M. Priscilla Short

A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor

Neurofibromatosis 2 (NF2) is a dominantly inherited disorder characterized by the occurrence of bilateral vestibular schwannomas and other central nervous system tumors including multiple meningiomas. Genetic linkage studies and investigations of both sporadic and familial tumors suggest that NF2 is caused by inactivation of a tumor suppressor gene in chromosome 22q12. We have identified a candidate gene for the NF2 tumor suppressor that has suffered nonoverlapping deletions in DNA from two independent NF2 families and alterations in meningiomas from two unrelated NF2 patients. The candidate gene encodes a 587 amino acid protein with striking similarity to several members of a family of proteins proposed to link cytoskeletal components with proteins in the cell membrane. The NF2 gene may therefore constitute a novel class of tumor suppressor gene.

Effects of biologically delivered NGF, BDNF and bFGF on striatal excitotoxic lesions

IMMORTALIZED rat fibroblasts, genetically altered to secrete NGF, BDNF, and bFGF, were implanted in rat brain near the striatum 7 days before striatal infusion of excitotoxic quantities of an NMDA-receptor agonist. Analysis of striatal damage 7 days after lesioning revealed that implantation of NGF-secreting cells reduced the size of the excitotoxic lesions by more than 80% when compared with control cells, while implanting of bFGF-secreting cells caused a 30% decrease in excitotoxic lesion size. BDNF-secreting fibroblasts caused no protective sparing in the striatum in this lesion model. This finding shows that biological delivery of NGF and bFGF by grafting of genetically altered cells protects against glutamate toxicity in the adult striatum while grafting of BDNF- producing cells does not. Such observations begin to define a spectrum of neurotrophic agents able to mitigate the cell loss seen in neurodegeneration.

Transplantation of a Polymer-Encapsulated Cell Line Genetically Engineered to Release NGF

The delivery of nerve growth factor (NGF) to the lateral ventricle of a fimbria-fornix-lesioned rat prevents the lesion-induced reduction in choline acetyltransferase (ChAT) expression by medial septal cells. Although delivery has been achieved through neural grafting of genetically engineered cell lines which release NGF, transplanted cells have grown beyond the implantation site and formed tumors. The encapsulation of cells within a permselective polymer capsule prior to transplantation allows cell growth only within the capsule space, while allowing molecular exchange between the host tissue and enclosed cells. Rat fibroblasts from the parent cell line (R208F) or fibroblasts genetically modified to produce NGF (R208N.8) were loaded within a thermoplastic hollow fiber-based capsule. Only the capsules loaded with the genetically engineered cells released measurable amounts of NGF in culture. Adult rats received unilateral aspirative fimbria-fornix lesions, followed by intraventricular implantation of a R208F capsule (n = 6) or a R208N.8 capsule (n = 6). After 2 weeks, rats receiving encapsulated cells showed no undue reaction to the implants. With both cell types, the cells remained viable and confined to the capsule space. R208N.8 capsules released sufficient NGF to prevent the lesion-induced loss of septal ChAT expression, whereas R208F capsules did not. This study suggests that encapsulated genetically engineered cells can provide an efficient means for future applications involving delivery of neurotrophic factors.

Do NF1 gene deletions result in a characteristic phenotype

Neurofibromatosis-1 (NF1) is an autosomal dominant disorder with marked variability of expression. Analysis of the NF1 gene (NF1) has detected a variety of mutations without any clear correlation with phenotype. However, deletions which remove all of NF1 have been reported in a small number of patients who have minor facial abnormalities, mental retardation, learning disabilities, and early or excessive burden of cutaneous or plexiform neurofibromas. The purpose of this study was to determine whether these phenotypic traits are associated with whole gene deletions. Out of 406 of our NF1 patients, 70 patients had manifestations previously associated with gene deletions. Thirty-five of these patients from 26 families were available for study. By fluorescence in situ hybridization (FISH) analysis, 4 were found to have deletions of the entire gene, including 2 sporadic cases, 1 familial case, and 1 case where family history could not be verified. In addition, the mother of the familial case was found to be mosaic for the deletion. Our results suggest that although large NF1 deletions occur with relatively high frequency in patients with certain findings, the presence of a deletion cannot be predicted solely on the basis of clinical phenotype.

Clinical, Neuropathological and Genetic Aspects of the Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome in which patients develop hamartomatous lesions in the nervous system and a host of other organs. While considerable experience has been gained in defining the clinical spectrum of TSC, a number of nosological questions remain. Neuropathological studies have continued to refine our knowledge of the nervous system abnormalities that characterize TSC. Molecular genetic studies have implicated two chromosomal regions in the genesis of TSC, one on chromosome 9q and the other on chromosome 16p. The chromosome 16p gene, designated TSC2, has been cloned, although its function remains speculative. The identification of the TSC1 gene on chromosome 9q, along with functional studies and mutational analyses of both TSC genes, will likely provide fascinating insights into the pathogenesis of TSC.

