Small fiber neuropathy is a condition characterized by severe pain attacks that typically begin in the feet or hands. As a person ages, the pain attacks can affect other regions. Some people initially experience a more generalized, whole-body pain. The attacks usually consist of pain described as stabbing or burning, or abnormal skin sensations such as tingling or itchiness. In some individuals, the pain is more severe during times of rest or at night. The signs and symptoms of small fiber neuropathy usually begin in adolescence to mid-adulthood.

Individuals with small fiber neuropathy cannot feel pain that is concentrated in a very small area, such as the prick of a pin. However, they have an increased sensitivity to pain in general (hyperalgesia) and experience pain from stimulation that typically does not cause pain (allodynia). People affected with this condition may also have a reduced ability to differentiate between hot and cold. However, in some individuals, the pain attacks are provoked by cold or warm triggers.

Some affected individuals have urinary or bowel problems, episodes of rapid heartbeat (palpitations), dry eyes or mouth, or abnormal sweating. They can also experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting.

Small fiber neuropathy 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.

Mutations in the SCN9A or SCN10A gene can cause small fiber neuropathy. These genes provide instructions for making pieces (the alpha subunits) of sodium channels. The SCN9A gene instructs the production of the alpha subunit for the NaV1.7 sodium channel and the SCN10A gene instructs the production of the alpha subunit for the NaV1.8 sodium channel. 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. The NaV1.7 and NaV1.8 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 small fiber neuropathy result in NaV1.7 sodium channels that do not close completely when the channel is turned off. Many SCN10A gene mutations result in NaV1.8 sodium channels that open more easily than usual. The altered channels allow sodium ions to flow abnormally into nociceptors. This increase in sodium ions enhances transmission of pain signals, causing individuals to be more sensitive to stimulation that might otherwise not cause pain. In this condition, the small fibers that extend from the nociceptors through which pain signals are transmitted (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 and pinprick sensation. The combination of increased pain signaling and degeneration of pain-transmitting fibers leads to a variable condition with signs and symptoms that can change over time.

SCN9A gene mutations have been found in approximately 30 percent of individuals with small fiber neuropathy; SCN10A gene mutations are responsible for about 5 percent of cases. In some instances, other health conditions cause this disorder. Diabetes mellitus and impaired glucose tolerance are the most common diseases that lead to this disorder, with 6 to 50 percent of diabetics or pre-diabetics developing small fiber neuropathy. Other causes of this condition include a metabolic disorder called Fabry disease, immune disorders such as celiac disease or Sjogren syndrome, an inflammatory condition called sarcoidosis, and human immunodeficiency virus (HIV) infection.

Normal Function

The SCN9A gene belongs to a family of genes that provide instructions for making sodium channels. These channels, which transport positively charged sodium atoms (sodium ions) into cells, play a key role in a cell's ability to generate and transmit electrical signals.

The SCN9A gene provides instructions for making one part (the alpha subunit) of a sodium channel called NaV1.7. NaV1.7 sodium channels are found in nerve cells called nociceptors. Nociceptors are part of the peripheral nervous system, which connects the brain and spinal cord to cells that detect sensations such as touch, smell, and pain. Nociceptors are primarily involved in transmitting pain signals. The cell bodies of nociceptors are located in the spinal cord. Fibers called axons extend from the cell bodies, reaching throughout the body to receive sensory information. Axons transmit the information back to the spinal cord, which then sends it to the brain.

NaV1.7 sodium channels are also found in olfactory sensory neurons, which are nerve cells in the nasal cavity that transmit smell-related signals to the brain.

Health Conditions Related to Genetic Changes

Channelopathy-associated congenital insensitivity to pain

Multiple variants (also called mutations) in the SCN9A gene have been found to cause channelopathy-associated congenital insensitivity to pain, a condition that inhibits the ability to perceive physical pain. Most of these SCN9A gene variants result in the production of a nonfunctional alpha subunit of the NaV1.7 sodium channel. These nonfunctional subunits do not allow NaV1.7 sodium channels to open, preventing the flow of sodium ions into nociceptors. This lack of sodium ions blocks nociceptors from transmitting pain signals from the site of an injury to the brain.

The loss of NaV1.7 sodium channel activity in olfactory sensory neurons likely prevents smell-related signals from reaching the brain, leading to a complete loss of the sense of smell (anosmia).

Erythromelalgia

Multiple variants 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 the identified variants change one protein building block (amino acid) in the NaV1.7 sodium channel. These variants cause cells to produce NaV1.7 sodium channels that opens more easily and stay open longer than normal, increasing the flow of sodium ions. This increase in sodium ions enhances the transmission of pain signals, leading to the signs and symptoms of erythromelalgia.

