giant axonal neuropathy 2

Giant Axonal Neuropathy (GAN) Description

Giant axonal neuropathy, also known as GAN, is an inherited degenerative disorder that affects both the central and peripheral nervous systems. It is an autosomal recessive disorder caused by biallelic mutations in the GAN gene located on chromosome 16q24.1 which encodes gigaxonin, a subunit of E3 ubiquitin ligase [2].

This rare condition is characterized by abnormalities in the peripheral and central nervous systems, including low muscle tone (hypotonia), muscle weakness, decreased reflexes, impaired coordination, and progressive nerve death [8]. The symptoms typically appear in early childhood and can progress to a pronounced difficulty in walking [7][6].

GAN is a loss of function disorder that results in disorganization of neurofilaments, which are essential for normal nerve function. A distinguishing feature of GAN is its association with kinky or curly hair [14].

Overall, giant axonal neuropathy is a rare and severe neurological disorder that affects both the central and peripheral nervous systems, leading to progressive symptoms and impaired coordination.

References:

[2] - The inherited degenerative disorder that affects both the central and peripheral nervous systems. [6] - Symptoms typically appear in early childhood and can progress to a pronounced difficulty in walking. [7] - Symptoms typically appear in early childhood and can progress to a pronounced difficulty in walking. [8] - A loss of function disorder that results in progressive nerve death. [14] - Association with kinky or curly hair.

Giant Axonal Neuropathy (GAN) Signs and Symptoms

Giant axonal neuropathy, also known as GAN, is a rare genetic disorder that affects the peripheral and central nervous systems. The signs and symptoms of GAN generally begin in early childhood and worsen over time.

• Motor and Sensory Neuropathy: GAN is characterized by progressive motor and sensory peripheral neuropathy, which affects movement and sensation in the arms and legs.
• Low Muscle Tone (Hypotonia): Individuals with GAN often experience low muscle tone, leading to weakness and decreased coordination.
• Difficulty Walking: One of the earliest signs of GAN is difficulty walking or a "waddling gait," which can progress to a pronounced difficulty in walking.
• Numbness and Weakness: As the condition progresses, individuals may experience numbness and weakness in their arms and legs.
• Central Nervous System Involvement: GAN also affects the central nervous system, leading to pyramidal and cerebellar signs.

These symptoms can vary in severity and progression from person to person. Early diagnosis and treatment are crucial for managing the condition and slowing its progression.

References:

• [1] The signs and symptoms of giant axonal neuropathy generally begin in early childhood and get worse over time.
• [3] The condition typically appears in infancy or early childhood with severe peripheral motor and sensory neuropathy (affecting movement and sensation in the arms and legs).
• [5] What are the symptoms of GAN? The typical symptoms of GAN are clumsiness and muscle weakness that progresses from a “waddling gait” to a pronounced difficulty in walking.
• [7] Aug 28, 2020 — The typical symptoms of GAN are clumsiness and muscle weakness that progresses from a “waddling gait” to a pronounced difficulty in walking.
• [8] Jul 1, 2020 — The loss of nerve cells leads to problems with walking and sensation in people with giant axonal neuropathy.

Diagnostic Tests for Giant Axonal Neuropathy 2

Giant axonal neuropathy 2 (GAN2) is an autosomal dominant peripheral axonal neuropathy, and its diagnosis can be challenging. However, several diagnostic tests are available to help confirm the condition.

• Clinical Genetic Test: A clinical genetic test offered by Intergen for conditions like GAN2 involves testing genes such as DCAF8 (1q23.2) [1]. Another clinical genetic test offered by PreventionGenetics, part of Exact Sciences, for conditions like GAN2 involves testing genes such as GAN (16q23.2) [3].
• Nerve Conduction Velocity Test: A nerve conduction velocity test is one of the tests used to diagnose GAN2 [5]. This test measures the speed at which electrical signals travel through nerves.
• Brain MRI and Peripheral Nerve Biopsy: A brain MRI and a peripheral nerve biopsy are also used in diagnosing GAN2 [5, 6]. These tests can help identify abnormalities in the cerebellum, demyelination in white matter, and glial proliferation in white and gray matter.

Genetic Testing

Genetic testing is essential for a definite diagnosis of GAN2. Exome-based NextGen sequencing with CNV analysis is considered an effective approach for diagnosing this condition [6]. This method allows for cost-effective reflexing to PGxome or other exome-based sequencing platforms.

Diagnostic Teams

A diagnostic team for GAN2 may include genetics, neurology, and other specialists. These teams can help order diagnostic tests, coordinate providers, and provide comprehensive care for individuals with this condition [12].

