GAN

Giant Axonal Neuropathy (GAN) is a rare, inherited neurodegenerative disorder caused by mutations in the GAN gene, which encodes gigaxonin, a protein essential for maintaining healthy nerve fibers.

Loss of functional gigaxonin leads to abnormal accumulation of neurofilaments, resulting in swollen axons and progressive damage to the peripheral and central nervous systems.

What is GAN (Giant Axonal Neuropathy)?

Giant Axonal Neuropathy (GAN) is a rare, progressive neurodegenerative disorder inherited in an autosomal recessive pattern. It is caused by mutations in the GAN gene located on chromosome 16, which encodes the protein gigaxonin. 

Gigaxonin is essential for the normal turnover of intermediate filaments in neurons and glial cells. Without functional gigaxonin, neurofilaments accumulate abnormally inside nerve cells, forming swollen, dysfunctional nerve fibers called giant axons. 

These pathological changes contribute to both peripheral (PNS) and central nervous system (CNS) degeneration.

GAN: A Rare Neurodegenerative Disorder

GAN typically presents in early childhood as a progressive motor and sensory neuropathy. Over time, both the PNS and CNS are affected. Children may first show unsteady gait, frequent falls, or clumsiness. 

As the disease advances, weakness, sensory loss, and motor impairments worsen, often leading to the loss of independent ambulation by age 8 to 10 years. 

CNS involvement is common and may manifest as cerebellar ataxia (incoordination), dysarthria, dysphagia, optic atrophy (vision loss), and cognitive decline. 

The autonomic nervous system is also frequently involved, leading to symptoms such as constipation, urinary difficulties, reduced sweating, and reduced tear production.

One unique physical feature is tightly curled or “kinky” hair, although this is not universally seen. 

The pathological hallmark of GAN is the accumulation of neurofilaments within swollen axons, which are often found in nerve biopsies.

Phenotypic Variability

There is significant variation in disease severity. Most patients develop the classic GAN phenotype, characterized by early onset and rapid progression involving both PNS and CNS dysfunction. 

However, some patients present with a milder form of GAN, sometimes called an "axonal CMT-plus" phenotype. These patients may retain the ability to walk into adolescence or adulthood, have fewer CNS symptoms, and may be initially misdiagnosed with Charcot-Marie-Tooth disease. 

Milder forms are typically associated with at least one missense mutation in the GAN gene.

Pathophysiology of GAN

Giant Axonal Neuropathy is caused by mutations in the GAN gene, which produces the protein gigaxonin. Normally, gigaxonin helps clear intermediate filaments through the ubiquitin-proteasome system. 

When gigaxonin is deficient, these filaments accumulate inside nerve cells, forming large clumps that cause the axons to swell abnormally, disrupting nerve function and leading to progressive damage in both the peripheral and central nervous systems.

GAN: A Model for Neurodegenerative Disease

GAN is a valuable model for studying neurodegenerative mechanisms, particularly those involving disruptions in the ubiquitin-proteasome system, which are also implicated in more common disorders such as amyotrophic lateral sclerosis (ALS) and Parkinson's disease.

When is GAN Genetic Testing Relevant?

GAN genetic testing may be beneficial in the following settings:

Patients Presenting with Symptoms of Giant Axonal Neuropathy

GAN genetic testing should be considered in patients presenting with progressive motor and sensory neuropathy starting in early childhood, especially when combined with cerebellar signs, cognitive changes, or characteristic hair findings. 

Testing is also appropriate when there is a family history of GAN or unexplained childhood-onset neuropathy.

Carrier Detection and Family Planning

Genetic testing is also useful for carrier detection and family planning. 

Differential Diagnosis

Identifying GAN in mildly affected individuals can help distinguish it from other inherited neuropathies such as Charcot-Marie-Tooth disease. 

It is strongly recommended that patients and families undergo genetic counseling before and after testing to understand inheritance patterns and reproductive risks.