Paroxysmal extreme pain disorder

Multiple variants 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 variants 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 the transmission of pain signals, leading to the pain attacks experienced by people with paroxysmal extreme pain disorder.

Small fiber neuropathy

Variants 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 variants 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 the transmission of pain signals. In people with this condition, the axons that extend from the nociceptors and transmit pain signals degenerate over time. The cause of this degeneration is unknown, but it likely accounts for the features of small fiber neuropathy.

Genetic epilepsy with febrile seizures plus

MedlinePlus Genetics provides information about Genetic epilepsy with febrile seizures plus

Hereditary sensory and autonomic neuropathy type II

MedlinePlus Genetics provides information about Hereditary sensory and autonomic neuropathy type II

Other disorders

At least three variants in the SCN9A gene have been found in a group of people 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 variants 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 genetic epilepsy with febrile seizures plus, type 7 (linked above). The variants 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 variants 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 that can last from hours to weeks. SCN1A gene variants are the most common cause of Dravet syndrome, but when an affected individual also has a SCN9A gene variant, 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 variants contribute to the signs and symptoms of Dravet syndrome.

Other Names for This Gene

• hNE
• Nav1.7
• NE-NA
• NENA
• PN1
• SCN9A_HUMAN
• sodium channel, voltage gated, type IX alpha subunit
• sodium channel, voltage-gated, type IX, alpha
• sodium channel, voltage-gated, type IX, alpha polypeptide
• sodium channel, voltage-gated, type IX, alpha subunit
• voltage-gated sodium channel alpha subunit Nav1.7

Genomic Location

Normal Function

The SCN10A gene belongs to a family of genes that provide instructions for making sodium channels. These channels, which transport positively charged sodium atoms (sodium ions) into cells, play a key role in a cell's ability to generate and transmit electrical signals.

The SCN10A gene provides instructions for making one part (the alpha subunit) of a sodium channel called NaV1.8. NaV1.8 sodium channels are found in nerve cells called nociceptors that transmit pain signals. Nociceptors are part of the peripheral nervous system, which connects the brain and spinal cord to cells that detect sensations such as touch, smell, and pain. Nociceptors are primarily involved in transmitting pain signals. The centers of nociceptors, known as the cell bodies, are located in a part of the spinal cord called the dorsal root ganglion. Fibers called axons extend from the cell bodies, reaching throughout the body to receive sensory information. In addition to nociceptors, NaV1.8 sodium channels have also been found in heart muscle cells where, by controlling the flow of sodium ions, they likely play a role in maintaining a normal heart rhythm.

Health Conditions Related to Genetic Changes

Small fiber neuropathy

Mutations in the SCN10A gene account for approximately 5 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 protein building blocks (amino acids) in the alpha subunit of the NaV1.8 sodium channel. Many of the mutations result in NaV1.8 sodium channels that open more easily than usual, increasing the flow of sodium ions that produce nerve impulses within nociceptors. This increase in sodium ions enhances transmission of pain signals, causing individuals to be more sensitive to stimulation that might otherwise not cause pain. 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.

Other disorders

Certain common variants (polymorphisms) in the SCN10A gene have been found to increase the risk of developing an irregular heartbeat (arrhythmia). These polymorphisms lead to the production of an altered NaV1.8 sodium channel that can disrupt the electrical signals that control the heartbeat. Specifically, changes in the SCN10A gene are associated with a type of arrhythmia known as heart block. Heart block occurs when the heart's electrical signals are slowed down or interrupted. It is unknown how changes to the NaV1.8 sodium channel lead to heart block.

Other Names for This Gene

• hPN3
• Nav1.8
• peripheral nerve sodium channel 3
• PN3
• SCNAA_HUMAN
• sodium channel protein type 10 subunit alpha
• sodium channel protein type X subunit alpha
• sodium channel, voltage gated, type X alpha subunit
• sodium channel, voltage-gated, type X, alpha polypeptide
• sodium channel, voltage-gated, type X, alpha subunit
• voltage-gated sodium channel subunit alpha Nav1.8

Genomic Location

Small fiber neuropathy is inherited in an autosomal dominant pattern, which means one copy of the altered SCN9A gene or SCN10A gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

When the genetic cause of small fiber neuropathy is unknown or when the condition is caused by another disorder, the inheritance pattern is unclear.

The prevalence of small fiber neuropathy is unknown.