HNPP · Physical Health

Can some exercises ‘induce sporadic HNPP’?

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It’s a fact that most people with HNPP know, but there are suggestions that certain exercises can actually do more damage than good. From walking to some types of yoga, while most forms of physical activity are encouraged by gym instructors, our bodies tend to rebel from the norm. But can exercise actually induce HNPP, even though it’s generally thought to be an hereditary condition?

As HNPP is an autosomal dominant disorder in which the condition is inherited and there is a deletion of one of the genes associated with PMP22, a child of an affected individual is at a 50 per cent risk of being affected by the condition. This suggests that the likelihood of a person developing HNPP out of nowhere is relatively low.

What are ‘sporadic’ cases of HNPP?

There have been recent reports that state that a few types of muscle training has actually brought about sporadic symptoms of HNPP without any previous familial history of the condition. Sporadic cases due to de novo deletion accounted for 21 per cent of the investigated HNPP families, as reported by some studies. De novo mutation is an alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell of one of the parents or in the fertilised egg itself.

According to a 2017 study carried out by researchers at the Department of Neurology and Rheumatology, Shinshu University School of Medicine, Matsumoto, Japan, this apparently was the case in a 15-year-old boy. The authors suggest that this is the first instance of an adolescent “that developed neurological symptoms during muscle training in a school baseball club activity”, the first signs in a sporadic case of HNPP. The teenager developed bilateral painless brachial plexopathy through short-term barbell training and plank exercises.

“Patients sometimes show an atypical clinical phenotype, and a diagnosis of HNPP can therefore be challenging, especially in sporadic cases as in our patient.”

“Muscle Training-induced Bilateral Brachial Plexopathy in an Adolescent with Sporadic HNPP” – Kodaira, M., et al – July 2017

While brachial plexopathy can be a common feature of HNPP, bilateral involvement is thought to be unusual because HNPP is usually associated as a mononeuropathic condition, where there is a focus in only one area of nerves.

The authors in this case say: “As his clinical and NCS [nerve conduction study] findings indicated muscle training-induced bilateral brachial plexopathy in HNPP, genetic analysis for this disorder was performed, which revealed deletion of the PMP22 gene. Patients sometimes show an atypical clinical phenotype, and a diagnosis of HNPP can therefore be challenging, especially in sporadic cases as in our patient.”

The major difference in this occasion is that not only did he suffer from a bilateral injury, he also developed a sporadic case of HNPP triggered by relatively straightforward exercises. This is unlike some of the other examples where those in military training are far more likely to develop symptoms linked to HNPP, due to the strenuous physical activity undertaken by soldiers. However, this is not the first time ‘push ups’ are seen to be the main culprit as a trigger.

In another 2017 report A Case of HNPP due to Push-up Exercise, a 17-year-old man with no familial history of the condition developed “motor and sensory disturbance of the left upper limb a few days after starting push-up exercise”. Scientists from the Department of Neurology, Hirosaki University Graduate School of Medicine, say that the patient also developed brachial plexopathy, similar to the case above.

In the abstract, they conclude that: “Genetic tests revealed a diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP). HNPP should be included in the differential diagnosis for neuropathy due to slight exercise or nerve compression even when familial history is negative.”

The original text is in Japanese – read full document here.

Researchers from the Division of Neurology and the Department of Pathology, University of Missouri School of Medicine, Columbia, USA, found a case in 2004 akin to the above studies. A 21-year-old in good health began to develop symptoms of HNPP on her first day of military training. She began to show symptoms of severe pain, weakness, and atrophy in her right shoulder, foot and hands. Her mother and her family had no history of neuromuscular disease. She did not know her father or his family history.

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(A) Teased fibre preparation of the right sural nerve showing focal sausage shaped enlargements of the myelin sheath (tomaculae) (indicated by solid arrows) and thinly remyelinated internodes (indicated by arrow head). (B) Epon section of sural nerve demonstrating marked variation in myelin thickness and several large hypermyelinated axons (indicated by solid arrows).

Researchers of the study Fulminant Development with Axonal Loss during Military Training say that the patient’s symptoms were “unique” and that she did not have the “cardinal features of HNPP” including inheritance and mononeuropathy.

They say: “While the presentation and severity of this patient’s condition may relate to a specific unknown genetic profile with very low PMP-22 mRNA levels, Schenone et al, in finding correlations between reduced PMP-22 mRNA levels and disease severity, also suggested that extrinsic factors—for example, level of physical activity, may be important in determining phenotypic features.

“This appears to be true of our patient—that she was neurologically normal, then developed symptoms on the first day of military physical training with progression as she continued the training over a three week period, suggests that disease severity and focal axonal damage were related to these intense activities.”

The authors add: “Additionally, as it has recently been recognised that sporadic cases of HNPP are common, either because of de novo mutations or asymptomatic carriers, her lack of family history did not preclude this diagnosis.”

How likely is it that a case of HNPP is sporadic?

It’s important to note that HNPP may not be easily traced in other family members, which means while it may appear sporadic, it could just have been overlooked. A 2013 case report reiterates this view, with authors saying that approximately one-third of deletion carriers are unambiguously detected on the basis of “electrophysiological criteria and confirmed by genetic analysis are asymptomatic and do not display significant signs at clinical examination.”

Researchers from Department of Paediatrics, Hospital de Guimarães, Portugal, say: “Thus, the family history is often uninformative, and a significant proportion of probands may be considered as apparently sporadic cases. However, a close questioning and examination of the relatives provided evidence for autosomal dominant inheritance in families that were originally stated by the probands to be normal. Therefore, HNPP can easily be overlooked in those cases in which familial involvement is not recognised unless intensive ascertainment techniques are used.”

Electrophysiologic studies are said to be “suggestive” and not “sufficient for diagnosis” which may be why it may be imperceptible to locate.

How exercise can trigger symptoms

The more frequent representations are in those who already have familial histories of HNPP, or in those who have already been diagnosed. In one such case in 2005, hiking and athletic training brought on the symptoms. A 10-year-old girl, who suffered from acute, recurrent monoplegic episodes affecting both the sciatic nerves and the left brachial
plexus since the age of 7, showed quite a lot extensive symptoms from relatively low impact exercise.

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Authors from the Department of Paediatrics, Yokohama City University Medical Centre, Japan, say: “This school child having HNPP is considered to be susceptible to the influence of abundant physical training, rather than minor trauma or compression at sites of entrapment of peripheral nerves.” However, this is hardly surprising given the nature of the condition. What’s more unusual are the situations where HNPP is not present beforehand or without familial background.

It goes without saying, exercise can cause many types of injuries even for those without HNPP depending on how extreme it may be. And as we have seen above, there have been at least several cases of ‘sporadic’ HNPP, which develops without any prior history of symptoms or familial connection.

However, it may be worth noting that without the correct tests to detect hereditary links, these may be incorrectly termed as ‘sporadic’. That being said, there have been established reports that suggest at least 21 per cent of HNPP cases are de novo mutations, so it may not be out of the realms of possibility that certain types of exercise can induce symptoms of HNPP.

Read: Is walking good for those with HNPP?

HNPP · Physical Health

The effects of HNPP during pregnancy

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There can be a lot of worry and anxiety that arises during pregnancy, one of which includes what to expect, especially with HNPP. Many can have a more or less seamless experience while others find that their symptoms are exacerbated during this time. So what is the ‘norm’ of HNPP during pregnancy?

“In my 30’s during pregnancy, I had sciatica because I had enormous babies resting on my spine. Bladder too, but peeing my pants when I sneezed or laughed – seemed like something that just happens to pregnant women.”

A mother with HNPP from the blog Chronic Pain Journal

First of all, HNPP does not affect the fetus or the pregnancy itself thankfully. However, during pregnancy, symptoms that manifest due to HNPP such as palsies, sciatica, or pain in the lumbar region, may be heightened as a result of added pressure on the body.

Disclaimer: Please ask your medical practitioner for more information. This article is based on various research, journals and testimonies.

How does HNPP manifest during pregnancy?

According to Dr. Rakesh B Vadhera, an obstetrics anaesthesiology consultant and professor at the University of Texas, alongside Dr. Michelle Simon, a paediatrician and neuropathology expert, peripheral entrapment neuropathies are common during pregnancy and may lead to “severe discomfort”.

Writing in the book Maternal Medicine published in 2015, Dr. Vadhera and Dr. Simon state: “Pregnancy itself may predispose patients to some of these entrapment neuropathies, which are mostly benign in their evolution and prognosis and will resolve spontaneously in the postpartum period.” This appears to be good news for expecting mothers concerned that the symptoms may not disappear after the birth of the child. For all that however, there have been cases of symptoms lingering postpartum.

