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A neurofibroma is a benign nerve sheath tumor in the peripheral nervous system.

Usually found in individuals with neurofibromatosis type I (NF1), an autosomal dominant genetically-inherited disease, they can result in a range of symptoms from physical disfiguration and pain to cognitive disability. Neurofibromas arise from nonmyelinating-type Schwann cells that exhibit biallelic inactivation of the NF1 gene that codes for the protein neurofibromin.[1] This protein is responsible for regulating the RAS-mediated cell growth signaling pathway. In contrast to schwannomas, another type of tumor arising from Schwann cells, neurofibromas incorporate many additional types of cells and structural elements in addition to Schwann cells, making it difficult to identify and understand all the mechanisms through which they originate and develop.[2]

Contents

1 Subtypes of Neurofibroma o 1.1 Dermal Neurofibroma 1.1.1 Anatomy 1.1.2 Age of onset 1.1.3 Medical complications o 1.2 Plexiform Neurofibroma 1.2.1 Anatomy 1.2.2 Age of onset 1.2.3 Medical complications 2 Etiology o 2.1 Neurofibromin 1 gene o 2.2 Schwann cells o 2.3 Loss of heterozygosity leads to loss of tumor suppressor function leads to neurofibroma formation 3 Diagnosis 4 Non-drug treatments for neurofibroma o 4.1 Dermal neurofibroma 4.1.1 Surgical treatment of dermal neurofibroma 4.1.2 CO2 laser treatment for dermal neurofibroma o 4.2 Plexiform neurofibroma 4.2.1 Surgical treatment of plexiform neurofibroma 4.2.2 Radiation treatment of plexiform neurofibroma 5 Drug treatment for neurofibroma o 5.1 Drug treatment targets 5.1.1 ACE inhibitors 5.1.2 Stabilisation of axon-Schwann cell interaction and reduction of mast cell infiltration 5.1.3 Gene therapy o 5.2 Drug studies which demonstrated no effect 5.2.1 Pirfenidone 5.2.2 Tipifarnib o 5.3 Drug studies currently active 5.3.1 Erlotinib (Tarceva) with Sirolimus 5.3.2 Imatinib (Gleevec)

5.3.3 Pegylated Interferon (Peg-Intron) 5.3.4 Sirolimus (Rapamycin) 5.3.5 Sorafenib (Nexavar) 5.3.6 Tranilast (Rizaben)

6 See also 7 References 8 External links

Subtypes of Neurofibroma

Neurofibroma of the skin in a patient suffering from Neurofibromatosis type I.

Neurofibromas have been subdivided into two broad categories: dermal and plexiform. Dermal neurofibromas are associated with a single peripheral nerve, while plexiform neurofibromas are associated with multiple nerve bundles. According to the World Health Organization classification system, dermal and plexiform neurofibromas are grade I tumors. Plexiform neurofibroma are more difficult to treat and can transform into malignant tumors. Dermal neurofibroma do not become malignant.

Dermal Neurofibroma
Anatomy

Dermal neurofibromas (sometimes referred to as cutaneous neurofibromas) originate in nerves in the skin. Three kinds are distinguished:[3]

Discrete cutaneous neurofibromas: Sessile or pedunculated masses on the skin, which are fleshy and non-tender, and can vary in size. Discrete subcutaneous neurofibromas: Lie below and look like bumps on the skin, which can sometimes be tender. Deep nodular neurofibromas: Involving tissues and organs underneath the dermis, but otherwise resembling cutaneous and subcutaneous neurofibromas.

Age of onset Dermal neurofibroma typically arise in the teenage years and are often associated with the onset of puberty. They continue to increase in number and size throughout adulthood, although there are limits to how big they get. Medical complications Dermal neurofibromas can lead to stinging, itching, pain and disfiguration. There is no evidence of malignant transformation.[1]

Dermal Neurofibroma in a patient arose in teenage years.

Plexiform Neurofibroma
Anatomy Plexiform neurofibromas can grow from nerves in the skin or from more internal nerve bundles, and can be very large. Internal plexiform neurofibromas are very difficult to remove completely because they extend through multiple layers of tissue and the attempt would damage healthy tissue or organs. Age of onset

Plexiform neurofibromas occur earlier in life and are thought to be congenital defects.[3] Medical complications Plexiform neurofibroma can cause pain, disfigurement, neurological and other clinical deficits. Plexiform neurofibromas have the potential to cause severe clinical complications if they occur in certain areas.[4] About 10% of plexiform neurofibromas undergo transformation into a malignant peripheral nerve sheath tumor (MPNST).[5] The formation of malignant cancers from neurofibromas is associated with the loss of expression of the CDKN2A or TP53 gene in non-myelinating Schwann cells that also exhibit biallelic inactivation of the NF1 gene.

Etiology
This section discusses the tumorigenesis of neurofibroma in terms of genetics, cell signaling, histology and the cell cycle.

Neurofibromin 1 gene

This picture illustrates the structure of the NF1 gene product, neurofibromin 1. This protein is 2818 amino acids long with 3 alternatively spiced exons, 9a, 23a, and 48a. The IRA domains are hypothesized to function as negative regulators of RAS, along with the GRD domain in between them.

The NF1 gene is composed of 60 exons spanning 350kb of genomic data, and maps to chromosomal region 17qll.2.[6] This gene codes for neurofibromin which is a large 220-250 KDa cytoplasmic protein that is composed of 2,818 amino acids with three alternatively spliced exons (9a, 23a and 48a). The functional part of neurofibromin is a GAP, or GTPase-activating protein. GAP accelerates the conversion of the active GTP-bound RAS to its inactive GDP-bound form, inactivating RAS and reducing RAS-mediated growth signaling. Loss of RAS control leads to increased activity of other signaling pathways including RAF, ERK1/2, PI3K, PAK and mTORS6 kinase. It is suspected that this increased activity of downstream RAS pathways might work together to increase cell growth and survival.[7] Genes that code for proteins that regulate cell growth, such as NF1 and TP53, are referred to as tumor suppressor genes. Neurofibromin has other growth-regulatory properties besides its ability to regulate RAS activity, but these other functions are poorly understood at this time.[8]

