Edited by Gareth Parry, M.D.
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Currently, in 70% of cases, HNPP has only one genotype or gene problem. This is the deletion of a segment of chromosome 17p11.2-12. This segment of the chromosome contains an important myelin gene, peripheral myelin protein-22 gene (PMP22). CMT1A, is genetically a mirror image, containing an extra copy of PMP22 at the same site that HNPP has a deletion. This one gene deletion, which causes HNPP, has different patterns of presentation.
Phenotype variability is basically a way of saying there are different ways that HNPP can look and act. These are the symptoms a doctor may see when a patient comes into the office. It is important for doctors to recognize the many different ways HNPP may manifest itself. Dr. Gareth Parry says, " We have tried to focus on the presenting feature of the disease. The rationale is that they need to be diagnosed correctly when they are first seen so we want people to recognize what the disease can look like when it first appears. Thus, the different phenotypes are those that are present at the time of the initial presentation." Dr Parry went on to explain that, over time, almost all patients go on to develop other features and they can change from one phenotype to another.
So, if phenotypes are a tool for the doctors, then why would we, as patients care about them? Actually for several reasons:
Some reviewers, of the medical literature, say, and with some justification, that a phenotype describes a clinical appearance and if the patients have no symptoms they don't have a clinical appearance. Thus the Oligiosymptomatic group cannot really be a phenotype. In keeping with the new thinking, the Oligiosymptomatic phenotype will be dropped. But a description of this largest group of HNPP carriers will be included after the four remaining phenotypes are discussed. 9/01
With the revised classifications there are currently four major phenotypes: Classic HNPP, Acute Arm Paralysis, Polyneuropathy resembling CMT (CMT) and Confluent Mononeuropathy Multiplex (CMM). In addition, many patients are asymptomatic or have so few symptoms that their disease is not recognized (previously the Oligiosymptomatic phenotype). The first two categories, Classic HNPP and Acute Arm Paralysis are characterized by episodic problems. Polyneuropathy resembling CMT (CMT) and Confluent Mononeuropathy Multiplex (CMM) Phenotypes are characterized by their more persistent and progressive symptoms that are moderate to severe. Both, CMT and CMM phenotypes can have numbness and weakness and other signs of a generalized neuropathy. A very simplified way to distinguish the latter two, is that in the CMT like phenotype symptoms are mostly symmetrical while in CMM they are not symmetrical. Each phenotype will be discussed in more detail below.
An Overview of Pressure Palsies
In order to understand the phenotypes of HNPP, one must first understand what is meant by the term "pressure palsy". When HNPP was first described by DeJong in 1949, it was called "bulb diggers disease". DeJong noted the periods of weakness and numbness (palsies), in bulb diggers, and thought they were caused by the kneeling position and pressure on the peroneal nerve. Thus the term pressure palsy. The spectrum of this disease, has evolved over the past 5 decades, but the concept of pressure palsies has remained. We do know that the pressure, which DeJong described, can and does cause the episodic numbness and weakness. But we also know that the nerves are in general very susceptible to injury and can also be injured by, external pressure, stretch, repetitive use and the build up of small injuries over time (cumulative effect). We also know that a progressive generalized neuropathy is an integral part of the disease, even in those patients who never recall having a pressure palsy episode (Parry).
Pressure palsies are typically described as transient (or intermittent or episodic), painless and often recurring symptoms of numbness (or tingling) and weakness. (Physicians will often use the term sensory and motor to describe the symptoms. Sensory means the sensations the patient feels, such as: tingling, numbness, or pain. And motor refers to strength or weakness). These episodes can be as brief as a few minutes, but can also last several days or even several months. Numbness may be as mild as the individual noticing that an area or limb does not have quite the same feeling as surrounding areas on the other side, or so severe as to feel like the area or limb has been shot full of Novocaine. Weakness also can vary between slight and barely there to so severe that the individual is unable to move a particular muscle group or the entire limb.
