No abstract

Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurologic manifestations. AHC is usually a sporadic disorder with unknown etiology. Using exome sequencing of seven patients with AHC, and their unaffected parents, we identified de novo nonsynonymous mutations in ATP1A3 in all seven AHC patients. Subsequent sequence analysis of ATP1A3 in 98 additional patients revealed that 78% of AHC cases have a likely causal ATP1A3 mutation, including one inherited mutation in a familial case of AHC. Remarkably, six ATP1A3 mutations explain the majority of patients, including one observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset-dystonia-parkinsonism, AHC-causing mutations revealed consistent reductions in ATPase activity without effects on protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC, and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in this gene.

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C-->T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.

Summary:Purpose: There is no adequate measure of healthrelated quality of life (HRQOL) specifically for children with epilepsy. The aim of this study was to develop an epilepsyspecific HRQOL questionnaire for children, covering five domains: physical function, emotional well-being, cognitive function, social function, and behavior. Second, we aimed to demonstrate the instrument's reliability and validity, and its sensitivity to differences in epilepsy severity.Methods: The subjects were guardians of children with refractory epilepsy, whose syndrome had been defined by using video-EEG monitoring. Each family completed the developed epilepsy-specific HRQOL scale for children and two standard, generic measures of HRQOL.Results: The results indicated that each of the scales of the questionnaire had good internal consistency reliability. Furthermore, each scale correlated more highly with theoretically similar scales on established, generic health measures than with theoretically dissimilar scales (construct validity). The sensitivity of the questionnaire to differences in epilepsy severity also was demonstrated. As seizure severity increased, HRQOL subscale scores decreased, independent of age, gender, age of seizure onset, and IQ. Further, there was a negative relation between the number of antiepileptic medications taken and measures of memory and language performance, which was independent of age, gender, age of seizure onset, IQ, and seizure severity.Conclusions: This study demonstrated that the developed HRQOL instrument is a reliable and valid measure and is sensitive to differences in epilepsy. These results indicate that this new instrument may be a viable medical or surgical outcome measure for children with epilepsy.