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Degenerative Disorders of Peripheral Nerves
CMT
SMA
Brachial Plexopathy
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First of all degenerative. It means that function that initially seemed to be normal is now failing. More specifically, structures that seemed normal in composition and form seem to lose their architecture and associated with that loss, lose function. This term adds little to the description of most diseases (liver failure, coronary artery disease etc.) which are, in general usage, degenerative. Medically, however, there is an inherent implication in "degeneration" as being self destruction. Degenerative disease is self induced from within the structure itself and not mediated by outside factors. Thus auto immune causes or wear and tear trauma are not usually called degenerative even though there is much that degenerates.
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So degenerative disorders of peripheral nerves describes a state in which nerves just start to lose architecture and form due to some innate maintenance mess up from within the nerves themselves. Remember that "nerves" - the big spaghetti-like structures going from here to there - are not just bundles of neurons. Nerves also contain a mix of cell types that support neuron form and function. Degenerative is generally taken to be a genetic flaw, although, some degenerative diseases are suspected to be from viruses with extremely long latencies (they hide in dormant form for decades). Prions are a weird protein that can infect (be spread) and which mutate the victim's own normal genetic material to make more prions and in the process cause neural destruction (mad cow disease). That these can cross species if very frightening.
So what is a "Peripheral" nerve? It is a nerve that is peripheral. Really, not being cute. Nerves don't just go to arms and legs, some go to heart, to liver, and even to other nerves. Those that go to the periphery have certain characteristics and therefore specificities that, if they fail, set them apart in disease processes.
All that generality aside, the category called degenerative peripheral nerve disease has such a prominent representative that the category name is hardly used. Most commonly the group is called by the name of its most prominent example: Charcot-Marie-Tooth or CMT.
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Hereditary Motor Sensory Neuropathy:
Technically, the CMT subgroup is Hereditary Motor Sensory Neuropathy Type I (HMSN-I). Diagnostics folks like that term because its - uh - longer and harder to say and makes you sound smarter if you can master it. Well, OK, it is more descriptive and precise, too.
The original name (well, approximately, as Drs. Charcot & Marie were French) familial peroneal muscular atrophy describes the appearance when the disorder first manifests. Most often others in the family have something similar, and involves muscles served by the peroneal nerve (crosses behind the knee at the top of the fibula). The larger muscles served by that nerve lift and outwardly divert the foot . Foot drop is what family members notice most. It is a floppy kind of toe walk wherein the ball of the foot hits the floor first, not because it is being thrust downward - as in spasticity - but simply not being lifted enough as the leg swings. It flops down. To clear the dangling foot, steps have to get higher and a bit march like.
As smaller muscles in the foot lose their relative balance to the larger muscles which cross them, the give and take of foot shape begins to alter. The arches get higher. This is a key point. High arches from birth may not mean much, other than a blue print for high arches. But normal arches that become higher always mean something and usually that something is neurologic. This may be so subtle that there are no other findings. In CMT, the process is typically symmetrical, so both feet get higher arches. Single foot high arch suggests other neurologic processes of which there are many candidates.
The posture of the foot begins to drift inward toward the body midline such that it no longer hits the ground flat on the ball area but on the outer edge just behind the small toe. The foot becomes smooth and baby's butt soft at the big toe area which now does no weight bearing and horny hard on the forward outer edge. Broken metatarsals at the outer edge of the foot can and do occur in those die-hards who wish to let nature be. We have seen patients who gave up only after their third fracture with two prior fractures still unhealed. Ouch. That's key. These folks are active and not much slowed down by all this. Given family members with milder variants, who never let doctors touch them, well, why bother? Then the teeth nearly go as falling becomes precipitous and embarrassing. Quote "I fell right in front of a vegetable truck which tossed peppers all over the road.... Imagine how embarrassed I was." And nearly squished.
But note, although the manifestations are most obvious in the feet, there are commonly findings in the hands - although they seldom bother folks. The muscle mass in the thumb web space is skinny. If fact that region may look like a hollow rather than a bulge. Making the "OK" or three ring hand gesture finds a square [] between the index and thumb rather than a circle ( ). There are other subtle things. Muscle nearer the hands or feet is involved more than that near hips and shoulders. Sometimes odd excessive sweat occurs and there may be circulation oddities with ruddy coloration and blanching.
