Elsevier

Neuroscience Research

Volume 104, March 2016, Pages 105-111
Neuroscience Research

Review article
Hereditary sensory and autonomic neuropathy types 4 and 5: Review and proposal of a new rehabilitation method

https://doi.org/10.1016/j.neures.2015.10.011Get rights and content

Highlights

  • Hereditary sensory and autonomic neuropathy types 4 and 5 are reviewed.

  • HSAN-4 and -5 are characterized by insensitivity to pain and thermal sensation.

  • HSAN-4 is additionally accompanied by decreased sweating and mental disabilities.

  • Orthopedic problems include destructive injuries such as multiple fractures.

  • We propose a new rehabilitation method for patients with HSAN-4 and -5.

Abstract

Although pain is unpleasant, it should serve as a reminder for individuals to avoid similar damaging incidents in the future. Hereditary sensory and autonomic neuropathy (HSAN) includes genetic disorders involving various sensory and autonomic dysfunctions. They are classified by the mode of inheritance, clinical features, and related genes. HSAN type 4 (HSAN-4) and type 5 (HSAN-5) are characterized by insensitivity to pain and thermal sensation. Further, HSAN-4 is accompanied by decreased sweating and intellectual disabilities. These characteristics of HSAN-4 and -5 result in many clinical features, such as pediatric, psychiatric, orthopedic, oral, dermatological, and ophthalmological problems. Orthopedic problems include destructive injuries such as multiple fractures and joint dislocation. Studies on gait have shown greater speed and higher heel contact angular velocity in HSAN-4 and -5 patients compared with controls. Studies on grasp-lift-holding tasks have shown higher grasp force and fluctuations in acceleration of the object. We believe that these findings represent outcomes of deficient motor learning. We propose a new rehabilitation method for patients with HSAN-4 and -5, with the aim of decreasing their destructive injuries.

Introduction

Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” by the International Association for the Study of Pain (Merskey and Bogduk, 1994). Although pain is unpleasant, it is necessary for individuals so that they will learn to avoid similar damaging experiences in the future.

Hereditary sensory and autonomic neuropathy (HSAN) consists of a group of genetic disorders involving various sensory and autonomic dysfunctions. These disorders are classified by the mode of inheritance, clinical features, and related genes (Table 1) (Dyck et al., 1983, Haga et al., 2015, Rotthier et al., 2012, Yuan et al., 2013). HSAN type 4 (HSAN-4) and type 5 (HSAN-5) are characterized by insensitivity to pain and thermal sensation. HSAN-4 (also called congenital insensitivity to pain with anhidrosis) is additionally accompanied by decreased sweating and intellectual disabilities.

In this article, we review the features of, and experimental studies on HSAN-4 and -5, and we discuss the findings regarding motor learning. We also propose a new rehabilitation method for HSAN-4 and -5.

Section snippets

Epidemiology

Although the prevalence of HSAN-4 and -5 has not been well established, they appear to be very rare, except in a few countries.

For HSAN-4, reports on more than 10 patients have come only from Japan and Israel (Haga et al., 2015, Shatzky et al., 2000). Half of the reported patients were offspring of consanguineous parents (Axelrod, 2002). We have previously collected epidemiological data from Japanese clinicians and estimated the number of Japanese HSAN-4 patients as 1 in 600,000–950,000. The

Cause of the disease

In HSAN-4, mutations in NTRK1 (TRKA) have been reported (Indo et al., 1996). NTRK1 encodes tropomyosin-related kinase A (TrkA), a receptor for nerve growth factor (NGF). TrkA normally exists in the target organs of NGF-dependent neurons. NGF is a neurotropic factor, and interaction between NGF and TrkA is essential for the survival and maintenance of NGF-dependent neurons (Reichardt, 2006). Therefore, patients with HSAN-4 have dysfunctions in NGF-dependent neurons (Indo, 2012).

NGF-dependent

Features of HSAN-4 and -5

The main characteristics of HSAN-4 and -5 are insensitivity to pain and impaired thermal sensations. In addition, anhidrosis (loss of sweating), mental retardation, and other symptoms are observed in HSAN-4 and partly in HSAN-5. These characteristics result in many clinical features including pediatric, psychiatric, orthopedic, oral, dermatological, and ophthalmological problems (Haga et al., 2015, Indo, 2014a).

Severity varies among HSAN-4, Swedish HSAN-5, and Arabic HSAN-5 (Table 2) (Capsoni,

Experimental studies of HSAN-4 and -5 patients

Clinical and experimental studies have been conducted on HSAN-4 and Swedish HSAN-5. In comparison, Arabic HSAN-5 has been studied infrequently.

Discussion

Features of HSAN-4 and -5 include destructive problems, such as multiple fractures and joint dislocation. Studies on gait have shown higher gait speed and higher heel contact angular velocity in HSAN-4 and -5 patients than in controls, which might produce a greater contact force and explain the traumas in lower extremities (Zhang et al., 2013). Studies on grasp-lift-holding tasks have shown higher grasp force and fluctuation in acceleration of the object, possibly leading to overuse of

Acknowledgments

This research was supported in part by the Japan Society for the Promotion of Science KAKENHI (# 25870170, 15K01361, and 26120008). Wiley-JAPAN permitted us the reuse of their figures and tables.

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