This fact sheet was provided by Jim Partington, courtesy of M.D.A. of New South Wales Australia. All the fact sheets are in the process of being updated by Prof. Graeme Morgan Medical Director of M.D.A. New South Wales and head of the muscle diseases clinic at the Prince of Wales Hospital in Sydney. FACT SHEET PERIPHERAL NEUROPATHIES (INCLUDING CHARCOT-MARIE-TOOTH DISEASE) What are Peripheral Neuropathies? Peripheral neuropathies are one category of neuromuscular diseases. Neuromuscular diseases affect muscle function because of something wrong in the pathway from the spinal cord to the muscle fibres, which is the final stage for messages from the brain to the muscles. Messages from the brain cells are transferred to cells in the spinal cord called anterior horn cells. The messages then pass along nerve fibres, which make up the peripheral nerves, finally reaching the muscles at the myoneural junctions (muscle nerve junctions). Neuromuscular diseases can arise at the anterior horn cells, in the peripheral nerves, at the myoneural junctions or in the muscle fibres. In peripheral neuropathies, the trouble is in the peripheral nerves. What causes peripheral neuropathies? The list of causes is enormous. Many peripheral neuropathies are hereditary, that is genetically determined. The hereditary peripheral neuropathies are the only ones to be dealt with in detail in this Fact Sheet. There are dozens of non-hereditary causes, including poisons such as alcohol, some drugs which are used in treatment, diabetes mellitus and other diseases. What is Charcot-Marie-Tooth Disease? The term, Charcot-Marie-Tooth disease covers a number of hereditary peripheral neuropathies. When first used it was thought to refer to one disease. Since then it has become evident it is not just one disease. The process of distinguishing these diseases from one another is still incomplete and, as knowledge continues to be gained, there will be additional categories of peripheral neuropathy which can not yet be distinguished from one another. How are different hereditary neuropathies distinguished from one another? They may be distinguished because of different effects on people, different appearances on nerve biopsy or different results on testing electrically the ability of nerves to conduct impulses. They may also be shown to be genetically different. Disease in two families, which seems to be otherwise identical, must be of different cause if the family trees show that the modes of inheritance are different. With the modern techniques of DNA testing, genetic differences may be demonstrated even when the modes of inheritance appear to be identical. The defective gene in two families, although apparently inherited in the same way, may be shown to be different genes on different chromosomes. Why is the term Charcot-Marie-Tooth Disease still used? The term describes a group of patients who have a lot more similarities than dissimilarities. It doesn't mean one disease process of a single cause, however if its limitations are understood it is still a useful term. Are there other names for different types of peripheral neuropathy? There are other old names and there are modern names. In the 19th Century when Charcot, Marie and Tooth were reporting their finding, other scientists were observing peripheral neuropathies and giving them different names. One such name is Roussy-Levy syndrome which is now thought to be of little or no value in categorising diseases. The modern classification put hereditary peripheral neuropathies into two main groups: Hereditary Sensory & Autonomic Neuropathy (HSAN) Hereditary Motor and Sensory Neuropathy (HMSN) Each of these is divided into sub-types, e.g. HMSN type 1 to HMSN type 7. What do motor, sensory and autonomic mean? These words refer to functions controlled in part by the peripheral nerves. Motor functions are the voluntary movements of our muscles. Sensory functions are those whereby we can feel touch, heat, cold and pain. The term special sensory functions is applied to seeing and hearing. Autonomic functions are those which we can not ordinarily control, such as blood pressure, heart rate, sweating and pallor or flushing of the skin. In peripheral neuropathies, the most notable disturbances of autonomic function are those seen in the skin, which is likely to be cold and pale in the affected parts. Do the two main categories cover all hereditary peripheral neuropathies? Not all peripheral neuropathies fit into the main categories. Peripheral neuropathy may be a relatively minor part of a more generalised disease process, which may be hereditary. An example is Friedreich's ataxia, of which the main effects are severe incoordination and heart disease. There is also peripheral neuropathy but the patient is usually not aware of it. What are typical effects of peripheral neuropathies? The most severe effects are at the furthest distances from the spinal cord. The hands and forearms are therefore affected more than the upper arms and shoulders and the feet and ankles more than the thighs and hips. Parts at the ends of limbs are called distal, those near the trunk are called proximal, so peripheral neuropathies affect distal structures and functions more than proximal ones. How do peripheral neuropathies affect motor functions? In the lower limbs, weakness of ankle movements often causes foot drop, so that the affected person may have to adopt a high stepping walk in order that his toes will clear the ground. Also, weakness of muscles between the knee and the ankle, and of muscles below the ankle, often leads to imbalance of muscle power. Persistent imbalance leads in turn to deformity, determined by the action of the stronger muscle. In the foot, the common deformity is an exceptionally high arch, called pes cavus (pronounced payz carvus). This is sometimes accompanied by