CMT is nearly half of the peripheral neuropathies, CMT running at about 1 case per 250,000 people. It is a dominant gene trait, but more than one gene is implicated in CMT. The larger myelinated (fat insulated) nerves are the most involved. They lose then regain the myelin and get a curious build up of those buddy cells layers which actually do the insulation (cell insulation does not come from the nerve cell itself but buddy cells whose job is to supply insulating myelin by wrapping around the nerve cells). The nerves thicken with repeated bouts of degeneration and repair. Measurement of the rate at which electrical impulses travel over nerve will nearly clinch the diagnosis because of both the degree of slowing and the distribution of what nerves are more involved.
There is a variant associated with a specific red blood cell peculiarity, another with cerebellum involvement and ataxia (wobbly balance disorder) and very high arches and more exaggerated foot deformity, and even tremor. One odd variant has cardiac abnormality as an additional feature - which is why EKG (cardiogram) exam is important in this category.
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The Type III subgroup of peripheral degenerative neuropathies called Dejerine-Sottas Disease or Hypertrophic Interstitial Neuropathy of Infancy is, as a category, in limbo. It is different enough to have grabbed its own name but is so much like CMT to wonder if it just ought to be called CMT plus some adjective. The key features are rapidity of progression with onset at or nearly at birth whereas CMT is slow to incomplete in manifestation (often only diagnosed because another family member has the diagnosis) and late in onset. Also D-S type is recessive. As you might expect from an early onset, high arches are not going to be what grabs attention but rather failed milestones of developmental skills. Ataxia is prominent. Sensory loss of certain types - vibratory sense especially - adds to the lost-in -space quality of stance and compounds the ataxia. Pupils of the eye become less reactive to light.
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Treatment
Treatment in CMT related disorders is generally aimed at keeping intact the specifics of movement needed for walking. There are a variety of things which can be done to assist elevating feet which flop down. These range from thin supportive assist splints worn inside the shoe to muscle-tendon procedures. The latter have to be carefully thought out as muscles which have power today may eventually fail in the future. Trends of involvement within the family may occasionally help sort out the options.
Problems of foot shape and weight distribution caused by deformation of the foot are dealt with by force diverting shoe inserts or by attaining better foot shape by surgery. There are some procedures which head off some of the foot deformation by better balancing the existing muscle forces. Of course these have to be done preemptively.
But people are people and many don't want something fixed that isn't demonstrably broken. That's OK too. The problems of CMT are seldom so onerous that there are lists of must-do surgeries or else. The or-elses have reasonable surgical remedies, so we do not need to get all weird over it.
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This is an embryopathy and not a degenerative process. This topic is here because this is where folks often erroneously THINK the problem is when it presents. Who really thinks of gills? Refer to the section on GILLS to make sense of this. But, as a generality, there is a schema by which nerves form in relation to the body segments they serve. That schema is most obvious around the embryologic gills, but, as a process, actually generalized.
Or it could be from trauma. Yes, yes, pulling on the baby's arm can stretch the nerves traveling to the arm from the neck and cause a traction palsy. But some cases of arm palsy are not from extreme fetal posture nor the birth process or anything mechanical.
If a specific branch of a developing and budding nerve from the spinal cord to a gill arch is missing its trigger to begin formation, it and a sequential series of similar nerve branches may fail to form and be missing along subsequent gill arches or equivalent gill-like early tissue organization. Such sequential punched out defects will show up as a spread loss of action in shoulder girdle muscles or region of sensation loss to the limb.
The devil is in the details. Trauma does not tease out sensory from motor fibers. Trauma makes sweeping geometric damage but not something distributed like genetic organization. Trauma to a nerve carrying sensory and motor nerves will have both motor and sensory consequences. Obvious.
Yet, some "birth" shoulder-arm plexus losses are too sensory or are way too purely motor. What kind of pull could do that? A tug on a gene, or sequential embryologic replication step, not a jerk on a fully developed mixed nerve. So a child with total paralysis of the shoulder and arm with intact sensation and - look closely - smaller calf on that same side has an embryologic fault, not a traumatic injury. There are motor and there are sensory versions of this type defect as there are sensory nerve developmental stages that can bugger and separately there are motor nerve formation steps that can be amiss.
The sensory deficits are followed by repeated additional limb and finger damage from trauma as protective senses are just that, protective. One of our children was observed in our play area happily pounding thick wooden pegs through a peg bench - big smile - whack whack whack - while holding the peg such that every hammer fall landed squarely on the peg holding thumb perched on the peg which assisted pushing the peg through to the other side - whack whack whack , turn it over - whack whack whack...
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Other Types
There are many other types of neuronal degeneration disorders. Specific diagnosis usually falls to the neurologists and geneticists. We can not cover them even in a cursory manner in the space available to our web site. But some of the more common ones do instruct us as to nature's scheme.
