Autosomal dominant lateral temporal epilepsy (EPT; OMIM 600512) is a form of epilepsy characterized by partial seizures, usually preceded by auditory signs. The gene for this disorder has been mapped by linkage studies to chromosomal region 10q24. Here we show that mutations in the LGI1 gene segregate with EPT in two families affected by this disorder. Both mutations introduce premature stop codons and thus prevent the production of the full-length protein from the affected allele. By immunohistochemical studies, we demonstrate that the LGI1 protein, which contains several leucine-rich repeats, is expressed ubiquitously in the neuronal cell compartment of the brain. Moreover, we provide evidence for genetic heterogeneity within this disorder, since several other families with a phenotype consistent with this type of epilepsy lack mutations in the LGI1 gene.

These findings emphasise the importance of deletion analysis in NF1 since frequent monitoring of tumour presence and growth could potentiate early surgical intervention thereby improving patient survival.

To determine the prevalence of neurofibromatosis 1 (NF1) among 6-year-old children in Germany.Setting and Patients: A total of 152 819 children aged 6 years in 6 German states were screened for NF1 during routine medical examinations at elementary school enrollment in cooperation with local health departments in 2000 and 2001.Main Outcome Measure: The prevalence of NF1 among 6-year-old German children was estimated to be 1:2996 (95% confidence interval, 1:2260 to 1:3984).Results: Fifty-one NF1 cases were identified and confirmed by evaluation by appropriate medical specialists.

Detailed analyses of 20 patients with sporadic neurofibromatosis type 1 (NF1) microdeletions revealed an unexpected high frequency of somatic mosaicism (8/20 [40%]). This proportion of mosaic deletions is much higher than previously anticipated. Of these deletions, 16 were identified by a screen of unselected patients with NF1. None of the eight patients with mosaic deletions exhibited the mental retardation and facial dysmorphism usually associated with NF1 microdeletions. Our study demonstrates the importance of a general screening for NF1 deletions, regardless of a special phenotype, because of a high estimated number of otherwise undetected mosaic NF1 microdeletions. In patients with mosaicism, the proportion of cells with the deletion was 91%-100% in peripheral leukocytes but was much lower (51%-80%) in buccal smears or peripheral skin fibroblasts. Therefore, the analysis of other tissues than blood is recommended, to exclude mosaicism with normal cells in patients with NF1 microdeletions. Furthermore, our study reveals breakpoint heterogeneity. The classic 1.4-Mb deletion was found in 13 patients. These type I deletions encompass 14 genes and have breakpoints in the NF1 low-copy repeats. However, we identified a second major type of NF1 microdeletion, which spans 1.2 Mb and affects 13 genes. This type II deletion was found in 8 (38%) of 21 patients and is mediated by recombination between the JJAZ1 gene and its pseudogene. The JJAZ1 gene, which is completely deleted in patients with type I NF1 microdeletions and is disrupted in deletions of type II, is highly expressed in brain structures associated with learning and memory. Thus, its haploinsufficiency might contribute to mental impairment in patients with constitutional NF1 microdeletions. Conspicuously, seven of the eight mosaic deletions are of type II, whereas only one was a classic type I deletion. Therefore, the JJAZ1 gene is a preferred target of strand exchange during mitotic nonallelic homologous recombination. Although type I NF1 microdeletions occur by interchromosomal recombination during meiosis, our findings imply that type II deletions are mediated by intrachromosomal recombination during mitosis. Thus, NF1 microdeletions acquired during mitotic cell divisions differ from those occurring in meiosis and are caused by different mechanisms.

Benign peripheral nerve sheath tumors (PNSTs) are a characteristic feature of neurofibromatosis type I (NF1) patients. NF1 individuals have an 8-13% lifetime risk of developing a malignant PNST (MPNST). Atypical neurofibromas are symptomatic, hypercellular PNSTs, composed of cells with hyperchromatic nuclei in the absence of mitoses. Little is known about the origin and nature of atypical neurofibromas in NF1 patients. In this study, we classified the atypical neurofibromas in the spectrum of NF1-associated PNSTs by analyzing 65 tumor samples from 48 NF1 patients. We compared tumor-specific chromosomal copy number alterations between benign neurofibromas, atypical neurofibromas, and MPNSTs (low-, intermediate-, and high-grade) by karyotyping and microarray-based comparative genome hybridization (aCGH). In 15 benign neurofibromas (4 subcutaneous and 11 plexiform), no copy number alterations were found, except a single event in a plexiform neurofibroma. One highly significant recurrent aberration (15/16) was identified in the atypical neurofibromas, namely a deletion with a minimal overlapping region (MOR) in chromosome band 9p21.3, including CDKN2A and CDKN2B. Copy number loss of the CDKN2A/B gene locus was one of the most common events in the group of MPNSTs, with deletions in low-, intermediate-, and high-grade MPNSTs. In one tumor, we observed a clear transition from a benign-atypical neurofibroma toward an intermediate-grade MPNST, confirmed by both histopathology and aCGH analysis. These data support the hypothesis that atypical neurofibromas are premalignant tumors, with the CDKN2A/B deletion as the first step in the progression toward MPNST.

