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This Roundup highlights a sampling of publications focused on neurofibromatosis research which have appeared in the literature in the past few months. References mentioned are listed at the end of this document. For more information on any paper mentioned visit PubMed at www.pubmed.gov. You will be able to access the abstract for any article, and in some cases the full article, at no charge.   

Proceedings from the 2009 NF Conference Published

We are excited to report that January saw the publication of ‘What’s new in Neurofibromatosis?’ the proceedings report from the Children’s Tumor Foundation 2009 Neurofibromatosis Conference, from Kissil et al.

NF1 Clinical Updates – Vascular Disease Breakthrough  

Though vascular abnormalities are known to occur in NF1, serious heart complications have not been high on the list of concerns for most persons with NF1.  However new research from Lasater et al. shows that NF1 carries an increased risk of cardiovascular disease, and  importantly that this could be a significant but under-recognized problem for young patients. The research was based on both mouse studies and human data. In the mouse, an NF1 gene mutation impacted the ability of circulating stem cells to repair damaged blood vessels.  And blood samples from NF1 patients apparently unaffected by vascular disease contained increased levels of inflammatory cells and growth factors – clinical indicators of vascular inflammation and vasoocclusive disease. A 2001 study of NF1 death certificates showed that those with NF1 who died at age 30 or younger were more than seven times as likely as the general population to have been diagnosed with a cardiovascular problem.  This study provides vital information that is now being transferred to the clinic by the research team in an effort to better understand, diagnose and intervene in cases of cardiovascular disease in NF1.

NF1 Clinical Updates – Focus on Cognitive Issues

The 2005 report by Alcino Silva’s group that mice with genetically-based NF1 related learning disabilities showed improved learning and memory abilities following treatment with statin drugs quickly advanced to patient testing, and these drugs are now in Phase II NF1 clinical trials.  However a challenge has been adapting the water maze (swimming) tests used to monitor mouse learning to one that can be used in humans, to see if the drug is working in patients.  Ullrich et al. address this by developing a computer-based virtual ‘Arena Maze’. Tests verified that the Arena Maze can differentiate between children with and without NF1, and should help improve design of future NF1 clinical trials.  Meanwhile Thompson et al. provide a comprehensive review of speech-language characteristics in children and adolescents with NF1 from a detailed study of nineteen three-to-five year olds and propose the need for early assessment of speech and language problems in NF1 for appropriate timely intervention.

Children with NF1 frequently exhibit T2-weighted hyperintensities in the brain called unidentified bright objects (UBOs) on brain magnetic resonance imaging (MRI). Chabernaud et al.  examined thalamo-striatal UBOs in 37 children with NF1: 24 had UBO’s, and 18 were thalamo-striatal UBOs.  Children with thalamo-striatal UBOs had significantly lower IQs and visuospatial performances than those without UBOs in this location suggesting that UBOs may contribute to NF1 cognitive impairments through thalamo-cortical dysfunction.  

Pride et al. showed that a larger total corpus callosum seen in NF1 was associated with significantly lower IQ and other cognitive deficits. An enlarged corpus callosum in NF1 may be an early predictor of children at risk of cognitive difficulties.  

Payne et al. review the structural and functional neuroimaging literature in individuals with NF1 and discuss findings that have emerged and might benefit the understanding and management of cognitive defects in his population.

Huijbregts et al. demonstrate that children and adolescents with NF1 can have some deficits in social information processing such as identification of facial emotions and matching facial emotions tasks.

Erdogan-Bakar et al. examine a range of cognitive defects in children with NF1 and their unaffected siblings. Interestingly unaffected siblings of children with NF1 had mildly but consistently low test scores compared to control subjects. This raises the question of the role of underlying genetic or environmental factors.

Gilboa et al. review the NF1 literature to assess quality of life for individuals with NF1 in the perspective of the World Health Organization's International Classification of Functioning, Disability and Health adapted for children and young people (ICF-CY) a framework for describing and classifying health and health-related states. NF1 related studies were classified using ICF-CY guidelines. In summary very little information is available on the impact of cognitive and other deficits the daily life of persons with NF1. 

