Autosomal recessive axonal neuropathy with neuromyotonia

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Autosomal recessive axonal neuropathy with neuromyotonia is a disorder that affects the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as 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, which are the extensions of nerve cells (neurons) that transmit nerve impulses. In people with autosomal recessive axonal neuropathy with neuromyotonia, 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).

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

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 autosomal recessive axonal neuropathy with neuromyotonia 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.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

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.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Autosomal recessive axonal neuropathy with neuromyotonia is a rare form of inherited peripheral neuropathy. This group of conditions affects an estimated 1 in 2,500 people. The prevalence of autosomal recessive axonal neuropathy with neuromyotonia is unknown.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Distal lower limb muscle weakness · Very frequent (99-80%)

Reduced strength of the distal musculature of the legs.

EMG: chronic denervation signs · Very frequent (99-80%)

Evidence of chronic denervation on electromyography.

EMG: myokymic discharges · Very frequent (99-80%)

The presence of spontaneous bursts of rapidly firing potentials that recur at regular intervals of 2-10 per second and are unaffected by voluntary effort. This is an electromyographic (EMG) finding.

Myokymia · Very frequent (99-80%)

Myokymia consists of involuntary, fine, continuous, undulating contractions that spread across the affected striated muscle.

Myotonia · Very frequent (99-80%)

An involuntary and painless delay in the relaxation of skeletal muscle following contraction or electrical stimulation.

Abnormal foot morphology · Frequent (79-30%)

An abnormality of the skeleton of foot.

Absent Achilles reflex · Frequent (79-30%)

Absence of the Achilles reflex (also known as the ankle jerk reflex), which can normally be elicited by tapping the tendon is tapped while the foot is dorsiflexed.

Elevated circulating creatine kinase concentration · Frequent (79-30%)

The activity of creatine kinase in the blood circulation is above the upper limit of normal.

Exercise intolerance · Frequent (79-30%)

A functional motor deficit where individuals whose responses to the challenges of exercise fail to achieve levels considered normal for their age and gender.

Exercise-induced muscle cramps · Frequent (79-30%)

Sudden and involuntary contractions of one or more muscles brought on by physical exertion.

Fatigable weakness of distal limb muscles · Frequent (79-30%)

A type of weakness of a skeletal muscle of distal part of a limb that occurs after a muscle group is used and lessens if the muscle group has some rest. That is, there is diminution of strength with repetitive muscle actions.

Gait disturbance · Frequent (79-30%)

The term gait disturbance can refer to any disruption of the ability to walk.

Handgrip myotonia · Frequent (79-30%)

Difficulty releasing one's grip associated with prolonged first handgrip relaxation times.

Limb fasciculations · Frequent (79-30%)

Fasciculations affecting the musculature of the arms and legs.

Other findings in the same source

From: Orphanet

Additional reported features include Motor axonal neuropathy (Frequent (79-30%)); Reduced tendon reflexes (Frequent (79-30%)); Frequent falls (Frequent (79-30%)); Motor polyneuropathy (Frequent (79-30%)); Achilles tendon contracture (Occasional (29-5%)); Areflexia (Occasional (29-5%)); Distal lower limb amyotrophy (Occasional (29-5%)); Distal sensory impairment of all modalities (Occasional (29-5%)); Exercise-induced leg cramps (Occasional (29-5%)); Flexion contracture (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Autosomal recessive axonal neuropathy with neuromyotonia is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Autosomal recessive axonal neuropathy with neuromyotonia. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.