Schwann cells
There are two kinds of Schwann cells, myelinating and nonmyelinating. While myelinating Schwann cells cover large diameter (>1 micrometer) peripheral nervous system (PNS) axons with myelin, nonmyelinating Schwann cells encapsulate small diameter PNS axons with their cytoplasmic processes. Nonmyelinating Schwann cells are the neoplastic element in neurofibromas. This conglomeration of nonmyelinating Schwann cells and axons is called a Remak bundle. While nonmyelinating Schwann cells are the origin of neurofibromas, the mutations that make them susceptible to this transformation occur in Schwann cell precursors during early nerve development. Mutated nonmyelinating Schwann cells do not form normal Remak bundles. Instead, they fail to properly surround and segregate target axons. It is unknown at this time why, if both types of Schwann cells exhibit bilallelic inactivation of the NF1 gene, only the nonmyelinating variety give rise to neurofibromas.[9]

Loss of heterozygosity leads to loss of tumor suppressor function leads to neurofibroma formation
Neurofibromas arise from nonmyelinating Schwann cells that are homozygous for the inactive version of the NF1 gene, which leads to a complete loss of expression of neurofibromin[disambiguation needed]. While one defective allele may be inherited, loss of heterozygosity (LOH) must occur before a neurofibroma can form; this is called the two-hit hypothesis. This LOH happens by the same mechanisms, such as oxidative DNA damage, that causes mutations in other cells. Once a nonmyelinating Schwann cell has suffered inactivation of its NF1 genes, it begins to proliferate rapidly. This condition is called hyperplasia, which is cell growth beyond what is normally seen. However, despite increased numbers of nonmyelinating Schwann cells, there is no neurofibroma yet. In order for the neurofibroma to develop, cells that are heterozygous for the NF1 gene must be recruited to the site. It has been hypothesized that the proliferating nonmyelinating Schwann cells secrete chemoattractants such as the KIT ligand, and angiogenic factors such as the heparin-binding growth factor midkine. These chemicals promote the migration of different kinds of cells that are heterozygous for the NF1 gene into the hyperplastic lesions created by the nonmyelinating Schwann cells. These cell types include fibroblasts, perineurial cells, endothelial cells, and mast cells. The mast cells then secrete mitogens or survival factors that alter the developing tumor microenvironment and result in neurofibroma formation. Dermal and plexiform neurofibromas differ in later development stages, but the details are unclear at this point.[7]

Diagnosis

A blood test for protein melanoma inhibitory activity may be used to detect the presence of neurofibromas.[10][11]

Non-drug treatments for neurofibroma


Dermal neurofibroma
Surgical treatment of dermal neurofibroma Dermal neurofibromas are not usually surgically removed unless they are painful or disfiguring, because there are generally so many of them and they are not dangerous. CO2 laser treatment for dermal neurofibroma CO2 lasers have been used to remove dermal neurofibromas. In a paper titled Hypertrophic Scars After Therapy with CO2 Laser for Treatment of Multiple Cutaneous Neurofibromas Ostertag et al. said this about treatment by laser: The cosmetic disfigurement is the most important issue in the decision to treat cutaneous symptoms of neurofibromatosis. Treating patients with extensive neurofibromas with [a] CO2 laser is still the best choice. However, it is strongly advised that a test treatment be performed to judge the effectiveness of the procedure and whether the developed scar is an acceptable trade-off. [12]

Plexiform neurofibroma
Surgical treatment of plexiform neurofibroma As of 2002, the primary treatment option for plexiform neurofibroma was surgery.[13] Removal of plexiform neurofibromas is difficult because they can be large and cross tissue boundaries. However, besides pain, plexiform neurofibromas are sometimes removed due to the possibility of malignant transformation. The following examples show that plexiform neurofibromas can form anywhere and can make surgical resection difficult:

A large plexiform neurofibroma in the leg of a 6-year old male. The authors state: Our case was operated, as both the cutaneous and deep branches of the peroneal nerve were involved causing pain and numbness in the leg, and because there was a possibility for malignant transformation, as growth in the mass was realized by the family members of the patient. In laymans terms, they decided to remove the neurofibroma because it was causing the boy pain and numbness in his leg, and because there was a possibility that it was undergoing a malignant transformation as his family noticed an increase in the tumor's size. The authors also note, However, complete resection is quite difficult due to invasion of the tumor into the surrounding soft tissues. [14] A neurofibroma on the left ventricle. The neurofibroma was removed and the patients mitral valve had to be replaced.[15]

A 14-year-old girl with NF1 was diagnosed with a neurofibroma involving her bladder, a rare location.[16]

Radiation treatment of plexiform neurofibroma Once a plexiform neurofibroma has undergone malignant transformation, radiation and chemotherapy can be used as treatment. However, radiation is generally not used as a treatment for plexiform neurofibromas because of concerns that this could actually promote malignant transformation. There has even been a documented case of a Schwannoma being induced from a neurofibroma due to radiation therapy.[17]

Drug treatment for neurofibroma


There are many drug therapies under study for neurofibromas.[18][19] These are in various stages of research; more time will be required to determine if these are viable options for the treatment of neurofibromas.

Drug treatment targets


ACE inhibitors ACE inhibitors have been proposed as a novel treatment of neurofibromas. ACE inhibitors are currently used to treat hypertension and congestive heart failure, to avert remodeling and reinfarction after myocardial infarction, and to ameliorate diabetic nephropathy and other renal diseases. ACE inhibitors work by indirectly down regulating TGF-beta, which is a growth factor that has been shown to influence the development of tumors.[20] Stabilisation of axon-Schwann cell interaction and reduction of mast cell infiltration Based on the recent discovery that the nonmyelinating Schwann cells that make up Remak bundles are the origin of neurofibromas, it has been proposed that therapies for prevention and treatment be based on stabilizing the axon-Schwann cell interactions and reducing mast cell infiltration. As it appears that these elements are needed for neurofibroma formation, prevention or reduction could prove an effective treatment.[9] Gene therapy Gene therapy for the neurofibromin 1 gene represents the ultimate solution to preventing the cluster of maladies which are enabled by the mutation.[21][22] As of 2006, therapy for NF1 tumors had not been tested due to the lack of an appropriate NF1 tumor model.[23]

Drug studies which demonstrated no effect


Pirfenidone

Pirfenidone inhibits fibroblast growth. Studies showed no improvement over controls. Tipifarnib Tipifarnib (also known as drug R115777) inhibits the activation of RAS. This drug is a Farnesyltransferase inhibitor which inhibits the Ras kinase in a post translational modification step before the kinase pathway becomes hyperactive. It successfully passed phase one clinical trials but was suspended (NCT00029354) in phase two after showing no improvement over controls.[24] [25]

