Born Painless (HSAN I)

We all experience some form of physical pain in our lifetimes. Pain doesn’t discriminate; it is a universal quality that is easy to recognize. Pain is a powerful learning tool. B.F. Skinner, the father of operant conditioning (instrumental learning), demonstrated how behavior can be modified through positive and negative reinforcement (pain and pleasure). As most parents can attest, this type of learning may display rapid results. An everyday example of this is when a parent buys a child a toy to stop them from crying or whining. Although this may stop the crying/whining, it has the opposite effect on the child. The child learns that if they repeat that negative behavior, they will get what they want. Unfortunately, by rewarding undesired behavior, the habit can be difficult to break.

Most people don’t like to experience pain. In fact, we wince when we see others in pain. Many would think that living a painless life would be great. This couldn’t be further from the truth. Pain is essential and it is a fundamental aspect of the human condition. It is our internal diagnostic system, signaling us when something is wrong. Pain is intrinsically designed to inform and protect us from danger, both present and future. Pain is nature’s negative reinforcement technique, which is called a negative feedback loop in biology. A negative feedback loop occurs when the rate of the process decreases as the concentration of the product increases, and it is designed to restore homeostasis. In humans, every negative feedback loop, except for child birth (a positive feedback loop; as the process increases, so does the response), is designed for this purpose. Imagine holding a hot coal with no concept that it is destroying tissue, or suffering a fall and never knowing your ankle is broken. It is because of the pain (and the subsequent negative feedback) that most of us drop the coal and mitigate the tissue damage to a first-degree burn. Even common injuries that children often receive, like abrasions or cuts, can become serious. Without the initial and/or subsequent pain identifying the problem, followed by proper treatment, infections can fester to the point where amputations may be necessary.

There is a small group of people with diminished ability to feel pain and some who cannot feel pain at all. They are born with hereditary sensory and autonomic neuropathy (HSAN). HSAN is a group of rare genetically heterogeneous disorders with sensory and autonomic dysfunctions coupled with/without variable motor involvement. In individuals with HSAN, the A-delta fibers and C fibers are the main area of concern.

Neurons involved in HSAN: a quick review

Sensory pain begins with a stimulus that triggers specialized nerve endings called primary afferent nociceptors. Nociceptors are activated in response to noxious stimuli or by the release of chemicals in response to an infectious agent/inflammation.

A-delta fibers: thin, myelinated nerve fibers that conduct signals rapidly. They are like first responders, indicating danger and reflex response (eg, touching a hot surface and quickly retracting your hand). They are used in both mechanical and thermal perception and are associated with acute, sharp pain.

C fibers: thin, non-myelinated nerve fibers that conduct signals more slowly. They are perhaps the most abundant of all nociceptive fibers (70%). They have mechanical and thermal properties but are triggered mainly by chemicals (eg, histamines, globulin, protein kinases, arachidonic acid, NGF, SP, CGRP, and many more). The pain is longer lasting, diffuse, and dull—it is typically described as a throbbing, aching, and/or a burning sensation.

HSAN type I, also known as hereditary sensory neuropathy type I (HSN I)

HSN I: a slowly progressive, autosomal dominant disease characterized by distal sensory loss, autonomic disturbances, with either a juvenile or adult onset. Its prevalence rate is unknown, and onset is typically seen between the second and fifth decade of life. There are 4 subsets of HSN I, with varying symptoms. Evidence suggests that axonal damage to both motor and sensory neurons exists. Sensory potential in the lower extremities is typically absent. However, the upper extremities may also demonstrate a slowing down of motor conduction, implying a demyelination process. The degree of motor involvement varies, even within families, and can include tingling sensations, muscle weakness, wasting of foot extensors, and gait issues. Open sores and ulcerations of the feet may occur. Wounds heal slowly, infections may linger, and amputations may be necessary due to osteomyelitis and necrosis. Presently, 2 gene mutations and 3 loci have been identified.

1. HSN IA: currently, one mutation has been identified. This missense mutation is found in the serine palmitoyltransferase, long-chain base subunit 1 (SPTLC1) gene, located on chromosome 9q22.1-q22.3. The SPTLC1 gene is responsible for encoding the enzyme serine palmitoyltransferase (SPT), the rate-limiting enzyme for the synthesis of sphingolipids, ceramides, and sphingomyelin. The disease is characterized by distal sensory disturbances (loss of pain and temperature sensations) with variable motor involvement. Some individuals may experience sharp shooting pains or burning sensations in their lower extremities. It has been suggested that this disease occurs because of reduced SPT enzyme activity, which results in diminished myelin formation. Because of this reduction and a buildup of harmful sphingolipid intermediates, nerve cells are less efficient and eventually die.
2. HSN IB or HSN with cough and gastroesophageal reflux: the affected gene/genes have not been identified, although it is linked to chromosome 3p24-p22. It is characterized by sensory neuropathy, cough, and gastroesophageal reflux with normal distal muscle strength.
3. HSN IC or Charcot-Marie-Tooth syndrome: 2 missense mutations have been identified. Both mutations are in the small GTPase late endosomal protein Rab7, and located on chromosome 3q13-q22. The Rab proteins are members of the Ras GTPase superfamily. The Rab proteins effectively act as molecular switches and are critical for regulating intracellular trafficking. However, their role in the progression of this disease is still undetermined. HSN IC is characterized by distal muscle weakness, wasting, and variable motor involvement. Sensory loss, foot ulcerations, and mutilations that may necessitate amputation have been reported.
4. HSN ID: the affected gene/genes have not been identified. It is characterized by prominent sensory loss in the hands and feet, mutilations, acropathy, and variable motor involvement.

HSAN can be difficult to diagnose. It has a wide spectrum of presentations and there are no diagnostic tests other than DNA. The only treatment is supportive care and education, including self-monitoring and prevention techniques. Unlike type I, types II-V are recessive and more severe. Perhaps the most tragic form is type IV, which will be discussed in subsequent reviews.

Reference

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