in-turning of the foot, so that the soles turn towards each other (foot inversion or varus deformity). In the upper limbs there is weakness of grip and of wrist movements and sometime a characteristic appearance of the hand due to muscle imbalance. Is distal involvement more serious than proximal? Generally, proximal weakness is more serious. The big, proximal muscles are the ones that we use to stand and walk. Some people with no muscle function at all below the knees can still stand and walk. Disease of comparable severity is often less gravely disabling, therefore, if it is distal than if it is proximal. On the other hand, peripheral disease is disabling so far as employment, requiring strength or fine control of the hands, is concerned. Are the proximal muscles ever involved? Proximal muscles are often slightly involved, to an extent which doesn't cause significant disability. In a small proportion of cases, they are severely involved. In those cases, the affected person may have to use a wheelchair, but that is very unusual. How is sensation affected? Sensation is not always affected in peripheral neuropathy. When it is, it may not be noticed by the affected person, although detectable on medical examination. Sometimes, though, the affected person is aware of impaired ability to appreciate touch or pain, or to distinguish degrees of warmth and coldness, especially towards the tips of the fingers or toes. When peripheral neuropathy affects sensation predominantly and severely, which is rare, the affected person is very aware that sensation is lost. The fingers and toes may then be severely injured or burnt, the tips of the fingers may be lost. In examining sensory function, the physician tests the ability to feel light touch, to distinguish warmth from cold, to distinguish the touch of pin from that of a blunt object, to recognise the vibration of a tuning fork and to distinguish, with the eyes closed, the direction in which a joint is being moved. Typically, the physician may find some or all of these functions impaired up to about ankle level or somewhere between knee and ankle, and to a corresponding level in the upper limbs. Sensory impairment is often accompanied by autonomic disturbance, as described earlier. What else may a doctor find on examination? Relatively rare findings include disturbance of the autonomic control of the pupil of the eye, or of the bowel. One relatively common finding, which is diagnostically very useful is thickening of the nerves so they may be felt under the skin. The presence of nerve thickening confirms the diagnosis of peripheral neuropathy beyond doubt. It occurs in only some types of neuropathy. How is a diagnosis of peripheral neuropathy confirmed? Usually the first test is a measure of the speed of conduction of impulses in the nerves. A nerve is stimulated electrically, some distance from the muscle which it suppliers, the time lapse between stimulation and muscle contraction is measured and from that is calculated the nerve conduction velocity, in metres per second. Measurements are also made of the time lapse when the stimulus is applied more distally, closer to the muscle, and this is called terminal latency. Similar measurements are made of the transmission of impulses in the opposite direction, that is towards the spinal cord, on sensory stimulation of the finger or toe. Usually the results of nerve conduction studies are clearly indicative of peripheral neuropathy, but sometimes results are borderline and difficult to interpret. The next possible investigation is a nerve biopsy, in which a small piece of peripheral nerve is taken for microscopic examination. The nerve usually chosen is the sural nerve, which supplies sensation to a small patch of skin on the side of the foot. After the biopsy the nerve usually repairs itself and sensation returns but, in the meantime, the loss of such a small area of sensation is no inconvenience to the patient. Other lines of investigation may be necessary to identify peripheral neuropathies of particular types or particular causes. Are peripheral neuropathies curable? Some peripheral neuropathies, of non-genetic cause, are curable. Hereditary neuropathies are generally not. None of the neuropathies in the two broad categories mentioned above, that is HSAN and HMSN is curable. Is much research being done? There is a great deal of research being done on peripheral neuropathies. Many lines of research are being followed. Genetic studies have been very actively followed in recent years and the gene localisations have been discovered for some peripheral neuropathies. It seems likely that genetic research will be the main line of research leading to an understanding of the basic causes of peripheral neuropathies, that is to an understanding of their basic defects. It is further very likely that an understanding of those basic defects will be necessary before progress can be made before curing these diseases. How are peripheral neuropathies inherited? There is no single mode of inheritance for the peripheral neuropathies. It may be necessary to investigate several members of a family, in order to discover which mode of inheritance applies in that family. Where only one person is affected in a family, the mode of inheritance may not be ascertained with certainty. In that case, it may be possible to state the probabilities for different modes of inheritance, based on the frequency with which they are seen in the population. The modes of inheritance are autosomal dominant, autosomal recessive and X-linked recessive, in that order, with X-linked dominant inheritance as a possible very rare, additional mode. These modes of inheritance, the way they behave in families and the genetic risks associated with them, are dealt with in the MDAA Fact Sheet entitled "Genetics and Neuromuscular Diseases".