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Ion Channel Gene Mutation and Pain
-  Dr. Debjyoti Dutta

Structure and function of human pain pathway is complex. It starts with the transductive processes in the periphery, conduction to the spinal cord through afferent neurons, and processing at multiple higher levels that include the dorsal horn, spinal projections, thalamus, and cortex. Transmission of painful stimulus and its processing involves different ion channels, receptors, and various chemical mediators. Certain factors of human pain experience are found to be inherited like acute pain thresholds, efficacy of analgesics. Mutation of the genes encoding for ion channels can cause heritable pain disorders by abnormal channel function or expression. The Na+ channels Nav1.7 (SCN9A) and Nav1.8 (SCN10A) are important in nociceptive pathways. These diseases caused by these gene mutations are rare but refractory to conventional treatment.

Inherited Primary Erythermalgia 

This is the first disease found to be linked with an ion channel mutation. Transmission pattern is autosomal dominant. The disease characterized by recurrent attacks of red, warm, and painful hands and feet. Pain is usually bilateral and symmetric. Pain is usually increased by standing, slight exercise, walking, and exposure to heat. Elevation and cooling of the affected extremities can give some relief. Analgesics and sedatives are only partially helpful, usually refractory to treatment and persist lifelong.

The disease sometimes resembles erythromelalgia that arises during middle age and is linked to thrombocythemia, which causes obliterative thrombosis of arterioles and digital arteries. [4]

The defect lies in chromosome 2q. 2q24.2-2q24.3 region that contains genes, SCN9A, coding for isoforms of voltage-gated sodium channel (Nav 1.7) α-subunits. These mutations primarily enhance activation of sodium channels. [5] 

Paroxysmal Extreme Pain Disorder (PEPD) 

Previously known as familial rectal pain syndrome, this is a rare autosomal dominant inherited disorder linked to SCN9A gene mutation. Mutations impair inactivation of voltage-gated sodium channel (Nav 1.7).

The disease is characterized by attacks of severe pain in various parts of the body. The pain attacks usually last seconds to minutes, but in some times can last for hours. This may be associated with flushing. Pain experienced by the patient in the anorectal region or around the eyes and submandibular region. Disease usually starts in childhood and the severity of the attacks generally diminishes with age but in some patients may persist into adulthood. Carbamazepine is found to be effective in controlling the symptoms in some PEPD patients by effectively blocking the persistent current at Nav 1.7.

Congenital insensitivity to pain (CIP)

Congenital insensitivity to pain (CIP) is a rare syndrome with various clinical expressions characterized by a dramatic impairment of pain perception since birth, but all other sensory modalities remain intact and is associated with a number of hereditary sensory and autonomic neuropathies, involving the small-calibre (A-delta and C) nerve fibers which normally transmit nociceptive inputs along sensory nerves. Nonsense mutations in SCN9A result in a loss of function in the Nav1.7 channel.

Familial hemiplegic migraine (FHM)

Familial hemiplegic migraine (FHM) is a form of migraine headache that runs in families. It is inheritated in autosomal dominant fashion, and aura symptoms may be associated with moderate to severe motor weakness, ataxia, and seizures. Mutations in the CACNA1A (on chromosome 19p3 coding for calcium channel Cav2.1), ATP1A2 (encoding the Na+/K+ ATPase α2 subunit leads to impaired pump function there by leading to loss of ion gradient at channels), SCN1A (mutation is in the highly conserved region of the sodium channel responsible for fast inactivation, and PRRT2 genes are found to cause familial hemiplegic migraine. The function of the protein produced from the PRRT2 gene is unknown although it interacts with a protein that helps control interneuronal signalling.

Familial episodic pain syndrome (FEPS)

Familial episodic pain syndrome (FEPS) is associated with episodes of upper body pain of severe intensity. The pain is triggered by fasting, physical stress, or fatigue. It was first found in a Colombian family and first disease linked with transient receptor potential channels (TRP channels). These are a group of ion channels located mostly on the plasma membrane of numerous human cell types and mediate a variety of sensations like pain, hotness, warmth, coldness, taste, pressure, and vision. A missense mutation in TRPA1 gene is found to be linked to the syndrome.


Irritable Bowel Syndrome (IBS) 

Several studies suggests a strong genetic component causing familial IBS but association of the candidate genes are yet to be found. [11]

In the field of management of chronic pain, we have not progressed a great deal. [12] Discovery of genetic mutations and of additional variants that will likely be identified in the future open up the possibility of understanding chronic pain more fully, at the molecular level. The understanding of the pain pathway at the molecular level may lead to new therapeutic strategies that will bring us closer to more effective treatments for pain.




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6.Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996;87:543-52.  

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8.Dichgans M, Freilinger T, Eckstein G, Babini E, Lorenz-Depiereux B, Biskup S, et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 2005;366:371-7.  

9.Heron SE, Dibbens LM. Role of PRRT2 in common paroxysmal neurological disorders a gene with remarkable pleiotropy. J Med Genet 2013;50:133-9.  

10.Kremeyer B, Lopera F, Cox JJ, Momin A, Rugiero F, Marsh S, et al. A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron 2010;66:671-80.  

11.Saito YA, Talley NJ. Genetics of irritable bowel syndrome. Am J Gastroenterol 2008;103:2100-4.  

12.Prithvi Raj P, Erdine S. Pain-relieving procedures: The illustrated guide. 1 st ed. Ch. 1. p. 7.  

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