GAN-Related Neurodegeneration

Clinical characteristics: GAN-related neurodegeneration comprises a phenotypic continuum ranging from severe (sometimes called classic giant axonal neuropathy) to milder pure early-onset peripheral motor and sensory neuropathies. The classic giant axonal neuropathy phenotype typically manifests as an infantile-onset neurodegenerative disorder, starting as a severe peripheral motor and sensory neuropathy and evolving into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most affected individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade. At the milder end of the spectrum are predominantly motor and sensory neuropathies (with little to no CNS involvement) that overlap with the axonal form of Charcot-Marie-Tooth neuropathies.

Diagnosis/testing: The diagnosis of GAN-related neuropathy is established in a proband with suggestive findings and biallelic GAN pathogenic variants identified by molecular genetic testing.

Management: Treatment of manifestations: Supportive care is focused on managing the clinical findings of the individual, and often involves a team including neurologists, orthopedic surgeons, physiotherapists, occupational and physical therapists, psychologists, and speech-language pathologists. Major goals are to optimize intellectual and physical development.

Surveillance: Surveillance is individualized to monitor response to ongoing interventions and identify new manifestations.

Genetic counseling: GAN-related neuropathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GAN pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the GAN pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.