The most common problem sites are the wrists with carpal tunnel syndrome; the elbows with cubital tunnel syndrome; and the knees with peroneal nerve injuries. But any peripheral nerve - outside the brain and spinal cord- can be affected. It would be rare to see problems with nerves in the trunk, but fingers, elbows, scalp, shoulders, toes and feet are also frequent trouble spots.
Progression of HNPP
As mentioned above, over time, individuals can change for one phenotype to another. This typically involves changing from a milder or episodic form to a more permanent and generalized neuropathy phenotype, such as CMT or CMM. Although people who carry the HNPP gene deletion may have no symptoms initially, as time goes by, and as people are evaluated more carefully, it has become clear that mildly affected individuals often have symptoms attributed to other common disorders such as Carpal Tunnel Syndrome or lumbar disc disease. Some researchers believe that eventually (and this may take a lifetime), all individuals will show signs of a generalized neuropathy. Generalized neuropathy usually means more widespread symptoms of permanent numbness and weakness. The numbness is often a "stocking and glove" distribution and the weakness can cause foot drop and hand weakness. And it may not be until the general neuropathy has developed that the person first sees a physician.
For some the HNPP symptoms progress to a generalized neuropathy very slowly. For others the progression is quite rapid. Some are younger, others are older when this happens. Medical science does not yet understand why there is such a wide variance in symptoms, speed of development or age of onset.
There also appears to be a cumulative component to HNPP symptoms and activity. We tend to think of each nerve as one single nerve. In fact, there are many nerve fibers making up the one nerve. Some people report being able to do an activity one day without any problems. But have increasing symptoms if they continue to do the same activity many days in a row. When people experience increasing problem such as this, they are thought to be damaging more and more of the nerve fibers. Although nerve fibers are probably damaged on the first day of the activity, there are enough fibers still functioning to compensate for the damaged ones. As the activity continues, more and more fibers are damaged and the symptoms become more apparent as the nerves are unable to continue to compensate for the injury. This cumulative component of HNPP can make pacing activities extremely difficult for individuals with frequent HNPP symptoms.
Because HNPP is primarily a demyelinating neuropathy, recovery from palsy episodes is usually complete at first with numbness and weakness going away entirely as the nerves remyelinate. So, at first, the nerves are damaged and eventually heal completely. Over time, with repeated injury, the nerves are damaged and only partially heal. And with further injury, the damaged nerves again only partially heal. So the progression of the disease is typically seen as a very slow step down pattern, with times of no progression, followed by progression. For some individuals, there may be years between pressure palsy episodes. Others have mild problems for years and then begin to progress at a more rapid rate. In rare instances, some individuals develop their first symptoms and remain on a fairly steady downward course.
Classic HNPP Phenotype of HNPP
Both of the above are examples of the Classic phenotype of HNPP. Classic HNPP was the first identified phenotype of HNPP and, as it's name suggests, is the most common form of HNPP. Essentially, describe pressure palsies (PP) and you have described the Classic phenotype- painless, recurring episodes of numbness, tingling and/or weakness in an arm or leg.
While pressure palsies, in general, are described as ranging from mild to severe, the pressure palsies of the Classic phenotype typically are the severe ones. They are severe in both duration and symptoms. This group may have some mild PP in addition to their severe ones. But it is the severe episodes that get their attention and send them off in search of medical help. And quickly. A few may try to wait a day or two and self treat, but these episodes are not going away that fast and can be quite alarming at first.
A pressure palsy in the hand can result in not being able to: make a fist; hold a pen, much less write; hold a bar of soap; dress, or any number of fine motor activities. Shoulder involvement may make an arm almost totally useless. Or maybe one has some use of their hand, but can't do any movements without the elbow tucked firmly at one's side -thus ruling out activities like, eating, dressing, reaching etc. A leg palsy can cause foot drop (unable to bring toes up while walking so foot clears floor) and/or leg weakness make walking, driving or climbing stair nearly or completely impossible. Dragging a leg during a palsy is not uncommon.
