Microsoft word - info_sheet=scn9a_inherited pain disorders.doc
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Genetic testing of the SCN9A Gene in
Inherited Pain Syndromes
Inherited erythromelalgia (IEM); Paroxysmal extreme pain disorder (PEPD); Small fiber neuropathy
(SFN); Congenital indifference to pain (CIP)
Mendelian Inheritance in Man Number
: 603415 (SCN9A gene); 133020 (primary erythermalgia and small fiber
neuropathy); 167400 (paroxysmal extreme pain disorder); 243000 (congenital indifference to pain)
Mutations in the SCN9A gene cause several distinct clinical disorders associated with increased pain sensitivity or indifference to pain, in some cases associated with autonomic or other symptoms. Inherited erythromelalgia (IEM) is characterized by recurrent attacks of bilateral, symmetric intense pain accompanied by redness, warmth, and swelling. Onset is typically in childhood or adolescence. Symptoms are noted first in the feet, followed by the hands, and in later stages can also involve the legs, arms, face, and ears. Episodes are often triggered by warmth, exercise, alcohol, or other vasodilating agents and may eventually occur multiple times per day or become constant. Paroxysmal extreme pain disorder (PEPD), previously called familial rectal pain, is characterized by episodes of burning pain in the rectal, ocular, and mandibular pain in association with autonomic symptoms such as skin flushing, tonic-nonepileptic seizures, bradycardia, or apnea. Symptoms are typically noted at birth and are triggered by bowel movements. Over time, the episodes of rectal pain decrease, but ocular and mandibular pain becomes more prominent and may be triggered by temperature changes, eating, or emotional stress. Many individuals with PEPD respond well to treatment with carbamazepine. Small fiber neuropathy (SFN) results in neuropathic pain that is often described as burning, tingling, or stabbing and typically begins in the distal extremities. Pain is often associated with autonomic symptoms such as orthostatic dizziness, palpitations, dry eyes, and dry mouth. Some individuals report that episodes are triggered by heat or exercise. The onset is typically in adulthood. Individuals with SFN have thinly myelinated and unmyelinated small diameter nerve fibers, and the clinical diagnosis is confirmed by demonstrating reduced intraepidermal nerve fiber density (IENFD) and/or abnormal quantitative sensory testing (QST) in the presence of normal nerve conduction studies. Congenital indifference to pain (CIP) is characterized by the inability to experience inflammatory, heat, or visceral pain sensations. All other sensory, motor, and autonomic functions are normal. Affected individuals have typically exhibited bone deformities and neuropathic joints secondary to untreated injuries, self-mutilating oral and extremity lesions from biting, and a history of burn-related injuries. They also experience anosmia or hyperosmia but have normal blood pressure, tear formation, sweating, and body temperature regulation.
Mutations in the SCN9A gene causing IEM, PEPD, and SFN are inherited in an autosomal dominant manner, while mutations causing CIP follow autosomal recessive inheritance.
Reasons for referral:
1. Confirmation of a clinical diagnosis
2. To differentiate SCN9A-related pain disorders from other genetic or environmental causes of pain
3. Carrier testing for individuals with a known familial SCN9A
4. Prenatal diagnosis in at-risk pregnancies
Page 1 of 2 GeneDx Creation Date: 09/2012
The SCN9A gene encodes the voltage-gated sodium channel Nav1.7, which is expressed primarily in the dorsal root ganglia of the peripheral nervous system. The protein contains four homologous domains (DI-DIV), each of which consists of six transmembrane segments (S1-S6). Within each domain, the S4 segment is the voltage sensor, and the S5 and S6 segments and their connecting loop make up the pore region.
Analysis is performed by bi-directional sequencing of the 27 coding exons and the exon/intron splice junctions of the SCN9A
gene. Any mutation identified is confirmed by repeat analysis using sequencing, restriction fragment analysis, or other methods as appropriate.
Mutations have been identified throughout the coding region of the SCN9A
gene. IEM, PEPD, and SFN are caused by gain-of-function missense mutations resulting in neuronal hyperexcitability (Dabby et al., 2012). Whereas most IEM mutations are typically seen in the first two transmembrane domains, a majority of the PEPD mutations are found in the last two transmembrane domains (Dib-Hajj et al., 2008). CIP is caused by loss-of-function nonsense, frameshift, splice site, or missense mutations (Goldberg et al., 2007; Dabby et al., 2012).
The likelihood of detecting a mutation in the SCN9A gene depends on an individual’s clinical phenotype, and, to date, the clinical sensitivity of SCN9A sequencing has only been evaluated in a small number of patients. An SCN9A mutation was identified in 5/6 (83%) probands with IEM, 8/13 (62%) probands with PEPD, and 8/28 (29%) probands with idiopathic SFN (Drenth et al., 2005; Fertleman et al., 2006; Faber et al., 2012). Additionally, homozygous or compound heterozygous mutations in SCN9A were detected in 9/9 (100%) probands from multiple ethnicities with CIP (Goldberg et al., 2007).
Specimen Requirements and Shipping/Handling:
: A single tube with 1-5 mL whole blood in EDTA. Ship overnight at ambient temperature, using a
cool pack in hot weather. Specimens may be refrigerated for 7 days prior to shipping.
• Buccal Brushes
: Not accepted for this test.
• Prenatal Diagnosis:
For prenatal testing for a known mutation in the SCN9A gene, please refer to the
specimen requirements table on our website at: http://www.genedx.com/test-catalog/prenatal/. Ship specimen overnight at ambient temperature, using a cool pack in hot weather.
• Sample Submission (Requisition) Form – complete both sides
• Payment Options Form or Institutional Billing Instructions
For test codes, contract prices, CPT codes, and turn-around-times, please refer to the
SCN9A page on our website: www.genedx.com
: Drenth et al., (2005) J Invest Dermatol 124:1233-1238. Fertleman et al., (2006) Neuron 52;767-
774. Faber et al., (2012) Ann Neurol 71 :26-39. Goldberg et al., (2007) Clin Genet 71:311-319. Dabby R., (2012)
Curr Neurol Neurosci Rep 12 :76-83. Fischer, T.Z. and Waxman, S.G., (2010) Ann NY Acad Sci 1184:196-207.
Dib-Hajj et al., (2008) Adv in Genet 63:85-110.
Page 2 of 2 GeneDx Creation Date: 09/2012
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