Sodium Channelopathies

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The α-subunit of voltage gated sodium channels have four homologous domains (I–IV).

Voltage gated sodium channels are transmembrane polypeptides. The α-subunits are made up of four domains (I-IV). Each domain has six helical transmembrane segments that span the lipid bilayer (S1-6). S1-4 control the gating, S4 senses voltage, while S5 and S6 form hydrophobic pore for ion conduction. There is also an ancillary beta unit for anchoring and kinetics.

Sodium channels can be in one of three states, closed, open, and inactivated.

They are vital for the generation of action potentials (See also Basic Neurophysiology and Channelopathies and Chronic Pain).

Classification

Disease associated mutations have been identified for all major voltage-gated ion channels (Na+, K+, Ca2+, Cl-) and several ligand gated channels (incl. Ach, Gly, GABA). The sodium channelopathies are amongst the most well researched.

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	Function	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, DRG, peripheral neurons and cardiac myocytes	Rapid activation and inactivation, 3x faster recovery after hyperpolarization than Nav1.7	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, peripheral terminals of sensory neurons, axons, central terminals of nociceptors, Schwann cells, and neuroendocrine cells,	Produces a substantial ramp current in response to small slow depolarisation, determining nociceptor terminal threshold. May regulate neurotransmitter release at central terminals. Rapid activation and inactivation.	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	crucial for transmission of nociceptive information carrying most of the depolarising phase of the action potential in the DRG following initiation by Nav1.7. Rapid activation and slow inactivation.	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	slow gating kinetics generating persistent currents at near-resting membrane potentials and so are important in regulation of membrane excitability.	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

Dravet Syndrome (SCN1A)

Sodium channels produce action potentials, so this raises the question as to why loss of function would result in increased neural activity. The explanation lies within understanding that Nav1.1 is expressed primarily in GABAergic inhibitory neurons. So reduced activity in inhibitory neurons results in an excitatory-inhibitory imbalance (EI imbalance) favouring excitatory impulses.

While this disease is not at face value relevant to Musculoskeletal Medicine, it is a useful learning point because it shows the importance of the EI balance. EI imbalance has been implicated in non genetic conditions such as head injury whereby there may be preferential injury to the inhibitory neurons and/or preferential post-injury sprouting of excitatory neurons.

Nondystrophic Myotonias

The primary sodium channel in skeletal muscle is Nav1.4 (SCN4A). There are two different conditions caused by mutations in this ion channel

• Paramyotonia congenita – the pathogenic variant results in slowing of the fast inactivation process. The channels stay open for too long resulting in repetitive action potentials and prolonged contractions. Episodic generalised stiffness in early childhood and pain. Worsens with repeated contractions, relieved by rest.
• Hyperkalaemic periodic paralysis – mutations that cause impairment of slow inactivation process. The muscles are predisposed to be depolarised, have action potential block, and therefore paralysis

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

Resources

Voltage gated sodium channels and blockers - Li 2019.pdf - 2.07 MB (f)

Literature Review

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