These Classic Pressure Palsies are the ones which may many last days, weeks or months. Six weeks to three months is a pretty common duration, of a "long" pressure palsy, but 6-12 months is not unheard of either; the longer lasting episodes tend to recover incompletely. These episodes are often recurring, though not always in the same limb. The numbness and weakness may gradually go away or it may remain severe for quite some time and then rapidly get better. And sometimes the numbness and weakness may only partially improve, meaning there is permanent nerve damage. There is no way to tell at the beginning of a pressure palsy whether there will be noticeable permanent damage or not. With a pressure palsy, it really is "only time will tell". The amount of time the nerve is compressed seems to play a role in the severity of symptoms.
Over a life time, the number of pressure palsies this group might experience ranges for only one or two to too many to remember. Many times cause the of these episodes can be identified. And the cause is usually something that puts pressure on or stretches the nerve and would not affect a normal person. Many individuals wake up to find an arm or leg weak and numb simply from sleeping in a wrong position. Examples of activities that cause symptoms of numbness, tingling and weakness are:
Acute Brachial ( Arm) Paralysis or Brachial Plexopathy Phenotype of HNPP
The two cases mentioned above are examples of the Acute Arm Paralysis Phenotype or brachial plexopathy or brachial plexus neuropathy. The brachial (arm) plexus (network of nerves) is a network of nerves running between the neck and the shoulder/arm pit. In this area, the nerves from the cervical spine come close togther before branching out to supply the muscles and skin of the shoulder, arm, elbow, wrist, and hand (A good picture of the brachial plexus can be found at http://www.tos-syndrome.com/newpage2.htm ).
The examples sound exactly like the Classic phenotype pressure palsies- painless, episodes of numbness and weakness. And they are, with two exceptions: This phenotype involves only the brachial plexus, while the classic phenotype involves many different areas (brachial plexus, shoulders, elbows, wrists, legs, etc.). In addition, it is unusual for these episodes to recur, while in Classic HNPP they frequently recur.
This may seem like splitting hairs, but remember the phenotyping is a way for doctors to recognize the different ways they may see this disease when the patient comes into the office. Acute brachial paralysis occurs with enough frequency to warrant it's own phenotype.
In Classic HNPP, one may have one or several episodes of acute arm paralysis, but these would be in addition to pressure palsies at other sites. Like Classic HNPP, the cause of acute arm paralysis may be some minor trauma, as well as more substantial trauma like getting pinned in a wrestling meet! Activities that involve repetitive or sustained overhead use of the arm, sleeping with arms over head, forward reaching, or excessive weight on the shoulder can cause symptoms. Episodes can also occur spontaneously. Although there may be some numbness and weakness, there is no pain. And recovery occurs over several weeks and is usually complete or nearly complete.
In Acute Brachial Paralysis, any or all of the arm muscles may be suddenly involved in varying degrees of weakness, from slight to completely paralysed (and unable to be moved by the individual). Symptoms can be variable depending or the part of the plexus that is compressed. The injury may involve only the shoulder area, only the upper arm or the entire arm and hand. The more areas involved, the longer it will take to heal. In addition to the weakness, there may be a lack of muscle control in the shoulder area, upper arm, wrist and hand, and lack of feeling or sensation in the arm or hand.
If the entire arm and hand is involved, the arm may be almost totally useless until some healing takes place. If the arm is very weak, but still moveable, a frequent scenario is the ability to do light activities with the hand as long as the elbow is supported. But activities which involve reaching or lifting the arm, to eat, or over the head, for instance to shampoo hair are impossible to do.
Polyneuropathy Resembling CMT Phenotype of HNPP (CMT)
Charcot-Marie-Tooth Disease or CMT is also an inherited neuromuscular disorder. In fact, it is considered the most common inherited neurological disorder affecting about 40/100,000 Americans. In CMT, the nerves in the arms and legs slowly degenerate causing symmetrical weakness and muscle wasting. Other symptoms include: absent reflexes, high arched feet (also called pes cavus- a hollow appearance to the sole of the foot) or sometimes flat feet; hammer toes; foot drop with steppage (marching like) gait, and hand weakness.