Hachon et al. review recent advances in analysis of cognitive deficits observed in children with NF1.

NF1 Clinical Updates – Genetics

Evans et al. reviewed data from genetic registries assembled in the UK in 1989 and 1990 to monitor a range of autosomal dominant tumor-prone genetic conditions including NF1 and NF2.  The initial purpose of these registries was to provide a basis for appropriate health-resources allocations. Birth incidence of NF1 and NF2 were found to be 1:2,699 and 1:33,000 respectively; 42% of NF1 cases and 56% of NF2 cases were found to be de novo mutations. 

Kaplan et al. present an intriguing family case of monozygotic twins discordant for NF1 (one twin with NF1 and one mosaic but with no clinical diagnosis) following their clinical history and examining genetics over their lifetime, as well as children of the affected twin (who also have NF1) and unaffected twin (who do not).

NF1 Clinical Updates – Other

Hivelin et al. present a review of 33 NF1 patients (15 men and 18 women) who have received facial surgery for treatment of severe plexiform neurofibromas and facial hemihypertrophy.  In a study of children with NF1, Moharir et al. demonstrate that PET/CT may contribute useful information to the surveillance of optic pathway glioma in childhood NF1-particularly to identify progressive, symptomatic tumors and to detect malignant transformation in plexiform neurofibromas in children with NF1.

From a population study of 55 NF1 patients and 51 matched controls, Caffarelli et al. suggest that reduced areal bone mineral density and quantitative ultrasound represent useful tools in evaluating skeletal abnormalities and bone status in NF1.

Case Reports: Okazaki et al. report autopsy of a 63-year-old man with NF1 and widespread ischemic brain lesions caused by vasculopathy associated with the disorder. Many arteries in the subarachnoid space of the brain had cell hyperplasia in the intimal layer resulting in narrowing and occlusion of the vascular lumen. Immunoblotting demonstrated a marked decrease of neurofibromin. Duarte et al. report case piebaldism – unusual skin  pigmentation - in a patient with NF1 and find this to be associated with a mutation in the KIT gene. This is especially interesting as the KIT gene has been implicated in causing growth of plexiform tumor cells and is the drug target of Imatinib (Gleevec) now in NF1 clinical trials. Helmers and Irwin present a case study showing efficacy of physical therapy for conservative management of musculoskeletal dysfunction, cervical pain and headaches in NF 1.  Interestingly, Becker et al. report on a 58 year old female with NF1 and multiple intracranial aneurysms – just one example of the implication of cardiovascular concerns for those with NF1 (highlighted above).  

Finally, Ferner provided a clinical review of NF1 and NF2 multidisciplinary clinical care approaches.

NF2 Clinical Updates – Avastin Studies

Last July the drug bevacizumab (Avastin) was reported to show promise in shrinking NF2 vestibular schwannomas, with some improved hearing seen in patients. That Massachusetts General Hospital study, published by Dr. Scott Plotkin and colleagues in the New England Journal of Medicine, has been followed up by a publication from Mautner et al. in Germany reporting 2 cases in which treatment with bevacizumab - for 3 months in one case and 6 months in the other – caused vestibular schwannoma shrinkage in both NF2 patients and improved hearing in the patient treated with drug for 6 months.

Legius Syndrome Updates

Legius Syndrome, caused by mutations in the SPRED1 gene, is a recently identified NF1 like syndrome that presents clinically with some features of NF1 but is believed to have a milder long-term prognosis. NF1 clinicians now face the challenge of integrating the possibility of a Legius Syndrome diagnosis into their clinical practice.  Muram-Zborovski et al. review the experience of doing this at the University of Utah NF Clinic (a member site of the CT NF Clinic Network), and do SPRED1 mutation analysis on 151 patients with a clinical diagnosis of NF1 to identify the frequency of Legius syndrome within the NF1 clinic population. 2 individuals were found to have SPRED1 mutations. This is consistent with other reports that frequency of SPRED1 mutations in patients meeting diagnostic criteria for NF1 in a hospital-based clinic is 1% to 2%.

