Neurology and genetics: JNNP leads the way.

Recently I was at a weekend lunch when I was quizzed by a recently retired general practitioner about what exactly I did on a day-to-day basis. I went through the usual spiel about research and teaching and the need to quarantine time for these pursuits, given the potentially large clinical load that one could end up taking on. I mentioned that I saw patients in areas of research interest, mainly neuromuscular disease and MS. After listening to this for about a minute, he turned to me and said, “so you are gradually getting to know more and more about less and less”. Bullseye.

On reflection though, that has to be the way of the future and this month’s cracking issue of JNNP http://jnnp.bmj.com/content/current only serves to highlight this point: SOD1, C9ORF72, TARDP, FUS, C12ORF65, ADCK3, Profilin1 E117G. What are these? They are not secret CIA codes, just names of genes that may play a role in both rare and relatively common neurological disorders. In this regard, Neurologists, it is time to starting becoming ‘neurogenetically literate’. With respect to this issue of the journal, I am talking about conditions such as amyotrophic lateral sclerosis, inherited neuropathy and cerebellar ataxia. Patients with these conditions may appear to all and sundry as suffering from rare diseases, but ultimately discussions of incidence and prevalence or of little value to these people….suffering is suffering, discomfort is discomfort and to deliver truly excellent subspecialist care for these patients, we are being called upon to rapidly integrate recent research findings, which seem to be accruing at lightning speed, with what we are seeing at the bedside. This speed of Bench to Bedside translation is not for the faint hearted!

The most fascinating aspect of this new genetics is that we are no longer talking about conditions which follow true Mendelian inheritance. These are not disorders that can be conveniently segregated into dominant and recessive inheritance-sometimes yes, but not always. We are now increasingly looking at the role of ‘genetic’ factors in ‘sporadic’ disease. While this may sound like an oxymoron, I use one of the papers in this issue as an example.  Han and colleagues (1) http://jnnp.bmj.com/content/85/5/499.abstract have investigated the role of genetic mutations in the development of small fibre neuropathy, a condition which causes intense pain and burning in limbs. This is a common condition that causes significant morbidity and poor quality of life. Many patients with this condition are either of middle age or elderly and there is hardly ever any point in taking a genetic history or drawing a pedigree. In many patients, we never identify a cause for the small fibre dysfunction and simply label the condition as ‘idiopathic’, which is frustrating for everyone and most of all for the patient. In this paper, the authors have provided strong evidence that a mutation in a gene coding for a sodium channel may be the underlying cause in many of the cases which we (possible erroneously) label as idiopathic. Will these findings change the way that we manage these patients? Not at the moment it won’t, but very possibly in the future as we develop drugs that are capable of targeting certain type of sodium channels. In the meantime, as most neurologists would know, we may soon be able to alleviate some of the mental anguish that a patient feels when a doctor tells them that there is simply no known reason for why they developed a particular neurological disorder and that is progress in itself.

(1)    Han et al., The G1662S NaV1.8 mutation in small fibre neuropathy: impaired inactivation underlying DRG neuron hyperexcitability. J Neurol Neurosurg Psychiatry2014;85:499-505 doi:10.1136/jnnp-2013-306095

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