Polyneuropathy refers to many nerves simultaneously involved. With the nerves of both the arms and legs involved, CMT is certainly a polyneuropathy. The polyneuropathy of CMT is always bilateral (both sides) and largely symmetrical (equal on both sides). CMT symptoms are generally considered to be permanent and slowly progressive. Given the descriptions of both a polyneuropathy and of CMT, one could conclude that when person has neurological problems involving both sides of their body and one side is pretty much as involved as the other side, AND testing or symptoms indicated HNPP, AND there are signs of CMT (hammer toes, high arches, etc.) than the person is considered to have the polyneuropathy resembling CMT phenotype of HNPP. And one would be correct. Partially. The individual may or may not have (or be aware of) the pressure palsies of HNPP. And they may or may not have signs of CMT. Some people never develop the episodes of weakness and numbness, but simply develop progressive weakness and atrophy of the feet and then the hands.
Obviously, there has to be someway to tell the two diseases apart. And there is. Actually, there are four key ways for the physician to distinguish HNPP from the CMT phenotype of HNPP: the history; the EMG; DNA testing; and if needed, a nerve biopsy. During the history' when the physician asks about the problem (when did it start?, how often does it happen?, etc) s/he may ask or the patient may volunteer information about intermittent numbness and /or weakness or of arms or legs going to sleep for more that a few minutes. This is suggestive of pressure palsies. And should be noted, especially if the patient has a generalized neuropathy. Secondly, the EMGs look quite different. In CMT there is widespread conduction slowing. In HNPP, conduction is slowed across common entrapment sites, such as the knee, wrist and elbow (there can be significant slowing across the elbow and normal conduction below the elbow). DNA testing, which is seen as the ultimate way to confirm the diagnosis, will be positive in 70- 80% of individuals with HNPP. If the DNA test is negative, a nerve biopsy may be needed to confirm the HNPP diagnosis. The biopsy would show sausage-like swellings of myelin sheaths called tomacula' in HNPP.
Given the similarities of the two diseases it is no wonder that researchers are recommending that at least one person in each family have the genetic blood test done to confirm the diagnosis. Once the diagnosis is confirmed in one family member, then any other family members who develop symptoms are presumed to have the same disorder. Many Physicians feel it is imperative to correctly diagnose the disease in the family. CMT is usually a more severe disease than HNPP. And treatments, especially surgery, which may be indicated for CMT, may be contraindicated for HNPP.
A word of caution here. As said previously, phenotypes are a way for the physician to recognize what the disease can look like when the patient appears in the office. One can have hammer toes and high arches, but only the transient pressure palsies. In this case they would be classified as the classic phenotype. Here the basic problem is the episodes of numbness and weakness not permanent problems with weakness and muscle wasting.
Confluent Mononeuropathy Multiplex Phenotype of HNPP (CMM)
Mononeuropathy refers to disease of a single nerve. Instead of disease of a single nerve', it may also be called an individual nerve lesion. Carpal Tunnel Syndrome (CTS), involving the median nerve, in one hand would be an example of mononeuropathy. Mononeuropathy Multiplex refers to disease in two or more nerves in separate locations. Carpal Tunnel Syndrome in both hands, though it is more often called bilateral (both sides) Carpal Tunnel Syndrome, would technically be an example of this. Carpal Tunnel Syndrome in one hand and Cubital Tunnel Syndrome, involving the ulnar nerve, in the other arm would also be an example of mononeuropathy multiplex.
Like the Polyneuropathy that resembles the CMT phenotype, patients with confluent mononeuropathy multiplex have permanent symptoms and signs and they tend to be moderately to severely involved. While CMT is symmetrical, CMM is not. CMM is asymmetrical or not equal on both sides. Though both sides may have problems, one side is significantly worse.
