RNase L and Chronic Fatigue Syndrome (ME/CFS)- A Channelopathy? An Overview from Patrick Englebienne

Nijs, J., Demanet, C., McGregor, N. R., Verhas, M., Englebienne, P. and K. De Meirleir. Monitoring a hypothetical channelopathy in Chronic Fatigue Syndrome. Journal of Chronic Fatigue Syndrome

(The ‘Belgian Research Group’ (as I think of them) responsible for most of the work on RNase L dysregulation is also in the forefront of attempts to characterize the different subtypes of CFS found. It has been apparent for several years that CFS can be invoked by different kinds of stressors (pathogens, toxins, psychological stress) and that the symptoms and the course of the disease can vary widely. The heterogeneous but still coherent patterns of symptom presentation and disease progression seen in CFS suggests that a central dysfunction capable of generating a wide variety of outcomes is present. The BRG believes that RNase L deregulation with its myriad possibilities for immune dysfunction is that central dysfunction This paper is one in an apparently continuing series that seeks, among other things, to define coherent subsets of CFS patients)

This study, while ‘preliminary’, is the first to look at ion levels in CFIDS patients and controls. The realization that RNase L fragmentation released ankyrin fragments with amino acid motifs that appear able to interact with the ABC transporters that regulate ion flow in and out of the cells sparked concerns about a channelopathy in CFS (see Pharmacogenomics Introduction / I: CFS ABA IV) (Channelopathies occur when cells exhibit ion imbalances. Because cellular activity is in part a function of the ion levels in cells, a channelopathy can disrupt cellular activity.)

The researchers compared ion levels in CFS patients and controls. As so often occurs in CFIDS the results are mixed and may be confounded to some degree by the inadequacy of the current testing techniques. Fifty percent of CFS patients had abnormal whole body potassium content. In a display of heterogeneity that researchers must (with a sigh) expect from CFS patients, about 60% of the patients had high and 40% low whole body potassium levels.

The authors note that because whole body potassium measures do not reveal potassium distribution patterns in the tissues or between intra and extracellular stores they are not sensitive enough to monitor discrete channelopathies. In an attempt to partially get around this the authors calculated the ratio of serum (extracellular) to non-serum (intracellular) potassium. Because the ratio of serum potassium to non-serum potassium was higher than was expected they concluded that a channelopathy involving intracellular potassium loss was suggested in about half of CFS patients

The SUR I channel controlling intracellular potassium levels seemed a likely candidate for malfunction in CFS patients. (The SUR I (sulfonylurea receptor) ATPase dependent K+ ion channel is of special interest because its activity is a function of ATP activity.

Low levels of ATP cause the SUR I channel to open and release K+. Dysregulation of the SUR I channel typically causes severe muscle weakness because of severe K+ losses.) The body attempts to rebalance ion distribution caused by SUR I channel dysfunction through increased aldosterone production (by the adrenal glands) which leads to increased tubular secretion. None of the CFS patients exhibited, however, the severe K+ losses typically associated with SUR I dysregulation.

About 15% of CFIDS patients did exhibit, however, measures – low serum calcium levels and lower whole body potassium levels – suggesting that a similar scenario was occurring. (Outflows of K result in increased calcium inflows into the cell. Lower serum calcium levels could suggest increased stores of intracellular calcium.

The finding of reduced serum calcium (and probably therefore increased intracellular calcium) in these patients supports that authors suggestion that two calcium induced proteases, calpain and caspase 12, are respectively, agents of RNase L destruction and/or increased apoptosis in CFS.)

A discriminant analysis involving percent fragmented RNase L, and immune cell (NK, T and B cells) and electrolyte levels revealed that reduced NK cell counts primarily differentiated CFIDS patients from controls. Reduced NK cells were also strongly correlated with increased dominance of the 37-kDa RNase L fragment and decreased serum calcium levels.

(Since the 37-kDa fragment produces the ankyrin motifs believed to possibly disrupt ion channel functioning this finding appears (at least to this laymen) to buttress the authors theory linking RNase L dysregulation and a calcium channelopathy. This finding links, for the first time, two of the most consistently observed abnormalities in CFS; RNase L dysregulation and reduced NK cell counts. Too bad NK cell activity was not measured.)

That reductions in serum calcium levels were not accompanied, as expected, by increased serum potassium levels, indicated once again, that nothing is simple in CFS. An expected association between increased extra-cellular potassium levels and activated T-cells was not found. The authors suggest, however, that the Il-1 increases seen in some CFIDS patients may be due to a channelopathy.


The results regarding a channelopathy in CFS patients are mixed. The current technology is inadequate to fully explore a potassium channelopathy but some evidence indicates one may be present in a large subset of patients. A channelopathy involving RNase L dysregulation, decreased serum (and therefore increased intracellular) calcium levels may also be occurring in a subset of CFS patients. The authors suggest that a further exploration of the linkage between calcium homeostasis and RNase L dysregulation would be valuable.

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