What Do Specific GAN Mutations Mean?

GAN is caused by biallelic (both copies) pathogenic mutations in the GAN gene. Variants include missense, splice-site, frameshift, nonsense mutations, and rare full gene deletions. 

There is no single hotspot for mutations, but a founder variant (c.851+1G>A) is common in individuals of Mexican descent.

Patients with biallelic null mutations (leading to no functional gigaxonin) typically present with the classic, severe form of GAN. In contrast, individuals with at least one missense variant often exhibit milder disease. 

While all pathogenic mutations result in disrupted intermediate filament clearance, the severity and progression of the disease may vary depending on the type of mutation.

Diagnostic Tools for GAN

Clinical suspicion is usually based on early-onset motor and sensory neuropathy, often with cerebellar signs and characteristic hair. 

Electrophysiological studies typically reveal a length-dependent axonal sensorimotor neuropathy with reduced compound motor action potentials (CMAPs) and sensory nerve action potentials (SNAPs).

Brain and spinal MRI often show progressive white matter abnormalities, especially in the cerebellum and periventricular regions, and spinal cord atrophy. 

Nerve or skin biopsies, while less commonly performed today, can demonstrate giant axons filled with neurofilaments.

The Motor Function Measure 32 (MFM-32) has proven to be the most reliable tool for tracking motor decline and disease progression in GAN. Other helpful scales include the Neuropathy Impairment Score (NIS), the Friedreich Ataxia Rating Scale (FARS), and CMAP amplitude measurements.

Prognosis

Most patients with classic GAN experience progressive motor decline, leading to loss of ambulation and respiratory failure. Life expectancy is typically limited to the second or third decade of life. 

However, individuals with milder GAN phenotypes may retain walking ability into adulthood and have a slower disease course. 

Autonomic dysfunction, respiratory insufficiency, and scoliosis contribute significantly to morbidity.

Management

There is currently no approved disease-modifying treatment for GAN. 

Care is supportive and requires a multidisciplinary team to address the wide range of symptoms. This may include physical, occupational, and speech therapy; management of scoliosis; respiratory support; nutritional guidance; and treatment of autonomic dysfunction.

Emerging Therapies

Gene therapy is the most advanced investigational approach. An ongoing clinical trial uses AAV9-mediated gene transfer to deliver functional copies of the GAN gene. Early preclinical studies have shown improvements in nerve structure and function. 

However, concerns such as potential dorsal root ganglion (DRG) toxicity and limited targeting of Schwann cells remain under investigation.

Other potential future therapies include:

• Antisense oligonucleotides (ASOs) for splicing mutations (~6.6% of cases)
• Gene editing approaches such as CRISPR/Cas9
• Autophagy-modulating drugs to improve intermediate filament clearance

Test Procedure and Interpretation

Testing for GAN is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for GAN genetic testing are considered to be without mutations that can alter the activity of the gigaxonin proteins.

Clinical Implications of Positive GAN Mutations

The clinical implications of a positive GAN mutation test result will vary by individual. However, GAN mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in early-onset neurodegenerative symptoms.

Patients or practitioners with questions about the clinical implications of GAN mutations should seek further assessment with a genetic counselor or expert. 

What Does the Absence of Pathogenic GAN Mutations Mean?

A negative GAN genetic test does not rule out all causes of neuropathy. Many other genetic and acquired conditions can produce similar symptoms. 

If GAN testing is negative but clinical suspicion for a genetic neuropathy remains high, further genetic testing for other conditions, such as Charcot-Marie-Tooth disease or leukodystrophies, should be pursued.

Key Takeaway for Clinicians

Consider GAN in any child with early-onset progressive neuropathy, especially when cerebellar signs or unusual hair texture are present. Confirm diagnosis through genetic testing. 

Early recognition is critical for supportive management and eligibility for emerging gene therapy trials. Genetic counseling is recommended for all affected families.

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