyme Q10 (ubiquinol-10) supplementation improves oxidative imbalance in children with trisomy 21.

Endogenous coenzyme Q10 is an essential cofactor in the mitochondrial respiratory chain, a potent antioxidant, and a potential biomarker for systemic oxidative status. Evidence of oxidative stress was reported in individuals with trisomy 21. In this study, 14 children with trisomy 21 had significantly increased (P < 0.0001) plasma ubiquinone-10 (the oxidized component of coenzyme Q10) compared with 12 age- and sex-matched healthy children (historical controls). Also, the mean ratio of ubiquinol-10 (the biochemically reduced component):total coenzyme Q10 was significantly decreased (P < 0.0001). After 3 months of ubiquinol-10 supplementation (10 mg/kg/day) to 10 patients with trisomy 21, the mean ubiquinol-10:total coenzyme Q10 ratio increased significantly (P < 0.0001) above baseline values, and 80% of individual ratios were within normal range. No significant or unexpected adverse effects were reported by participants. To our knowledge, this is the first study to indicate that the pro-oxidant state in plasma of children with trisomy 21, as assessed by ubiquinol-10:total coenzyme Q10 ratio, may be normalized with ubiquinol-10 supplementation. Further studies are needed to determine whether correction of this oxidant imbalance improves clinical outcomes of children with trisomy 21.

Levetiracetam for the Treatment of Seizures in Neonatal Hypoxic Ischemic Encephalopathy.

The objective of this study was to determine the efficacy and safety of levetiracetam in treatment of neonatal seizures due to hypoxic ischemic encephalopathy. Seizures often persist in neonates with hypoxic ischemic encephalopathy despite phenobarbital. A retrospective single-center study was conducted in neonates ≥36 weeks gestation with hypoxic ischemic encephalopathy. A total of 127 neonates were identified born 2008-2015. Clinical seizures occurred in 83 infants. Fifty-one neonates (61%) had cessation of seizures with only phenobarbital. Thirty-two neonates received levetiracetam after phenobarbital, and the seizures stopped in 27 of these neonates. The mean total loading dose of levetiracetam was 63 mg/kg. Mean maintenance dose of levetiracetam was 65 mg/kg/d. We found no negative side effects in neonates following levetiracetam use. Our study finds that levetiracetam is an efficacious medication in treatment of seizures in the setting of neonatal hypoxic ischemic encephalopathy. Future prospective studies should explore its use as a first-line medication.

Prenatal and postnatal evaluation of polymicrogyria with band heterotopia.

The coexistence of band heterotopia and polymicrogyria is extremely rare though it has been reported in the presence of corpus callosum anomalies and megalencephaly. We present prenatal and postnatal MRI findings of a rare case of diffuse cortical malformation characterized by polymicrogyria and band heterotopia. Agenesis of the corpus callosum and megalencephaly were also noted. In addition, bilateral closed-lip schizencephaly was identified on postnatal MRI, which has not been previously reported with this combination of imaging findings. Polymicrogyria with band heterotopia can occur and can be diagnosed with fetal MRI. The coexistence of corpus callosum anomalies and megalencephaly comprises a rare phenotype that has been previously described, suggesting an underlying genetic abnormality.

Coenzyme Q10 absorption and tolerance in children with Down syndrome: a dose-ranging trial.

Controlled studies of coenzyme Q(10) dosing and tolerance have been reported in adults, but not in pediatric patients. This study compares low- and high-dose coenzyme Q(10) (LiQ-NOL syrup) absorption and tolerance in children with Down syndrome. After a 1-month low-dose (1.0 mg/kg/day) run-in period, all participants received high-dose coenzyme Q(10) (10.0 mg/kg/day) for two additional months (in randomized sequence as one daily dose or split into two daily doses). Chemistry profiles and complete blood counts were determined just before and at the study completion. Plasma coenzyme Q(10) concentrations were determined initially and at each study visit. Parents reported adverse events and study drug evaluations using standardized forms. Most of the 16 children who completed this study tolerated high-dose coenzyme Q(10) well. Uncooperative behavior resulted in premature withdrawal of two participants, and may have been treatment-related. Pre- and posttreatment laboratory test changes were considered to be clinically nonsignificant. Study results indicate that high-dose coenzyme Q(10) (10 mg/kg/day) is well-absorbed and well-tolerated by most children with Down syndrome, and appears to provide plasma concentrations which are comparable to previous adult studies administering much higher coenzyme Q(10) dosages.

