What Is Giant Axonal Neuropathy?

Introduction to giant axonal neuropathy (GAN)

Giant axonal neuropathy (GAN) is a rare hereditary condition impacting both the peripheral and central nervous systems. The peripheral nervous system serves as the conduit for transmitting signals governing motion and sensation between the central nervous system (comprising the brain and spinal cord) and all other body parts. GAN arises when alterations occur in the GAN1 gene, leading to the enlargement of axons; these are the messengers within nerve cells, beyond normal proportions and causing them to malfunction. Over time, these enlarged axons undergo degradation, disrupting movement and sensation due to impaired intercellular communication among nerve cells. 

The name for this disorder originates from the observation of enlarged axons or axonal enlargements resulting from the buildup of intermediate filaments within peripheral sensory and motor nerves. This abnormal accumulation also extends to the central nervous system (CNS), encompassing regions such as cerebral and cerebellar white matter, middle cerebellar peduncles, brainstem tegmentum, corticospinal tracts, and posterior columns.¹ 

The progression of GAN is gradual, signifying its continued deterioration over time. Most children typically manifest GAN-related symptoms before reaching the age of five. By the second decade of life, a majority of these children will need a wheelchair. Presently, no remedy or intervention exists to arrest the progressive advancement of this disorder.  The typical prognosis is often severe, with mortality occurring during the second or third decade of life. However, in some patients, a less severe trajectory has been observed.²

Symptoms and clinical presentation

The symptoms associated with giant axonal neuropathy typically manifest in early childhood and progressively worsen over time. Initial indications frequently involve challenges with walking. Subsequently, affected individuals may experience a diminishing sense of touch, weakened muscles, and diminished reflexes in their limbs. Coordination difficulties (ataxia) become apparent, often necessitating the use of wheelchairs. Scoliosis, an abnormal spinal curvature, is commonly observed. Visual and auditory impairments can also arise. Many individuals afflicted by this condition exhibit distinctly coiled hair, markedly different from that of their family members.
The symptoms encompass:

• Motor Difficulties: Awkwardness and muscle weakness frequently serve as the initial indicators of the disorder.
• Gait Issues: Early-stage symptoms may involve difficulties with walking.
• Sensory Loss: Gradual loss of sensation in the arms and legs.
• Impaired Motor Control: Decline in the ability to control bodily movements.
• Seizures: Epileptic seizures may occur.
• Nystagmus: Rapid, involuntary back-and-forth movement of the eyes.
• Cognitive Decline: Gradual regression of mental development and cognitive function.
• Distinct Hair: Remarkably tightly curled hair, differing significantly in texture and appearance from parental hair.

Causes and genetic basis 

The nerve biopsy displays a variable count of oversized axons containing neurofilaments, serving as the distinctive pathological hallmark of the disease. This feature is typically accompanied by varying degrees of axonal loss and demyelination. Within the central nervous system, these giant axons are also evident, often linked with Rosenthal fibres, and coupled with fluctuating extents of white matter involvement and neuronal decline.³ 

The underlying cause of this disorder lies in mutations within the GAN gene, which encodes gigatons—a constituent of the BTB-Kelch family. As of now, 37 distinct mutations in the GAN gene have been documented. These mutations are distributed across the gene's 11 exons, lacking a definitive genotype-phenotype correlation. These mutations, culminating in gigatons insufficiency, contribute to a slowdown in ubiquitin-mediated protein degradation, possibly impacting unidentified proteins as well. GAN serves as an effective model for comprehending neurodegenerative disorders wherein a fundamental anomaly exists within the ubiquitin-proteasome system, along with its intricate interplay with neurofilaments.³

Diagnosis and medical evaluation 

The diagnosis and medical assessment of GAN involves a holistic strategy that incorporates clinical evaluations and specialized examinations. Initial indicators are drawn from clinical observations revealing muscle weakness, compromised coordination, sensory deficits, and developmental delays. Specialized procedures, including assessments of nerve conduction velocity (NCV), brain magnetic resonance imaging (MRI), peripheral nerve biopsies, and electroencephalogram (EEG), contribute to the diagnostic process. A notable feature identified through peripheral nerve biopsies is the presence of "giant axons," arising from abnormal accumulation of neurofilaments. 

While genetic testing for GAN gene mutations can affirm the diagnosis, definitive confirmation using genetic analysis is typically accessible in research contexts. It's imperative to recognize that a lack of positive findings in gene mutation screening does not rule out the diagnosis. This multifaceted diagnostic approach facilitates a comprehensive appraisal and accurate delineation of GAN, ultimately aiding effective clinical oversight and formulation of treatment strategies.⁴ 

A physical examination also plays a crucial role in guiding the diagnosis process, which may involve a combination of tests to accurately identify and characterise the disorder, such as the following:

• Reduced muscle tone
• Muscle weakness
• Diminished reflexes
• Impaired muscle coordination
• Altered sensation
• Developmental delay

Current and emerging treatment approaches

A definitive cure for this disorder remains elusive. The approach GAN centres on addressing specific symptoms and providing supportive care. Pediatric patients with GAN typically collaborate with a multidisciplinary medical team, including a pediatric neurologist, orthopaedic surgeon, physiotherapist, psychologist, and specialists in speech and occupational therapy. Treatment's primary objective revolves around optimising cognitive and physical development while enhancing adaptive capabilities. Remarkably, many children with GAN exhibit normal intellectual growth and can actively participate in mainstream education. Nevertheless, as the disorder progresses, neurological deterioration may manifest. Regular monitoring, at least once a year, becomes essential during school years to assess cognitive abilities and identify neurological decline indicators.

Symptomatic therapy rests on two core objectives: first, to enhance cognitive and physical development, and later, to mitigate the decline in both physical and intellectual capacities. This therapeutic approach encompasses speech, physical, and occupational therapies. Prompt initiation of these interventions is crucial early in the disease's progression to forestall joint deformities. Regular reassessment of these therapies is necessary. Services tailored for individuals dealing with visual and/or mobility challenges can prove invaluable for those affected by giant axonal neuropathy.

In addition, genetic counselling holds significant value for patients and their families, providing essential guidance in understanding the condition's hereditary aspects and assisting in making informed decisions.

Conclusion

In summation, giant axonal neuropathy (GAN) is a rare and progressive genetic disorder impacting the nervous system. Distinguished by the buildup of atypical neurofilaments leading to the development of "giant axons," GAN gives rise to a spectrum of symptoms, including weakened muscles, compromised coordination, diminished sensory perception, and delays in development. While a definitive remedy is currently lacking, a holistic therapeutic strategy is directed towards symptom management and the enhancement of both cognitive and physical advancement. The pivotal role of diverse medical teams, encompassing neurologists, orthopaedic surgeons, therapists, and psychologists, cannot be overstated in tending to the multifaceted needs of GAN-afflicted individuals. 

Early commencement of interventions, spanning speech, physical, and occupational therapies, assumes significance in averting joint abnormalities and fostering adaptive capabilities. Consistent surveillance alongside genetic counselling offers indispensable backing to patients and families, fostering comprehension of the disorder's trajectory and enabling well-informed choices. GAN serves as a poignant testament to the critical importance of early intervention, tailored care, and ongoing research in effectively managing this intricate and demanding neurodegenerative ailment.