Saturday, April 6, 2019

Congenital insensitivity to pain: a new etiology

A Scottish woman who feels virtually no pain has left British researchers not only astounded but looking for a way to harness her previously unidentified genetic mutation to guide new treatments for a range of conditions.

The woman's genetic microdeletion in dorsal root ganglia and brain-expressed pseudogene — which the researchers called FAAH-OUT — is consistent with a phenotype resulting from enhanced endocannabinoid signaling and a loss of function of fatty acid amide hydrolase (FAAH).

"We have identified a novel cause of human pain insensitivity in a patient with a non-anxious, happy, talkative disposition," study author James Cox, PhD, told Medscape Medical News.

"FAAH was already a heavily studied gene in the pain and anxiety fields, and FAAH inhibitors have been tested in clinical trials for pain," added Cox, senior lecturer at University College London in England…
"This case report is the first patient with a hypomorphic mutation in the FAAH gene and a microdeletion in a novel downstream gene, which we have called FAAH-OUT. FAAH-OUT is exciting as it was previously unknown and encodes a long non-coding RNA and is a potential new analgesic drug target in itself."

As surprising as the circumstances were to investigators, the FAAH gene is far from obscure in pain research. Indeed, it has previously been found to be involved in endocannabinoid signaling central to pain sensation, mood, and memory. Nevertheless, FAAH-OUT was previously assumed to be a nonfunctional "junk" gene.

However, such is not the experience of 71-year-old Jo Cameron, who has lived a virtually pain-free life…and notoriety. That began to change 6 years ago, when Cameron sought treatment for an issue with her hip. As it turns out, she was suffering from severe joint degeneration, but felt no pain. A year later, she underwent otherwise painful surgery on her hand. Once again, she felt no pain.

This has been a common occurrence throughout her life. She has often experienced burns and cuts without pain, occasionally not realizing she was burning herself until she smelled her own flesh. She has never needed painkillers after surgery, and often found that her wounds healed quickly, with little or no residual scar.

Yet as commonplace as this may have been for Cameron, it came as quite as shock to study coauthor Devjit Srivastava, MD, MBBS, from Raigmore Hospital in Inverness, Scotland, who first saw Cameron, and subsequently referred her to pain geneticists at University College London and the University of Oxford.

Quantitative sensory testing at these institutions confirmed Cameron's hyposensitivity to noxious heat in both her hands and feet. Genetic analyses were then performed.

The scientists isolated genomic DNA from Cameron, her two children, and her mother for exome sequencing. After filtering variants, they identified four candidate mutations, though none were considered likely to be causal for the phenotype. 

The investigators then broadened the genetic analyses and searched for cytogenetic copy number changes across the genome.

These tests revealed two notable mutations. Of these, one was a microdeletion in a pseudogene. Although the microdeletion had been briefly annotated in previous literature, Cox and his team described it for the first time, calling it FAAH-OUT. Cameron also had a mutation in a neighboring gene that controls the FAAH enzyme.

Interestingly, while Cameron's unaffected mother and daughter did not carry the microdeletion, her son — who also has some pain-sensitivity deficits — was heterozygous for it.

The investigators then explored ways in which the microdeletion could be pathogenic. Tissue expression analyses showed that FAAH-OUT was expressed in a wide range of tissues, including fetal and adult brain, as well as dorsal root ganglia.

Further tests by collaborators at the University of Calgary in Canada, revealed elevated blood levels of neurotransmitters that are normally degraded by FAAH. This, the scientists said, provides further evidence for a loss of FAAH function.

Although Cameron's insensitivity to pain is certainly rare, the researchers believe it may be possible that other people are living with the same mutation. Nevertheless, they continue to conduct further tests on Cameron's cell samples to help better understand her novel pseudogene…

Commenting on the case and related findings for Medscape Medical News, Frances M.K. Williams, PhD, who was not involved in the study, said there are many examples where pain-related genetic mutations have been identified in families.

"This case is unusual because the other families have shown mutations in genes coding for ion channels, which start the electrical impulses in nerves, carrying the message of touch or pain to the brain," said Williams, professor of genomic epidemiology and honorary consultant rheumatologist at King's College London in England.

Cameron's genetic profile sheds light on past — and future — efforts to develop analgesic medications based on such mutations, Williams said.

"The protein made by the FAAH gene — fatty acid amide hydrolase — has already been targeted as a possible painkiller, without much success," she said. "It is an enzyme that breaks down the cannabinoids made naturally in the body, so was an obvious choice to try and block.

"More interesting is the FAAH-OUT pseudogene. This is the first time it has been linked to pain, but we don't have much idea what pseudogenes do. It seems that the combination of two different types of genetic change in this lady leads to a very pain-resistant phenotype, as can be seen in her family, as no one else has the same two mutations that she has."

Habib AM, Okorokov AL, Hill MN, Bras JT, Lee MC, Li S, Gossage SJ, van Drimmelen M, Morena M, Houlden H, Ramirez JD, Bennett DLH, Srivastava D, Cox JJ. Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrationsand pain insensitivity. Br J Anaesth. 2019 Mar 28. pii:S0007-0912(19)30138-2. doi: 10.1016/j.bja.2019.02.019. [Epub ahead of print]

The study of rare families with inherited pain insensitivity can identify new human-validated analgesic drug targets. Here, a 66-yr-old female presented with nil requirement for postoperative analgesia after a normally painful orthopaedic hand surgery (trapeziectomy). Further investigations revealed a lifelong history of painless injuries, such as frequent cuts and burns, which were observed to heal quickly. We report the causative mutations for this new pain insensitivity disorder: the co-inheritance of (i) a microdeletion in dorsal root ganglia and brain-expressed pseudogene, FAAH-OUT, which we cloned from the fatty-acid amide hydrolase (FAAH) chromosomal region; and (ii) a common functional single-nucleotide polymorphism in FAAH conferring reduced expression and activity. Circulating concentrations of anandamide and related fatty-acid amides (palmitoylethanolamide and oleoylethanolamine) that are all normally degraded by FAAH were significantly elevated in peripheral blood compared with normal control carriers of the hypomorphic single-nucleotide polymorphism. The genetic findings and elevated circulating fatty-acid amides are consistent with a phenotype resulting from enhanced endocannabinoid signalling and a loss of function of FAAH. Our results highlight previously unknown complexity at the FAAH genomic locus involving the expression of FAAH-OUT, a novel pseudogene and long non-coding RNA. These data suggest new routes to develop FAAH-based analgesia by targeting of FAAH-OUT, which could significantly improve the treatment of postoperative pain and potentially chronic pain and anxiety disorders. 

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