They add: “Delivery may predispose patients to compression or stretching of some nerves and plexuses that may precipitate symptoms. Prompt clinical evaluation and, when necessary, an electrophysiologic evaluation may aid in the diagnosis and subsequent management.” As briefly mentioned in the article Is surgery worth it with HNPP?, it’s vital to let your medical team know how to make you comfortable during this time as well as through labour, to avoid further nerve-related damage. This is addressed in more detail below.

What symptoms to expect when you’re expecting

In some extreme cases of Charcot Marie-tooth-related disorders, the obstetricians above say pregnancy can affect respiratory muscles and thoracic vertebral anatomy, “impacting patient respiratory function during pregnancy and affecting delivery and anesthetic care”. But this may be evident during the third trimester when there is added strain on the body, and therefore you may have enough warning to consult a health professional beforehand.

Author Dr. Pierre Bouche, based in the Department of Clinical Neurophysiology, Salpêtrière Hospital, Paris, France, says that in some neuromuscular disorders, carpel tunnel syndrome (CTS) could also manifest during pregnancy.

In the edition Peripheral Nerve Disorders as part of the Handbook of Clinical Neurology, Dr. Bouche states: “[Carpal tunnel syndrome] can develop at any time in pregnancy, but it is most frequent during the third trimester and may be due to fluid retention exerting pressure on the median nerve.” However, this can vary from person to person depending on how sensitive the nerves are around the wrist and upper arm.

Other areas that may be affected can also differ. Authors of the medical reference guide Obstetric Anesthesia and Uncommon Disorders, 2008, reiterate that HNPP may exacerbate neuropathies associated with pregnancy and delivery. They say HNPP symptoms such as “lumbosacral plexus, femoral, lateral femoral cutaneous, obturator or peroneal nerve palsies” may be aggravated during this time.

But that’s just some of the ways the symptoms may manifest. There are some mothers featured in the Facebook HNPP groups, who have spoken about pain in the ribs, loss of functionality in the legs, arm and leg aches, and the list goes on. On the other hand, there are others who faced symptoms no worse than pre-pregnancy.

How to prepare for labour and delivery

Similar to the diverse responses on how mothers are affected during pregnancy, the same is apparent with the delivery itself. Some mothers elect to have a natural birth, while others require or request cesareans. Using gas, on the other hand, may pose a risk as it is considered a neurotoxin. There have been reports of “heightened pain” with gas according to some users in the HNPP support networks.

“I was 33 when I had the epidural – which triggered my chronic neuropathic pain. The majority of my pain, travelling along the entire right side of my body. Strongest in all the places I had experienced pain during my life. It was like it was the “Red Button” got pushed and a bomb exploded in my Central Nervous System.”

A mother with HNPP from the blog Chronic Pain Journal

According to Dr. Guy Lepski and Dr. J.D. Alderson of the Department of Anaesthesia, Northern General Hospital, Sheffield, UK, dense local anaesthetic blockade should be avoided as it may mask a compression neuropathy. They recommend the following management principles for doctors in the 2001 study Epidural Analgesia in Labour for a Patient with Hereditary Neuropathy with Liability to Pressure Palsies:

  • Consult with a neurologist and anaesthesiologist in the antenatal period
  • Assess neurological status antepartum
  • Avoid prolonged immobilisation in labour
  • Avoid instrumental delivery
  • Avoid dense epidural blockage
  • Consider operative delivery if a pressure palsy develops during labour
  • If a cesarean section is selected, HNPP.org gives the following advice to the surgical team:
    • Position arms out to sides. An angle of less than a 90 degree angle will help to alleviate stretch on the brachial plexus (shoulder area).
    • Move arms (supinate/pronate) every 15 minutes while under general anaesthesia.
    • Pad arms and legs/feet in stirrups. As a general rule: pad everything. The need to pad arms and legs is dependent upon the individual patient (frequency and severity of palsies). One inch foam or similar type material is usually sufficient.
    • If possible avoid leaning against the patient, especially against the arms and legs.
    • Tape endotracheal tube more centrally so that the tube is fully supported by the tape and not at all by the mouth. Tape other tubing in a similar manner as appropriate. Consider positioning while awake.
  • In order not to mask any developing neuropathy, anything but the mildest block for postoperative pain should be avoided.

Both Dr. Lepski and Dr. Alderson say that the “Labour progressed uneventfully and there were no neurological sequelae following delivery”.

In addition to these suggestions, David H. Chestnut alongside several other authors have written about safeguards to minimise peripheral nerve compression. In Chestnut’s Obstetric Anesthesia: Principles and Practice E-Book, they advise:

  • Be watchful for patient position that contributes to nerve compression, particularly with neuraxial blockade.
  • Avoid prolonged use of the lithotomy position; regularly reduce hip flexion and abduction.
  • Avoid prolonged positioning that may cause compression of the sciatic or peroneal nerve.
  • Place the hip wedge under the bony pelvis rather than the buttock.
  • Use low-dose local anaesthetic / opioid combinations during labour to minimise numbness and allow maximum mobility.
  • Encourage the parturient to change position regularly.
  • Ensure that those caring for women receiving low-dose local anaesthetic / opioid combinations understand that numbness or weakness may be signs of nerve compression; such symptoms should prompt and immediate change of position.

A report by French researchers S. Berdai and D. Benhamou from the Department of Anaesthesia and Resuscitation, Bicêtre Hospital, Le Kremlin-Bicêtre, suggests that it is possible to have an epidural as well as spinal anaesthesia during labour. In the report Regional Anaesthesia for Labor and Delivery in a Parturient with Neuropathy with Liability to Pressure Palsy, a woman had two cesarean sections, one with an epidural that resulted in no “neurologic complaints in the postpartum periods”.

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They say: “For the first delivery, epidural analgesia was performed for labour pain control but a caesarean section was necessary because of failure to progress (0.0625% bupivacaine with 0,2 μg/ml sufentanil for labour then 2% lidocaine with adrenaline for surgery).

“Two years later, the patient was again seen for a preanaesthetic visit because elective Caesarean section was planned. Spinal anaesthesia using hyperbaric bupivacaine and sufentanil was used. Both deliveries were uneventful”. Uneventful being the operative word.

It is essential to get the right advice while pregnant as well as during childbirth itself, and also on how to manage any symptoms that appear postpartum. Creating a birthing plan will therefore be necessary to avoid any extra issues. That being said, symptoms fluctuate from person to person, which means you may be fortunate enough to have hardly any bumps in the road.

Read: What to avoid with HNPP

HNPP · Physical Health

Are facial issues associated with HNPP?

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When your face unexpectedly becomes numb, or begins to spasm, many HNPP sufferers do wonder what godforsaken cause could be behind it. Yet, it isn’t as uncommon as many may believe. Health professionals say that facial issues tend not to be associated with the condition, hence multitudes have been diagnosed with Bell’s Palsy instead.

What is Bell’s Palsy?

Bell’s palsy, or idiopathic facial paralysis (IFP), is the most common cause of unilateral, lower motor facial palsy. It’s origins remain uncertain. However, the first familial occurrence was found in 1887, hence hereditary factors have been considered to play a role in the etiology of the disease. It is believed to occur when the nerve that controls the muscles in your face becomes compressed and IFP is generally linked to inflammation or viral infections.

“In the last year and a half I have been dealing with one sided facial pain and numbness. It has evolved into a burning that sequentially involves the tongue, then lips, then cheek, then eye, then ear and finally throat all on the left side. It waxes and wanes and seems to do so based on my stress levels. I have had CT and MRI, normal; as well as a battery of blood tests, normal; seen a neurologist who said I’m fine (ahem!) and an ear nose and throat doc who says I have non-motor Bell’s Palsy (my research indicates there is no such thing).”

User on the BrainTalk Communities Forum

It’s obvious that there could be secondary condition causing facial issues, but several members of various HNPP groups have spoken about pain, weakness numbness, and spasms associated with the head and face.

Scientists have been studying the link between IFP and HNPP in order to get a better understanding of both causes. A letter in the Journal of Clinical Neuroscience in 2013 shows how the two conditions are not connected. Researchers at the Department of Neurology, Eginition Hospital, in Athens, Greece, hypothesised that a handful of participants in a study for Bell’s Palsy could have the same mutation for HNPP.

They say: “There are a few case reports of patients belonging to these subcategories of Bell’s palsy, on whom the characteristic deletion of a 1.5-Mb region on chromosome 17q11.2-12 which includes the peripheral myelin protein 22 (PMP22) gene, was detected.”

Out of a 145 unrelated Greek patients with Bell’s palsy, 28 patients with recurrent facial palsy and 18 patients with familial facial palsy were tested for a deletion of the PMP22 gene. However, none of the participants had this mutation.

“These cases could be part of a diverse spectrum of miscellaneous disorders including HNPP.”

