Orphanet study/review of PMP22 mediated Neuropathies

Orphanet provides information on Rare diseases, or as their tag line tells us

The portal for rare diseases and orphan drugs: “There is no disease so rare that it does not deserve attention”

The last part is in quotes, so I guess someone must have said this at sometime.

They are supporters of the ‘Rare Disease Day‘ events which take place worldwide on the last day of February each year.

One of their aims is to promote research into ‘orphan’ drugs, ie drugs which having been developed and tested have not been found to be ‘economically viable’, because there is only a very small market for these drugs. They may have been developed during research for other more ‘mainstream’ diseases but other drugs were selected in their place. Some of these medications show much promise in treatment of various rare diseases, but without being spotlighted by Orphanet (and other agencies) they would become obsolete.

Orphanet have some brief information about HNPP, it is short fairly concise, but does not go into a great deal of detail about the signs and symptoms that it mentions. Neither are there any references for the studies that first described these signs and symptoms.


There is also the Orphanet Journal of Rare Diseases

This has an in depth article on all diseases caused by mutations of PMP22, (the title below is also a link to the original article)

PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies

Covering both CMT1a  and HNPP it is based on a review of the literature/studies from the first reported studies on CMT by messrs. Charcot, Marie and Tooth, to present day studies particularly from the past 20-25 years since the molecular basis of the diseases have been known.

189 references in total, so that should keep any researcher busy for quite some time. The Lion’s share are on CMT1a, but over 40 are included for HNPP, and several for the rare types of PMP22 mutation whose phenotypes are either HNPP or CMT1a or a mixture of both.

I haven’t read the article in depth, just a bit of skip and speed reading,  mostly it is a good review, but prattles on about clinical presentation of painless palsy.

Just as a side note about clinical presentation of painless palsy. I don’t believe this means the condition as a whole is painless, this is just Doctor speak for what they see in the clinic at that particular moment in time. It is a snapshot, and is based on what they see and can clinically assess. Mostly they are not interested in what the patient has to say when they are making their clinical judgement. Although that does not excuse them for not listening before or after they have performed their examination. This study also goes on to mention, muscle cramps, paraesthesias and exercise induced myalgia. It could have also mentioned joint pain associated with recurrent palsy but failed to do so. So in summary, in my view, HNPP may well present with a ‘clinical’ painless palsy, but that does not mean or should not be taken to mean that HNPP as a whole is painless.

Below is my summary of the article.

focal motor and sensory peripheral neuropathy
common sites,  median, radial, with ulnar,  peroneal, the most common,
Brachial plexopathy – Erb’s paresis.
axonal thinning at sites of tomacula,
changes at nodes of ranvier,
conduction block ,
Cranial nerve involvement in some cases, ie  trigeminal, hypoglossal, facial nerve, auditory nerve involvement.
CNS involvement in some patients has been found, but this requires further study.

A further summary of the HNPP section follows (my annotations in brackets)

Direct link to HNPP section



Gives a brief description of genetic causes, ie PMP22 deletion on chromosome 17, autosomal dominant ie (50 % chance of inheritance both sexes)

Episodic, Multifocal neuropathy.

Typical presentation, recurrent, transient pressure palsies without pain (pain is more common than these studies would have people believe), focal motor and sensory symptoms in territory of nerves involved.


Prevalence is not well known, figures  vary from 7.3 per 100,000 to 16 per 100,000.

( In 2001, I was told the prevalence was approximately 2-3 per 100,000. Others have been told various other figures, but 2-5 per 100,000 is the most common statistic given.)

Clinical Description.

Episodic, recurrent, transient palsies. Causing numbness, muscular weakness and atrophy. Episodes can be preceded by many minor compressions of a nerve. Common sites (in high to low order),  ulnar, peroneal, brachial, median, radial

Age of onset 2nd to 3rd decade common, but reports exist from birth (Erb’s palsy) to eighth decade.

(My first symptoms were relatively minor, but occurred at around the age of 7 or 8 whilst cutting material with scissors, and losing sensation in the thumb and finger)

The article claims that most patients, 60- 70 %, present with a single focal acute neuropathy ( which may be true but is again only a snapshot, and follow ups over a long period do not yet exist or only in small numbers, a point mentioned in the Prognosis section)

Cranial nerve involvement in some cases, ie  trigeminal, hypoglossal, facial nerve, auditory nerve involvement.

Other uncommon features, short-term positional sensory symptoms, chronic sensory polyneuropathy, chronic sensorimotor polyneuropathy, and subacute peripheral quadriparetic episodes.

Clinical examination can reveal, muscle weakness, atrophy, sensory signs of involvement, reduced or absent tendon reflexes, Pes Cavus (high arches) is common.

The article claims 50% full recovery of an individual palsy. Chronic, long lasting, residual weakness occurs in 10 – 15%

Chronic symptoms include, cramps,  paresthesias and exercise-induced myalgia…. (isn’t this generally referred to as pain, does not matter a jot if it’s secondary, primary or any other -ary, HNPP can be painful,)

Large clinical variability, asymptomatic patients estimated at 6 – 23 %. At the other extreme chronic deficits may mimic a CMT phenotype (albeit with further acute episodes of palsy).