It is not unusual for a person to have small injuries to individual nerves which are ignored at the time they develop because the symptoms are so minimal. However, with time- and this may be years, even decades- the effects of these small injuries merge together to form a confluent (means flowing or coming together) pattern of neuropathy, involving two or more nerves, which closely resembles a polyneuropathy. But in other cases, the nerve injuries are more significant and not ignored. They just do not go away and may get progressively worse. While there is a clear cut evidence of injury to individual nerves, there is also an overall pattern of many nerves involved, in a non-symmetrical pattern.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is as an acquired neuropathy which may evolve this way. Since both CIDP and HNPP cause demyelination and both have a confluent mononeuropathy multiplex pattern, they can be confused, particularly if there is no overt family history of neuropathy. The two disorders can be distinguished based on the nerve biopsy. It is very important that these two disorders are not confused since CIDP is treatable. On rare occasions the CMM pattern may develop very rapidly and become very severe, including respiratory failure, and may be misdiagnosed as Guillain-Barre syndrome, another inflammatory disease of nerves.
Confluent Mononeuropathy Multiplex has also been called Progressive mononeuropathy and CIDP like polyneuropathy.
The Oligiosymptomatic Group (formerly Phenotype) of HNPP
All three of the above individuals represent the Oligiosymptomatic Group of HNPP. Oligiosymptomatic means few symptoms. By far, this is the largest group of people with HNPP. It is believed that the majority of people with HNPP (80-90%) are either undiagnosed or incorrectly diagnosed, and those numbers include the Oligiosymptomatic group.
In this phenotype, there is a wide range of symptoms, which are mostly mild and episodic. Though mild and more permanent problems such as a mild carpal tunnel syndrome are also included in this group. Some people deny having any symptoms even though they carry the gene (Researchers studying families frequently discover abnormalities in the EMG's of these people despite having no symptoms). In others, the symptoms may be so mild that they may be ignored.
Currently, individuals with classic pressure palsies, lasting less than 24 hours are classified here. Oligiosymtomatic individuals may notice that an arm or leg stays asleep a bit longer (a few minutes) in some of their family or that it happens a bit more often than other people they know. It may be brushed off as just something unique to their family. They may mention it to a doctor only to be told that every one's arms and legs go to sleep from time to time.
This group many also have a family member or two that develops neurological symptoms that are thought to be something else: back problems; carpal tunnel syndrome; Bell's palsy (a temporary facial paralysis), small stroke, etc. Most of these other neuropathies, just listed, would be considered "acquired" meaning that they developed later in life and are not hereditary. So, making the connection to an inherited disorder would be difficult. For individuals and families with few or no symptoms, they usually discover that they have HNPP when more symptoms develop in themselves or another family member is identified as having HNPP.
There are other symptoms which people with HNPP are reporting (Note: This does NOT mean that everyone with HNPP will develop these symptoms). Many of these are typical symptoms of anyone who has a generalized neuropathy. And for the most part, it is those with more severe symptoms who are reporting them.
As people with HNPP meet on the Internet, they tend to compare other symptoms and problems which they are experiencing. These problems range from headaches to digestion to bladder problems, etc. It is not yet known if these problems are indeed related to HNPP. More medical studies need to be done. This is not to say that discussions should not continue. But all problems that a person with HNPP is experiencing, should be reported to the attending neurologist and to the neurologist involved in any studies in which the person is involved.
Anyone studying HNPP quickly learns that the symptoms of HNPP are almost as varied as the number of individuals with the disease. When and how symptoms begin, where they are located, how they progress, whether there is fatigue, pain or weakness is all over the map. While the majority of those with HNPP do share the symptom of pressure palsies, there is great variance in this symptom alone. Pressure Palsies can last minutes to months to as long as a year. They can involve any and all combinations of entire arms, elbows, wrist, hands, fingers, legs, feet, toes, and scalps. Right side and or left side. They can cause varying degrees of weakness or numbness or both. The list of things that cause the pressure palsies is long. This is truly a fascinating disease!
This article based on conversations with Dr Parry and personal knowledge.
Last updated 3/08, Last reviewed 3/08