Giant axonal neuropathy
Rare neurological disorder with neurofilament disorganization and kinky hair.
Giant axonal neuropathy is a rare, autosomal recessive neurological disorder characterized by disorganization of neurofilaments, which are essential for normal nerve function. A distinguishing feature is its association with kinky or curly hair, leading to the designation Giant axonal neuropathy with curly hair. Over 100 patients and 75 families have been recorded as of 2024.
Quick Facts
- Onset
- By age 3.
- Causes
- Mutation in GAN gene.
- Differential
- Charcot-Marie-Tooth disease, Late-infantile metachromatic leukodystrophy
- Prevention
- Genetic counseling
- Prognosis
- Generally poor
Facts from the source article.
Signs and symptoms
Very frequent signs include abnormality of the Achilles tendon, absent reflexes, deficiency of myelin sheath in the CNS, diffuse swelling of the axon, impaired gait, kinky hair, generalized decreased muscle tone, and weakness in upper arm and upper leg muscles. Patients commonly experience cerebellar abnormalities, abnormal hand shape, distal sensory impairment, spasticity, facial nerve paralysis, cognitive impairment, scoliosis, cavus foot, and club feet. Occasional features include knock knees. A mild form resembles Charcot-Marie-Tooth disease with milder curled hair. Classic GAN shows abnormal signals in white matter of the brain and cerebellum. Patients usually do not survive past the third decade due to complications.
Genetics
Mutations in the GAN gene, which codes for gigaxonin, cause giant axonal neuropathy. The altered protein shape changes its interactions with other proteins involved in organizing neuronal structure. This disorder is autosomal recessive, meaning both parents must carry one defective gene copy to have an affected child; carriers are typically unaffected.
Pathophysiology
Gigaxonin normally forms a complex with CUL3 and RBX1, targeting substrates such as neurofilaments (INA and NEFL) and actin filament–associated regulatory proteins (CNN2, TPM1) for degradation. Mutated gigaxonin leads to accumulation of excess neurofilaments in the axon, causing enlargement or 'giant' axons that cannot transmit signals properly and eventually deteriorate. In a zebrafish model, gigaxonin was shown to be important in the SHH signaling pathway, inducing degradation of Ptch to disinhibit SMO and transduce SHH signaling; defective SHH pathway hampered motor neuron development.
Diagnosis
This progressive disorder typically begins in infancy or early childhood. The first symptoms usually involve the peripheral nerves, making walking difficult. Over time, sensation, coordination, strength, and reflexes are impaired, and hearing or vision can decline. Nearly all affected individuals have unusually kinky hair. As the condition advances, the central nervous system is affected, potentially leading to a gradual loss of mental abilities, poor motor control, and seizures.
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