Deep Sylvian Fissure Meningioma without Dural Attachment in an Adult

Meningiomas are thought to arise from arachnoid cap or meningothelial cells that not only cluster on the surface of pacchionian granulations but also can cover the arachnoid membrane in other locations. This frequent apposition to the dura mater probably accounts for the usual attachment of the neoplasm to this layer. We report a deep sylvian fissure meningioma without dural attachments in the right hemisphere of an adult patient. The patient initially presented with simple partial seizures. Magnetic resonance imaging revealed a contrast-enhancing circular mass in the superior aspect of the insular region, deep to the inferior parietal lobule. Surgical exploration confirmed the absence of dural attachments. Microscopically, the tumor was found to be a sparsely cellular meningioma with an extensive collagenous matrix. A survey of the literature reveals that the majority of cases of meningiomas without dural attachments occur either in children or below the tentorium. Extremely rare cases of supratentorial meningiomas without dural attachment have been described in adults. The uncommon locations of these tumors at sites distant from the dura mater is postulated to reflect the rare occurrence of arachnoidal cap cells in the Virchow-Robin spaces along the cerebral vasculature or in pial layers distant from the dura mater.

A clinical study of patients with multiple isolated neurofibromas

Editor—Neurofibromas are benign nerve sheath tumours of a heterogeneous nature consisting of Schwann cells, fibroblastic elements, and embedded axons. Neurofibromas may occur singly in genetically normal people at any point along the peripheral nervous system. Multiple neurofibromas are nearly pathognomonic for neurofibromatosis 1 (NF1). In patients with NF1, neurofibromas may be congenital and plexiform or, more commonly, may be smaller masses that begin to accumulate around the time of puberty. Cutaneous and subcutaneous neurofibromas may cause considerable cosmetic disfigurement, but rarely result in neurological dysfunction. Conversely, deep seated neurofibromas on peripheral nerves and spinal roots frequently lead to neurological disability. Inevitably, adult patients with NF1 have other stigmata of the disorder with the most common being cafe au lait spots, skin fold freckling, and Lisch nodules.1 2 NF1 is an autosomal dominant disorder with full penetrance and a defined genetic aetiology that shows no evidence of locus heterogeneity.3Neurofibromatosis 2 patients are rarely found to have one or more neurofibromas.4 5 Recently, we have become aware of a small number of patients with multiple pathologically proven neurofibromas, who have no other stigmata of NF1. Here we report the clinical characteristics and pathological findings of these patients, and propose the terminology “multiple isolated neurofibromas” to describe this rare condition. The criteria for inclusion in the study were multiple, pathologically proven neurofibromas without other defining features of NF1. Careful family histories were obtained in order to document other family members potentially affected, extending to all second degree relatives. Each participant underwent a clinical examination by one or more of the authors (PB, MM, MPS), which included a detailed neurological evaluation and inspection of the skin with a Woods lamp. For patients who gave a positive family history, medical records from the potentially affected family member and tumour specimens …

A Child With Neurofibromatosis-1 and a Lumbar Epidural Arteriovenous Malformation:

A 10-year-old child with neurofibromatosis-1 was evaluated for progressive lumbar scoliosis, back pain, and foot numbness. Magnetic resonance imaging showed several lumbar intraspinal and extraspinal masses consistent with neurofibromas. The mass at L3-L5 compressed the thecal sac and was thought to be the source of the symptoms. On operative exploration, a lumbar epidural arteriovenous malformation was found, which was removed in its entirety. The childs back pain and foot numbness resolved. Epidural arteriovenous malformations in patients with neurofibromatosis-1 are rare and have been reported only in the cervical spine. Our finding of a lumbar epidural arteriovenous malformation in a child with neurofibromatosis-1 demonstrates that vascular anomalies can be present throughout the spine of patients with neurofibromatosis-1 and should be considered in the differential diagnosis of any neurofibromatosis-1-related epidural mass. (J Child Neurol 2000;15:273-275).

Gene Transfer into the Central Nervous System: Neurotrophic Factors

Neurotrophic factors, such as nerve growth factor (NGF), in addition to their role in neuronal development, have protective effects on neuronal survival and stimulatory effects on neuronal regeneration in adult animals (Barde, 1988; Snider and Johnson, 1989; Johnson et al, 1992). For this reason, treatment strategies for human neurodegenerative disease have focused on techniques by which neurotrophic factor gene products can be introduced into the adult central nervous system (CNS) (Hefti, 1986; Gage et al, 1987; Kromer, 1987; Dreyfus, 1989; Morgan, 1989; Gage et al, 1990; Olson, 1990; Lindvall, 1991).