Drug studies currently active


Erlotinib (Tarceva) with Sirolimus The combination of Erlotinib with Sirolimus is being studied to treat low-grade gliomas.[26] Imatinib (Gleevec) Early research has shown potential for using the c-kit tyrosine kinase blocking properties of Imatinib to treat plexiform neurofibromas.[27][28] [29] Pegylated Interferon (Peg-Intron) Peginterferon alfa-2b is being studied to treat plexiform neurofibromas.[30][31] [32][33][34] Sirolimus (Rapamycin) Sirolimus is an antibiotic developed as an antifungal agent. It inhibits mTOR signalling. It is being studied to treat plexiform neurofibromas.[35][36][37] Sorafenib (Nexavar) Sorafenib is being studied for treatment of unresectable plexiform neurofibroma and low-grade astrocytomas.[38][39][40][41] Tranilast (Rizaben) In vitro, Tranilast, inhibits growth of neurofibroma cells.[42]

Neurofibromatosis
From Wikipedia, the free encyclopedia Jump to: navigation, search

Neurofibromatosis

Classification and external resources

Back of an elderly woman with neurofibromatosis Neurofibromatosis (commonly abbreviated NF; neurofibromatosis type 1 is also known as von Recklinghausen disease) is a genetically-inherited disorder in which the nerve tissue grows tumors (neurofibromas) that may be benign or may cause serious damage by compressing nerves and other tissues. The disorder affects all neural crest cells (Schwann cells, melanocytes and endoneurial fibroblasts). Cellular elements from these cell types proliferate excessively throughout the body, forming tumors; melanocytes also function abnormally in this disease, resulting in disordered skin pigmentation and caf au lait spots. The tumors may cause bumps under the skin, colored spots, skeletal problems, pressure on spinal nerve roots, and other neurological problems.[1][2] Neurofibromatosis is an autosomal dominant disorder, which means only one copy of the affected gene is needed for the disorder to develop. Therefore, if only one parent has neurofibromatosis, his or her children have a 50% chance of developing the condition as well. The severity in affected individuals can vary, this may be due to variable expressivity. Approximately half of cases are due to de novo mutations and no other affected family members are seen. It affects males and females equally.

Contents

1 Classification o 1.1 Neurofibromatosis type 1 (NF 1) o 1.2 Neurofibromatosis type 2 (NF 2) o 1.3 Schwannomatosis o 1.4 Other variants o 1.5 Related disorders

2 Signs and symptoms 3 Diagnosis o 3.1 Prenatal testing 3.1.1 Embryo 3.1.2 Fetus 4 Genetics 5 Pathophysiology 6 Treatment 7 History 8 Notable cases 9 Research o 9.1 Foundations o 9.2 Academic Research and Clinical Centers 9.2.1 France 9.2.2 United States o 9.3 Drug Companies 10 References

Classification
Neurofibromatosis type 1 (NF 1)

Plexiform neurofibroma on the neck of a patient; plexiform neurofibromas are a cause of morbidity in the affected individuals. Main article: Neurofibromatosis type I Neurofibromatosis type 1 (also known as "von Recklinghausen disease"[1]) is the most common form of NF, accounting for up to 90% of all cases. NF 1 has a disorder frequency of 1 in 4,000, making it more common than neurofibromatosis type 2, with a frequency of 1 in 45,000 people.[3] It occurs following the mutation of neurofibromin 1 on chromosome 17q11.2; the large size of the NF1 gene (286kbp)[1] and presence of many homologous regions may predispose it to mutations. 100,000 Americans have neurofibromatosis. Neurofibromin is a tumor suppressor gene whose function is to inhibit the p21 ras oncoprotein.[3] In absence of this tumor suppressor's inhibitory control on the ras oncoprotein, cellular proliferation is erratic and uncontrolled,

resulting in unbalanced cellular proliferation and tumor development. The diagnosis of NF1 is made if any two of the following nine criteria are met:

Patient with multiple small cutaneous neurofibromas and a 'caf au lait spot' (bottom of photo, to the right of centre). A biopsy has been taken of one of the lesions.

Two or more neurofibromas on or under the skin, or one plexiform neurofibroma (a large cluster of tumors involving multiple nerves); neurofibromas are the subcutaneous bumps characteristic of the disease, and increase in number with age. Freckling of the groin or the axilla (arm pit). Caf au lait spots (pigmented, light brown macules located on nerves, with smooth edged, "coast of California"[4] birthmarks). Six or more measuring 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals. Skeletal abnormalities, such as sphenoid dysplasia or thinning of the cortex of the long bones of the body (i.e. bones of the leg, potentially resulting in bowing of the legs)[1] Lisch nodules (hamartomas of iris), freckling in the iris Tumors on the optic nerve, also known as an optic glioma A first-degree relative (parent, sibling, or child) with NF-1 according to the preceding criteria.

Other features that may be seen in individuals with NF-1 are:


Scoliosis with or without kyphosis Macrocephaly in 3050% of the pediatric population without any hydrocephalus[5] Epilepsy (seizures) Juvenile posterior lenticular opacity[1]

NF 1 also increases the risk of tumor development, particularly, gliomas and pheochromocytomas. Unlike NF 2, NF 1 is not associated with an increased risk for meningiomas.[6]

hydrocoele early puberty

Neurofibromatosis type 2 (NF 2)


Main article: Neurofibromatosis type II

Neurofibromatosis type 2 (also called "central neurofibromatosis"[1]) is the result of mutation of the protein merlin (also known as "Neurofibromin 2" or "schwannomin"[1]) in chromosome 22q12. It accounts for only 10% of all cases of NF, and its frequency is lower than NF1. It is also caused by a mutation in a tumor suppressor gene NF2 (whose gene product is schwannomin or merlin). The normal function of merlin is not well understood.[3] The disorder manifests in the following fashion:

bilateral acoustic neuromas (tumors of the vestibulocochlear nerve or cranial nerve 8 (CN VIII) also known as schwannoma), often leading to hearing loss. In fact, the hallmark of NF 2 is hearing loss due to acoustic neuromas around the age of twenty. The tumors may cause: o headaches o balance problems, and peripheral vertigo often due to schwannoma and involvement of the inner ear o facial weakness/paralysis due to involvement or compression of the facial nerve (cranial nerve 7 or CN VII) o patients with NF2 may also develop other brain tumors, as well as spinal tumors. o deafness and tinnitus

NF 2 increases the risk of meningiomas and ependymomas.[3]

Schwannomatosis
Main article: Schwannomatosis Schwannomatosis mutation in both chromosomes 17 and 22 1. 2. 3. 4. Multiple schwannomas occur. The schwannomas develop on cranial, spinal and peripheral nerves. Chronic pain, and sometimes numbness, tingling and weakness About 1/3 of patients have segmental schwannomatosis, which means the schwannomas are limited to a single part of the body, such as an arm, a leg or the spine. 5. Unlike the other forms of NF, the schwannomas do not develop on vestibular nerves, and as a result, no loss of hearing is associated with schwannomatosis. 6. Patients with schwannomatosis do not have learning disabilities related to the disorder. One must keep in mind, however, that neurofibromatosis can occur in or affect any of the organ systems, whether that entails simply compressing them (from tumor growth) or in fact altering the organs in some fundamental way. This disparity in the disorder is one of many factors that makes it difficult to diagnose, and eventually find a prognosis for.