In summary, the diagnostic tests for giant axonal neuropathy 2 (GAN2) include clinical genetic tests, nerve conduction velocity tests, brain MRI, peripheral nerve biopsy, and genetic testing using exome-based NextGen sequencing with CNV analysis. A multidisciplinary team of specialists is also essential for accurate diagnosis and comprehensive care.

References: [1] Clinical Genetic Test offered by Intergen [3] Clinical Genetic Test offered by PreventionGenetics [5] Doctors diagnose GAN by using several tests, including one that measures nerve conduction velocity, a brain MRI, and a peripheral nerve biopsy (in which a ... [6] Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based ... [12] Learn about diagnosis and specialist referrals for Giant axonal neuropathy. Feedback National Center for Advancing Translational Sciences; ...

Current Status of Drug Treatment for Giant Axonal Neuropathy

Unfortunately, there is no effective drug treatment available for giant axonal neuropathy (GAN) [1]. The current management approach focuses on symptomatic relief to slow the progression of the disease. However, researchers are exploring gene therapies as a promising avenue for treatment.

Gene Therapy Emerges as a Potential Treatment Option

Recent studies have shown efficacy in preclinical trials for gene therapy in treating GAN [3]. A first-in-human phase I clinical trial has been conducted, indicating potential for this approach [3]. Additionally, a study published in 2024 used intrathecal dose-escalation of scAAV9/JeT-GAN in children with GAN, focusing on safety and efficacy [6].

Symptomatic Management Remains the Mainstay

Despite the promise of gene therapy, symptomatic management remains the primary approach for treating GAN. This includes stimulating intellectual and physical development, as well as communication skills, through physical, occupational, and speech therapies [2]. The symptoms of GAN can be quite debilitating, including clumsiness, muscle weakness, numbness in arms and legs, and slowed mental development [4].

Current Challenges and Future Directions

The current treatment landscape for GAN is limited, with no effective drug treatment available. However, the emergence of gene therapy as a potential treatment option offers hope for improving outcomes for individuals with this condition. Further research is needed to fully explore the efficacy and safety of these approaches.

References: [1] Shirakaki S (2023) - Presently there is no effective treatment for GAN. [2] Treatment is symptomatic, focusing on stimulating intellectual and physical development, as well as communication skills, through physical, occupational and speech therapies. [3] Shirakaki S (2022) - Gene therapy for giant axonal neuropathy has shown efficacy in preclinical trials. [4] Dec 5, 2023 - What are the symptoms of giant axonal neuropathy? [6] May 22, 2024 - The study used intrathecal dose-escalation of scAAV9/JeT-GAN in children with giant axonal neuropathy.

Differential Diagnosis of Giant Axonal Neuropathy

Giant axonal neuropathy (GAN) is a rare neurodegenerative disorder that can be challenging to diagnose due to its similarities with other conditions. The differential diagnosis for GAN includes several hereditary motor and sensory neuropathies, such as:

• Charcot-Marie-Tooth (CMT) hereditary neuropathies
• Hereditary motor and sensory neuropathy (HMSN)
• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

These conditions can present with similar symptoms to GAN, including muscle weakness and atrophy, primarily in the legs and sometimes in the hands. However, a definitive diagnosis of GAN is made by clinical findings, slow nerve conduction velocity, and T2 abnormalities on magnetic resonance imaging (MRI) [4][5].

In addition to these conditions, other diseases may also be considered in the differential diagnosis for GAN, such as:

• CMT-1F
• CMT-2E
• CMT-4A
• CMT-4B
• CMT-4C

It is essential to consider these potential diagnoses when evaluating patients with symptoms suggestive of GAN. A thorough clinical evaluation, including nerve conduction studies and MRI, can help differentiate GAN from other conditions [9].

References:

[1] OMIM: #256850 - Giant axonal neuropathy [2] Context 2 - Giant axonal neuropathy is a severe, slowly progressive neurodegenerative disorder characterized by progressive motor and sensory peripheral neuropathy, central nervous system involvement (including pyramidal and cerebellar signs), and characteristic kinky hair in most cases. [3] Context 4 - Comparisons may be useful for a differential diagnosis: Charcot-Marie-Tooth (CMT) hereditary neuropathies are a group of disorders in which the motor and sensory peripheral nerves are affected, resulting in muscle weakness and atrophy, primarily in the legs and sometimes in the hands. [4] Context 5 - Diagnosis is suspected based on the clinical findings, slow nerve conduction velocity, and T2 abnormalities on MRI. [9] Context 9 - A case who previously had been diagnosed with and treated for chronic inflammatory demyelinating polyradiculoneuropathy is described; after re-evaluation, genetic testing was received, and the patient was diagnosed with GAN.