Pharmacological modulation of prefrontal cortical activity during a working memory task in young and older humans: a PET study with physostigmine.

OBJECTIVE: Age-associated cholinergic dysfunction may contribute to the cognitive decline observed during aging, including a decline in working memory. The current study was designed to determine how healthy aging influences the neural response to working memory before and during pharmacological potentiation of the cholinergic system. METHOD: In 13 young and 13 older healthy volunteers, regional cerebral blood flow (rCBF) was measured by using [15O]H2O and positron emission tomography across 10 scans that alternated between a working-memory-for-faces task and rest. In all subjects, the first two scans were obtained during intravenous saline infusion. Seven young and eight older subjects then received intravenous infusion of physostigmine, a cholinesterase inhibitor, and the remaining six young and five older subjects continued to receive saline. RESULTS: In the placebo condition, task-specific rCBF increases in prefrontal regions were observed in the right middle and inferior frontal cortices in young subjects and in more anterior and ventral prefrontal regions in older individuals. Physostigmine during the working memory task significantly improved performance in both age groups. The right prefrontal regions that were selectively recruited in each age group during the placebo condition showed significantly lower rCBF during physostigmine administration. CONCLUSIONS: Cholinergic enhancement does not affect structurally defined cortical regions but rather modulates neural activity in functionally defined regions, that is, in task-related prefrontal cortical areas that are selectively and distinctively recruited in young and older subjects.

Incidence of brain creatine transporter deficiency in males with developmental delay referred for brain magnetic resonance imaging.

Several case reports describe children with global developmental delay who have brain creatine deficiency, where the deficiency was due to a lack of creatine transport into the brain or altered creatine synthesis. The purpose of this study was to determine what percentage of males with developmental delay referred for brain magnetic resonance imaging (MRI) at the authors' institution in a 12-month period was found to have brain creatine deficiency due to a defect in the creatine transporter gene. In the authors' facility, single voxel proton magnetic resonance spectroscopy (MRS) is routinely performed on any male child age 2 to 18 years with a history of language and/or developmental delay referred for a brain MRI. Charts for the 12-month time period were retrospectively reviewed. Fourteen subjects met inclusion criteria for global developmental delay. Two of the 14 patients had brain creatine deficiency on MRS. In the remaining 12, other structural and white matter abnormalities were identified. This study suggests that brain creatine deficiency is an important consideration in the differential diagnosis of males with global developmental delay referred for brain MRI; brain MRS should be considered in such cases.

New power for "Old Europe".

The European Union's growing political clout is leading to new paradigms of environmental and health regulation. The E.U. is putting teeth behind new guidelines governing the toxicity of chemicals in consumer products, cosmetics, and automobiles that are forcing American companies to reconsider longstanding production practices. While U.S. government oversight over environmental and health concerns is being weakened, the E.U.'s strengthened governance over these and other arenas is rapidly, through the leverage of international trade, setting the stage for a new global standard. Europe's new standards present a historic choice to U.S. manufacturers: either conform to the E.U.'s preemptive screening for toxicity, or risk sacrificing the 450-million strong European market. The author explores the American response, and how the United States is slipping to the lower rungs of a double standard for protecting the health of citizens.

Unanticipated findings in pediatric neuroimaging research: prevalence of abnormalities and process for reporting and clinical follow-up.

MRI is a powerful tool to evaluate brain anatomy and function in normal children and its use in research applications has steadily increased. As imaging technology improves, and sensitivity to brain pathology increases, unanticipated (and potentially clinically important) findings on research neuroimaging studies will also increase. We evaluated the prevalence and type of unanticipated and potentially clinically significant imaging findings in a group of 114 normal children enrolled in an ongoing MRI imaging study of normal brain development for the Pediatric Functional Neuroimaging Research Network. Brain imaging findings were classified using standardized scales developed for the Network and findings were reported to participants and their primary healthcare provider according to a standard reporting pathway. Classification scales, reporting processes, and illustrated examples of findings are included and discussed. Unanticipated imaging findings were identified in approximately 12.5 % of children participating in this study.

Inositol monophosphatase activity in normal, Down syndrome and dementia of the Alzheimer type CSF.