“Is there a common genetic background?” Karadima, G. et al, 2013

They conclude: “Bell’s palsy seems to have a different etiology than HNPP. The same applies to familial or recurrent Bell’s palsy. A molecular genetic investigation for HNPP seems to be indicated in cases of recurrent or familial facial palsy accompanied by peripheral nervous system damage or exhibiting a family history of peripheral neuropathy. These cases could be part of a diverse spectrum of miscellaneous disorders including HNPP.”

This is reiterated in the 2009 case report Familial Recurrent Bell’s palsy conducted by researchers from the Department of Neurology, Zhejiang University, Hangzhou, China. Three families in which eight patients had a total of 12 episodes of typical Bell’s palsy were recorded in a bid to find the etiology of the condition.

In spite of this, the researchers infer: “Recurrent facial palsy can occur in neurological disorders such as Melkersson-Rosenthal syndrome (MRS), Moebius syndrome, Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsy (HNPP). These conditions however, have additional features that distinguish them from idiopathic familials Bell’s palsy. None of our patients have any symptoms indicative of such diseases.”

So what’s the reasons behind facial numbness?

There are several possible causes of facial numbness, also known as hypesthesia. Most of these causes can be traced to a problem in or affecting the trigeminal nerve.

It is one of twelve cranial nerves and is one of the most widely distributed nerves in the head. The cranial nerves can be categorised as two main nerve types: those that control motor responses such as blinking, chewing, or eye muscle movement, and those that respond to the sensations of taste, smell, hearing, and touch.

Gray778

The trigeminal nerve has three branches, which controls both the sense of touch in areas in the face as well as the motor function associated with chewing. Damage to this nerve could, therefore, make chewing difficult, if not impossible. Some sufferers of face numbness also experience numb lips. Or it could create either a ‘pins and needles’ sensation or a loss of feeling in parts of the face. Of the twelve facial nerves, it is usually considered number five. Other parts affected include:

  • Olfactory nerve (number 1) –  relays the sense of smell to the brain.
  • Oculomotor nerve (number 3) – controls the external muscles of the eye.
  • Facial nerve (number 7) – controls the muscles used in facial expressions and should not be confused with the trigeminal nerve, despite its name. It does not relay a sense of touch.
  • Auditory nerve (number 8) – controls balance and hearing.

While most of these are connected with the central nervous system, and HNPP is yet to have established links to the CNS, there have been cases where some with the condition have had issues with this particular nerve.

According to a 2015 study carried out by Japanese researchers from Department of Neurology, Osaka Red Cross Hospital, Osaka, there were two cases with cranial involvement without progressive muscular atrophy (PMA). They state: “a 40-year-old female case of HNPP with the involvement of the trigeminal, facial and hypoglossal nerves, and a case of 7-year-old boy having a homozygous deletion of PMP22, who had the LMN [lower motor neuron] impairment in the cranial nerves of VII and III, sensory disturbance in extremities.”

Like many other publications, the researchers state that because of limited studies, “additional investigations are warranted to better understand PMP22 regulation in the CNS and the peripheral nervous system”.

The rarity of such finding is highlighted in a Brazilian study from the Department of Neuroscience at the University of São Paulo. In the 2016 study Clinical and Neurophysiological Features of HNPP, 39 patients were reviewed for neurological symptoms while 33 were given nerve conduction tests. Only one presented cranial nerve related symptoms in terms of “involvement of the trigeminal nerve and other one an episodic involvement of the eyelid branch of the oculomotor nerve”.

They go on to restate: “Cranial nerve involvement was rare in our population […] It seems that this is the pattern in most studies  Interestingly, we have previously described a HNPP patient that developed dysphagia. Other rare manifestations in our patients were pes cavus and nerve thickening, as seems to be the case in most studies.”

In the 2006 book Differential Diagnosis in Neurology by Robert J. Schwartzman, MD, the Professor of Neurology documents daily morning reports with neurology residents and the examination of patients in front of colleagues over the last 30 years. The Emeritus Professor of Neurology at the Drexel University College of Medicine in Philadelphia, recounts that “facial nerve involvement occurs rarely” with HNPP.

Therefore, it’s important to realise the symptoms instead of the condition as knowing that it is HNPP, or in this case, may not be HNPP-related, does not change the fact that these symptoms are manifesting.

For many with facial issues, including those suffering from HNPP, it’s vital to get it checked by a medical professional as it could be associated with another underlying or even acute disorder. In many situations, doctors may dismiss it as HNPP and then resort to medication associated with the inherited disorder, because they aren’t certain of what it may be, which is where your persistence to get  the correct treatment will be absolutely key.

Read: The difference between HNPP, CMT and CIDP

HNPP · Physical Health

The difference between HNPP, CMT and CIDP

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One of the first responses that seems to appear on search engines about Hereditary Neuropathy with Liability to Pressure Palsies is its relation to the inherited condition Charcot Marie-tooth syndrome (group of disorders). While CMT1A – a subtype of the CMT – is thought to be the most common inherited neuropathic condition, little research is still available to its ‘sister’ condition HNPP. So how do the conditions diverge and converge?

The irony of the conditions being similar in nature, is the fact HNPP is the genetic opposite of CMT1A. HNPP is associated with a deletion on the same chromosomal site where CMT1A (the most common type of CMT) has been found to have a duplication, and it contains an important myelin gene, peripheral myelin protein-22 gene (PMP22).

The chromosome in question is chromosome 17, where CMT1A has an extra copy of PMP22, and HNPP results from the loss of a copy of PMP22. The PMP22 gene encodes for peripheral myelin protein, and disruption of this gene leads to a dysfunctional myelin sheath on nerves.

dna

What is a chromosome?

Going back a step and remembering the old science lessons from school, a cell’s nucleus contains chromosomes – rod shaped bodies found in the nucleus of cells that contain genetic information in the form of DNA.

DNA (deoxyribose nucleic acid) is made up of short sections of genes – inherited from parents, and makes up DNA which controls part of a cell’s chemistry, particularly protein production. Each gene codes for a specific protein by specifying the order in which amino acids must be joined together.

CMT

In total, humans normally have 46 chromosomes in each cell, divided into 23 pairs. Two copies of chromosome 17, one copy inherited from each parent, form one of the pairs. In one of the arms of the chromosome 17 (if you think about it as an ‘X’ type shape), specifically the ‘P-arm’ lies the gene PMP22 labelled as 17p11.2, which is the area where it resides. The genetic defect in most HNPP patients is a 1.5 Mb deletion (used to describe the length of a DNA/RNA molecule) on this chromosome containing the PMP22 gene.

HNPP is usually caused by an autosomal dominant gene, which means one parent must be affected. While there should be two copies of the PMP22 gene, there usually is only one or some form of mutation, unlike with CMT1A which tends to be a duplication of the gene. As a result, HNPP and CMT tend to be lumped together under one category and while there may be an overlap, there are other forms of CMT and HNPP that do not follow this rule.

The result of this is that the symptoms of each condition resemble one another because they both end up becoming a form of demyelinating neuropathy.

Rare forms of HNPP

Point mutations in the PMP22 gene are a rare cause of HNPP. In one case, a novel PMP22 splice site mutation – a genetic mutation that inserts, deletes or changes a number of nucleotides in the specific site – was reported in an HNPP family. Nucleotides are organic molecules that form DNA and RNA (ribonucleic acid, which is an important molecule with long chains of nucleotides).

DNA_to_protein_or_ncRNA.svg

According to a 2006 study, a mutation at nucleotide c.179+1 was found in the PMP22 gene. This mutation causes the synthesis of an abnormal mRNA. Messenger RNA (mRNA), are molecules in cells that carries codes from the DNA in the nucleus to the sites of protein synthesis in the cytoplasm (the ribosomes).

Point mutations of PMP22 gene cause a wide variety of demyelinating neuropathies including HNPP, Charcot‐Marie‐Tooth disease type 1A (CMT1A), Dejerine‐Sottas syndrome (DSS), and congenital hypomyelination (CH). Authors of the 2006 study say: “To date, 11 mutations have been reported in HNPP patients and all of them are likely to cause a loss of function of the protein.” An earlier 2003 report suggested there were “fewer than 10 point mutations of the PMP22 gene” associated with HNPP.

Rare forms of CMT

CMT1B

CMT1B is the second most common subtype of CMT1. CMT1B is caused by a defect within the MPZ gene, which lies on chromosome 1. The MPZ gene produces myelin protein zero, and disruption of this gene also causes deficits within the myelin sheath. CMT1B patients have onset and symptoms similar to those of CMT1A patients, although there is a wide range of variability within CMT1B. As discussed in the article When HNPP ‘Causes Breathing Problems’, the MPZ gene is known to be associated with respiratory issues which is less common with HNPP.

CMT1E

Similar to point mutations in HNPP, instead of having a duplication of the normal PMP22 gene, CMT1E patients harbour different genetic abnormalities in the PMP22 gene.

