Sodium Channelopathies

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Voltage gated sodium channels are transmembrane polypeptides with four domains. A pore is made with all four domains through which sodium can enter the cell. There is also an ancillary beta unit for anchoring and kinetics. They are responsible for signalling the nerve fibres for generation of action potentials (See also Basic Neurophysiology and Channelopathies and Chronic Pain).

Classification

There are nine known members of sodium channels labelled Na_v1.1 through Na_v1.9. The associated genes are named SCN1A through SCN11A (the SCN6/7A gene is part of the Na_x sub-family and has uncertain function)

Table 1. Nomenclature and some functions of voltage-gated sodium channel alpha subunits

Protein name	Gene	Expression profile	Associated channelopathies
Nav1.1	SCN1A	Central neurons, [peripheral neurons] and cardiac myocytes	febrile epilepsy, GEFS+, Dravet syndrome (also known as severe myclonic epilepsy of infancy or SMEI), borderline SMEI (SMEB), West syndrome (also known as infantile spasms), Doose syndrome (also known as myoclonic astatic epilepsy), intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC), Panayiotopoulos syndrome, familial hemiplegic migraine (FHM), familial autism, Rasmussens's encephalitis and Lennox-Gastaut syndrome
Nav1.2	SCN2A	Central neurons, peripheral neurons	inherited febrile seizures, epilepsy, and autism spectrum disorder
Nav1.3	SCN3A	Central neurons, peripheral neurons and cardiac myocytes	epilepsy, pain, brain malformations, ?trigeminal neuralgia
Nav1.4	SCN4A	Skeletal muscle	Certain non-dystrophic myotonias: Sodium channel myotonia, Paramyotonia congenita, Hyperkalaemic periodic paralysis
Nav1.5	SCN5A	Cardiac myocytes, uninnervated skeletal muscle, central neurons, gastrointestinal smooth muscle cells and Interstitial cells of Cajal	Cardiac: Long QT syndrome Type 3, Brugada syndrome, progressive cardiac conduction disease, familial atrial fibrillation and idiopathic ventricular fibrillation; Gastrointestinal: Irritable bowel syndrome;
Nav1.6	SCN8A	Central neurons, dorsal root ganglia, peripheral neurons, heart, glia cells	Epilepsy, ataxia, dystonia, tremor
Nav1.7	SCN9A	Dorsal root ganglia, sympathetic neurons, Schwann cells, and neuroendocrine cells	Gain of function: SCN9A neuropathic pain syndromes: erythromelalgia,Small fibre neuropathy, paroxysmal extreme pain disorder Loss of function: Congenital Insensitivity to Pain (CIP) a.k.a hereditary sensory and autonomic neuropathy type 2D (HSAN2D)
Nav1.8	SCN10A	Dorsal root ganglia	Small fibre neuropathy, familial episodic pain syndrome type 2, autosomal recessive neuromuscular disease and epileptic encephalopathy, Brugada syndrome, and congenital abnormalities of the kidney and urinary tract.
Nav1.9	SCN11A	Dorsal root ganglia	Small fibre neuropathy, familial episodic pain syndrome type 3, autosomal dominant hereditary sensory and autonomic neuropathy type 7 (HSAN7)
Nax	SCN7A	heart, uterus, skeletal muscle, astrocytes, dorsal root ganglion cells	none known

Clinical Features

Primary (SCN9A) Erythromelalgia

Primary Erythromelalgia is characterized by recurrent, bilateral episodes of intense burning pain, redness, warmth, and sometimes swelling, SCN9A-EM most commonly affects the feet. However, severely affected individuals may also experience involvement of the hands, legs, arms, face, and/or ears.

Paroxysmal Extreme Pain Disorder

Paroxysmal Extreme Pain Disorder typically begins during infancy or the neonatal period and includes autonomic symptoms such as skin flushing, patchy or asymmetric colour changes (harlequin), non-epileptic tonic attacks (stiffening), and fainting accompanied by a slow heart rate (syncope with bradycardia). Later manifestations involve severe, deep burning pain in the rectal, ocular, or submandibular regions, along with erythematous skin changes (flushing).

Inherited Small Fibre Neuropathy

Small Fibre Neuropathy is an adult-onset condition marked by neuropathic pain in a stocking and glove distribution, often described as burning. Autonomic symptoms may include dry eyes and mouth, orthostatic dizziness, palpitations, and bowel or bladder disturbances. Large nerve fiber functions, such as normal strength, tendon reflexes, and vibration sense, are preserved.

See Also

GeneReviews - SCN9A Pain Conditions

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