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Genetics is believed to have an important role in many epilepsy syndromes; however, specific genes have been discovered in only a small proportion of cases. Genome-wide association studies for both [...], Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown (1). Here we report a screen for denovo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ~4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 x [10.sup.-3]). Among these are GABRB3, with denovo mutations in four patients, and ALG13,with thesame de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 x [10.sup.-10] and P= 7.8 x [10.sup.-12], respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile x protein (P< [10.sup.-8]), as has been reported previously for autism spectrum disorders (2).

The gene MECP2 is a well-known determinant of brain structure. Mutations in the MECP2 protein cause microencephalopathy and are associated with several neurodevelopmental disorders that affect both brain morphology and cognition. Although mutations in MECP2 result in severe neurological phenotypes, the effect of common variation in this genetic region is unknown. We find that common sequence variations in a region in and around MECP2 show association with structural brain size measures in 2 independent cohorts, a discovery sample from the Thematic Organized Psychosis research group, and a replication sample from the Alzheimer's Disease Neuroimaging Initiative. The most statistically significant replicated association (P < 0.025 in both cohorts) involved the minor allele of SNP rs2239464 with reduced cortical surface area, and the finding was specific to male gender in both populations. Variations in the MECP2 region were associated with cortical surface area but not cortical thickness. Secondary analysis showed that this allele was also associated with reduced surface area in specific cortical regions (cuneus, fusiform gyrus, pars triangularis) in both populations. MRI | neuroscience | imaging genetics

The identification of 7 Mb intervals containing a susceptibility locus (ANE1) in a family segregating recurrent acute necrotizing encephalopathy (ANE) as an incompletely penetrant, autosomal-dominant trait is demonstrated. The results obtained suggested that missense mutations in the nuclear pore protein Ran Binding protein 2 (RANBP2) are susceptibility alleles for familial and recurrent cases in ANE.

A study is conducted to identify two de novo heterozygous missense mutations of a conserved amino acid in the basic region of the TCF4 gene in three subjects with Pitt-Hopkins syndrome (PHS). The findings demonstrate that TCF4 anomalies are responsible for PHS and provide the evidence of a human disorder related to class I basic helix-loop-helix transcription-factor defects.

A study is reported involving two infants affected by neonatal lactic acidosis, rapidly progressive encephalopathy, severely decreased mitochondrial protein synthesis and combined deficiency of mitochondrial DNA (mtDNA)-related mitochondrial respiratory chain (MRC) complexes. Genetic investigation of this defective mtDNA translation reveals novel mutations in the mitochondrial elongation factor G1 (EFG 1) and mitochondrial elongation factor Tu (EFTu) in the infants.

Studies related to lissencephaly gene LIS1 and doublecortin RNAi have revealed that reduced expression in either of these genes causes formation of neural progenitors in the subventricular zone. Some of the evidence regarding the cellular defects contributing to classical lissencephaly is presented with emphasis on recent live analysis of LIS1-deficient neutral progenitor cell motility in brain tissue.

Disrupted-in-Schizophrenia-1 (DISC-1) is a gene whose mutant truncation is associated with major psychiatric illness with a predominance of schizophrenic symptomatology. We have cloned and characterized rodent DISC-1. DISC-1 expression displays pronounced developmental regulation with the highest levels in late embryonic life when the cerebral cortex develops. In yeast two-hybrid analyses, DISC-1 interacts with a variety of cytoskeletal proteins. One of these, NudE-like (NUDEL), is associated with cortical development and is linked to LIS-1, the disease gene for a form of lissencephaly, a disorder of cortical development. The disease mutant form of DISC-1 fails to bind NUDEL. Expression of mutant, but not wild-type, DISC-1 in PC12 cells reduces neurite extension. As schizophrenia is thought to reflect defects in cortical development that are determined by cytoskeletal protein activities, the cellular disturbances we observe with mutant DISC-1 may be relevant to psychopathologic mechanisms.

A family with mitochondrial disease was found to have an mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II (COX II) gene. The mutation brings lower levels of the protein and a mitochondrial encephalomyopathy. It is predicted that the T-->C transition changes the initiating methionine to threonine. The mutation load was at 67% in muscle from the index case and at 91% in muscle from the clinically affected son of the patient. An isolated COX deficiency was seen in muscle biopsy samples. The mutation is a new mechanism through which mtDNA mutations can cause disease-defective translation initiation.

Mitochondrial disorders and the identification of respiratory chain-enzyme genes responsible for Leigh syndrome (subacute necrotizing encephalomyelopathy) or Leigh-like syndrome, which might be called mitochondrial encephalopathy, are discussed. Mutations in mtDNA that bring on Leigh syndrome are known and work on pathways that lead to successful import/assembly/function of respiratory chain enzymes can be undertaken using some proposed elegant ways of identifying nuclear-encoded mitochondrial genes.

Mutations of SURF-1 in Leigh disease (subacute necrotizing encephalomyelopathy) linked to cytochrome c oxidase (COX) deficiency are discussed. Eleven patients in nine families were studied with mutation analysis of candidate genes which included SURF-1, the yeast homologue of which codes for a mitochondrial protein required for maintenance of COX respiration and activity.