Schwannomatosis is a third major form of neurofibromatosis that has recently been linked to mutations in the SMARCB1 (hSnf5/INI1) tumor suppressor gene. We analyzed the coding region of SMARCB1 by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) in genomic DNA from 19 schwannomatosis kindreds. Microsatellite markers in the SMARCB1 region were developed to determine loss of heterozygosity (LOH) in associated tumors. We detected four alterations in conserved splice acceptor or donor sequences of exons 3, 4 and 6. Two alterations that likely affect splicing were seen in introns 4 and 5. An additional four alterations of unclear pathogenicity were found to segregate on the affected allele in eight families including two non-conservative missense alterations in three families. No constitutional deletions or duplications were detected by MLPA. Nine of 13 tumors examined showed partial LOH of the SMARCB1 region consistent with 'second hits.' Alterations were detected in tumors both with and without somatic NF2 gene changes. These findings support the hypothesis that SMARCB1 is a tumor suppressor for schwannomas in the context of familial disease. Further work is needed to determine its role in other multiple and single tumor syndromes.

People with neurofibromatosis 1 (NF1) have multiple benign neurofibromas and a 10% lifetime risk of developing malignant peripheral nerve sheath tumors (MPNSTs). Most MPNSTs develop from benign plexiform neurofibromas, so the burden of benign tumors may be a risk factor for developing MPNST. We studied 13 NF1 patients with MPNSTs and 26 age- and sex-matched controls (NF1 patients who did not have MPNSTs) with detailed clinical examinations and whole-body MRI to characterize their body burden of internal benign neurofibromas. Internal plexiform neurofibromas were identified in 22 (56%) of the 39 NF1 patients studied. All six of the NF1 patients with MPNSTs under 30 years of age had neurofibromas visualized on whole-body MRI, compared to only 3 of 11 matched NF1 controls under age 30 (p < 0.05). Both the median number of plexiform neurofibromas (p < 0.05) and the median neurofibroma volume (p < 0.01) on whole-body MRI were significantly greater among MPNST patients younger than 30 years of age than among controls. No significant differences in whole-body MRI findings were observed between NF1 patients with MPNSTs and controls who were 30 years of age or older. Whole-body MRI of NF1 patients allows assessment of the burden of internal neurofibromas, most of which are not apparent on physical examination. Whole-body imaging of young NF1 patients may allow those at highest risk for developing MPNST to be identified early in life. Close surveillance of these high-risk patients may permit earlier diagnosis and more effective treatment of MPNSTs that develop.

Forty-six of 93 children with neurofibromatosis type 1 (NF1) were found to satisfy the diagnostic criteria for attention-deficit-hyperactivity disorder (ADHD). Detailed comparisons were made among 20 children with NF1 and ADHD (12 males, 8 females; mean age 10.7 years, SD 2.2), 26 control children with NF1 (15 males, 11 females; mean age 11.3 years, SD 2.3), 14 control children with ADHD (7 males; mean age 9.9 years, SD 1.9), and 14 normally developing control children (7 males; mean age 11.2 years, SD 2.8). Children with NF1 and ADHD had the lowest IQ scores among the four groups. Test of Variables of Attention (TOVA) scores were poorer in the NF1-ADHD and ADHD control groups than in the two non-ADHD groups. Those with NF1 and ADHD were rated significantly poorer on the Child Behavior Checklist (CBCL) than were the NF1 control group. By administrating low doses (5 to 15 mg) of methylphenidate to the NF1-ADHD group, significantly improved TOVA scores were obtained. One-year follow-up yielded significantly improved CBCL scores. Our results show a high incidence of ADHD in NF1 and support an association between ADHD and learning and social problems in children with NF1. It was demonstrated that stimulant medication can lead to improvement in cognitive, academic, and social problems of children with NF1 and ADHD.