Lane et al. published a retraction of a paper which we reported last Roundup which claimed identification of a patient with a SPRED1 mutation and an orbital tumor. The patient in fact had an NF1 mutation; therefore SPRED1 remains a disorder in which to date tumors have not been identified.

NF1 Cell and Molecular Biology – Bone Advances

Statin drugs, widely prescribed for cholesterol management, are in ongoing Phase II clinical trials of the drug Lovastatin for the treatment of NF1-related learning disabilities. Now - in a study initiated with a CTF Drug Discovery Initiative Award - Lovastatin may also have promise for the treatment of NF1-related bone fractures.  Pseudarthrosis or ‘false joint’ can occur in children with NF1 when a long bone such as in the leg fractures but fails to heal because new bone is unable to be generated.  Pseudarthrosis is often untreatable and may require amputation.  Wang et al. use a mouse model in which neurofibromin is eliminated in osteoblasts - cells that usually make new bone. As seen in NF1 patients, these mice are unable to heal fractures as fast as normal mice; and instead of the fracture healing, a weak callus remains at the site of injury, presenting (as in humans) a risk of re-breakage.  However, when these mice are treated with Lovastatin –here, delivered to the site of bone injury in tiny nanoparticles, to facilitate the drug’s rapid release – healing was markedly improved. Given that Lovastatin can safely be given to children, as evidenced by the NF1 learning disabilities trials, these exciting findings could quickly advance to Lovastatin trials to treat NF1-related bone dysplasia. 

NF1 Cell and Molecular Biology – Tumors and Signaling

Foundation Young Investigator Awardee Sutapa Banerjee led a study identifying STAT3 as a cell signal that could be targeted with drugs effectively independent of TORC1- and Rac1with drugs to halt tumor growth without interference from other cell signals.

Former CTF Young Investigator Award recipient Vernon Phan et al. provide evidence from yeast studies that conserved ubiquitination pathways regulating the RasGAP proteins Ira2 in yeast and neurofibromin in humans.

Pemov et al. examine human and mouse NF1-haploinsufficiency - when loss of one allele of a gene is sufficient to give rise to disease – which has been traditionally been viewed as a passive state. Their studies show haploinsufficiency to be less passive than believed, as it perturbed and up-regulated cell cycle and DNA repair pathways.

Staser et al. review the increasingly important role of the mast cell in promoting the growth of NF1 tumors, and as a candidate drug target for treatment of these tumors.

Hawes and Reilly describe a new genetically engineered mouse model of NF1 in which the tumors literally become illuminated due to an E2F1 promoter-driving luciferase (ELUX) reporter gene that ‘lights up’ a cell whenever and wherever tumor cells are growing. ‘Glowing’ cells can be detected through bioluminescence imaging of the living animal. This system can be used to identify tumors at different stages and to understand how and where spontaneous NF1 tumors initiate. The new mouse model will have tremendous value in screening candidate tumor drugs. Reilly provides a review of what we know and what challenges remain in understanding the cell subsets in NF1 tumor that may serve as the miscreants with metastatic cancerous potential.

NF2 Cell and Molecular Biology – Insights from the Lens

Over half of individuals with NF2 will develop cataracts in the lens of the eye called PSCs. Wiley et al. present some ideas for the biological basis of these cataracts.  The NF2 gene was inactivated in a genetic mouse model only in the developing cells that will give rise to the lens, called fiber cells. Unlike normal fiber cells, the NF2 inactivated fiber cells were unable to stop dividing at the correct time in development, and also continued to express genes associate with their immature stage. These fiber cells failed to take on their usual elongated shape in the lens and do not form appropriate connections and associations with neighboring cells. Overall the lens failed to detach from other tissues as it should but continued to grow into a tumor-like mass. These findings highlight the molecular events underpinning NF2 related cataracts and this new mouse model will be helpful for screening candidate NF2 drug therapies.