CMTX

CMTX is caused by mutations in the gene for connexin 32, which normally codes for a protein located in myelin, the insulating sheath that surrounds nerve fibres. It has many of the same symptoms of CMT1 and CMT2, including muscle weakness and atrophy, and changes in sensation, mostly in the feet, lower legs, hands and forearms. However, because of its linkage to the X chromosome, CMTX often affects males more severely than females.

CMT2

CMT Type 2 (CMT2) is a subtype of CMT that is similar to CMT1 but is less common. It is typically autosomal dominant, but in some cases can be recessive. CMT2 is caused by direct damage to the nerve axon itself in comparison to CMT1 which results from damage to the myelin sheath insulating the axon. CMT2 is commonly referred to as “axonal” CMT.

CMT2A is the most common subtype of CMT2 and is caused by defects in the MFN2 gene. The MFN2 gene encodes for Mitofusin 2, which is a protein involved in the fusion of cellular mitochondria. Other more rare forms of CMT2 and their gene defects include:

  • CMT2B is caused by defects in the RAB7 gene.
  • CMT2C is caused by defects in the TRPV4 gene.
  • CMT2D is caused by defects in the GARS gene.
  • CMT2E is caused by defects in the NEFL gene.

CMT4

CMT4 is a rare subtype of CMT that is inherited in an autosomal recessive pattern. Generally, cases of CMT4 present with more severe symptoms compared to CMT1 or CMT2. In general, CMT4 is caused by defects in the myelin sheath which insulates the axon. However, other variations include:

  • CMT4A is caused by defects in the GDAP1 gene.
  • CMT4B is caused by defects in the genes MTMR2 (CMT4B1), or MTMR13 (CMT4B2).
  • CMT4C is caused by defects in the SH3TC2 gene.
  • CMT4D is caused by defects in the NDRG1 gene.
  • CMT4E is caused by defects in the EGR2 gene.
  • CMT4F is caused by defects in the PRX gene.
  • CMT4H is caused by defects in the FDG4 gene.
  • CMT4J is caused by defects in the FIG4 gene.

Source: CMT USA

Chronic Inflammatory Demyelinating Polyneuropathy

Asked about the similarities of Chronic inflammatory demyelinating polyneuropathy with HNPP and CMT, the symptoms that manifest seem to overlap with HNPP and CMT. However, the major difference is the fact that it is not an inherited condition, but a neurological disorder that causes progressive weakness and impaired sensory function in the legs and arms. No clear genetic predisposition or other predisposing factors for CIDP have been identified.

CIDP is thought to be caused by the immune system mistakenly attacking and damaging the myelin sheath of the peripheral nerves hence the symptoms may appear to be similar to HNPP and CMT. It is said that many people with CMT are initially diagnosed with CIDP due to these symptoms.

After that short science lesson, it’s clear to see how easily one condition can be mistakenly diagnosed for another. The symptoms tend to overlap with one another because the end result can include damage to the myelin sheath and neuropathic tendencies. As a result, it requires careful analysis by health professionals, and the necessity that all essential medical tests are undertaken to get the correct answers.

Read: Why do some HNPP results appear negative?

Read: HNPP, belief and the impact of misdiagnosis

 

HNPP · Physical Health

Feeling hot and cold with HNPP

hnpp hereditary neuropathy cold hot temperature

Four weeks of having hot flushes made me wonder if I was getting my menopause 20 years too early. Or whether it could be related to medications. An even more plausible explanation could be that our internal temperature gauge may be functioning improperly with HNPP. So how sensitive are our bodies to hot and cold?

Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Damage to the peripheral nerves can result in loss of sensation as well as wasting (atrophy) of muscles in the feet, legs, and hands.

In spite of this, the control of body temperature takes place in the central nervous system at different levels, from the spinal cord to the upper parts of the brain. According to the 1996 report The Autonomic Nervous System and Body Temperature by R. H. Johnson, the maintenance of body temperature depends upon a balance between heat loss and heat production. The mechanisms by which heat loss and production are regulated are very similar; each may be regulated in two ways:

  • By reflexes from peripheral temperature receptors in the skin: the reflex pathway probably passes through the brain and its activity may be determined by the level of central temperature.
  • By means of receptors within the brain which respond to changes in blood temperature. [1]

However, instead of feeling the extremes of hot and cold due to autonomic neuropathy, studies suggest that we’re more likely to feel nothing at all. HNPP’ers on the other hand have spoken about becoming particularly sensitive to the weather.

“It’s been cold this week, I’m now sporting three pairs of socks and my feet still feel cold! I don’t think it’s to do with circulation, more misfiring nerve-endings, which just scream ‘cold’. The odd thing is though is that I’ve been getting burning sensations in my feet… burning cold.”

From Jon Leonard’s blog – My Life with HNPP

The idea of loss of sensation can be seen in PMP22 Mutation Causes Partial Loss of Function and HNPP-like Neuropathy. Both a 35-year-old man and woman complained of a “decrease in pain and temperature sensation”. The authors say in these cases “heterozygous T118M mutations mildly disrupt myelin to an extent that mild symptoms are likely to develop; homozygous mutations more severely disrupt peripheral nerve and disable patients”. But this appears only in this  kind of specific mutation.

According to the 1997 study Hereditary Thermosensitive Neuropathy: An Autosomal Dominant Disorder of the Peripheral Nervous System, both Charcot Marie-Tooth disorder and HNPP had no links to this condition. HTN is also autosomal and inherited, with patients suffering from body temperatures of over 38.5 C.

The reason the authors give for it being unrelated was: “We excluded loci causing other hereditary demyelinating neuropathies, such as Charcot-Marie-Tooth disease type I (CMT type I) and hereditary neuropathy with liability to pressure palsies (HNPP), by linkage analysis; thus, HTN is not allelic to either CMT type I or to HNPP.”

This is reiterated in the book Peripheral Neuropathy in Childhood in which the authors  Robert A. Ouvrier, J. G. Mcleod, and J. D. Pollard mention the above study adding that Hereditary sensory and motor neuropathy (HSMN) was also excluded from the research. That being said, there is very little research into this condition, with many journals relying simply on the 1997 report.

Why temperature is seen to be connected

Interestingly, the report by R. H. Johnson as mentioned above, does put a small disclaimer about body temperature being controlled by the central nervous system, saying: “Strictly speaking heat production by shivering is mediated by motor nerves but is included so that temperature regulation may be kept in proportion.”

He goes on to say that there is a combination of peripheral nerve issues as well as the central nervous system that causes problems with temperature: “The abnormalities of temperature regulation occur with failure of peripheral effector structures, alteration of function of central controlling structures or with lesions of interconnecting nerves.”

Why temperature in HNPP is seen to unrelated

This can be seen in several studies including Thermoregulation in Peripheral Nerve Injury-Induced Cold-Intolerant Rats. In 2012, scientists from the University Medical Centre Rotterdam, Netherlands, tested cold temperatures on rats that had peripheral nerve injuries. By attempting to re-warm the paws of the animals over three to nine weeks, the researchers concluded that “re-warming patterns are not altered after peripheral nerve injury in these rat models despite the fact that these animals did develop cold intolerance”.

They go on to add: “This suggests that disturbed thermoregulation may not be the prime mechanism for cold intolerance and that, other, most likely, neurological mechanisms may play a more important role.

“There is no direct correlation between cold intolerance and re-warming patterns in different peripheral nerve injury rat models.”

Peripheral nerves and thermoregulation

It’s obvious that the peripheral nerve system does play a part in feeling the differences between temperatures. In an 2009 study, nerve conduction tests were carried out on 45 Indian women between the ages of 18-25. The researchers say: “Patients with impaired circulation may have a reduced tissue temperature and additional reduction of nerve conduction velocity.” Information carried from peripheral temperature sensors tends to effect the temperature of the skin.

Authors of the 1985 research Skin-Temperature Stability between Sides of the Body reinforce this notion saying: “In normal persons, the skin temperature difference between sides of the body was only 0.24 degree +/- 0.073 degree C. In contrast, in patients with peripheral nerve injury, the temperature of the skin innervated by the damaged nerve deviated an average of 1.55 degrees C.”

It’s evident that the central nervous system, and more importantly key brain centres are mainly concerned with temperature control as well as the preoptic area and anterior hypothalamus – a portion of the brain that contains a number of small nuclei with a variety of functions.

temperature
Simplified cartoon depicting thermoregulatory pathways – Max Delbrück Center for Molecular Medicine

However, scientists at the Max Delbrück Center for Molecular Medicine in Berlin, Germany, states that these hypothalamic regions harbour neurons not only detect changes in core body temperature, but are also believed to “receive and integrate input from ascending somatosensory pathways carrying information from peripheral temperature sensors”.

