Tag: channelopathies

A Woman With Multiple Neuropathic Symptoms, Hypersensitivity to Heat, Peppers, and Alcohol, With a Variant in the TRPV1 Capsaicin Receptor Gene: Possible Implications to ME/CFS

Abstract:

Transient receptor potential vanilloid 1 (TRPV1) is a ligand and heat-gated ion channel expressed on nociceptors that plays a central role in thermal and chemical pain signaling. Loss-of-function variants in TRPV1 have been associated with reduced nociception. We report a 65-year-old woman with disabling polyneurofunctional/neuropathic symptomatology including migraine, functional gastrointestinal disorders, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Diagnostic evaluation revealed sensory polyneuropathy and autonomic instability. Whole genome sequencing reanalysis identified a heterozygous TRPV1 c.2174A > T (p.Lys725Met) Likely Pathogenic variant that is very rare and highly conserved.

Our patient reports consistent, longstanding, marked hypersensitivity to heat, capsaicin, and alcohol, all of which are known TRPV1 agonists, supporting a gain-of-function mechanism for this variant. Furthermore, prior studies have implicated TRPV1 hyperactivity in migraine, nociceptive sensitization, and ME/CFS. Despite the excellent clinical correlation, causality of the variant cannot be definitively established without functional studies.

This case expands the potential phenotypic spectrum associated with TRPV1, and highlights a possible role for TRPV1-mediated channelopathies in complex neurofunctional disorders including ME/CFS.

Source: Zimmermann PM, Boles RG. A Woman With Multiple Neuropathic Symptoms, Hypersensitivity to Heat, Peppers, and Alcohol, With a Variant in the TRPV1 Capsaicin Receptor Gene: Possible Implications to ME/CFS. Case Rep Genet. 2026 Nov 3;2026:1920171. doi: 10.1155/crig/1920171. PMID: 42979319; PMCID: PMC13729082. https://pmc.ncbi.nlm.nih.gov/articles/PMC13729082/ (Full text)

Altered TRPM7-Dependent Calcium Influx in Natural Killer Cells of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystemic condition. The pathomechanism of ME/CFS remains unestablished; however, impaired natural killer (NK) cell cytotoxicity is a consistent feature of this condition. Calcium (Ca2+) is crucial for NK cell effector functions.
Growing research recognises Ca2+ signalling dysregulation in ME/CFS patients and implicates transient receptor potential ion channel dysfunction. TRPM7 (melastatin) was recently considered in the pathoaetiology of ME/CFS as it participates in several Ca2+-dependent processes that are central to NK cell cytotoxicity which may be compromised in ME/CFS. TRPM7-dependent Ca2+ influx was assessed in NK cells isolated from n = 9 ME/CFS patients and n = 9 age- and sex-matched healthy controls (HCs) using live cell fluorescent imaging techniques.
Slope (p < 0.05) was significantly reduced in ME/CFS patients compared with HCs following TRPM7 activation. Half-time of maximal response (p < 0.05) and amplitude (p < 0.001) were significantly reduced in the HCs compared with the ME/CFS patients following TRPM7 desensitisation.
Findings from this investigation suggest that TRPM7-dependent Ca2+ influx is reduced with agonism and increased with antagonism in ME/CFS patients relative to the age- and sex-matched HCs. The outcomes reported here potentially reflect TRPM3 dysfunction identified in this condition suggesting that ME/CFS is a TRP ion channelopathy.
Source: Du Preez S, Eaton-Fitch N, Smith PK, Marshall-Gradisnik S. Altered TRPM7-Dependent Calcium Influx in Natural Killer Cells of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Biomolecules. 2023; 13(7):1039. https://doi.org/10.3390/biom13071039 https://www.mdpi.com/2218-273X/13/7/1039 (Full text)

Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response

Abstract:

The exacerbation of symptoms after exercise differentiates Chronic fatigue syndrome (CFS) from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune deregulations in CFS patients. This manuscript explores the hypothetical interactions between these two separately reported observations.

First, it is explained that the deregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in CFS patients.

Second, the activation of the protein kinase R enzyme, a characteristic feature in at least subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasodilation, which may limit CFS patients to increase blood flow during exercise, and may even cause and enhanced postexercise hypotension.

Finally, it is explored how several types of infections, frequently identified in CFS patients, fit into these hypothetical pathophysiological interactions.

 

Source: Nijs J, De Meirleir K, Meeus M, McGregor NR, Englebienne P. Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. Med Hypotheses. 2004;62(5):759-65. http://www.ncbi.nlm.nih.gov/pubmed/15082102

 

The symptoms of chronic fatigue syndrome are related to abnormal ion channel function

Abstract:

The pathogenesis of chronic fatigue syndrome (CFS) is unknown but one of the most characteristic features of the illness is fluctuation in symptoms which can be induced by physical and/or mental stress. Other conditions in which fluctuating fatigue occurs are caused by abnormal ion channels in the cell membrane.

These include genetically determined channelopathies, e.g. hypokalemic periodic paralysis, episodic ataxia type 2 and acquired conditions such as neuromyotonia, myasthenic syndromes, multiple sclerosis and inflammatory demyelinating polyneuropathies.

Our hypothesis is that abnormal ion channel function underlies the symptoms of CFS and this is supported also by the finding of abnormal cardiac-thallium201 SPECT scans in CFS, similar to that found in syndrome X, another disorder of ion channels. CFS and syndrome X can have identical clinical symptoms. CFS may begin after exposure to specific toxins which are known to produce abnormal sodium ion channels.

Finally, in CFS, increased resting energy expenditure (REE) occurs, a state influenced by transmembrane ion transport. The hypothesis that ion channels are abnormal in CFS may help to explain the fluctuating fatigue and other symptoms.

Comment in:

Chronic fatigue syndrome and channelopathies. [Med Hypotheses. 2000]

Re: Letter from professors Waxman and Ptacek (Med Hypotheses 2000; 55: 457). [Med Hypotheses. 2000]

 

Source: Chaudhuri A, Watson WS, Pearn J, Behan PO. The symptoms of chronic fatigue syndrome are related to abnormal ion channel function. Med Hypotheses. 2000 Jan;54(1):59-63. http://www.ncbi.nlm.nih.gov/pubmed/10790725