Neuropathy, Hereditary Sensory, Type IV

Neuropathy, Hereditary Sensory, Type IV

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Neuropathy, Hereditary Sensory, Type IV is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Familial Dysautonomia, Type II
  • Hereditary Sensory and Autonomic Neuropathy IV
  • HSAN IV
  • HSN IV
  • Insensitivity to Pain, Congenital, with Anhydrosis; CIPA
  • Neuropathy, Congenital Sensory, with Anhydrosis

Disorder Subdivisions

  • None

General Discussion

The hereditary sensory neuropathies (HSN) include 4-6 similar but distinct inherited degenerative disorders of the nervous system (neurodegenerative) that frequently progress to loss of feeling, especially in the hands and feet. The classification of these diseases is complicated, and sometimes a source of disagreement among the experts.



Hereditary sensory neuropathy type IV (HSN4) is a rare genetic disorder characterized by the loss of sensation (sensory loss), especially in the feet and legs and, less severely, in the hands and forearms. The sensory loss is due to abnormal functioning of small, unmyelinated nerve fibers and portions of the spinal cord that control responses to pain and temperature as well as other involuntary or automatic body processes. Sweating is almost completely absent with this disorder. Mental retardation is usually present.



The disorder is inherited as an autosomal recessive trait. The gene involved is located on chromosome 1.



HSNs of various types may attack a single nerve (mononeuropathy) or many nerves simultaneously (polyneuropathy). The resulting symptoms may involve sensory, motor, reflex, or blood vessel (vasomotor) functions.

Symptoms

HSN type IV is most frequently recognized by associating the combination of (1) lack of sweating (anhidrosis) with (2) lack of response to stimuli that should produce pain and (3) developmental delays (mental retardation). Also, affected individuals often show signs of self-mutilating behavior and have periodic episodes of unexplained fever and infection.



Frequently, those affected have joint dislocations and deformities (Charcot joints); multiple, slowly healing bone fractures; skin infections; bruises; corneal ulcerations and aggressive behavior. In a few cases, body temperatures have become so elevated (hyperpyrexia) as to be life-threatening.



It is important to treat open sores with care. When these sores of the feet become infected, in combination with degeneration of the bones of the feet, amputation of toes and/or the foot may be necessary.

Causes

Hereditary sensory neuropathy type IV is inherited as an autosomal recessive trait. The gene identified with this disorder, known as TRKA, is involved in the production of an enzyme essential for the proper positioning of the nerve growth factor receptor. This gene is located on the long arm of chromosome 1 (1q21-q22).



Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 1q21-22" refers to a region on the long arm of chromosome 1 between bands 21 and 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.



Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.



Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.



Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.



All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected Populations

HSN type IV is present at birth (congenital). Its prevalence has not been determined but it does not appear to affect any particular ethnic group more than others.

Standard Therapies

Diagnosis

Diagnosis of HSN type IV is based on clinical, physiological and neuropathological criteria. Recently, a method of molecular analysis of the responsible gene has become available. Biopsy of nerve fibers may be used to confirm the diagnosis.



Treatment

Treatment of HSN type IV is symptomatic and supportive. Genetic counseling may be of benefit for patients and their families.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact

www.centerwatch.com

References

TEXTBOOKS

Rowland LP, ed. Merritt's Neurology. 10th ed. Lippincott Williams & Wilkins. Philadelphia, PA. 2000:611.



Menkes JH, Pine Jr JW, et al., eds. Textbook of Child Neurology. 5th ed. Williams & Wilkins. Baltimore, MD; 1995:184.



REVIEW ARTICLES

Auer-Grumbach M. Hereditary sensory neuropathies. Drugs Today (Barc). 2004;40:385-94.



Axelrod FB, Hilz MJ. Inherited autonomic neuropathies. Semin Neurol. 2003;23:381-90.



Hilz MJ. Assessment and evaluation of hereditary sensory and autonomic neuropathies with autonomic and neurophysiological examinations. Clin Auton Res. 2002;12 Suppl 1:I33-43



Indo Y. Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV. Clinical, biological and molecular aspects of mutations in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Clin Auton Res. 2002;12 Suppl 1:I20-32.



JOURNAL ARTICLES

Einarsdottir E, Carlsson A, Minde J, et al. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception, Hum Mol Genet. 2004;13:799-805.



Ohto T, Iwasaki N, Fujiwara J, et al. The evaluation of autonomic nervous function in a patient with hereditary sensory and autonomic neuropathy type IV with novel mutations of the TRKA gene. Neuropediatr. 2004;35:274-78.



Sakae N, Yamada T, Arakawa K, et al. Adult-onset hereditary sensory and autonomic neuropathy accompanied by anosmia but without skin ulceration. Acta Neurol Scand. 2001;104:316.



Verze L, Viglietta-Panzica C, Plumari L, et al. Cutaneous innervation in hereditary sensory and autonomic neuropathy type IV. Neurology. 2000;55:126-28.



Hilz MJ, Stemper B, Axelrod FB. Sympathetic skin response differentiates hereditary sensory and autonomic neuropathies III and IV. Neurology. 1999;52:1652.



Berkovitch m, Copeliovitch L, Tauber T, et al. Hereditary insensitivity to pain with anhidrosis. Pediatr neurol. 1998;19:227-29.



FROM THE INTERNET

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Insensitivity to Pain, Congenital, with Anhidrosis; CIPA. Entry Number; 256800: Last Edit Date; 5/24/2004.



Toscano E. Hereditary sensory and autonomic neuropathy type IV. Orphanet. Creation date: December 2003. 5pp.

www.orpha.net/data/patho/GB/uk-HSANIV.pdf



Hereditary sensory and autonomic neuropathy type IV. Orphanet. Update: 28/11/2004. 1p.

www.orpha.net/static/GB/hereditary_sensory_and_autonomic_neuropathy_4.html



Toth C. Autonomic Meuropathy. emedicine. Last Updated: August 17, 2004. 27pp.

www.emedicine.com/neuro/topic720.htm

Resources

Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Center for Peripheral Neuropathy

University of Chicago

5841 South Maryland Ave, MC 2030

Chicago, IL 60637

Tel: (773)702-5659

Fax: (773)702-5577

Internet: http://peripheralneuropathycenter.uchicago.edu/



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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