Despite those with HNPP clearly suffering from problems with temperature regulation, unless the connection between the autonomic nervous system is more distinctly laid out, research in this area will continually be put on the back burner. Nonetheless, there are reasons behind why we may feel cold during particularly bad weather so you’re not the only one.

  • 1. “The Autonomic Nervous System and Body Temperature” – R. H. Johnson, 1966

Read: HNPP and digestion issues

HNPP · Physical Health

HNPP and digestion issues

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It’s considered one of the more taboo subjects given the ’embarrassing’ nature of the topic, but a large amount of HNPP sufferers appear to experience problems with their gut. And not in the instinctual kind of way. Digestive issues could be more closely linked to the condition than you may think.

While research surrounding this particular issue is limited, linking HNPP to other areas of the body could provide more information surrounding this topic. Quoting those who have spoken to noted medical practitioners researching HNPP, sufferers with the inherited disorder are more susceptible to problems with digestion “due to Schwann cells not forming properly in the embryonic stage”.

“I would take the position that unless a problem clearly has a neurological basis then it should not be attributed to HNPP.”

– Gareth J. Parry, M.D

Disclaimer: Please ask your medical practitioner for more information. This article is based on various research, journals and testimonies.

Prior to this new information, Gareth Parry MD, the Professor and Head, Department of Neurology, University of Minnesota said that symptoms such as digestion issues should not be attributed to HNPP.

Dr Parry stated: “I would take the position that unless a problem clearly has a neurological basis then it should not be attributed to HNPP. The only symptoms that I would attribute to HNPP largely without question would be numbness, paresthesias (pins and needles, tingling, etc) and weakness.”

Why is this important?

Schwann cells are vital in functioning to support neurons in the peripheral nervous system. A nerve cell communicates information to distant targets by sending electrical signals down a long, thin part of the cell called the axon. In order to increase the speed at which these electrical signals travel, the axon is insulated by myelin, which is produced by the Schwann cell. It is affected in a number of demyelinating disorders including the sister condition of HNPP called Charcot Marie-Tooth disorder.

640px-Complete_neuron_cell_diagram_en.svg

Myelin twists around the axon like a jelly-roll cake and prevents the loss of electrical signals. Without an intact axon and myelin sheath, peripheral nerve cells are unable to activate target muscles or relay sensory information from the limbs back to the brain.

Changeable environment within nerve injury especially the scarring time can limit Schwann cells proliferation, according to a 2011 study. Unlike in CMT, the number of total Schwann cells is seen to increase, as stated by authors of the 1998 report Fate of Schwann cells in CMT1A and HNPP.

This is reiterated in the 1998 research Neuronal Degeneration and Regeneration, where the authors state: “The reduced expression [of PMP22] would result in an extended proliferation [of Schwann cells] and in excess of myelination and thus the formation of hypermyelinated tomacula as observed in HNPP. The observation of two Schwann cells forming one myelin sheath in HNPP is in line with this theory.”

Similar to autonomic neuropathies, such as diabetic neuropathy, abnormalities reported include proliferation of Schwann cells, atrophy of denervated bands of Schwann cells, axonal degeneration in nerve fibres, primary demyelination resulting from secondary segmental demyelination related to impairment of the axonal control of myelination, remyelination, as well as onion-bulb formations.

At present, the link between how the proliferation of Schwann cells itself can cause issues with digestion and HNPP has not been established, so it may be some time before the research is more widely available.

Autonomic neuropathy and HNPP

It’s vital to understand the connection between HNPP and autonomic neuropathy because AN has been proven to include symptoms such as gastrointestinal issues. As the name implies, the autonomic nervous system is responsible for monitoring the functioning of the organs that act largely unconsciously and regulates bodily functions such as the heart rate, digestion, and respiratory rate. While there are many elements where hereditary neuropathy and AN diverge, there are certain areas where they converge but haven’t been studied.

Saltatory_Conduction

In the 2015 report Two Siblings with Genetically Proven HNPP and Autonomic Neuropathy, a brother and sister who both had the deletion of PMP22, also had symptomatic autonomic dysfunction confirmed by autonomic testing.

The researchers say: “Autonomic testing, performed due to autonomic symptoms including positional dizziness, confirmed the presence of autonomic dysfunction. The brother had neurocardiogenic syncope and adrenergic dysfunction but a normal QSART. The sister showed distal reduction of QSART response, mild symptomatic orthostatic intolerance with mild adrenergic dysfunction and intact cardiovagal and sudomotor function.”

It may be coincidental that the siblings had autonomic dysfunction on top of HNPP, however the authors conclude: “HNPP can uncommonly be associated with an autonomic neuropathy. It is important for clinicians to be aware of the potential presence of autonomic symptoms, which may contribute to poor quality of life for these patients.”

In a 2015 investigation into the link, a patient with HNPP was found to also have severe orthostatic hypotension – low blood pressure – which is generally associated with autonomic neuropathic symptoms which affects the central nervous system.

The authors say: “through exome-sequencing analysis, we identified two novel mutations in the dopamine beta hydroxylase gene. Moreover, with interactome analysis, we excluded a further influence on the origin of the disease by variants in other genes. This case increases the number of unique patients presenting with dopamine-β-hydroxylase deficiency and of cases with genetically proven double trouble.”

Dopamine-β-hydroxylase deficiency is rare form of autonomic dysfunction which affects the central nervous system attacking the functioning of the heart, bladder, intestines, sweat glands, pupils, and blood vessels. Not all are neuropathy related.

Again, these cases could be purely serendipitous given how rare they are portrayed to be, but it is apparent that more research in this area is required.

Other types of autonomic neuropathy

In the case of autonomic diabetic neuropathy, George King, MD, Director of Research and Head of the Section on Vascular Cell Biology at Joslin Diabetes Center says: “Nerves are surrounded by a covering of cells, just like an electric wire is surrounded by insulation. The cells surrounding a nerve are called Schwann cells. One theory suggests that excess sugar circulating throughout the body interacts with an enzyme in the Schwann cells, called aldose reductase. Aldose reductase transforms the sugar into sorbitol, which in turn draws water into the Schwann cells, causing them to swell.

“This in turn pinches the nerves themselves, causing damage and in many cases pain. Unless the process is stopped and reversed, both the Schwann cells and the nerves they surround die.” Sorbitol, which can be taken as an enzyme, is said to have laxative effects and does not get broken down in the small intestine, and causes water to be retained. When glucose is converted to sorbitol via the enzyme aldose reductase it results in a decrease in tissue myoinositol, with far-reaching effects throughout the nervous system.

According to the 2000 study The Diabetic Stomach: Management Strategies for Clinicians and Patients, author Gerald Berstein, M.D., says: “In the gastrointestinal tract, [diabetic neuropathy] causes, in effect, an autovagotomy […] hyperglycemia results in cellular anatomic disruption throughout the gastrointestinal tract, but especially in the stomach. Nerve cells may swell with the loss of myelinated fibers […] In the stomach, motility may be reduced in the antrum and proximal stomach. There may also be pylorospasm.”

Gastroparesis, or delayed gastric emptying, is a rare feature of diabetic autonomic neuropathy. This long-term condition means food passes through the stomach more slowly than usual. It’s not always clear what leads to gastroparesis. But in many cases, gastroparesis is believed to be caused by damage to the vagus nerve that controls the stomach muscles.

“A doctor explained it as if it was similar to diabetes. Where our bodies should be able to digest at any given moment but in ours the signals just don’t always get there. Resulting in a case of this food ready and there but unable to be digested for my self it always results in diarrhoea and horrible stomach pains. But as with everything with this disease it varies greatly from person to person.”

Charcot Marie-Tooth disorder forum on Reddit

As with the above, there is virtually no information in regards to gastroparesis linked to HNPP, however, episodes of gastroparesis has been recorded in those with Charcot Marie-Tooth disorder.

The vagus nerve and HNPP

The vagus nerve helps manage the complex processes in your digestive tract, including signalling the muscles in your stomach to contract and push food into the small intestine. A damaged vagus nerve can’t send signals normally to your stomach muscles. This may cause food to remain in your stomach longer, rather than move normally into your small intestine to be digested.

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In one study, esophageal dysphagia in HNPP – the sensation of food sticking or getting hung up in the base of your throat or in your chest after you’ve started to swallow – was compared to bovine tomaculous neuropathy. In this particular condition, cows were seen to have “bilateral vagus nerve degeneration, with nerve lesions similar to those seen in tomaculous neuropathy in humans.”

The research surrounding HNPP by Brazilian scientists at the Neurology Division, Internal Medicine Department, Universidade Federal do Paraná (UFPR), however, concludes that this was seen to be “rare” and that HNPP “should be considered in the differential diagnosis of patients with atypical swallowing dysfunction.”