(Nerve conduction tests)

eveyone diagnosed with HNPP, whether symptomatic or not will show, increased distal latencies, focal motor slowing at entrapment sites  but can be near to normal at other sites. Sensory nerve velocities are decreased, along with sensory nevre action potentials.

Nerve Biopsy shows, segmental demyelination with some large fibre loss. A pathological hallmark of Tomacula described as “massive redundancies or overfolding of layers of variable thickness in the myelin sheath”


(What causes the disease)

85%-90% have the common 1.5 mb pair deletion on chromosome 17p11.2 which causes the complete deletion of the PMP22 gene on that chromosome. Some rarer cases involving smaller deletions exist, but all result in  deletion of PMP22 or mutation of PMP22.

Gene dosage hypothesis is supported by findings of low PMP22 protein and low PMP22 mRNA , the levels correspond with phenotype severity.

Focal symptoms caused by reversible conduction block. Structural changes at nodes of Ranvier explain changes in axonal excitability, and lead to conduction block due to pressure or stretch.

(As far as I recall, a Node of Ranvier is a small gap between segments of myelin along the axon. It has the effect of helping to speed up the nerve impulse, through the ability of the impulse to ‘skip’ or jump across the gaps by ‘saltatory’ action. I am not sure how HNPP affects these nodes, but my guess would be that they elongate due to demyelination and tomacula formation which causes the ‘skipping’ to stall… )

Axonal constrictions within tomacula, increasing resistance to action potential propagation, making nerve prone to conduction block. When compressed may causes further axonal thinning.

(I’ve not heard of this before, but if thinning continues through repeated compression is it possible that the axon would eventually be ‘pinched-off’ leading to distal trophic changes and axonal loss. Brings to mind the ‘fulminant presentation during military service’ study)


Clinical signs and symptoms of acute, recurrent peripheral nerve palsies, but also less common manifestations, ie cranial nerve, pain – parethesias, a family history with autosomal dominant pattern is often noted, but not always found. Some posibility of de novo (new mutation) can exist.

Electrophysiology helps with diagnosis, and more recently sonography (ultrasound) has been used to show enlargement of nerves at typical entrapment sites.

If suspected, DNA testing can be performed for the deletion of PMP22, and if negative, further sequencing of the PMP22 gene for possible and rarer mutations.

Nerve Biopsy has been largely superceded.

Differential Diagnosis

Acquired compressive neuropathy, such as carpal tunnel syndrome. But it has been noted in one study that of 50 patients with carpal tunnel syndrome, none were positive for HNPP. HNPP will normally present with recurrence, and often with multiple palsies, and family history.

Mononeuropathies (unrelated to HNPP) can be caused by tumour, bleeding or abscess.

HNA  (hereditary neuralgic amyotrophy) is mentioned as it causes brachial plexopathy. It is said that in HNA it causes pain whereas HNPP it doesn’t. (not in my experience it doesn’t. I have a long standing shoulder injury caused by going over the handlebars (age 16), which caused an Erb’s palsy, I had a dead arm for months, forced movement was extremely painful. It has become a problem in latter years, with chronic variable left arm weakness and intense shoulder, upper arm and neck pain, it needs to be reviewed and assessed, but mostly my neurologists have ignored my requests to do so, due to their ascertainment bias which is reinforced by statements such as the above, ie that HNPP only causes painless palsy.)

Genetic counselling and antenatal diagnosis

Refers reader to CMT section on Genetic counselling. Briefly, autosomal dominant, 50% chance of inheritance both for males and females. Talks about a concensus of not carrying out predictive testing on children to prevent psychological harm, and briefly about pre-implantation testing, pregnancy testing not being frequently requested. (Not sure about this, I’ve heard of quite a few people having requested such testing, but generally it has been refused, or reluctantly performed.)

Management including treatment

Treatment is symptomatic, bracing for palsies either temporarily or if residual weakness occurs permanently.

Avoid activities with risk factors for palsy, ie sitting crossed legged, repetitive activity in hands, leaning on elbows, rapid weight loss.

Avoid Toxins or medications known to cause worsening of neuropathy, vincristine is of particular note.

Studies on surgical decompression of nerves have not been completed, and generally surgery is not considered favourable.


No natural history studies exist. Prognosis unsure.  A study for electrophysiological tests with aging show increased impairment with age at sites of common entrapment, but not correlated with symptoms.

Recovery for acute palsy is often complete, but residual chronic symptoms (and presumably signs) can remain. These can, over time, resemble a CMT phenotype.

” Symptomatic individuals have the frustration and disability associated with recurrent pressure palsies”

Does not affect life expectancy.

PMP22 Mutations

The article has a small section about PMP22 mutations, missense, non-sense, frameshift, and splice-site mutations are discussed. Phenotype is variable, from asymptomatic to severe, from CMT1a to HNPP to phenotypes having complex symptoms characteristic of both phenotypes.

Some discussion of where these mutations fit within the CMT/HMSN classification.


End of Summary…. Please read the full article. Many references are included, that should satisfy the most devoted of researchers.



One thought on “Orphanet study/review of PMP22 mediated Neuropathies

  1. Pingback: Tomacula, Conduction Block, and Axonal Constriction | Jon's Slice Of Life

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