In that scheme the spinal cord has a front and a back side. The motor nerves arise more on the front (belly) surface of the spinal cord and the sensory nerves enter the spinal cord more on the back surface. Nerves are long conduits which carry many very long nerve cell (neuron) extensions (axons) in bundles to various destinations. Nerves do not usually contain the neuron cell bodies, but just the long filament-like axons which actually conduct the signals. Neuron cell bodies of similar kind tend to cluster together outside the nerves (they don't block the road).
The motor neuron cell bodies cluster toward the front side of the spinal cord. There, if attacked by a virus (as with Polio or Guillian Barre) we get motor loss as the long neuron axons die if their nurturing source cell bodies die even though far away.
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There is a degenerative neuron disease, not too unlike polio. But minus the virus, as in polio, there is
an extensive degeneration of motor cells of the spinal cord. Spinal Muscular Atrophy or SMA, at one
time was listed as three different diseases which seemed unrelated as they looked different due to the appearance consequences of different ages of onset and severity. But the commonality of source of
pathology in each of the three, pulled the three differing names under one umbrella diagnostic umbrella, SMA.
The 2 prominent subtypes, the early and severe Werdnig-Hoffmann, and the later and milder Kugelberg-Welander diseases are now refered to as early and severe SMA or late and milder SMA with allowance for a middle version. Some folks just number them types I, II, and III. Obviously all this is sillyness if naming were the issue. It isn't. The big question - the immediate question - very early at the onset is PROGNOSIS. How will it behave? Will this get worse? How much worse?
Early onset means bad. Paralysis will be extensive and very debilitating. There will be many deformities that will need extensive surgeries. There may well be respiratory collapse. Late onset means less bad. Less of everything and less severe. But that middle group? It merges with the two extremes. It's anybody's guess. Often the predictions fail in this murky group.
The early infantile onset subtype - once called
Infantile Muscular Atrophy
or
Werdnig-Hoffmann disease - is both earlier and immediately nastier. As with many of the very nasty
degenerations, it is a from a recessive gene defect. Recessive gene defects are those which fail to produce a working product which is vital to something (not just a less efficient version or a version
that does something oddly extra). As long as the other chromosome has a working version, things get by. Something vital to the motor neurons situated along the front of the spinal cord isn't there, so those cells die.
Not all motor neurons living in the anterior "horn" of the spinal cord are lost, though, or else the defect would be immediately lethal. The upper neck region is more spared, for example. But, in the early onset most nasty form, there is even some sensory side (dorsal) nerves rendered abnormal as well. The thought is that the actual disease of the motor cells is a result of something amiss in the supportive cells which attend neurons. Some of these buddy cells also attend certain sensory neurons and thus would cause such a mixed pathology when the defect was severe.
Of the severe form, about half are well apparent by 1 month of age. Less than 10% manifest after age one. That defines the basis of prognostication of inclusion into the nasty group. It isn't what we'd like. We would prefer some enzyme measurement, or whatever, which matches the degree of severity and scope of body involvement point for point. From DNA examination we get something like that.
There are two genes positions SMN1 & SMN2 with the gene sequence named by the position to which it belongs (there are also multiple copies). The composition of SMN2 is only a bit different from SMN1. Indeed, a common mutation of the SMA sequence makes it look like the SMN2 sequence. If SMN1 is totally lacking in the cell, the disease is severe. But if one of two abnormal SMN1s isn't missing but rather mutated to look like an SMN2, then the disease is milder as, at least something functional is left. If both SMN1s are mutated to SMN2s, the disease is mildest.
Looking at the two gene positions, there ought to be an SMN1 looking gene in the SMN1 position (position 1) and an SM2 looking gene in the SMN2 position (position 2). Keeping in mind maternal and paternal chrosomes:
Normal:
Position1 SMN1 SMN1
Position2 SMN2 SMN2
In SMA, a useless or nonsense code that produces no actual useful
product is described as deleted (here as zip).
Severe SMA
Position1 -zip- - zip-
Position2 SMN2 SMN2
Moderate SMA
Position1 -zip- SMN2
Position2 SMN2 SMN2
Moderate SMA
Position1 SMN2 SMN2
Position2 SMN2 SMN2
The above is simplified. Additional complications inlude that degree of abnormality relates to backward flip segments and how many copies of these genes are present (there are multiple copies). Additionally, there is another gene, which (in females) if it is a certain way, it interacts such that outcome is sure to be severe. These DNA markers turn out to be very complex in that failure winds up having many ways of coming to pass just as there are many ways for a bridge to not get built.
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