Giant axonal neuropathy

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Giant axonal neuropathy is an inherited condition characterized by abnormally large and dysfunctional axons called giant axons. Axons are specialized extensions of nerve cells (neurons) that transmit nerve impulses. Symptoms of the disorder first become apparent in the peripheral nervous system, in which long axons connect the brain and spinal cord (central nervous system) to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. However, axons in the central nervous system are affected as well.

The signs and symptoms of giant axonal neuropathy generally begin in early childhood and get worse over time. Most affected individuals first have problems with walking. Later they may lose sensation, strength, and reflexes in their limbs; experience difficulty coordinating movements (ataxia); and require wheelchair assistance. Many affected individuals have an abnormal curvature of the spine (scoliosis). Visual and hearing problems may also occur. Many individuals with this condition have extremely kinky hair as compared to others in their family.

Giant axonal neuropathy can also impact the autonomic nervous system, which controls involuntary body processes. Affected individuals may experience problems with constipation, heat intolerance, and the release of urine (neurogenic bladder), and a reduction in or loss of the ability to sweat.

As the disorder worsens, paralysis, seizures, difficulty breathing or swallowing, and a gradual decline in mental function (dementia) can also occur. Most people with giant axonal neuropathy do not survive past their twenties.

Some affected individuals have a milder form of giant axonal neuropathy that begins later in life. Movement problems in these individuals are less severe, and the signs and symptoms usually worsen at a slower rate than in the classic form of the condition. Individuals with the milder form often have straight hair, and they may survive into adulthood.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Giant axonal neuropathy is caused by mutations in the GAN gene, which provides instructions for making a protein called gigaxonin. Gigaxonin is part of the ubiquitin-proteasome system, which is a process that identifies and gets rid of excess or damaged proteins within cells. In particular, gigaxonin plays a role in the breakdown of neurofilaments, which comprise the structural framework that establishes the size and shape of axons.

The GAN gene mutations that have been identified in people with giant axonal neuropathy result in an unstable gigaxonin protein that breaks down more easily than normal, resulting in much less gigaxonin in cells. In neurons without enough functional gigaxonin, neurofilaments that would otherwise have been broken down by the ubiquitin-proteasome system accumulate. The neurofilaments become densely packed in the giant axons of people with giant axonal neuropathy. These giant axons do not transmit signals properly and eventually deteriorate, resulting in the death of neurons. The loss of nerve cells leads to problems with walking and sensation in people with giant axonal neuropathy.

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

Giant axonal neuropathy is a very rare disorder; only about 50 affected families have been described in the medical literature. The condition is thought to be underdiagnosed because its early symptoms resemble those of other, more common disorders affecting the peripheral nervous system, such as Charcot-Marie-Tooth disease.

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.

Abnormality of the Achilles tendon · Very frequent (99-80%)

An abnormality of the Achilles tendon.

Areflexia · Very frequent (99-80%)

Absence of neurologic reflexes such as the knee-jerk reaction.

CNS hypomyelination · Very frequent (99-80%)

Reduced amount of myelin in the central nervous system resulting from defective myelinogenesis.

Gait disturbance · Very frequent (99-80%)

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

Generalized hypotonia · Very frequent (99-80%)

Generalized muscular hypotonia (abnormally low muscle tone).

Joint hypermobility · Very frequent (99-80%)

The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.

Pili canaliculi · Very frequent (99-80%)

A characteristic triangular, kidney- or heat-shaped diameter of hair shafts with typical longitudinal canalicular deformation as observable by scanning electron microscopy.

Proximal muscle weakness · Very frequent (99-80%)

A lack of strength of the proximal muscles.

Other findings in the same source

From: Orphanet

Additional reported features include Diffuse axonal swelling (Very frequent (99-80%)); Abnormal cerebellum morphology (Frequent (79-30%)); Abnormal hand morphology (Frequent (79-30%)); Distal muscle weakness (Frequent (79-30%)); Distal sensory impairment (Frequent (79-30%)); Facial palsy (Frequent (79-30%)); Intellectual disability (Frequent (79-30%)); Pes cavus (Frequent (79-30%)); Scoliosis (Frequent (79-30%)); Spasticity (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Giant axonal neuropathy 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 Giant axonal neuropathy. 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.