Born Painless (HSAN II and III)

Unlike hereditary sensory and autonomic neuropathy type I (HSAN I), HSAN II and HSAN III are inherited in an autosomal recessive pattern. Both conditions are characterized by a deficit in distal sensory perception, with the lower limbs more severely affected than the upper limbs. Touch and temperature perception are affected to varying degrees in these individuals, with some depressed deep tendon reflexes. However, their ability to sense vibration may be normal. The extent of autonomic neuropathy and dysfunction varies greatly between types II and III. Type III is more severe, not only in sensory manifestations but also to the degree in which the autonomic system is affected.

Sensory 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 but larger, nonmyelinated nerve fibers that conduct signals more slowly. They are 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 II

Presently there are 3 subtypes of HSAN II (HSAN 2A, 2B, and 2C). All subtypes present in a similar fashion and have the similar characteristics. Their grouping is based on 3 separate mutations. However, as more cases appear, these 3 groups may become more distinguishable from one another. It has also been reported as Morvan’s disease, neurogenic neuropathy, and hereditary sensory radicular neuropathy. HSAN I is marked by a gradual loss of distal A- and C-fibers and/or a reduction in their density. However, in type II, A-fibers are noticeably absent and there are fewer C-fibers.

HSAN II genes

• HSAN 2A: Is associated with a dysfunctioning protein encoded by the WNK1 gene located on chromosome 12p13.33. More succinctly, it is associated with a particularly isoform of the WNK1 protein designated WNK1/HSN2. It is believed that the HSN2 protein plays a critical role in the development and maintenance of peripheral sensory neurons.
• HSAN 2B: There are 3 missense mutations and 1 nonsense mutation that have currently been identified in the gene FAM134B on chromosome 5p15.1. And 2 out of the 4 mutations, 1 missense and the nonsense mutation, have arisen from consanguineous parents. The FAM134B gene is responsible for encoding the FAM134B protein in the Golgi apparatus. The exact function of the protein is unknown, although, it is important for the survival of sensory and autonomic neurons. Studies have demonstrated that neurons without the FAM134B protein self-destruct (apoptosis).
• HSAN 2C: Is associated with a nonsense mutation in the KIF1A gene on chromosome 2q37.3. The KIF1A gene encodes a protein essential for transporting synaptic vesicle precursors. Therefore, this action plays a critical role in viability, maintenance, and function of neurons.

HSAN II typically presents in infancy or early childhood. With the exception of some clustering of HSAN 2A in eastern Canada, its prevalence is generally uniform. It crosses all ethnic and sexual boundaries. Initial symptoms include swallowing and feeding problems, apnea, and self-mutilation. The sensory deficits begin with numbness in the hands and feet. There is some disagreement whether or not this disease is progressive. Regardless, these individuals have a severely reduced sense of pain, temperature, and touch. Deep tendon reflexes may be depressed. However, in most cases, muscle tone and strength appear normal and mental development is not affected.

A real concern is neuropathic skin. Over time, their skin may produce an excess of keratin and the resulting hyperkeratosis may push down into deep tissue. This process can cause soft tissue to crack, become ulcerated and infected, and may result in spontaneous amputation or a need to surgically remove the affected digits. Gastroesophageal reflux problems have been reported, as well as some cases of a loss of lingual fungiform papillae (more common in type III). Fractures may go unnoticed and osteomyelitis is an issue. There are reports of Charcot joints in these individuals due to repeated bone injury and the destruction of surrounding soft tissue/joints. Autonomic disturbances are variable; they include excessive sweating, tonic pupils, and incontinence.

HSAN III (familial dysautonomia or FD)

FD is also a recessive trait. It presents at birth and affects sensory, sympathetic, and parasympathetic neurons. FD is a progressively degenerative process with high mortality rates and incidences of sudden death. Nearly every affected individual can trace their lineage back to Ashkenazi Jewish descent (99%). The incidence rate of persons with Ashkenazi Jewish descent is approximately 1:3,700 live births, or a carrier frequency of 1:36.

HSAN III gene

• The main culprit stems from missense mutations of the IKBKAP gene on chromosome 9q31.3. The IKBKAP gene is responsible for encoding a protein called IKK complex–associated protein (IKAP). In FD, the majority of people have 2 copies of the mutation reducing IKAP production. This reduction may impair the growth and development of nerve cells by disrupting the cytoskeleton and cell motility. In FD, there are also reports of decreased dopamine-beta-hydroxylase (DBH), as well as a depletion of substance P. DBH is an enzyme needed for the synthesis of noradrenaline, and substance P is involved in transmission of nociceptive information at synapses of primary sensory neurons.

Unlike HSAN II, in persons with FD, insensitivity to pain typically doesn’t affect the hands or soles of their feet. Their neck and genitalia are spared as well. However, there are significant developmental issues. Delayed motor milestones have been reported with varying degrees of hypertonia. They tend to have broad-based gaits and ataxia issues that worsen with age. There may also be decreased or absent deep tendon refluxes, and decreased taste due to absent lingual fungiform papillae. Emotional tears are absent (alacrima); this is especially noticeable in newborns who don’t cry. There is a lack of axonal flare response, and as they grow, their renal function deteriorates. It has been suggested that 19% of individuals who live to the age of 25 years will need dialysis.

FD individuals have gastroesophageal reflux and digestive problems. Episodes of protracted vomiting and/or excessive sweating may be seen. They tend to have very low blood pressure, spinal curvature (spinal fusion may be necessary), optic nerve atrophy, and cross-eyes or walleyes. Incontinence, dizzy spells, and/or light-headedness have been reported. Osteomyelitis and Charcot joints are a concern. Intelligence is generally not affected, although there are some reports of persistent phobias. Chronic lung disease and pulmonary aspiration are relatively common and may be problematic. Of all deaths, 26% are attributed to pulmonary problems.

Autonomic crises are common with FD and occur in 40% of individuals. They are characterized by:

• Excessive sweating of the head and trunk
• Erythematous blotching of the face and trunk
• Mottling (cutis marmorata) of distal extremities
• Hypertension and tachycardia
• Nausea/vomiting
• Severe dysphagia/drooling
• Irritability
• Insomnia
• Worsening of muscle tone

Differential diagnosis for HSAN may be based on the symptom presentations, and type III is more readily assessed. However, as with all HSANs, the only conclusive test is genomic testing. There is significant symptom overlap between HSANs, so a differential diagnosis based on clinical presentations can prove difficult. Diabetic neuropathy shares some aspects with HSAN I, and the various forms have also been mistaken for leprosy. There is no cure for HSAN. Treatments are generally based on particular manifestations. Adequate nutrition and education are essential. In FD, supportive care is important. An annual spine examination for scoliosis is suggested, as well as adequate hydration during general anesthesia. Supportive care has raised the likelihood to 60% that individuals with FD will reach the age of 20 years.

Reference

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