The bovine study should also be taken with a pinch of salt given the difference of the physiognomy between animals and humans. Authors of A Study of the Pathology of a Bovine Primary Peripheral Myelinopathy, state similar traits such as the thickening of myelin sheaths within HNPP was observed in the cows in question. At the same time, 1995 research reports: “Clinical signs of dysphagia and chronic rumenal bloat developed after weaning which were attributable to bilateral vagus nerve degeneration.”

They go on to add: “The lesions are similar to those seen in the tomaculous neuropathies
of man.”

It may be the first signs of the scientific community attempting to make the leap between hereditary peripheral neuropathy with the vagus nerve as well as autonomic-type dysfunctions attacking the digestive system. However, without the words on paper and significant credibility, it’s hard to make a judgement.

Read: When HNPP ’causes breathing problems’

HNPP · Physical Health

Can hearing be affected by HNPP?

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A discussion about the effect of HNPP on hearing arose in a group forum, and the possibility of damage to the auditory nerve. Some members have said they are suffering from auditory-related issues including tinnitus and hearing loss, which could be seen as a potential manifestation of this inherited condition, but does the research back the claims?

A survey conducted by one of the groups in December 2016 showed that 41 people out of 73 individuals with HNPP suffered from tinnitus, a term for hearing sounds that come from inside your body, rather than from an outside source. This can include ringing in the ears, or even music and singing. It could be purely coincidental, or related to another underlying issue.

So what do the academics say?

How HNPP could be connected to hearing issues

In 2005, Wim Verhagen along with five other researchers from the Department of Neurology, Canisius-Wilhelmina Hospital, Nijmegen, in the Netherlands, held a study measuring sensorineural hearing impairment in participants with HNPP and hereditary motor and sensory neuropathy (HMSN-1a). A sensorineural hearing loss is damage to the hair cells in the cochlea (sensory hearing organ) or damage to the hearing nerve.

“The progressive SNHI in HNPP might be explained by the liability for exogenous factors associated with this disorder.”

Sensorineural Hearing Impairment in Patients with PMP22 Duplication, Deletion, and Frameshift Mutations – Verhagen WI et al, 2005

Sixteen patients with HNPP and another eleven with a frame shift mutation of the PMP22 gene within the same condition were given hearing tests via an audiogram. The authors found that those with HNPP had hearing regression beyond presbycusis – hearing loss that is commonly associated with natural ageing.

640px-Anatomy_of_the_Human_Ear_en.svg

They state: “Patients with HNPP showed postnatal onset at age 11 years with progression of SNHI [sensorineural hearing impairment] in excess of presbyacusis by 0.4 dB per year.” The researchers explain that after a certain age, the degree of hearing was recorded to have decreased more than the average person without this type of neuropathy.

They add: “The differences in SNHI may be explained by the differences in PMP22 expression. The progressive SNHI in HNPP might be explained by the liability for exogenous factors associated with this disorder.”

A 2015 case report produced by Martin Gencik and Josef Finsterer from the Human Genetic Laboratory in Vienna, Austria, presented a 37-year-old man with HNPP who had quite serious hearing loss after a fracture in the skull due to a gunshot behind the right ear, as well as a whole host of other issues. Without a question, it is obvious that a gunshot wound would have a significant impact on a person’s functionality, with or without HNPP.

“Since hypoacusis is a frequent phenotypic feature of HNPP, the phenotype suggested hereditary neuropathy rather than any of the other possible differential diagnoses.”

Hereditary Neuropathy with Liability to Pressure Palsies Masked by Previous Gunshots and Tuberculosis – Martin Gencik and Josef Finsterer, 2015

The authors however, attribute the man’s left-side hypoacusis – a medical term which simply means hearing impairment, a partial or total inability to hear – to HNPP stating: “Although it was initially attributed to the trauma from the gunshot, there was no explanation for hypoacusis on the left side.”

Using the 2005 study as the basis of the diagnosis, the authors go on to say: “Since hypoacusis is a frequent phenotypic feature of HNPP, the phenotype suggested hereditary neuropathy rather than any of the other possible differential diagnoses.”

The authors importantly add that a link to HNPP and cerebral cavernoma i.e. collections of small blood vessels (capillaries) in the brain that are enlarged and irregular in structure, has not been established thus the report is purely speculative.

In a German translated study, researchers at the Paediatric Centre, Olga Hospital, Stuttgart, reported that a six-year-old boy with HNPP was suffering from progressive deafness. The translated report states: “Searching for the reason of the deafness we found mild peripheral neuropathy with reduced motor nerve conduction velocity. The MR of the brain showed demyelinated lesions and CSF [cerebrospinal fluid] protein was elevated. Biopsy of the suralis nerve demonstrated thickenings of the nerve, called tomaculae, which are typical for HNPP.”

As a result, they made the assumption: “Because there were no signs of any other disease, we assume that PMP22 has also influence of central myelination or the described chromosomal deletion is responsible for the expression of a other unknown protein with a central function.”

As well-intentioned the authors may be, the report is still highly questionable and much of the diagnoses is based on conjecture.

How HNPP could not be linked to hearing issues

In a more recent report for the Acta Neurologica Scandinavica Journal, the opposite seem to have been revealed.

Researchers from the University Hospital of Leicester, UK, tested eight patients with HNPP, among 23 others with other “demyelinating neuropathies”. A demyelinating neuropathy is any condition that results in damage to the protective covering (myelin sheath) that surrounds nerve fibres. When the myelin sheath is damaged, nerve impulses slow or even stop, causing neurological or neuropathic problems.

The participants were examined on their brain stem auditory and visual responses, focusing more on the central nervous system rather than the peripheral nervous system, which is where most HNPP symptoms derive from.

“Peripheral auditory nerves may be spared in HNPP possibly due to absence of local compression.”

Optic and Auditory Pathway Dysfunction in Demyelinating Neuropathies – Knopp M et al, 2014

According to the research, there were more HNPP participants suffering from optical issues rather than peripheral auditory nerve-related problems. And brain stem involvement was “exceptional” in all groups.

The authors state that lack of hearing issues within HNPP could be down to the fact that compression is required for nerves to become damaged, adding: “Peripheral auditory nerves may be spared in HNPP possibly due to absence of local compression. Evidence for central brainstem pathology appeared infrequent in all four studied neuropathies.

“This study suggests that acquired and genetic demyelinating polyneuropathies may be associated with optic and auditory nerve involvement, which may contribute to neurological disability, and require greater awareness.”

As a fellow HNPP sufferer says the study “poses more questions than it answers” given that they provide opposing evidence to the 2005 report.

There have been frequent reports of bilateral sensorineural hearing loss in patients with various types of peripheral neuropathies including hereditary motor and sensory neuropathy [1], and hereditary sensory and autonomic neuropathy [2]. However, research is mostly based on Charcot Marie-Tooth disorder, and more widely diagnosed inherited neuropathies as well as those suffering from multimorbidities.

And while there may be a fair few HNPP sufferers with complaints of hearing loss, it’s still very unclear there is a direct correlation.

  • 1. Musiek et al., 1982; Raglan et al., 1987; Perez et al., 1988
  • 2. Denny-Brown, 1951; Hallpike et al., 1980; Wright and Dyck, 1995
HNPP · Physical Health

Do HNPP sufferers get brain fog?

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You walk into a room, knowing you’re there for a reason, but within moments you’ve forgotten why you’re there. Some sufferers of HNPP claim to suffer from forgetfulness, memory blanks, and being in a haze. I write this completely woozy, the computer screen and mobile phone a complete blur, so it will be less detailed than usual.

“Brain fog” isn’t a medical condition in itself, rather a symptom of an underlying health issue or even a side effect from a medication. It can affect your ability to think and you may feel confused or disorganised or find it hard to focus or put your thoughts into words. It can be fleeting, but for others dealing with multiple chronic conditions, it tends to last longer.

While some individuals with HNPP may face this, it’s still questionable whether it is a direct symptom of this inherited disorder.

Watch HNPP sufferer Jessica Kellgren-Fozard speak about her experiences of brain fog:

Asked if memory problems such as forgetting words or conversations, as well as losing your train of thought are common occurrences with HNPP, Gareth Parry, M.D, appears to disagree.

According to HNPP.info, the Professor and Head, Department of Neurology, University of Minnesota, says: “I am not aware of forgetfulness being a problem with HNPP patients other than related to drugs. One of the commonest causes of forgetfulness in young people is distractibility. For example, when one is anxious about an exam or some such life crisis, one tends to forget the less pressing things associated with every day life.”

“It is a possibility, but I suppose there may also be some direct effect on the brain although the protein for which the gene encodes is not a CNS protein.”

– Gareth J. Parry, M.D

While he doesn’t completely discount it, he adds: “I frequently see patients with serious illnesses have major problems with memory. If HNPP is creating significant problems perhaps it is distracting the victim from their everyday activities. It is a possibility, but I suppose there may also be some direct effect on the brain although the protein for which the gene encodes is not a CNS [central nervous system] protein.”

