2.1. Congenital insensitivity to pain

At least 13 mutations in the SCN9A gene have been found to cause congenital insensitivity to pain, a condition that inhibits the ability to perceive physical pain. The SCN9A gene mutations that cause congenital insensitivity to pain create a premature stop signal in the instructions for making the alpha subunit of the NaV1.7 sodium channel. As a result, a shortened, nonfunctional subunit is produced which cannot be incorporated into the channel, leading to a loss of functional NaV1.7 sodium channels. The loss of these channels impairs the transmission of pain signals from the site of injury to the brain, causing those affected to be insensitive to pain. Loss of this channel in olfactory sensory neurons likely impairs the transmission of smell-related signals to the brain, leading to a complete loss of the sense of smell (anosmia).

2.2. Erythromelalgia

More than 10 mutations in the SCN9A gene have been found to cause erythromelalgia, a condition characterized by episodes of pain, redness, and swelling in various parts of the body, particularly the hands and feet. All identified mutations change one protein building block (amino acid) in the NaV1.7 sodium channel. These mutations result in a NaV1.7 sodium channel that opens more easily than usual and stays open longer than normal, increasing the flow of sodium ions that produce nerve impulses within nociceptors. This increase in sodium ions enhances transmission of pain signals, leading to the signs and symptoms of erythromelalgia.

2.3. Paroxysmal extreme pain disorder

Approximately 10 mutations in the SCN9A gene have been found to cause paroxysmal extreme pain disorder. This condition is characterized by severe pain attacks accompanied by skin redness and warmth (flushing) and, sometimes, seizures and changes in breathing and heart rate. The mutations that cause this condition change single amino acids in the alpha subunit of the NaV1.7 sodium channel. As a result, the sodium channel does not completely close 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.

2.4. Small fiber neuropathy

Mutations in the SCN9A gene account for approximately 30 percent of cases of small fiber neuropathy, a condition characterized by severe pain attacks and a reduced ability to differentiate between hot and cold. The mutations that cause this condition change single amino acids in the alpha subunit of the NaV1.7 sodium channel. As a result of the altered alpha subunit, the sodium channel does not completely close when it is turned off, allowing sodium ions to flow abnormally into nociceptors. This increase in sodium ions enhances transmission of pain signals. In this condition, the small fibers that extend from the nociceptors and transmit pain signals (axons) degenerate over time. The cause of this degeneration is unknown, but it likely accounts for signs and symptoms such as the loss of temperature differentiation.

2.5. Other disorders

At least three mutations in the SCN9A gene have been found in a group of people affected with febrile seizures, which are seizures that are triggered by a high fever. Febrile seizures are the most common type of seizures in young children, affecting 2 to 5 percent of children in Europe and North America. Children who have febrile seizures have a 2 to 9 percent chance of developing non-fever-related seizures later in life. When febrile seizures are associated with mutations in the SCN9A gene, the condition is known as familial febrile seizures 3B. If these individuals go on to develop seizures without fevers, the condition is then known as generalized epilepsy with febrile seizures plus, type 7. The mutations that cause these conditions change single amino acids in the alpha subunit of the NaV1.7 sodium channel. It is unknown how a change in the sodium channel leads to febrile seizures.

Variants in the SCN9A gene, when coupled with mutations in another gene called SCN1A, alter the progression of a seizure disorder called Dravet syndrome in some individuals. Dravet syndrome is characterized by convulsive seizures in infancy, followed in childhood by absence seizures, which cause loss of consciousness for short periods. In mid-childhood, the seizures change to the generalized tonic-clonic type, which involve muscle rigidity, convulsions, and loss of consciousness. Generalized tonic-clonic seizures are also associated with prolonged episodes of seizure activity known as nonconvulsive status epilepticus. These episodes can cause confusion and a loss of alertness lasting from hours to weeks. SCN1A gene mutations are the most common cause of Dravet syndrome, but when an affected individual also has a SCN9A gene change, which might not otherwise cause health problems, the signs and symptoms of Dravet syndrome are more severe. For example, individuals with both SCN1A and SCN9A gene changes may have status epilepticus in infancy and experience a variety of seizures at any time. It is unknown how SCN9A gene changes contribute to the signs and symptoms of Dravet syndrome.