NF2 Cell and Molecular Biology –Signaling

A study with first author Children’s Tumor Foundation Young Investigator Awardee Geoffrey Kilili has uncovered novel ideas about merlin signaling. In the fruit fly, merlin protein function acts by promoting Hippo. The mammalian Hippo homolog is Mst2 and, as in flies, it mediates merlin tumor suppressor function/prevention of excess cell proliferation. Meanwhile Mst2 itself is negatively regulated by Raf-1.   Kilili found that merlin did not necessarily promote Mst2 signaling in mammalian cells; and, inhibiting Mst2 impairs Raf-1 signaling, after which cell proliferation ceases. This research reveals a potentially more complex role for Mst2 than previously thought, perhaps dual roles for Mst2 as a tumor suppressor and as a cell growth promoter. Yu et al. shed light on mechanisms of merlin function and identify Kibra, another upstream component of the Hippo signaling pathway that functions together with Mer and Ex in a protein complex localized to the apical domain of epithelial cells, and that this protein complex regulates the Hippo kinase cascade and implicate Kibra as a potential tumor suppressor with relevance to neurofibromatosis.

Bosco et al. endeavor to shed light on the mechanism through which merlin normally exerts its tumor-suppressive function, and thereby, on how this is disrupted in NF2 tumors. Through a series of elegant experiments using NF2 knockout mouse embryonic fibroblasts the group proposes an essential role for Rac1-mediated canonical Wnt signaling in the loss of contact inhibition in NF2-deficient cells.

In one third of glioblastomas NF2 gene function is inactivated. Morales et al. report that this inactivation can happen in 2 ways: decreased NF2 protein expression, or, due to increased levels of related protein ezrin, which disables NF2 function by intermolecular association and aberrant intracellular recruitment.

Yi et al. describe efforts to optimize drugs that target the p21-activated kinases (PAKs), candidate drug targets in NF2.  This is also the focus of current CTF Drug Discovery Initiative Award recipient Dr. Joe Kissil (The Wistar Institute).

References

Banerjee S, Byrd JN, Gianino SM, Harpstrite SE, Rodriguez FJ, Tuskan RG, Reilly KM, Piwnica-Worms DR, Gutmann DH. (2010) The Neurofibromatosis Type 1 Tumor Suppressor Controls Cell Growth by Regulating Signal Transducer and Activator of Transcription-3 Activity In vitro and In vivo. Cancer Res. 70:1356-66.

Becker C, Roth C, Reith W, Fassbender K, Spiegel J. (2010) Multiple Aneurysms of Intracranial Arteries in Neurofibromatosis Recklinghausen Type 1. Fortschr Neurol Psychiatr. Mar 12. [Epub ahead of print]

Bosco EE, Nakai Y, Hennigan RF, Ratner N, Zheng Y. (2010). NF2-deficient cells depend on the Rac1-canonical Wnt signaling pathway to promote the loss of contact inhibition of proliferation. Oncogene. Feb 15. [Epub ahead of print]

Caffarelli C, Gonnelli S, Tanzilli L, Vivarelli R, Tamburello S, Balestri P, Nuti R. (2010) Quantitative Ultrasound and Dual-Energy X-ray Absorptiometry in Children and Adolescents With Neurofibromatosis of Type 1. J Clin Densitom. January - March;13(1):77-83.

Chabernaud C, Sirinelli D, Barbier C, Cottier JP, Sembely C, Giraudeau B, Deseille-Turlotte G, Lorette G, Barthez MA, Castelnau P. (2009)Thalamo-striatal t2-weighted hyperintensities (unidentified bright objects) correlate with cognitive impairments in neurofibromatosis type 1 during childhood. Dev Neuropsychol. Nov;34(6):736-48.

Duarte AF, Mota A, Baudrier T, Morais P, Santos A, Cerqueira R, Tavares P, Azevedo F. (2010). Piebaldism and neurofibromatosis type 1: family report. Dermatol Online J. 16:11.

