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Giant axonal neuropathy
Giant axonal neuropathy (GAN) 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.
The prevalence is unknown, but to date approximately 50 families have been reported. The frequency of this disease however, is likely to be underestimated, due to patients with incomplete phenotypes and high level of consanguinity among some populations. It occurs equally in both sexes.
Onset of GAN ranges from early infancy to late childhood. Clinical hallmarks include progressive gait disturbance (frequent falls due to muscle weakness, sensory neuropathy and ataxia), everted feet, crouched gait, tightly curled hair, and early-onset central nervous system (CNS) involvement, including pyramidal and cerebellar signs that, when present together almost clinch the diagnosis. Patients usually present with intellectual disability, epilepsy, nystagmus and dysarthria that worsens in the second decade of life, and mortality typically occurs in the third decade. Other clinical signs include facial weakness, optic atrophy, ophthalmoplegia, skeletal deformations (e.g. foot deformities, scoliosis) and tremor. Clinically heterogeneous cases, with GAN presenting with a mild Charcot-Marie-Tooth (CMT)-like phenotype or manifesting with a later age of onset, absence of kinky hair, and slower progression, have recently been documented.
GAN is associated with more than 50 different causative mutations in GAN gene (16q24.1), encoding the ubiquitously expressed cytoskeletal protein gigaxonin.
Diagnosis is based on clinical findings and imaging. Cerebellum abnormalities, demyelination in white matter and glial proliferation in white and gray matter are shown by magnetic resonance imaging. Due to the presence of giant axons in other diseases, peripheral nerve biopsy is not sufficient to diagnose GAN. Genetic molecular testing or immunodetection of gigaxonin confirms diagnosis.
Differential diagnosis includes CMT-1F, -2E, -4A, -4B, -4C, -4D and -4E, the classic form of infantile neuroaxonal dystrophy, arylsulfatase A deficiency, spinal muscular atrophy, Friedreich ataxia, globoid cell leukodystrophy, n-hexane toxicity, and acrylamide toxicity.
Prenatal diagnosis is possible in families with a known disease-causing mutation.
GAN is inherited as an autosomal recessive trait. Parents of an affected child are obligate heterozygotes and asymptomatic. Genetic counseling can inform parents that the risk of having an affected child is 25%. Carrier testing requires the GAN pathogenic variant to have been identified in an affected member of the family.
Management and treatment
Treatment is symptomatic, focusing on stimulating intellectual and physical development, as well as communication skills, through physical, occupational and speech therapy, since the initiation of symptoms. Skeletal deformities and ophthalmoplegia may need surgery. Intrathecal administration of an AAV9-based gene therapy to restore GAN expression is currently being explored.
The prognosis varies but is usually poor. Most patients become wheelchair-dependent in the second decade of life and eventually progress to a bedridden state in early adulthood. Secondary complications, such as respiratory failure, may occur. Life expectancy does not exceed the third decade. Lack of curly hair is correlated with milder disease and slower disease progression, which would suggest a less stark prognosis.
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