Neurofibromatosis type 2

Neurofibromatosis Type II (or "MISME Syndrome", for "Multiple Inherited Schwannomas, Meningiomas, and Ependymomas") is an inherited disease. The main manifestation of the disease is the development of symmetric, non-malignant brain tumours in the region of the cranial nerve VIII, which is the auditory nerve that transmits sensory information from the inner ear to the brain. Most people with this condition also experience problems in their eyes. NF II is caused by mutations of a gene which probably influences the form and movement of cells. The principal treatments consist of neurosurgical removal of the tumors and surgical treatment of the eye lesions. more...

There is no therapy for the underlying disorder of cell function caused by the genetic mutation.

Causes

Incidence, Mode of transmission, Epidemiology

NF II is an inheritable disorder with an autosomal dominant mode of transmission. Incidence of the disease is about 1 in 35,000. There is a broad clinical spectrum known, but all patients checked have been found to have the same mutation of a gene on chromosome 22. It is suspected that statistically, one half of cases are inherited, and one half are the result of new, de novo mutations.

Pathogenesis, Molecular Biology and pathophysiological relations

NF II is caused by a defect in the gene that normally gives rise to a product called "Merlin" or "Schwannomin", located on chromosome 22 band q11-13.1. This peptide is thought to have a tumor-suppressive function. The NF II gene is presumed to result in either a failure to synthesize Merlin, or the production of a defective peptide that lacks the normal tumor suppressive effect. The Schwannomin-peptide consists of 595 amino acids. Comparison of Schwannomin with other proteins shows similarities to proteins that connect the cytoskeleton to the cell membrane. Mutations in the Schwannomin-gene are thought to alter the movement and shape of affected cells with loss of contact inhibition.

Pathology

The so called acoustic neuroma of NF II is in fact a Schwannoma of the nervus vestibularis. The wrong term is used despite better knowledge in the whole scientific and medical literature. The vestibular Schwannomas grow slowly at the inner entrance of the internal auditory meatus (meatus acousticus internus). They derive from the nerve sheaths of the upper part of the nervus vestibularis in the region between the central and peripheral myelin (Obersteiner-Redlich-Zone) within the area of the porus acousticus, 1 cm from the brainstem.

Genotype-Phenotype-Correlation

Many patients with NF II were included in studies which were designed to compare disease type and progression with exact determination of the associated mutation. The goal of such comparisons of genotype and phenotype is to determine whether specific mutations cause respective combinations of symptoms. This would be extremely valuable for the prediction of disease progression and planning of therapy even at children age. The results of such studies are the following:

• In most cases the mutation in the NF II gene causes shortened peptides.
• There are no mutational hot-spots.
• Patients with Frameshiftmutation- or Nonsense mutations suffer poor prognosis.
• Patients with Missense mutations have a better prognosis.
• In cases with Mutations in the splice-acceptor-region there is no good correlation to determine.
• Point mutations may have only minor effects.
• Cases are published in which exactly the same mutation is associated with clearly different outcome.

These results suggest, that probably other factors (Environment, other mutations) will determine the clinical outcome.

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