What Are the Causes of Small Fiber Neuropathy?

Although the exact process by which small fiber neuropathy (SFN) develops is not fully understood, researchers have identified many conditions that can damage the small nerve fibers responsible for transmitting pain, temperature, and autonomic signals. Approximately 50% of SFN cases are considered idiopathic, meaning no underlying cause can be identified despite thorough evaluation.

Small fiber neuropathy occurs when thinly myelinated (Aδ) nerve fibers and unmyelinated C fibers become damaged. These nerve fibers help regulate autonomic functions and transmit pain and temperature sensations. Damage to these nerves can result in neuropathic pain, numbness, tingling, and autonomic symptoms.

Diabetes is the most common identifiable cause of small fiber neuropathy. It can also develop in people with prediabetes or impaired glucose tolerance. According to recent research, small fiber neuropathy may occur in up to 50% of people with diabetes or prediabetes.

Certain inherited mutations in the SCN9A and SCN10A genes can also cause small fiber neuropathy. According to the National Institutes of Health (NIH), these genes produce sodium channels that help generate and transmit electrical signals in nerve cells. Mutations can prevent these channels from functioning normally, leading to increased pain signaling and the development of SFN. SCN9A mutations have been identified more frequently than SCN10A mutations in people with inherited or idiopathic forms of the disease.

The following are examples of medical conditions that can result in small fiber neuropathy:

• HIV
• Fibromyalgia
• Lupus
• Sarcoidosis
• Fabry disease
• Familial amyloidosis
• Primary systemic amyloidosis
• Sjogren’s syndrome
• Celiac disease
• Metabolic and endocrine disorders

Other causes include:

• Illicit or prescription drug use
• Physical injuries
• Exposure to chemotherapy
• Alcohol use disorder
• Vitamin B-12 deficiency

If no underlying cause is identified after a thorough medical evaluation, the condition is classified as idiopathic small fiber neuropathy. In a 2018 study involving 921 people with SFN, 53% had no identifiable underlying condition.

Risk Factors

Several factors can increase the risk of developing small fiber neuropathy, with diabetes being the most significant. Research indicates that approximately 40% to 50% of people with diabetes develop some form of diabetic neuropathy during their lifetime. Although small fiber neuropathy is less common than other forms of diabetic neuropathy, it remains a significant complication. 

Research has also shown that people with idiopathic small fiber neuropathy have a higher prevalence of impaired glucose tolerance than the general population. Because impaired glucose tolerance is an early stage of prediabetes, some researchers believe SFN may be one of its earliest neurological complications. 

Age is another important risk factor. Small fiber neuropathy becomes more common after age 65, and may occur slightly more often in men than in women.