Other variants

Neurofibromatosis type 3 Neurofibromatosis type 4 Neurofibromatosis type 5[citation needed]

Related disorders
Neurofibromatosis is considered a member of the neurocutaneous syndromes (phakomatoses).[2] In addition to the types of neurofibromatosis, the phakomatoses also include tuberous sclerosis, Sturge-Weber syndrome and von Hippel-Lindau disease. This grouping is an artifact of an earlier time in medicine, before the distinct genetic basis of each of these diseases was understood.

Signs and symptoms


Patients with neurofibromatosis can be affected in many different ways. Morbidity is often a result of plexiform neuromas, optic gliomas, or acoustic neuromas, but mortality can also be associated with malignant transformation of the neuromas, such as neurofibrosarcomas[1] (often there is a malignant transformation in less than 3% of the cases of NF1[3]). There is a high incidence of learning disabilities or cognitive deficit[1][5] in patients with NF, particularly NF-1, however severe retardation is not part of the syndrome. Because of the tumor generating nature of the disorder and its involvement of the nervous system and also because of early onset macrocephaly in the pediatric population, there is often an increased chance of development of epilepsy in those affected. Neurofibromatosis also increases the risk of leukemia particularly in children; Children with NF-1 have 200 to 500 times the normal risk of developing leukemia compared to the general population.[1] Since the tumors grow where there are nerves, they can also grow in areas that are visible, causing considerable social suffering for those affected. The tumors can also grow in places that can cause other medical issues that may require them to be removed for the patient's safety.[7] Affected individuals may need multiple surgeries (such as reduction surgery, or Gamma knife surgery), depending on where the tumors are located. For instance, those affected with NF 2 might benefit from a surgical decompression of the vestibular tumors to prevent deafness.[2]

Diagnosis
Prenatal testing
Embryo For embryos produced via in vitro fertilisation, it is possible via preimplantation genetic diagnosis (PGD) to screen for NF-1.[8] "PGD has about 9598% accuracy but requires that the partner with NF2 have a recognizeable genetic mutation, which is only the case for about 60% of people with a clinical diagnosis of NF2. Having the initial genetic testing to determine if the mutation is recognizeable takes approximately 6 months, and then preparing the probes for the PDG testing takes approximately another 6 months."[9] PGD can not be used to detect Schwannomatosis, because the gene for it has not yet been identified.[10]

Fetus Chorionic villus sampling or amniocentesis can be used:[11]


To detect Neurofibromatosis type I. To detect Neurofibromatosis type II with 95% accuracy. Can not be used to detect Schwannomatosis, because the gene for it has not yet been identified.

Genetics

NF-1 and NF-2 may be inherited in an autosomal dominant fashion, as well as through random mutation. Neurofibromatosis type 1 is caused by mutation on chromosome 17q11.2, the gene product being neurofibromin[disambiguation needed] (a regulator of the GTPase activating enzyme (GAP)).[1][12] Neurofibromatosis type 2 is due to mutation on chromosome 22q, the gene product is merlin, a cytoskeletal protein.[1] Both NF-1 and NF-2 are autosomal dominant disorders, meaning only one copy of the mutated gene need be inherited to pass the disorder. A child of a parent with NF-1 or NF-2 and an unaffected parent will have a 50100% chance of inheriting the disorder, depending on whether the affected parent is heterozygous (Aa) or homozygous (AA) for the trait ("A" depicts the affected dominant allele, while "a" depics the recessive allele). Complicating the question of heritability is the distinction between genotype and phenotype, that is, between the genetics and the actual manifestation of the disorder. In the case of NF1, no clear links between genotype and phenotype have been found, and the severity and the specific nature of the symptoms may vary widely among family members with the disorder. This is a good example of the phenomenon of variable expressivity: the differing severities of disease in different individuals with the same genotype.[13] In the case of NF-2, however, manifestations are similar among family members; a strong genotype-phenotype correlation is believed to exist.[13]

Both NF-1 and NF-2 can also appear to be spontaneous de novo mutations, with no family history. These cases account for about one half of neurofibromatosis cases.[13] Similar to polydactyly, NF is also an autosomally dominant mutation, that is not prevalent in the society. Neurofibromatosis-1 is found in approximately 1 in 2,5003,000[3] live births (carrier incidence 0.0004, gene frequency 0.0002) and is more common than NF-2.

Pathophysiology
The gene affected in NF-1, is located on the long arm of the chromosome 17 (q11.2). It encodes for a protein called neurofibromin, otherwise known as a "tumor suppressor" protein. This protein is a negative regulator of the Ras kinase pathway (p21 oncoprotein).[14] Neurofibromatosis alters or weakens this protein (due to deletion, missense mutation, or nonsense mutations,[1]) allowing rapid, radical growth of cells all over the body, especially around the nervous system. The essential problem is the inability to inactivate GTP due to a defective GTP-ase (neurofibromin). This leads to the common symptoms for neurofibromatosis clumpings of the tumors, called neurofibromas and schwannomas. Less is known about the NF-2 linked gene and its product, merlin. However, it is on the long arm of the chromosome 22q(11.1-13.1[1]) and codes for the protein.

