If I look at my total symptom list,
- Neuropathic- Multi-focal – pins, needles, loss of sensation, weakness,
- Migraines:- Prolonged auras, vestibular symptoms,
- Meniere’s Disease:- deafness, tinnitus, vertigo,
- Respiratory:- Asthma,COPD, diaphragmatic weakness and Intercostal muscle neuropathy,
- Cardiac Arrhythmias,
- Difficulties swallowing (intermittent and probably neuropathic – ie laryngeal palsies)
- Unstable joints:- neuropathic,
- Fatigue:- periods of unremitting tiredness after minimal exertion
I match the ME / CFS / FMS list almost in it’s entirety. But I don’t think I have that at all. Chronic fatigue, yes, but not syndrome, as I think it’s perfectly rational to think that HMSN amongst other things (Meniere’s, Migraine, IBS etc), is a great contributor to this. Just the physical effort of fighting against the ever changing weakness and loss of sensation, which seems to follow every activity I do, or at least those activities where repetitive movement, high impact strength or a combination of the two is required. Not only does this affect the muscles that are inefficiently innervated, but also the muscles that are needed to help compensate for this varying weakness. Then there’s the secondary strain on ligaments and tendons and the joints that they are attached to. Fatigue can be quite devastating after fairly trivial activity one day, and then bearable on the next, generally though I now need a longer recovery period. It makes it very difficult to judge just how much energy is available for any given task.
However, it might be that HNPP actually has a further complicating factor within the actual deletion itself. PMP22 is not the only gene affected in the deleted region.
For example. What about the effects of the COX10 gene? It is also disrupted by the HNPP/CMT1a mutation, in the case of HNPP there is one working copy, and one which has the last section of this gene deleted. With CMT1a there should be two copies plus an extra part of the gene. This may mean that the effects of this are more likely to manifest in those with HNPP rather than CMT1a… but I’m guessing…
COX10 is thought to cause a whole range of Mitochondrial diseases, which may well account for some of fatigue symptoms, and a large potential for far more besides. For it to be symptomatic, in a person with HNPP, other genes may need to be mutated. Unlike PMP22, COX10 isn’t thought to be a Dosage sensitive gene, and or environmental factors or other illness may be triggering factors. But it might account for the wide variability of expression for HNPP, or for as yet unrecorded and unknown phenotypes. If so the effects would manifest as wide ranging symptoms not necessarily confined to the Peripheral Nervous System (PNS). It is unlikely that this causes florid clinical disease, as these would have been previously noted, but it may have implications for the development of disorders such as FMS, CFS and ME, the diagnosis of which occurs rather too often in the HNPP community. There has been much speculation and hypotheses about the role of mitochondrial function and CFS, ME and Fibromyalgia, there have however been few medical studies to support this, but it is an evolving field of study, and it would still seem very possible that mitochondrial function might be a great contributor to these syndromes, at least for some people.
It’s also quite interesting that other CMT types have been found to be caused by other genes which have an effect on the function of mitochondria. One form of CMT2 has a mutation of the Mitofusin2 MFN2, and yet another form of CMT2 by the neurofilament light gene, which also seems to affect the mitochondria.
So it has been established that mitochondrial disruption in critial nerve cells, is a potential cause for neuropathy.
What about pmp22 and the other genes disrupted, duplicated or deleted with the common CMT1a / HNPP mutation? Is it possible that not only PMP22 is responsible for the neuropathy, is there some interaction going on that could be modified by other genetic (normally benign) factors, hence leading to a wide range in variability, and potentially other symptoms which are outside of the current medical model.
There is a study by Michael Shy and team, which would suggest that only pmp22 is responsible for the neuropathy of HNPP. So this would discount that the other mutated genes would have an effect on the neuropathy. But this research does not consider signs and symptoms outside of their pre-defined model of HNPP. They were only looking to confirm the known neuropathic aspect, not any other system wide signs and symptoms. And in the confines of this research it would seem to suggest HNPP can be fully described by the pmp22 deletion. That is an HNPP that only causes painless palsies, multi-focal PNS lesions in response to minimal pressure or mechanical trauma, and a diffuse length-dependent mild polyneuropathy.
However, it is my belief that the deletion responsible for HNPP has far wider effects that while not causing significant clinical disease, may affect many other body functions. However as these are outside of the neurological sphere of thought, they are usually dismissed or attributed to other causes. The division of labour, specialisms, impedes medical research. The patient will experience this as being bounced from one speciality to another, whilst important observations are lost, dismissed or discounted.
It was really quite startling but not surprising that in the recent British TV show, Britain’s Missing Top Model, that one contestant with HNPP also suffered from unilateral deafness, Blindness in one eye thought to be related to Migraines, and had a co-diagnosis of Myalgic Encephalopathy.
While physicians (Neurologists and Geneticists) continue to describe HNPP as mild in comparison to other HMSNs, further research and possibly cures and treatments not only for HNPP but for CMT1a and other CMT types will remain elusive. It is time to stop this arbitary ‘clinical’ selectivism and to start to study science.