Inherited Peripheral Neuropathies
As They Relate to GBS and CIDP

Richard A. Lewis, MD and Karen Krajewski, MS
Department of Neurology, Wayne State University School of Medicine, Detroit, MI

The completion of the Human Genome Project in 2000 brought to public attention the incredible explosion of knowledge of the genetic factors that play a major role in health and disease. This has been of particular interest to clinicians and scientists interested in peripheral nerve disorders. Beginning to emerge is an appreciation of a potential relationship between genetic neuropathies and inflammatory neuropathies, such as GBS and CIDP. In particular, more complete knowledge of the biology of peripheral nerve has important implications to our understanding of both inherited and acquired neuropathies. This review is intended to provide an overview of the inherited peripheral neuropathies, particularly those that fall under the rubric of Charcot-Marie-Tooth Disease (CMT), and point out some of the ways these genetic disorders impact on our understanding of GBS and CIDP.

CMT is the most common inherited neurological disorder, affecting approximately 150,000 Americans or 1 person per 2500 population. CMT is found world- wide in all races and ethnic groups. It was recognized in 1886 by three physicians, Jean-Marie-charcot and his student Pierre Marie in France, and coincidentally in England by Howard Henry tooth. The disorder is characterized by foot deformities due to flexed (hammer) toes and high arches called ''pas cavus'' (Figure), atrophy of the muscles below the knee and frequently of the handshake symptoms tend to be noticeable during childhood or adolescence and gradually progress, but some people are unaware of problems until middle age. Usually the disorder does not shorten life and most people can walk throughout their life, but may need braces, canes or other adaptive aids to ambulate. However, severe forms of the disease can occur.

Bides of Genetics
The inheritance of genetic diseases can be either autosomal dominant, or X-linked, where a mutation of one of the pairs of non-sex chromosomes (there are 22 pairs of chromosomes plus 2 sex chromosomes X and Y) or recessive in which the disease only manifests if both alleles (one of the pairs) have the mutation. It is much more common to have autosomal dominant diseases than recessive. Frequently recessive disorders occur when the parents have a familial connection so that the same mutation is more likely to occur in each parent. The X-linked disorders occur when the mutation is on the X-chromosome. Since women have two X-chromosomes, a recessive disorder may not manifest in females but will affect all men since they have only one X-chromosome.

CMT-1 and CMT-2
Similar to GBS, which is now recognized as being comprised of disorders that primarily affect myelin (Acute Inflammatory Demyelinating Polyneuropathy-AIDP), and disorders that primarily affect the axon (Acute Motor [and Sensory] Axonal Neuropathy-AMAN and AMSAN), CMT has been determined to have an autosomal dominant a Demyelinating form called CMT-1 and an axonal form called CMT-2. Families can usually be determined to have CMT-1 if there is significant slowing of nerve conduction velocities below 35 meters/second in the arms (normal velocities in the arms are over 50 m/sec). Recessive forms, both axonal and demyelinating, are currently categorized as CMT-4. There are also forms of CMT that are due to mutations (an alteration in the DNA structure) of the X-chromosome, classified as CMT-x. Although some women with CMT-X have no symptoms it is not uncommon that mailwomen will have at least minor complaints. This occurs (clinically unaffected people who can pass on a mutation are called ''carriers'') because the abnormal X-chromosome may dominate function and cause symptoms despite having the other normal X-chromosome.

Specific Genetic Disorders Causing CMT
The ability to identify specific genetic mutations has led to the recognition of specific disorders that affect different structures of peripheral nerve. The most common form of CMT is GMT-1A, which is caused by a duplication of DNA In a portion of chromosome 17 that encodes for a myelin protean called Peripheral Myelin Protein-22 or PMP-22. Since this duplication usually is only on one of the alleles, patients with CMT1A have 3 copies of PMP-22 rather than the normal 2 copies. PMP-22 normally only accounts for <1% of the myelin proteins and yet an extra copy of this protean causes nerves to conduct very slowly (usually 25 m/sec) and for axons to die in a length-dependent fashion. Interestingly, the loss of one copy of PMP22, causes a disorder called Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). These patients will develop nerve dysfunction after trivial trauma. The nerve conduction studies in HNPP frequently reveal conduction block (CB) during the episode. CB, occurs when the impulses down the nerve fiber are focally blocked, but the structure of the axon remains intact. This is usually associated with focal damage to myelin, particularly just near the Node of Ranvier, at the paranoiac region.

The Node of Ranvier is the region of axon without myelin and is the region that the nerve action potential (NAP) is generated. The NAP Jumps from one node to the next because the myelin in between nodes prevents the action potential from activating in the internodal region. This ''jumping NAP'' called saltatory conduction is what allows nerves to conduct as fast as they do-it provides a remarkably efficient system of getting messages from our brain to our extremities (and vice versa) in as short a time as possible. CB blocks saltatory conduction and can cause paralysis relatively quickly. CB is the cause of paralyses from certain toxins and is considered a major physiologic cause of nerve dysfunction, in GBS and CIDP, particularly in the early phases. This is why people can become so dramatically weak in a relatively short period of time. Recovery from CB can occur over a few weeks, as may happen in GBS and HNPR. It is interesting to consider that either the addition or the loss of one copy of a manor component of peripheral nerve muslin, PMP-22, can have such profound effects on the structure and function of myelin. The fact that a genetic disorder, such as HNPP and inflammatory disorders such as GBS and CIDP can both cause CB pointed common physiologic mechanisms that apply to both forms of peripheral nerve disease. It is therefore reasonable to expect that research on these genetic disorders may be implications on inflammatory disorders and vice versa.