Erdoğan-Bakar E, Cinbiş M, Ozyürek H, Kiriş N, Altunbaşak S, Anlar B. (2009) Cognitive functions in neurofibromatosis type 1 patients and unaffected siblings. Turk J Pediatr. Nov-Dec;51(6):565-71.

Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F. (2010). Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 152A:327-32.

Ferner (2010) The neurofibromatoses. Pract Neurol. Apr;10(2):82-93.

Gilboa Y, Rosenblum S, Fattal-Valevski A, Josman N. (2010) Application of the International Classification of Functioning, Disability and Health in children with neurofibromatosis type 1: a review. Dev Med Child Neurol. Feb 19. [Epub ahead of print]

Hachon C, Iannuzzi S, Chaix Y. (2010). Behavioural and cognitive phenotypes in children with neurofibromatosis type 1 (NF1): The link with the neurobiological level. Brain Dev. Jan 25. [Epub ahead of print]

Hawes JJ, Reilly KM. (2010). Bioluminescent approaches for measuring tumor growth in a mouse model of neurofibromatosis. Toxicol Pathol. 38(1):123-30.

Helmers KM, Irwin KE. (2009) Physical therapy as conservative management for cervical pain and headaches in an adolescent with neurofibromatosis type 1: a case study. J Neurol Phys Ther. Dec;33(4):212-23.

Hivelin M, Wolkenstein P, Lepage C, Valeyrie-Allanore L, Meningaud JP, Lantieri L. (2010) Facial aesthetic unit remodeling procedure for neurofibromatosis type 1 hemifacial hypertrophy: report on 33 consecutive adult patients. Plast Reconstr Surg. Apr;125(4):1197-207.

Huijbregts S, Jahja R, DE Sonneville L, DE Breij S, Swaab-Barneveld H. (2010) Social information processing in children and adolescents with neurofibromatosis type 1. Dev Med Child Neurol. Feb 24. [Epub ahead of print]

Huttner AJ, Kieran MW, Yao X, Cruz L, Ladner J, Quayle K, Goumnerova LC, Irons MB, Ullrich NJ. (2010) Clinicopathologic study of glioblastoma in children with neurofibromatosis type 1. Pediatr Blood Cancer. Mar 22. [Epub ahead of print]

Kaplan L, Foster R, Shen Y, Parry DM, McMaster ML, O'Leary MC, Gusella JF. (2010) Monozygotic twins discordant for neurofibromatosis 1. Am J Med Genet A. Mar;152A(3):601-6.

Kilili GK, Kyriakis JM. (2010).Mammalian Ste20-like kinase (Mst2) indirectly supports Raf-1/ERK pathway activity Via maintenance of protein phosphatase-2A catalytic subunit levels and consequent suppression of inhibitory Raf-1 phosphorylation. J Biol Chem. Mar 8. [Epub ahead of print]

Kissil JL, Blakeley JO, Ferner RE, Huson SM, Kalamarides M, Mautner VF, McCormick F, Morrison H, Packer R, Ramesh V, Ratner N, Rauen KA, Stevenson DA, Hunter-Schaedle K, North K. (2010). What's new in neurofibromatosis? Proceedings from the 2009 NF Conference: new frontiers. Am J Med Genet A. 152A:269-83.

Lane KA, Anninger WV, Katowitz JA. Retraction. (2010) Expanding the phenotype of a neurofibromatosis type 1-like syndrome: a patient with SPRED1 mutation and orbital manifestations: retraction. Ophthal Plast Reconstr Surg. Mar-Apr;26(2):145.

Lasater EA, Li F, Bessler WK, Estes ML, Vemula S, Hingtgen CM, Dinauer MC, Kapur R, Conway SJ, Ingram DA Jr. (2010) Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans. J Clin Invest. Feb 15. pii: 41443. doi: 10.1172/JCI41443. [Epub ahead of print]

Mautner VF, Nguyen R, Kutta H, Fuensterer C, Bokemeyer C, Hagel C, Friedrich RE, Panse J. (2010) Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2. Neuro Oncol. 12:14-8.