Cognitive fog may not be a direct symptom of HNPP, however, a 2013 study reports that some with either a duplication or deletion of the PMP22 gene, which is a fundamental tenet of the condition, had cognitive impairment.

Authors of the report Central Nervous System Abnormalities in Patients with PMP22 Gene Mutations said: “We found a decrease in the volume of WM [white matter] in 70% of patients, a reduced creatine level in WM in 28% and a cognitive impairment in 70%.”

White matter makes up half the human brain and has only recently been linked to cognition, the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses. Research suggests that “white matter tracts mediate the essential connectivity by which human behaviour is organised, working in concert with grey matter to enable the extraordinary repertoire of human cognitive capacities.”

White matter HNPP hereditary neuropathy

Writing in the Journal of Neurology, Neurosurgery, and Psychiatry, researchers of the above 2013 study say that the results showed that 47 per cent of the patients with HNPP and those with CMT1A had “abnormal” levels of white matter volume, creatine level in white matter as well as cognitive testing.

They conclude: “The study demonstrates that altered PMP22 gene expression induces significant CNS alterations in patients with HNPP and CMT1A, including cerebral WM abnormalities and cognitive impairment.”

In the 2013 edition of Nervous System Diseases: New Insights for the Healthcare Professional, reporters from VerticalNews based in Strasbourg, France, reiterates the research, quoting the authors above: “Mutations of the peripheral myelin protein-22 (PMP22) gene are the most common cause of inherited diseases of the peripheral nervous system (PNS), with its deletion resulting in hereditary neuropathy with liability to pressure palsies (HNPP), and its duplication inducing Charcot Marie-Tooth 1A (CMT1A) diseases.

“Although mainly expressed in the PNS, PMP22 mRNA and protein are also present in the central nervous system (CNS).”

With only 30 participants tested in total, further research may be required for more definitive results.

What other causes could be a factor?

Medications

Some drugs – either prescribed or over the counter – can cause brain fog. If you take medicine and notice that your thinking isn’t as clear as it should be or you suddenly can’t remember things, it might be worth asking your medical practitioner if there is an alternative or if the side effects will pass.

Chronic Fatigue

An obvious part of feeling ‘foggy’ is dealing with chronic fatigue. With chronic fatigue, your body and mind are tired for a long time. You may feel confused, forgetful, and unable to focus.

Sleep

You need sleep to help your brain work the way it should, but too much can make you feel foggy, too. Aim for 7 to 9 hours.

Blogger Mark from Developing The Human Brain recommends allowing your body to wake up slowly and begin to move slowly. He adds: “Sit up in your bed for at least 12 sec after you wake up for stabilizing your blood flow.”

Dehydration

If you’re even the slightest bit dehydrated, it’s impossible to function at your full capacity. Every single cell in your body needs water, including those in your brain and your muscles. As the brain and heart is made up of 73 per cent water, it is the first organs to show signs of dehydration. Mild dehydration may affect your ability to take on mental tasks and cause you to feel foggy headed, according to a study from the British Journal of Nutrition.

Tips to reduce brain fog
  • Sleep – get enough sleep at night and stick to a reasonable bedtime. Also, find ways to manage mental and emotional stressors, such as conscious breathing or purposeful exercise.
  • Take note – either write down anything you need to do or create reminders and lists. Whether using post-it notes, a notebook, calendars or whatever works for you personally, all of these things help keep a record of what you need to remember.
  • Ask for help – if you have people around you, ask them to remind you of anything important.
  • Mobile apps – there are a whole host of mobile apps that can help you plan ahead including:
    • Cozi – marketed as a “family app”, you can keep everyone’s activities and appointments; as well as create and share shopping lists, chores.
    • MedCoach – medical app that helps you remember to take your medications and pills at the right time and day.
    • Evernote – you can capture, organise, and share notes from anywhere including taking pictures, websites, and making voice notes. It can be synced as well.
    •  Todoist – like Evernote – automatically syncs wherever you log in, which is useful for those moments of clarity when you need to write something down quickly.
  • Vitamin D – increased exposure to sunlight may help you to think more clearly. “The beauty of nature will give your prefrontal cortex – the area of your brain that helps you focus – an opportunity to recharge,” says neurologist Marie Palinski, at Massachusetts General Hospital.
  • Flare-up tool kit – just like with chronic pain, you may need to put everything you need to help you make it through your flare in the same place/in a flare-up tool-kit box.
  • Engage yourself – reading a book, seeing a play, or working a crossword puzzle or word game challenges your mind and stimulates your brain and your memory.  Dr Palinski, also a faculty member at Harvard Medical School and author of Beautiful Brain, Beautiful You says, “When stuck in a rut, we’re constantly treading the same brain pathways. Engaging in a new activity literally wakes up our brains.” That’s because the brain has to lay new neural pathways to process new information. At the same time too much stimulation can be overwhelming.
  • Postpone engagements – when you’re too tired and full of fog to think, put things off until the next day and get extra rest instead. Listen to the needs and signals your body gives. Use the presence of brain fog as a signal to slow down.
  • Manage your environment – move to a quiet place to minimise distractions when you are trying to concentrate. Reducing clutter in your living space helps you to be more organised, and remember where things are. Create a daily routine for yourself. Sticking to a routine may help you remember what tasks you have to do each day, and in what order to do them.
  • Relaxation techniques – relaxing activities such as yoga, tai chi and meditation can improve problems with sleep, fatigue, poor memory and anxiety – all of which are linked to brain fog, according to many studies.

While not everyone suffers from memory issues or general forgetfulness, it’s good to be prepared for any circumstance when you end up in a daze.

Read: When small tasks become daunting with HNPP

HNPP · Physical Health

When HNPP ’causes breathing problems’

Lungs

If you didn’t think it was possible, but some individuals with HNPP claim they suffer from breathing problems due to anomalies with certain nerves. Breathing problems associated with hereditary neuropathy are often ignored because most doctors don’t know they can be part of the disorder.

While hyperventilation is less common, weakness of the thoracic diaphragm, which enables people to breathe, and the nerve linked to it is suggested to cause problems with breathing.

Disclaimer: Please ask your medical practitioner or doctor for more information. This article is based on various research, journals and testimonies.

Why does it happen?

HNPP makes the nerves very susceptible to trauma, which plays a pivotal role when it comes to the act of inhaling and exhaling. There are several major issues that create specific problems:

Hypoglossal Nerve

The hypoglossal nerve is the twelfth paired nerve in the brain. Its name is derived from ancient Greek, ‘hypo‘ meaning under, and ‘glossal’ meaning tongue. The nerve has a purely somatic motor function, innervating the majority of the muscles of the tongue.

According to the 2015 study Disorders of the Lower Cranial Nerves by authors Josef Finsterer and Wolfgang Grisold, the nerve directs not only voluntary activities of the tongue, but also involuntary functions, such as clearing the mouth of saliva by swallowing. They report that some people with HNPP have been reported to have issues with this specific nerve. The authors state: “Another [lower cranial nerve] involved in HNPP is the hypoglossal nerve. The affection of the hypoglossal nerve has been also reported in other types of hereditary neuropathy.”

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Researchers at the Department of Neurobiology, Tokyo Metropolitan Institute for Neuroscience, say that there is a distinct link between swallowing and breathing. Using six rats, they report: “The XII nerve activity preceding that of the phrenic nerve (pre-I XII nerve activity) was markedly exaggerated during periods when this relation was disrupted”.

The phrenic nerve plays an important role in breathing because the nerve originates in the neck passes down between the lung and heart to reach the diaphragm. It is responsible for controlling the contractions of the diaphragm, which allows the lungs to take in and release air and make us breathe properly. During the above experiment with the rats, the authors say that “nerve activity was also shown to couple with swallowing in the same manner as ‘real’ inspiratory activity.”

You may experience this when your breath arrests for a moment while attempting to swallow, which brings me neatly on to the significance of the phrenic nerve.

Phrenic Nerve

Nerve fibres of the phrenic nerve, spinal nerves, and laryngeus recurrens nerve project to the diaphragm, abdominal, intercostal, and laryngeal muscles. While it is considered “exceptional”, some HNPP sufferers do face these symptoms.

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In the 2016 report Laryngeal and Phrenic Nerve Involvement in a Patient with Hereditary Neuropathy with Liability to Pressure Palsies, the participant is said to have had vocal cord paralysis as well as “latency of the right phrenic nerve” and reduced right hemi-diaphragm – the muscle that separates the chest cavity from the abdomen and that serves as the main muscle of respiration.

The study suggests that a person with comorbidity, or someone who suffers from several separate illnesses which in this case was chronic obstructive pulmonary disease (COPD), can consequently end up with breathing issues. They also say that this was rectified through COPD treatment. Potential weight loss from HNPP could be a triggering factor.