Another genetic disorder of peripheral nerve myelin is CMT-1B, caused by mutations of Myelin Protein Zero (MPZ or P-O). MPZ is the most abundant peripheral myelin protein accounting for approximately 50% of the proteins but is not seen in central nervous system myelin. It is found in compact myosin (the region in the middle of the internode in which the wraps of myelin are closely apposed) and is thought to act as an adhesion molecule (“the glue of peripheral myelin”). In contrast to GMT-1A, the changes in MPZ are not due to duplications or deletions but usually are caused by ''point mutations'' in which one of the DNA codes is altered changing the structure of the gene and the protein that it forms (there are also point mutations in PMP-22 but these not nearly as frequently as the duplication). It is now recognized that the clinical form of CMT- 1B can be markedly different depending on which piece of DNA and amino acid (the building blocks of proteins) are affected. One concept is that if the MPZ is altered such that its ability to act as an adhesion molecule is affected (weakening the glue) then the symptoms usually begin in infancy or early childhood, and the weakness is very severe to the point that the child may not be able to walk. Nerve conduction slowing is also severe, reduced to less than 10 meters/second, (normal is greater than 50 m/sec), and there is a great deal of axonal loss. If the MPZ mutation does not affect adhesion, the disorder may not manifest until the person is 30 or 40 years old. Although the disorder may progress cause significant problems in subsequent years, prior to the age of 30 these patients are fully active without any signs of the disease. Nerve conduction velocities may not be very slow and some of these patients have been considered to have CMT-2 or a primary axonal disorder. This raises an intriguing issue - how can a mutation of a myelin gene (there is no MPZ in axons) cause primarily loss of axons without significantly affecting the speed of conduction, long considered the major role of myelin in peripheral nerve function? The answer is likely to be that myelin and the Schwann Cell (the cell that makes myelin) must have an affect on the integrity of the axon and that the function of myelin and the Schwann Cell goes well beyond their effect on the speed of conduction. This Schwann Cell-axonal interaction is now the focus of much research and is important not just for the inherited neuropathies but also for GBS and CIDP. In fact there are also important implications for diseases of the central nervous system such as Multiple Sclerosis. It is increasingly apparent that while changes in myelin can cause temporary disability, the major cause of persistent and irreversible deficits in CMX, GBS, CIDP and MS is damage to the axons. If one could prevent axonal degeneration, permanent neurotoxic dysfunction could largely be prevented.

A third genetic disorder of peripheral nerve myelin is CMT-X, caused by point mutations in the gene that encodes the protein Connexin-32. As opposed to MPZ and PMP-22 which are found in compact myelin, Conexin-32 is one of the proteins found primarily in the paranoiac loops of myelin and in Schmidt-Lanterman incisures. The paranoiac region is the region of the nerve fiber just next to the Node of Ranvier, and is not only important for salutatory conduction but is also very important region in the communication of the Schwann cell to the axon. In a somewhat similar way, the Schmidt-Lanterman incisures which spiral within the myelin may also act as a more direct path to send signals from the Schwann Cell to the axon. Connexin-32 proteins come together to form gap junctions which are channels that probably contribute to this more direct communication between the Schwann Cell and the axon. How these gap junctions work and what is actually communicated or transported through these channels is not known. It is thought that one possible effect of mutations in the gene encoding Connexin-32 is by altering the function of these gap junctions. Similar to the adult form of CMT-1b, CMT-X frequently does not cause as much conduction slowing as it does axonal loss. Research on Connexin-32 may help provide an understanding of the role of the palinode in the Schwann cell-axon interaction.

Our knowledge of how these genes and their proteins work and what happens when they are altered comes from research in the laboratory. The ability of scientists to create transgenic animals, with genetic changes that can mimic human diseases, is providing important insights. As an example, a mouse model in which one allele has a deleted MPZ gene and the other allele is normal, called a MPZ ''plus minus'' (+-) mouse, has been found to have significant amounts of inflammation in the nerve roots. The neuropathy in these animals appears to correlate with the integrity of the immune system, and as such, tends to mimic to some extent, CIDP. This raises the question as to whether some genetic mutations may predispose to inflammatory neuropathies, such as CIDP. Whether the inflammation is a reaction to damage that the genetic disorder is causing or whether there is a primary involvement of the immune system is not clear. However, it is possible that by suppressing or changing the immune reaction may be beneficial to some patients with CMT. To this end, there are reports of patients with CMT who have responded to immunosuppressive such as corticosteroids. In addition, there are reports of patients with CMT who have developed GBS or CIDP. Whether CMT actually predisposes to inflammatory neuropathies remains unclear. However, it is clear that the majority of patients with GBS and CIDP do not have CMT and that in general, there is no clear genetic predisposition to these inflammatory disorders.

We are just beginning to identify the genes that cause CMT-Z, the axonal form. Many of these genes appeared relate to the trafficking of substances down the axon from the cell body (neuron). Other causes of CMT 1 and 2 are being discovered and with each new gene identified, another piece of the puzzle of how peripheral nerves work and how disease might cause dysfunction falls into place. With this knowledge new therapeutic strategies can be developed that will benefit patients with both inherited as well as acquired neuropathies.