Moharir M, London K, Howman-Giles R, North K. (2010) Utility of positron emission tomography for tumour surveillance in children with neurofibromatosis type 1. Eur J Nucl Med Mol Imaging. Feb 24. [Epub ahead of print]

Morales FC, Molina JR, Hayashi Y, Georgescu MM. (2010). Overexpression of ezrin inactivates NF2 tumor suppressor in glioblastoma. Neuro Oncol. Feb 14. [Epub ahead of print]

Muram-Zborovski TM, Stevenson DA, Viskochil DH, Dries DC, Wilson AR, Mao R. (2010) SPRED1 Mutations in a Neurofibromatosis Clinic. J Child Neurol. Feb 22. [Epub ahead of print]

Okazaki K, Kakita A, Tanaka H, Kimura K, Minagawa M, Morita T, Takahashi H. (2010)Widespread ischemic brain lesions caused by vasculopathy associated with neurofibromatosis type 1. Neuropathology. Jan 26. [Epub ahead of print]

Payne JM, Moharir MD, Webster R, North KN. (2010) Brain structure and function in neurofibromatosis type 1: current concepts and future directions. J Neurol Neurosurg Psychiatry. Mar;81(3):304-9.

Pemov A, Park C, Reilly KM, Stewart DR. (2010) Evidence of perturbations of cell cycle and DNA repair pathways as a consequence of human and murine NF1-haploinsufficiency. BMC Genomics. Mar 22;11(1):194. [Epub ahead of print]

Phan VT, Ding VW, Li F, Chalkley RJ, Burlingame A, McCormick F. (2010). The RasGAP Proteins Ira2/Neurofibromin Are Negatively Regulated by Gpb1 in Yeast and ETEA in Humans. Mol Cell Biol. Feb 16. [Epub ahead of print]

Pride N, Payne JM, Webster R, Shores EA, Rae C, North KN. (2010). Corpus Callosum Morphology and Its Relationship to Cognitive Function in Neurofibromatosis Type 1. J Child Neurol. Feb 8. [Epub ahead of print]

Reilly KM. (2009).Neurofibromatosis and lessons for the war on cancer. EMBO Mol Med. 1:198-200.

Thompson HL, Viskochil DH, Stevenson DA, Chapman KL. (2010). Speech-language characteristics of children with neurofibromatosis type 1. Am J Med Genet A. 152A:284-90.

Staser K, Yang FC, Clapp DW. (2010) Mast cells and the neurofibroma microenvironment. Blood. Mar 16. [Epub ahead of print]

Ullrich NJ, Ayr L, Leaffer E, Irons MB, Rey-Casserly C. (2010) Pilot Study of a Novel Computerized Task to Assess Spatial Learning in Children and Adolescents With Neurofibromatosis Type 1. J Child Neurol. Feb 5. [Epub ahead of print]

Wang W, Nyman J, Moss H, Gutierrez G, Mundy G, Yang X, Elefteriou F. (2010) Local low dose lovastatin delivery improves the bone healing defect caused by Nf1 loss-of-function in osteoblasts. J Bone Miner Res.  Jan 29. [Epub ahead of print]

Wiley LA, Dattilo L, Kang KB, Giovannini M, Beebe DC. (2010) The tumor suppressor, Merlin, is required for cell cycle exit, terminal differentiation, and cell polarity in the developing murine lens. Invest Ophthalmol Vis Sci. Feb 24. [Epub ahead of print]

Yi C, Maksimoska J, Marmorstein R, Kissil JL. (2010) Development of small-molecule inhibitors of the group I p21-activated kinases, emerging therapeutic targets in cancer. Biochem Pharmacol. Mar 16. [Epub ahead of print]

Yu J, Zheng Y, Dong J, Klusza S, Deng WM, Pan D. (2010) Kibra Functions as a Tumor Suppressor Protein that Regulates Hippo Signaling in Conjunction with Merlin and Expanded. Dev Cell. 18:288-299.