Paroxysmal extreme pain disorder

Paroxysmal extreme pain disorder is a condition characterized by skin redness and warmth (flushing) and attacks of severe pain in various parts of the body. The area of flushing typically corresponds to the site of the pain. The pain attacks experienced by people with paroxysmal extreme pain disorder usually last seconds to minutes, but in some cases can last hours. These attacks can start as early as infancy. Early in life, the pain is typically concentrated in the lower part of the body, especially around the rectum, and is usually triggered by a bowel movement. Some children may develop constipation, which is thought to be due to fear of triggering a pain attack. Pain attacks in these young children may also be accompanied by seizures, slow heartbeat, or short pauses in breathing (apnea).

As a person with paroxysmal extreme pain disorder ages, the location of pain changes. Pain attacks switch from affecting the lower body to affecting the head and face, especially the eyes and jaw. Triggers of these pain attacks include changes in temperature (such as a cold wind) and emotional distress as well as eating spicy foods and drinking cold drinks.

Paroxysmal extreme pain disorder is considered a form of peripheral neuropathy because it affects the peripheral nervous system, which connects the brain and spinal cord to muscles and to cells that detect sensations such as touch, smell, and pain.

Paroxysmal extreme pain disorder is a rare condition; approximately 80 affected individuals have been described in the scientific literature.

Mutations in the SCN9A gene cause paroxysmal extreme pain disorder. The SCN9A gene provides instructions for making one part (the alpha subunit) of a sodium channel called NaV1.7. Sodium channels transport positively charged sodium atoms (sodium ions) into cells and play a key role in a cell's ability to generate and transmit electrical signals. NaV1.7 sodium channels are found in nerve cells called nociceptors that transmit pain signals to the spinal cord and brain.

The SCN9A gene mutations that cause paroxysmal extreme pain disorder result in NaV1.7 sodium channels that do not close completely when it is turned off, allowing sodium ions to flow abnormally into nociceptors. This increase in sodium ions enhances transmission of pain signals, leading to the pain attacks experienced by people with paroxysmal extreme pain disorder. It is unknown why the pain attacks associated with this condition change location over time or what causes the other features of this condition such as seizures and changes in breathing.

Genetic Testing Information

• Genetic Testing Registry: Paroxysmal extreme pain disorder

Genetic and Rare Diseases Information Center

• Paroxysmal extreme pain disorder

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• PAROXYSMAL EXTREME PAIN DISORDER; PEXPD

Scientific Articles on PubMed

• PubMed

• Dabby R. Pain disorders and erythromelalgia caused by voltage-gated sodium channel mutations. Curr Neurol Neurosci Rep. 2012 Feb;12(1):76-83. doi: 10.1007/s11910-011-0233-8. Citation on PubMed
• Estacion M, Han C, Choi JS, Hoeijmakers JG, Lauria G, Drenth JP, Gerrits MM, Dib-Hajj SD, Faber CG, Merkies IS, Waxman SG. Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of NaV1.7. Mol Pain. 2011 Dec 2;7:92. doi: 10.1186/1744-8069-7-92. Citation on PubMed or Free article on PubMed Central
• Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, Ostman J, Klugbauer N, Wood JN, Gardiner RM, Rees M. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron. 2006 Dec 7;52(5):767-74. doi: 10.1016/j.neuron.2006.10.006. Citation on PubMed
• Fertleman CR, Ferrie CD, Aicardi J, Bednarek NA, Eeg-Olofsson O, Elmslie FV, Griesemer DA, Goutieres F, Kirkpatrick M, Malmros IN, Pollitzer M, Rossiter M, Roulet-Perez E, Schubert R, Smith VV, Testard H, Wong V, Stephenson JB. Paroxysmal extreme pain disorder (previously familial rectal pain syndrome). Neurology. 2007 Aug 7;69(6):586-95. doi: 10.1212/01.wnl.0000268065.16865.5f. Citation on PubMed
• Fischer TZ, Waxman SG. Familial pain syndromes from mutations of the NaV1.7 sodium channel. Ann N Y Acad Sci. 2010 Jan;1184:196-207. doi: 10.1111/j.1749-6632.2009.05110.x. Citation on PubMed
• Lampert A, O'Reilly AO, Reeh P, Leffler A. Sodium channelopathies and pain. Pflugers Arch. 2010 Jul;460(2):249-63. doi: 10.1007/s00424-009-0779-3. Epub 2010 Jan 26. Citation on PubMed