Inositol monophosphatase (IMPase), a cytoplasmic enzyme that hydrolyses inositol monophosphates to produce inositol is also found in the cerebrospinal fluid (CSF). Since levels of inositol have been previously reported to be elevated in Down syndrome (DS) CSF, IMPase activity was measured in CSF of DS subjects to establish whether altered inositol levels may be related to changes in IMPase activity. In addition, and to better understand the regulation of IMPase expression in the CSF, enzyme activity was measured in normal aging, patients with Alzheimer-type or multi-infarct dementia (DAT and MID, respectively) and in CSF obtained by repeat lumbar puncture or from sequential aliquots of CSF from along the rostro-caudal axis. IMPase activity was relatively constant in CSF obtained from repeated lumbar puncture and there was no significant rostro-caudal gradient of activity in either normal or DS subjects, indicating that the enzyme originates from both brain and spinal cord. Compared to respective age-matched normal subjects, CSF IMPase activity was unaltered in DS, DAT and MID. However, in normal volunteers there was a significant positive correlation between age and CSF IMPase activity. Furthermore, there were significant correlations between CSF IMPase activity and acetylcholinesterase and butyrylcholinesterase activities and total protein, suggesting co-regulation of these parameters within the CSF.

Relation of medial temporal lobe volumes to age and memory function in nondemented adults with Down's syndrome: implications for the prodromal phase of Alzheimer's disease.

OBJECTIVE: In Down's syndrome (trisomy 21), a dementia syndrome occurs that is phenotypically similar to Alzheimer's disease; the initial phase is characterized by memory loss. The authors used an in vivo structural technique in the predementia stage of Alzheimer's disease in adults with Down's syndrome to investigate whether atrophy of medial temporal lobe structures occurs in these subjects and whether volumes of these structures correlate specifically with performance on memory tests. METHOD: The subjects were 34 nondemented Down's syndrome adults (mean age=41.6 years, 17 women and 17 men) and 33 healthy comparison subjects (mean age=41.3, 15 women and 18 men). By using T(1)-weighted magnetic resonance imaging slices taken perpendicular to the Sylvian fissure, volumes of the hippocampus, amygdala, anterior and posterior parahippocampal gyrus, and temporal pole CSF were measured in both hemispheres. These data were normalized to the total intracranial volume. RESULTS: For Down's syndrome, smaller volumes of the right and left amygdala, hippocampus, and posterior parahippocampal gyrus were significantly associated with greater age; this association was not seen in the anterior parahippocampal gyrus. The amygdala and hippocampus volumes were positively correlated with memory measures. For the comparison group, there was no relationship between volume and age in any region. CONCLUSIONS: In the predementia phase of Down's syndrome, significant volume changes in medial temporal lobe structures occur with age and are related to memory. These structures are affected early in Alzheimer's disease in Down's syndrome, and their evaluation may help identify people in the preclinical stages of Alzheimer's disease.

Relation of corpus callosum and hippocampal size to age in nondemented adults with Down's syndrome.

OBJECTIVE: Aging in Down's syndrome is accompanied by amyloid and neurofibrillary pathology, the regional and laminar distribution of which resembles pathological changes seen in Alzheimer's disease. Previous studies using magnetic resonance imaging (MRI) demonstrated age-related atrophy of medial temporal lobe structures in nondemented older subjects with Down's syndrome, reflecting early allocortical pathology. Corpus callosum atrophy has been established as a marker of neocortical neuronal loss in Alzheimer's disease. This study investigated whether atrophy of the corpus callosum and hippocampus occurs in nondemented subjects with Down's syndrome and compared the degree of age-related atrophy between these structures. METHOD: Hippocampus and corpus callosum measures were obtained from volumetric T(1)-weighted MRI scans of 34 nondemented Down's syndrome adults (mean age=41.6 years, 17 women) and 31 healthy comparison subjects (mean age=41.8 years, 14 women). RESULTS: Down's syndrome subjects had smaller corpus callosum areas and hippocampal volumes relative to age-matched healthy comparison subjects, even after age and total intracranial volume were controlled. There was an age-related decrease of corpus callosum area (most prominent in posterior regions) and hippocampal volume in the Down's syndrome group. The degree of the age effect was comparable between the total corpus callosum and hippocampus, and corpus callosum size was correlated with cognitive performance in the Down's syndrome subjects. There was no correlation between age and corpus callosum or hippocampal size in the comparison group. CONCLUSIONS: Comparable decrease of corpus callosum and hippocampal size with age in nondemented subjects with Down's syndrome suggests that neocortical neuronal alterations accompany allocortical changes in the predementia phase of Down's syndrome.