This video by Professor Mary Reilly from the National Hospital for Neurology in London, UK, explains breathing issues for those suffering from the inherited condition Charcot Marie-Tooth syndrome:

Brachial plexopathy can be an issue withh HNPP sufferers. It is a form of peripheral neuropathy which occurs when there is damage to the brachial plexus, an area on each side of the neck where nerve roots from the spinal cord split into each arm’s nerves. Nerves outside the brachial plexus, extends from the spinal cord, through the cervicoaxillary canal in the neck, over the first rib, and into the armpit.

The phrenic nerve receives stimuli from parts of both the cervical plexus and the brachial plexus of nerves. As Satish Khadilkar and Snehaldatta Khade state in the Official Journal of Indian Academy of Neurology: “Hereditary neuropathy with pressure palsies can present phenotypically like acute brachial plexopathy. But, unlike the classical phenotype, recurrence is unusual.”

Hence damage to this area could potentially weaken signals and cause breathing difficulties.

How likely is it occur?

However, it’s important to note that respiratory issues are more common with the inherited condition Charcot Marie-Tooth syndrome. In a 2016 study including 49 patients with genetically confirmed CMT or HNPP, those with a duplication of the PMP22 gene as well as those with a mutation of the MPZ gene were more likely to face issues with breathing. The HNPP participants were recorded not to have faced respiratory problems.

The authors of Underestimated Associated Features in CMT Neuropathies say that those with the CMT2-I/J (Charcot Marie-Tooth syndrome Type 2) condition had certain mutations in the MPZ gene causing “respiratory insufficiency”, which obviously reiterates the rarity of this occurring when a person suffers from HNPP.

This video, made by CMTA, explains what’s going on in more detail:

The organisation CMT UK has recommended the following, which may be applicable to those with HNPP if you feel that you are suffering from breathing issues.

What to do if you think you’re having breathing difficulties

  • Have your doctor send you to a cardio-pulmonary specialist for a sleep study.
  • Suggest that your maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) be tested both sitting and lying down.
  • If you are having bad morning headaches you could be retaining CO2. The above tests will show that.
  • You can elevate the head (from the waist) of your bed two or three inches by putting bricks under the legs or a suitcase under the mattress.
  • You can keep your weight down.
  • Make sure you have had a pneumonia and flu vaccinations (ask your GP) and treat respiratory infections aggressively.

As mentioned, breathing problems is rather a rare symptom to be associated with HNPP. That being said, there is still a lot of research to be undertaken to establish other symptoms associated with the condition. The main thing is not to hold back and visit your medical practitioner if you feel there may be a problem.

Read: Can HNPP lead to bone-related issues?

HNPP · Physical Health

Can HNPP lead to bone-related issues?

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There appears to be a common trend of patients with HNPP having joint-related issues, which seems to go hand-in-hand with the fact that over-compensation on certain limbs, nerve damage, and issues with the feet eventually leads to problems with bones in general.

From osteoporosis to bone spur, entrapments of the nerves can cause a range of complications. Damage due to bone and joint problems at the elbow can be exacerbated by chronic pressure on the elbow and full elbow flexion and vice versa.

Disclaimer: Please ask your medical practitioner or occupational therapist for more information. This article is based on various research, journals and testimonies.

Why does it happen?

Compression of the nerves is an inability to transmit nerve impulses because compression has damaged nerve fibres either directly, or indirectly by restricting their supply of oxygen.

According to the 2000 study Is Bone a Target-Tissue for the Nervous System?, the authors state that there is strong evidence to suggest that bone can be a “target” of the nervous system.

The authors describe: “it seems reasonable that neural control could also apply to bone tissue, and several clinical and experimental observations support this concept, including Charcot’s neuropathy”.

“The distribution of different nerves during bone formation, combined with the observed effects of transmitters on bone metabolism in vitro, suggest that there is neuroendocrine regulation of bone physiology.”

“Is Bone a Target-Tissue for the Nervous System?” – García-Castellano, J. et al, Nov. 2014

Although there are few nerve fibres in bone, their presence may represent sophisticated and specialised regulatory elements able to deliver time- and site-specific stimuli according to demand.  This suggests that the peripheral nervous system is critically involved in bone metabolism, osteogenesis, and bone remodelling through nerve fibres. Various cells of the musculoskeletal system have receptors for sensory and sympathetic neurotransmitters.

This can be seen in the research Neurogenic Arthropathy and Recurring Fractures with Subclinical Inherited Neuropathy. Neurogenic Arthropathy, common in the hereditary condition Charcot Marie-tooth syndrome, is where due to damaged pain perception and position sense, the bones in the foot can rapidly degenerate. The authors say that patients with neuropathic arthropathy also suffer from recurrent long bone fractures owing to underlying sensory neuropathy.

With fractures, the researchers of the 2000 study for the Iowa Orthopaedic Journal explain: “This difference in healing may imply that in fractures with an abnormal nerve supply the sensory innervation does not recognize anomalous movement of the fracture and, with unstable fixation, nerves may mediate signals that lead to altered bone healing.”

They also suggest that with a neurectomy (surgical removal of all or some of the nerve), bones were less likely to grow back adequately, instead there is a decrease in bone mass.

How can nerves become compressed?

Compression can come from herniated discs in the spine, osteoarthritis can cause bone spurs that can compress a nerve, severe muscle injuries can compress nerves, and even prolonged use of tight clothing such as shoes or skinny jeans. It all depends on the nerve compressed.

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This type of pathology produces pain called radicular pain or nerve root pain leading to pain that may radiate to other parts of the body, such as from the low back down the leg or from the neck down the arm. Leg pain from a pinched nerve is usually described as sciatica.

With a herniated disc most compressed nerves will cause inflammation. This is likely to cause problems when the nerve is squashed between the disc and an adjacent bone.

What happens with injuries?

Traumatic injuries caused by accidents for example, can cause nerves to be partially or completely severed, crushed, compressed, or stretched, sometimes so forcefully that they are partially or completely detached from the spinal cord. Broken or dislocated bones can exert damaging pressure on neighbouring nerves, and slipped disks between vertebrae can compress nerve fibres where they emerge from the spinal cord.

What are the different types of musculoskeletal pain?

Musculoskeletal pain has varying symptoms and causes. Some of the more common types of pain include:

  • Bone pain: This is usually deep, penetrating, or dull. It most commonly results from injury. It is important to be sure that the pain is not related to a fracture or tumour.
  • Muscle pain: This is often less intense than bone pain, but it can still be debilitating. Muscle pain can be caused by an injury, an autoimmune reaction, loss of blood flow to the muscle, infection, or a tumour. The pain can also include muscle spasms and cramps.
  • Tendon and ligament pain: Pains in the tendons or ligaments are often caused by injuries, including sprains. This type of musculoskeletal pain often becomes worse when the affected area is stretched or moved.
  • Fibromyalgia: This is a condition that may cause pain in the muscles, tendons, or ligaments. The pain is usually in multiple locations and can be difficult to describe. Fibromyalgia is usually accompanied by other symptoms.
  • Joint pain: Joint injuries and diseases usually produce a stiff, aching, “arthritic” pain. The pain may range from mild to severe and worsens when moving the joint. The joints may also swell. Joint inflammation (arthritis) is a common cause of pain.
  • “Tunnel” syndromes: This refers to musculoskeletal disorders that cause pain due to nerve compression. The disorders include carpal tunnel syndrome, cubital tunnel syndrome, and tarsal tunnel syndrome. The pain tends to spread along the path supplied by the nerve and may feel like burning. These disorders are often caused by overuse.

How is musculoskeletal pain diagnosed?

Your doctor will begin by conducting a thorough medical history. They will then look for possible causes of your pain, and will also ask if the pain is ongoing or acute.

The doctor will then conduct a hands-on examination looking for the source of the pain. This may include palpating the affected area. This helps him or her locate the origin of the pain. However, to determine the underlying cause of the pain, the doctor will often follow the exam with laboratory tests and X-rays.

How is musculoskeletal pain treated?

Different types of physical therapy, or mobilisation, can be used to treat people with spinal alignment problems.

Medications such as nonsteroidal anti-inflammatories (NSAIDs) may be used to treat inflammation or pain.

In patients with musculoskeletal disorders such as fibromyalgia, medications to increase the body’s level of serotonin and norepinephrine (neurotransmitters that modulate sleep, pain, and immune system function) may be prescribed in low doses.

As if HNPP is not enough to deal with, it seems that there is a corresponding issue of joint problems. In this case, you may have to be extra careful with certain activities that may aggravate both issues, such as walking where it may not only cause numbness in the legs, but actual pain on the bone itself. Keeping vigilant is going to be absolutely vital as a result.

Read: Coping with multiple conditions including HNPP