Treatment
Because there is no cure for the condition itself, the only therapy for patients with neurofibromatosis is a program of treatment by a team of specialists to manage symptoms or complications. Surgery may be needed when the tumors compress organs or other structures. Less than 10% of people with neurofibromatosis develop cancerous growths; in these cases, chemotherapy may be successful.[15] For families with NF, genetic screening and counselling is available.[16]

History
Neurofibromatosis (or von Recklinghausen disease[2]) was first described in 1882 by the German pathologist, Friedrich Daniel von Recklinghausen. As a young scientist, Recklinghausen was the student of the then renowned Rudolf Virchow in Berlin. Recklinghausen was successful in generating some of the most descriptive medical observations of his time, making him the first person to describe and coin the term "hemachromatosis" (Hmochromatose, Tageblatt der Naturforschenden Versammlung). Recklinghausen is now known for his contributions to staining methods, and most importantly for his important paper on neurofibromatosis published in 1881, to honor Rudolf Virchows 25 year jubilee, in which he describes neurofibromatosis. Recognized as a distinguished histopathologist, and a great scientist to this date, he lends his name to the syndrome, which he himself elucidated.[17]

Notable cases

In May 2011, a case was reported in the United Kingdom in which a 15-month-old child who turned out to have Neurofibromatosis type I was misdiagnosed as being abused under the assumption that the mother had Mnchausen syndrome by proxy, because the child gained weight while in hospital and lost weight while at home.[18] The child was placed in foster care for 6 months and then returned to his parents after he was correctly diagnosed. In January 2008, 32-year-old Huang Chuncai of China underwent a second operation to remove another 4.5 kg (9.9 lb) of tumor from his face. A previous operation removed 15 kg (33 lb) from what was originally a 23 kg (55.7 lb) tumor.[19][20] In March 2007, the treatment of 30-year-old neurofibromatosis patient Pascal Coler of France ended after he had received what his doctors call the world's first successful full face transplant.[21][22] In November 2006, there was an hour-long documentary on the British television network Channel 4 about Facing the World, an organization that helps children with severe facial disfigurements in developing countries. One of the children featured on the documentary was Arianto, an Indonesian boy who suffered from a severe form of neurofibroma resulting in hemifacial giganticism. Also in that year, another documentary on BBC2 (edge of life) featured a neurofibromatosis case. On that documentary was a young teenager, Amit Ghose, who had decided for himself to have corrective surgery at the age of 14. In this case, the neurofibroma occurred on the face, resulting in the loss of sight in one eye and having to have it removed. This was a case of NF-2, resulting in the disfigurement of the one side of the face, while leaving the other side completely normal. In 2012, surgeons removed a 200-pound tumor caused by neurofibromatosis from a Vietnamese man's leg; the tumor weighed twice as much as the rest of his body.[23] Joseph Merrick, the Elephant Man, was once considered to have been affected with neurofibromatosis type I. It is likely, however, that Merrick suffered from the very rare Proteus syndrome. This has produced a common misconception that neurofibromatosis and the "Elephant Man disease" are one and the same. [24]

Research
The St. Louis Children's Hospital Neurofibromatosis Center maintains a comprehensivelist of current NF research studies.

Foundations
Several national organizations provide support for those challenged by neurofibromatosis. Some include:

Australia: NF Australia incorporating the Children's Tumour Foundation of Australia (a nonprofit charitable organisation supporting research and providing awareness, resources and support

Little Frog Foundation (a nonprofit organization working providing information and resources for families dealing with NF1, NF2, and tumour-related neurofibromatosis in Australia)

Belgium: NF KONTAKT.be (a nonprofit organization providing information and resources for families, Schools and Health Care workers dealing with NF1, NF2, and tumour-related neurofibromatosis in Belgium and providing awareness and support of Neurofibromatosis in Europe) Canada: The Neurofibromatosis Association of Quebec Canada: NF Society of Ontario France: o The Neurofibromatosis and Recklinghausen Association o Centre de Rfrence labellis NEUROFIBROMATOSES United Kingdom: The Neuro Foundation United States: o The Children's Tumor Foundation (CTF) (a nonprofit organization working towards finding a cure and improving care for individuals living with neurofibromatosis) o Neurofibromatosis Inc. (a nonprofit organization working towards neurofibromatosis patient support) o Neurofibromatosis Cafe (a nonprofit organization working providing patient education, awareness and support of Neurofibromatosis)

Academic Research and Clinical Centers


France

At the Neurosurgery Clinic of the Hpital Beaujon in Clichy, Hauts-de-Seine, and in collaboration with the Black Laboratory at Harvard University which focuses on meningioma research, Michel Kalamarides focuses on mouse modeling of NF2 meningioma.

United States

California: o House Ear Institute in Los Angeles is a CTF NFPC focussing on NF2 schwannoma and meningioma. o The NF/Ras Pathway Clinic at UCSF Medical Center in San Francisco. This is a CTF NFPC focussing on NF1 myeloid leukemia. Florida: o The Wallace Lab and Muir Lab at the University of Florida in Gainesville, Florida focus on the molecular study of benign Schwann cell tumors and the development of new therapies for NF1.

The Neurofibromatosis Center at Miami Children's Hospital. Illinois: The Neurofibromatosis Program at University of Chicago Medical Center. Indiana: The Neurofibromatosis Clinic at Indiana University. This clinic has pioneered the use of Imatinib to treat neurofibromas.[25] Maryland: The Johns Hopkins Comprehensive Neurofibromatosis Center at Johns Hopkins Hospital Massachusetts: o The Center for Neurofibromatosis and Allied Disorders at Harvard Medical School and Massachusetts General Hospital. This is a CTF NFPC focussing on NF2 schwannoma and meningioma. o Brigham and Women's Hospital at Harvard Medical School is a CTF NFPC focussing on NF1 malignant peripheral nerve sheath tumors. o The Center for Human Genetics at Boston University School of Medicine provides genetic testing laboratory service for Neurofibromatosis type I and Legius syndrome. Testing includes DNA sequencing and Multiplex ligationdependent probe amplification. Missouri: The Neurofibromatosis Center at St. Louis Children's Hospital.[26] This is a CTF NFPC focussing on NF1 optic pathway glioma. They maintain a comprehensive list of current NF research studies. New Jersey: The Neurofibromatosis Center of New Jersey and Institute of Genomic Medicine at University Hospital (Newark, New Jersey) New York: o The Neurofibromatosis Center at North Shore-LIJ Health System o The Neurofibromatosis Center at NYU Langone Medical Center (see also Department of Otolaryngology). o The Comprehensive Neurofibromatosis Clinic at NewYorkPresbyterian Hospital. Ohio: The Cincinnati Neurofibromatosis Center at Cincinnati Children's Hospital Medical Center. This is a CTF NFPC focusing on NF1 plexiform neurofibromas. The Ratner Lab focuses on interactions between glial cells and axons during nervous system development and how those interactions go awry to lead to NF1 and NF2 conditions. Pennsylvania: The Neurofibromatosis Program at Children's Hospital of Philadelphia Texas: o The Comprehensive Neurofibromatosis Clinic at University of Texas Southwestern Medical Center. o The Neurofibromatosis Clinic at Children's Medical Center (Dallas)

Drug Companies
The following drug companies are supporters of the Children's Tumor Foundation and are actively developing NF-related drugs:

Avila Therapeutics Genentech Merck Novartis

Pfizer
A single gene disorder is the result of a single mutated gene. Over 4000 human diseases are caused by single gene defects. Single gene disorders can be passed on to subsequent generations in several ways. Genomic imprinting and uniparental disomy, however, may affect inheritance patterns. The divisions between recessive and dominant types are not "hard and fast", although the divisions between autosomal and X-linked types are (since the latter types are distinguished purely based on the chromosomal location of the gene). For example, achondroplasia is typically considered a dominant disorder, but children with two genes for achondroplasia have a severe skeletal disorder of which achondroplasics could be viewed as carriers. Sickle-cell anemia is also considered a recessive condition, but heterozygous carriers have increased resistance to malaria in early childhood, which could be described as a related dominant condition.[4] When a couple where one partner or both are sufferers or carriers of a single gene disorder and wish to have a child, they can do so through in vitro fertilization, which means they can then have a preimplantation genetic diagnosis to check whether the embryo has the genetic disorder.[5]

Autosomal dominant
Main article: Autosomal dominant#Autosomal dominant gene

Only one mutated copy of the gene will be necessary for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent.[6] The chance a child will inherit the mutated gene is 50%. Autosomal dominant conditions sometimes have reduced penetrance, which means although only one mutated copy is needed, not all individuals who inherit that mutation go on to develop the disease. Examples of this type of disorder are Huntington's disease,[7] neurofibromatosis type 1, neurofibromatosis type 2, Marfan syndrome, hereditary nonpolyposis colorectal cancer, and hereditary multiple exostoses, which is a highly penetrant autosomal dominant disorder. Birth defects are also called congenital anomalies.

Autosomal recessive
Main article: Autosomal dominant#Autosomal recessive allele

Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Two unaffected people who each carry one copy of the mutated gene have a 25% chance with each pregnancy of having a child affected by the disorder. Examples of this type of disorder are cystic fibrosis, sickle-cell disease, Tay-Sachs disease, Niemann-Pick disease, spinal muscular atrophy, and Roberts syndrome. Certain other phenotypes, such as wet versus dry earwax, are also determined in an autosomal recessive fashion.[8][9]

X-linked dominant
Main article: X-linked dominant

X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern, with a prime example being X-linked hypophosphatemic rickets. Males and females are both affected in these disorders, with males typically being more severely affected than females. Some X-linked dominant conditions, such as Rett syndrome, incontinentia pigmenti type 2 and Aicardi syndrome, are usually fatal in males either in utero or shortly after birth, and are therefore predominantly seen in females. Exceptions to this finding are extremely rare cases in which boys with Klinefelter syndrome (47,XXY) also inherit an Xlinked dominant condition and exhibit symptoms more similar to those of a female in terms of disease severity. The chance of passing on an X-linked dominant disorder differs between men and women. The sons of a man with an X-linked dominant disorder will all be unaffected (since they receive their father's Y chromosome), and his daughters will all inherit the condition. A woman with an X-linked dominant disorder has a 50% chance of having an affected fetus with each pregnancy, although it should be noted that in cases such as incontinentia pigmenti, only female offspring are generally viable. In addition, although these conditions do not alter fertility per se, individuals with Rett syndrome or Aicardi syndrome rarely reproduce.[citation needed]

X-linked recessive
Main article: X-linked recessive

X-linked recessive conditions are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. A woman who is a carrier of an X-linked recessive disorder (XRXr) has a 50% chance of having sons who are affected and a 50% chance of having daughters who carry one copy of the mutated gene and are therefore carriers. X-linked recessive conditions include the serious diseases hemophilia A, Duchenne muscular dystrophy, and Lesch-Nyhan syndrome, as well as common and less serious conditions such as male pattern baldness and red-green color blindness. X-linked recessive conditions can sometimes manifest in females due to skewed X-inactivation or monosomy X (Turner syndrome).

Y-linked
Main article: Y linkage

Y-linked disorders are caused by mutations on the Y chromosome. Because males inherit a Y chromosome from their fathers, every son of an affected father will be affected. Because females only inherit an X chromosome from their fathers, and never a Y chromosome, female offspring of affected fathers are never affected. Since the Y chromosome is relatively small and contains very few genes, relatively few Y-linked disorders occur.[citation needed] Often, the symptoms include infertility, which may be circumvented with the help of some fertility treatments. Examples are male infertility.[citation needed]

Mitochondrial

Main article: Mitochondrial disease

This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Because only egg cells contribute mitochondria to the developing embryo, only mothers can pass on mitochondrial conditions to their children. An example of this type of disorder is Leber's hereditary optic neuropathy.

Multifactorial and polygenic (complex) disorders


Genetic disorders may also be complex, multifactorial, or polygenic, meaning they are likely associated with the effects of multiple genes in combination with lifestyles and environmental factors. Multifactorial disorders include heart disease and diabetes. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a persons risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. On a pedigree, polygenic diseases do tend to "run in families", but the inheritance does not fit simple patterns as with Mendelian diseases. But this does not mean that the genes cannot eventually be located and studied. There is also a strong environmental component to many of them (e.g., blood pressure). n allele (UK /lil/ or US /lil/) is one of two or more forms of a gene or a genetic locus (generally a group of genes).[1][2] The form "allel" is also used, an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation. However, many variations at the genetic level result in little or no observable variation. Most multicellular organisms have two sets of chromosomes, that is, they are diploid. These chromosomes are referred to as homologous chromosomes. Diploid organisms have one copy of each gene (and therefore one allele) on each chromosome. If both alleles are the same, they are homozygotes. If the alleles are different, they are heterozygotes. A population or species of organisms typically includes multiple alleles at each locus among various individuals. Allelic variation at a locus is measurable as the number of alleles (polymorphism) present, or the proportion of heterozygotes in the population. For example, at the gene locus for the ABO blood type carbohydrate antigens in humans,[3] classical genetics recognizes three alleles, IA, IB, and IO, that determine compatibility of blood transfusions. Any individual has one of six possible genotypes (AA, AO, BB, BO, AB, and OO) that produce one of four possible phenotypes: "A" (produced by AA homozygous and AO heterozygous genotypes), "B" (produced by BB homozygous and BO heterozygous genotypes), "AB" heterozygotes, and "O" homozygotes. It is now known that each of the A, B, and O alleles is actually a class of multiple alleles with different DNA sequences that produce proteins with identical properties: more than 70 alleles are known at the ABO locus.[4] An individual with

