Novel gain-of-function mechanism in K(+) channel-related long-QT syndrome: altered gating and selectivity in the HERG1 N629D mutant.

The N629D mutation, adjacent to the GFG signature sequence of the HERG1 A K(+) channel, causes long-QT syndrome (LQTS). Expression of N629D in Xenopus oocytes produces a rapidly activating, noninactivating current. N629D is nonselective among monovalent cations; permeation of K(+) was similar to that of Na(+) or Cs(+). During repolarization to potentials between -30 and -70 mV, N629D manifested an inward tail current, which was abolished by replacement of extracellular Na(+) (Na(+)(e)) with extracellular N-methyl-D-glucamine (NMG(e)). Because LQTS occurs in heterozygous patients, we coexpressed N629D and wild type (WT) at equimolar concentrations. Heteromultimer formation was demonstrated by analyzing the response to 0 [K(+)](e). The outward time-dependent current was nearly eliminated for WT at 0 [K(+)](e), whereas no reduction was observed for homomultimeric N629D or for the equimolar coexpressed current. To assess physiological significance, dofetilide-sensitive currents were recorded during application of simulated action potential clamps. During phase 3 repolarization, WT manifested outward currents, whereas homomultimeric N629D manifested inward depolarizing currents. During coexpression studies, variable phenotypes were observed ranging from a reduction in outward repolarizing current to net inward depolarizing current during phase 3. In summary, N629D replaces the WT outward repolarizing tail current with an inward depolarizing sodium current, which is expected to delay later stages of repolarization and contribute to arrhythmogenesis. Thus, the consequences of N629D resemble the pathophysiology seen in LQT3 Na(+) channel mutations and may be considered the first LQTS K(+) channel mutation that exhibits gain of function.

Regional brain tissue composition in children with hydrocephalus. Relationships with cognitive development.

OBJECTIVE: To determine whether children with shunted hydrocephalus show variations in regional brain tissue composition that relate to cognitive functions. DESIGN: Nonequivalent control group. PATIENTS AND METHODS: Magnetic resonance imaging (MRI) and cognitive skills assessments were obtained on 28 children, 6 to 9 years of age, with shunted hydrocephalus and 13 normal control subjects comparable in age, gender, ethnicity, and socioeconomic status. Three consecutive MRI slices below the vertex were segmented using a fuzzy clustering algorithm to separate pixels into gray matter, white matter, and cerebrospinal fluid (CSF) in quadrants representing left and right anterior and posterior brain regions. The cognitive skills assessments included the Wechsler Intelligence Scale for Children-Revised verbal and performance IQ scores, neuropsychological composites of language and visuospatial skills, a measure of visuomotor dexterity, and 2 measures of problem-solving abilities. The MRI data were analyzed in a group x tissue x hemisphere x region analysis of variance. Spearman rho correlations were computed within the hydrocephalus group between the MRI and cognitive measures. RESULTS: Children with hydrocephalus showed reductions in overall gray matter percentages and corresponding increased CSF percentages that were more pronounced in posterior than anterior regions of both hemispheres. White matter percentages were reduced in children with hydrocephalus only in the left posterior quadrant. Correlations of posterior, but not anterior, CSF and gray matter percentages were significant with verbal and performance IQ scores and language, visuospatial, and visuomotor dexterity skills, but not with problem-solving abilities. Children with hydrocephalus who had proportionately greater posterior than anterior CSF percentages had significantly poorer visuomotor dexterity and visuospatial skills than did hydrocephalic children with proportionate CSF percentages. CONCLUSION: Regional variations in brain tissue composition in children with shunted hydrocephalus correlate with a variety of cognitive and visuomotor functions.

Morphometric evaluation of the hydrocephalic brain: relationships with cognitive development.

The effects of early hydrocephalus and related brain anomalies on cognitive skills are not well understood. In this study, magnetic resonance scans were obtained from 99 children aged from 6 to 13 years with either shunted hydrocephalus (n = 42) or arrested (unshunted) hydrocephalus (n = 19), from patient controls with no hydrocephalus (n = 23), and from normal, nonpatient controls (n = 15). Lateral ventricle volumes and area measurements of the internal capsules and centra semiovale in both hemispheres were obtained from these scans, along with area measurements of the corpus callosum. Results revealed reductions in the size of the corpus callosum in the shunted hydrocephalus group. In addition, lateral ventricle volumes were larger and internal capsule areas were smaller in both hemispheres in children with shunted and arrested hydrocephalus. The centra semiovale measurements did not differentiate the groups. Correlating these measurements with concurrent assessments of verbal and nonverbal cognitive skills, motor abilities, and executive functions revealed robust relationships only between the area of the corpus callosum and nonverbal cognitive skills and motor abilities. These results support the theory of a prominent role for the corpus callosum defects characteristic of many children with shunted hydrocephalus in the spatial cognition deficits commonly observed in these children.

Reliability of brain structure morphometry in hydrocephalic children using MR images.

To assess the ability of human operators to make decisions about region boundaries in significantly malformed brains, we performed a study of the reliability of morphometric measurements of specific brain structures from MRI in children with hydrocephalus and controls. Cross-sectional area measures of the corpus callosum, internal capsules and centrum semiovale, and volumes of the lateral ventricles were made in 50 children. Independent measurements were made by two raters on T1 and T2-weighted MR images. Pearson's correlation coefficients (r) and intraclass correlation coefficients (ICC) between the two rater's sets of measures were computed for each structure across all subjects. ICCs ranged from a low of 0.7502 to a high of 0.9895. All ICCs were significant at the p < .0001 level and were generally less than or equal to the corresponding Pearson's r value in every case. Therefore, the Pearson's r may overestimate the reliability. The results of this study support the claim that the ICC should be used rather than the Pearson's r when assessing interater reliability in situations where large between-group differences are present. In addition, the results show that brains malformed by disorders, such as hydrocephalus, can be reliably assessed using morphometric measures of MR images.