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Autosomal recessive axonal neuropathy with neuromyotonia
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

Autosomal Recessive Axonal Neuropathy with Neuromyotonia

Autosomal recessive axonal neuropathy with neuromyotonia is a rare inherited disorder that damages peripheral nerve axons, leading to progressive muscle weakness and the hyperexcitability of nerves known as neuromyotonia.

Overview

Autosomal recessive axonal neuropathy with neuromyotonia is a disorder that affects the peripheral nerves, which connect the brain and spinal cord to muscles and sensory cells that detect touch, pain, heat, and sound.

Axonal neuropathy, a characteristic feature of this condition, is caused by damage to a particular part of peripheral nerves called axons, the extensions of nerve cells (neurons) that transmit nerve impulses. In people with this disorder, the damage primarily causes progressive weakness and wasting (atrophy) of muscles in the feet, legs, and hands. Muscle weakness may be especially apparent during exercise (exercise intolerance) and can lead to an unusual walking style (gait), frequent falls, and joint deformities (contractures) in the hands and feet. In some affected individuals, axonal neuropathy also causes decreased sensitivity to touch, heat, or cold, particularly in the lower arms or legs.

Another feature of this condition is neuromyotonia (also known as Isaac syndrome). Neuromyotonia results from overactivation (hyperexcitability) of peripheral nerves, which leads to delayed relaxation of muscles after voluntary tensing (contraction), muscle cramps, and involuntary rippling movement of the muscles (myokymia).

Symptoms

  • Progressive muscle weakness and wasting in feet, legs, and hands
  • Exercise intolerance
  • Abnormal gait and frequent falls
  • Joint contractures in hands and feet
  • Decreased sensitivity to touch, heat, or cold in lower arms or legs
  • Neuromyotonia: delayed muscle relaxation, cramps, and myokymia

Causes

Autosomal recessive axonal neuropathy with neuromyotonia is caused by mutations in the HINT1 gene. This gene provides instructions for making a protein that is involved in the function of the nervous system; however its specific role is not well understood. Laboratory studies show that the HINT1 protein has the ability to carry out a chemical reaction called hydrolysis that breaks down certain molecules; however, it is not known what effects the reaction has in the body.

HINT1 gene mutations that cause this disorder lead to production of a HINT1 protein with little or no function. Sometimes the abnormal protein is broken down prematurely. Researchers are working to determine how loss of functional HINT1 protein affects the peripheral nerves and leads to the signs and symptoms of this condition.

Learn more about the gene associated with Autosomal recessive axonal neuropathy with neuromyotonia

  • HINT1

Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

  • ARAN‑NM
  • Autosomal recessive Charcot‑Marie‑Tooth disease type 2 with neuromyotonia
  • Autosomal recessive neuromyotonia and axonal neuropathy
  • Gamstorp‑Wohlfart syndrome
  • Myokymia, myotonia, and muscle wasting
  • NMAN

Resources

Genetic Testing Information

  • Genetic Testing Registry: Autosomal recessive axonal neuropathy with neuromyotonia

Genetic and Rare Diseases Information Center

  • Autosomal recessive axonal neuropathy with neuromyotonia

Patient Support and Advocacy Resources

  • National Organization for Rare Disorders (NORD)

Clinical Trials

  • ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

  • NEUROMYOTONIA AND AXONAL NEUROPATHY, AUTOSOMAL RECESSIVE; NMAN

Scientific Articles on PubMed

  • PubMed

References

  • Caetano JS, Costa C, Baets J, Zimon Phd M, Venancio Phd M, Saraiva Phd J, Negrao L, Fineza I. Autosomal recessive axonal neuropathy with neuromyotonia: a rare entity. Pediatr Neurol. 2014 Jan;50(1):104-7. doi: 10.1016/j.pediatrneurol.2013.08.028.
  • Zhao H, Race V, Matthijs G, De Jonghe P, Robberecht W, Lambrechts D, Van Damme P. Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy. Eur J Hum Genet. 2014 Jun;22(6):847-50. doi: 10.1038/ejhg.2013.231.
  • Zhou X, Chou TF, Aubol BE, Park CJ, Wolfenden R, Adams J, Wagner CR. Kinetic mechanism of human histidine triad nucleotide binding protein 1. Biochemistry. 2013 May 21;52(20):3588-600. doi: 10.1021/bi301616c.
  • Zimon M, Baets J, Almeida‑Souza L, De Vriendt E, Nikodinovic J, Parman Y, Battaloglu E, Matur Z, Guergueltcheva V, Tournev I, Auer‑Grumbach M, De Rijk P, Petersen BS, Muller T, Fransen E, Van Damme P, Loscher WN, Barisic N, Mitrovic Z, Previtali SC, Topaloglu H, Bernert G, Beleza‑Meireles A, Todorovic S, Savic‑Pavicevic D, Ishpekova B, Lechner S, Peeters K, Ooms T, Hahn AF, Zuchner S, Timmerman V, Van Dijck P, Rasic VM, Janecke AR, De Jonghe P, Jordanova A. Loss‑of‑function mutations in HINT1 cause axonal neuropathy with neuromyotonia. Nat Genet. 2012 Oct;44(10):1080-3. doi: 10.1038/ng.2406.

Frequently Asked Questions

Early signs often include progressive muscle weakness and wasting, particularly in the feet, legs, and hands. Parents might notice an unusual walking style (gait), frequent falls, or difficulty with exercise (exercise intolerance). Muscle cramps, delayed muscle relaxation after tensing, and involuntary muscle rippling (myokymia) are also key indicators of neuromyotonia.
Management focuses on supportive care to improve quality of life. Physical and occupational therapy can help maintain muscle strength, flexibility, and function, and prevent joint contractures. Assistive devices like braces or orthotics may aid mobility. Medications can sometimes help manage specific symptoms like muscle cramps or stiffness associated with neuromyotonia.
This condition is autosomal recessive, meaning a child must inherit two copies of a mutated HINT1 gene (one from each parent) to be affected. If both parents are carriers (each having one mutated and one normal gene), there is a 25% chance with each pregnancy that their child will inherit the condition, a 50% chance the child will be a carrier, and a 25% chance the child will not be affected and not be a carrier.
Regular, gentle exercise tailored to individual ability can help maintain muscle function, but overexertion should be avoided due to exercise intolerance. Preventing falls is crucial, which may involve home modifications or mobility aids. Monitoring for skin breakdown due to decreased sensation and managing joint contractures through stretching or splinting are also important.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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