"Type A" blood may be an AO heterozygote, an AA homozygote, or an A'A heterozygote with two different 'A' alleles. The word "allele" is a short form of allelomorph ('other form'), which was used in the early days of genetics to describe variant forms of a gene detected as different phenotypes. It derives from the Greek root , and alius (Latin) meaning "other"; then the word , allelos, meaning "each other". Neurofibromin 1 also known as neurofibromatosis-related protein NF-1 is a protein that in humans is encoded by the NF1 gene.[2] Mutations in the NF1 gene are associated with neurofibromatosis type I (also known as neurofibromatosis, von Recklinghausen disease, and Watson disease).[3]

Contents

1 Function 2 Clinical significance 3 RNA editing o 3.1 Type o 3.2 Location 3.2.1 Regulation 3.2.2 Conservation o 3.3 Consequences 3.3.1 Structure 3.3.2 Function 3.3.2.1 Neurofibromitosis 4 Model organisms 5 Patent 6 See also 7 References 8 Further reading 9 External links

Function
NF1 encodes the protein neurofibromin, which appears to be a negative regulator of the ras signal transduction pathway. NF1 is found within the mammalian postsynapse, where it is known to bind to the NMDA receptor complex. It has been found to lead to deficits in learning, and it is suspected that this is a result of its regulation of the Ras pathway. It is known to regulate the GTPase HRAS, causing the hydrolyzation of GTP and thereby inactivating it.[4] Within the synapse HRAS is known to activate Src, which itself phosphorylates GRIN2A, leading to its inclusion in the synaptic membrane.

NF1 is also known to interact with CASK through syndecan, a protein which is involved in the KIF17/ABPA1/CASK/LIN7A complex, which is involved in trafficking GRIN2B to the synapse. This suggests that NF1 has a role in the transportation of the NMDA receptor subunits to the synapse and its membrane. NF1 is also believed to be involved in the synaptic ATP-PKA-cAMP pathway, through modulation of adenylyl cyclase. It is also known to bind the caveolin 1, a protein which regualtes p21ras, PKC and growth response factors.[4]

Clinical significance
Mutations linked to neurofibromatosis type 1 led to the identification of the NF1 gene. The neurofibromin gene may be mutated in thousands of ways, resulting in many possible clinical outcomes.[5] In addition to neurofibromatosis type I, mutations in NF1 can also lead to juvenile myelomonocytic leukemia, Watson syndrome,[6] and breast cancer.[7] Types of mutations include frameshift, nonsense, missense, splicing alteration and deletion mutations, and loss of heterozygosity.[8][9][10][11] c Schwann cells (named after physiologist Theodor Schwann) or neurolemmocytes are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle. There are two types of Schwann cell, myelinating and nonmyelinating. Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. Schwann cells are involved in many important aspects of peripheral nerve biologythe conduction of nervous impulses along axons, nerve development and regeneration, trophic support for neurons, production of the nerve extracellular matrix, modulation of neuromuscular synaptic activity, and presentation of antigens to T-lymphocytes. Charcot-Marie-Tooth disease (CMT), Guillain-Barr syndrome (GBS), schwannomatosis and chronic inflammatory demyelinating polyneuropathy (CIDP) are all neuropathies involving Schwann cells.

Contents

1 Description 2 Schwann cell lineage 3 Immunoreactivity 4 See also 5 References 6 External links

Description

A Schwann cell in culture. Named after the German physiologist Theodor Schwann, Schwann cells are a variety of glial cell that keep peripheral nerve fibres (both myelinated and unmyelinated) alive. In myelinated axons, Schwann cells form the myelin sheath (see above). The sheath is not continuous. Individual myelinating Schwann cells cover about 100 micrometres of an axonequating to approximately 10,000 Schwann cells along a 1 metre length of the axonwhich can be up to a metre or more in length. The gaps between adjacent Schwann cells are called nodes of Ranvier (see above). The vertebrate nervous system relies on the myelin sheath for insulation and as a method of decreasing membrane capacitance in the axon. The action potential jumps from node to node, in a process called saltatory conduction, which can increase conduction velocity up to ten times, without an increase in axonal diameter. In this sense, Schwann cells are the peripheral nervous system's analogues of the central nervous system's oligodendrocytes. However, unlike oligodendrocytes, each myelinating Schwann cell provides insulation to only one axon (see image). This arrangement permits saltatory conduction of action potentials with repropagation at the nodes of Ranvier. In this way, myelination greatly increases speed of conduction and saves energy.[1] Non-myelinating Schwann cells are involved in maintenance of axons and are crucial for neuronal survival. Some group around smaller axons (External image here) and form Remak bundles.[2]

Myelinating Schwann cells begin to form the myelin sheath in mammals during fetal development and work by spiraling around the axon, sometimes with as many as 100 revolutions. A well-developed Schwann cell is shaped like a rolled-up sheet of paper, with layers of myelin in between each coil. The inner layers of the wrapping, which are predominantly membrane material, form the myelin sheath while the outermost layer of nucleated cytoplasm forms the neurolemma. Only a small volume of residual cytoplasm communicates the inner from the outer layers. This is seen histologically as the Schmidt-Lantermann incisure. A number of experimental studies since 2001 have implanted Schwann cells in an attempt to induce remyelination in multiple sclerosis-afflicted patients.[3] In the past two decades, many studies have demonstrated positive results and potential for Schwann cell transplantation as a therapy for spinal cord injury, both in aiding regrowth and myelination of damaged CNS axons.[4] Indeed, Schwann cells are known for their roles in supporting nerve regeneration.[5] Nerves in the PNS consist of many axons myelinated by Schwann cells. If damage occurs to a nerve, the Schwann cells will aid in digestion of its axons (phagocytosis). Following this process, the Schwann cells can guide regeneration by forming a type of tunnel that leads toward the target neurons. The stump of the damaged axon is able to sprout, and those sprouts that grow through the Schwann-cell tunnel do so at the rate of approximately 1mm/day in good conditions. The rate of regeneration decreases with time. Successful axons can therefore reconnect with the muscles or organs they previously controlled with the help of Schwann cells, however, specificity is not maintained and errors are frequent, especially when long distances are involved.[6] If Schwann cells are prevented from associating with axons, the axons die. Regenerating axons will not reach any target unless Schwann cells are there to support them and guide them. They have been shown to be in advance of the growth cones. Schwann cells are essential for the maintenance of healthy axons. They produce a variety of factors, including neurotrophins, and also transfer essential molecules across to axons.

Schwann cell lineage


Schwann cells are of neural crest origin. During mouse embryonic development, neural crest cells first differentiate into Schwann cell precursors (SCPs) at around embryonic day (E) 1213. These precursor cells subsequently differentiate into immature Schwann cells at approximately E1516, persisting until birth. The postnatal fate of the immature Schwann cell depends on its random association with axons. In a process called radial sorting, whereby Schwann cells segregate axons by extending processes into axon bundles, the Schwann cells that happen to associate with a large diameter axon (>1 m) will develop into myelinating Schwann cells. Small diameter axons become entrenched in the invaginations of non-myelinating Schwann cells, also called Remak bundles. A key regulator of this process is the axonally-derived signal Neuregulin1, which binds to cell surface receptors on the Schwann cell and promotes myelination of large diameter axons and sorting of small diameter axons in Remak bundles, dependent on the activity of the -secretase BACE1 ([7][8][9][10][11]). A further class of non-myelinating Schwann cell, the terminal (or perisynaptic) Schwann cell, exists at the neuromuscular junction, in close proximity to the neuron-muscle synapse. The transition from immature Schwann cell to myelinating/nonmyelinating Schwann cell is reversible. When the nerve is injured, Schwann cells can dedifferentiate to form a cell type resembling the immature Schwann cell, often referred to as a

denervated or dedifferentiated Schwann cell. This allows them to re-enter the cell cycle in order to proliferate and aid nerve regeneration.[12]

Immunoreactivity
The different classes of Schwann cells express characteristic antigenic markers that can be targeted with antibodies. Myelinating Schwann cells can be visualised by immunohistochemistry using antibodies against the proteins S-100, Myelin protein zero (P-Zero) and Myelin basic protein (MBP). Non-myelinating Schwann cells such as those that form Remak bundles and terminal Schwann cells are positive for S-100 and Glial fibrillary acidic protein (GFAP). Neural crest cells are a transient, multipotent, migratory cell population unique to vertebrates that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia.[1] After gastrulation, neural crest cells are specified at the border of the neural plate and the nonneural ectoderm. During neurulation, the borders of the neural plate, also known as the neural folds, converge at the dorsal midline to form the neural tube. Subsequently, neural crest cells from the roof plate of the neural tube undergo an epithelial to mesenchymal transition, delaminating from the neuroepithelium and migrating through the periphery where they differentiate into varied cell types.[1] The emergence of neural crest was important in vertebrate evolution because many of its structural derivatives are defining features of the vertebrate clade.[2] Underlying the development of neural crest is a gene regulatory network, described as a set of interacting signals, transcription factors, and downstream effector genes that confer cell characteristics such as multipotency and migratory capabilities.[3] Understanding the molecular mechanisms of neural crest formation is important for our knowledge of human disease because of its contributions to multiple cell lineages. Abnormalities in neural crest development cause neurocristopathies, which include conditions such as frontonasal dysplasia, Waardenburg-Shah syndrome, and DiGeorge syndrome.[1] Glial cells, sometimes called neuroglia or simply glia (Greek , "glue"; pronounced in English as either /li/ or /la/), are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomic nervous system.[1] As the Greek name implies, glia are commonly known as the glue of the nervous system; however, this is not fully accurate. Neuroscience currently identifies four main functions of glial cells: to surround neurons and hold them in place, to supply nutrients and oxygen to neurons, to insulate one neuron from another, and to destroy pathogens and remove dead neurons. For over a century, it was believed that they did not play any role in neurotransmission. That idea is now discredited;[2] they do modulate neurotransmission, although the mechanisms are not yet well understood.[2][3][4]

Neurulation is the stage of organogenesis in vertebrate embryos, during which the neural tube is transformed into the primitive structures that will later develop into the central nervous system.[1] The process begins when the notochord induces the formation of the central nervous system (CNS) by signaling the ectoderm germ layer above it to form the thick and flat neural plate. The neural plate folds in upon itself to form the neural tube, which will later differentiate into the spinal cord and the brain, eventually forming the central nervous system.[citation needed] Different portions of the neural tube formed by two different processes, called primary and secondary neurulation, in different species.[citation needed]

In primary neurulation, the neural plate creases inward until the edges come in contact and fuse. In secondary neurulation, the tube forms by hollowing out of the interior of a solid precursor.

In the developing vertebrate, the neural tube is the embryo's precursor to the central nervous system, which comprises the brain and spinal cord. The neural groove gradually deepens as the neural folds become elevated, and ultimately the folds meet and coalesce in the middle line and convert the groove into a closed tube, the neural tube or neural canal (which strictly speaking is the center of the neural tube), the ectodermal wall of which forms the rudiment of the nervous system.

Development
There are 2 ways in which the neural tube develops: Primary neurulation and Secondary neurulation.
1. Primary neurulation divides the ectoderm into three cell types, the neural tube, which is internally located, the epidermis, which is externally located, and the neural crest cells, which develop in the region between the neural tube and epidermis but then migrate to new locations. Primary neurulation begins after the neural plate has formed. The edges of the neural plate start to thicken and lift upward forming the neural folds. The center of the neural plate remains grounded allowing a U-shaped neural groove to form. This neural groove sets the boundary between the right and left sides of the embryo. The neural folds pinch in towards the midline of the embryo and fuse together to form the neural tube.[1] 2. In secondary neurulation, the cells of the neural plate form a cord-like structure that migrates inside the embryo and hollows to form the tube.

Each organism uses primary and secondary neurulation to varying degrees.


Neurulation in fish proceeds only via the secondary form. In avian species the posterior regions of the tube develop using secondary neurulation and the anterior regions develop by primary neurulation.

In mammals, a similar pattern is observed where secondary neurulation begins around the 35th somite.

The manner in which the neural tube closes in mammals in the head is inverted in respect to the manner of closure in the trunk:

In the head:

1. Neural crest cells migrate 2. Neural tube closes 3. Overlying ectoderm closes

In the trunk:

1. Overlying ectoderm closes 2. Neural tube closes 3. Neural crest cells migrate

Structure
There are four subdivisions of the neural tube that will each eventually develop into distinct regions of the central nervous system by the division of neuroepithelial cells: The prosencephalon, the mesencephalon, the rhombencephalon and the spinal cord.

The prosencephalon further goes on to develop into the telencephalon (the forebrain or cerebrum) and the diencephalon (the optic vesicles and hypothalamus). The mesencephalon develops into the midbrain. The rhombencephalon develops into the metencephalon (the pons and cerebellum) and the myelencephalon (the medulla oblongata).

For a short time, the neural tube is open both cranially and caudally. These openings, called neuropores, close during the fourth week in the human. Improper closure of the neuropores can result in neural tube defects such as anencephaly or spina bifida. The dorsal part of the neural tube contains the alar plate, which is primarily associated with sensation. The ventral part of the neural tube contains the basal plate, which is primarily associated with motor (i.e., muscle) control.

Dorsal-ventral patterning