GAN – Giant Axonal Neuropathy

Giant Axonal Neuropathy (GAN) is a rare autosomal recessive disorder characterized by early-onset sensorimotor polyneuropathy, central nervous system involvement, and striking hair abnormalities. The responsible gene, GAN (HGNC:4137), was localized to chromosome 16q24.1 by homozygosity mapping in multiple families (PMID:10732815). Clinically, patients present with progressive ataxia, areflexia, hypotonia, global developmental delay, and frizzy or curly hair.

Over 45 distinct disease-causing GAN variants have been described in more than 100 unrelated probands, establishing a consistent autosomal recessive inheritance (PMID:23332420). Segregation analyses in at least three consanguineous families confirm co-segregation of biallelic variants with disease (PMID:15897506). For example, the c.224T>A (p.Leu75His) missense variant was identified in a compound heterozygous proband and shown to be inherited from asymptomatic carrier parents (PMID:19295179).

The mutational spectrum includes missense (e.g., c.224T>A (p.Leu75His)), nonsense (e.g., c.484C>T (p.Arg162Ter)), splice-site (e.g., c.1502+1G>T), frameshift (e.g., c.27delC (p.Pro10LeufsTer?)), small intragenic deletions, and Alu-mediated complex rearrangements. No clear genotype–phenotype correlation has been established, though variants in the Kelch domain often associate with more severe CNS features.

Functional studies demonstrate that loss of gigaxonin impairs ubiquitin-proteasome–mediated degradation of intermediate filament proteins. GAN knockout mice accumulate MAP8, disrupt microtubule networks, trap dynein motors, and recapitulate the human neurodegenerative phenotype, including impaired retrograde axonal transport (PMID:16565160). Cellular assays further show gigaxonin’s role in IF turnover and neurofilament clearance.

There is no conflicting evidence disputing the GAN–Giant Axonal Neuropathy association. The broad range of variant types, consistent segregation, and robust in vivo and in vitro functional concordance support a Definitive ClinGen classification. Genetic testing for biallelic GAN variants is essential for early diagnosis, genetic counseling, and eligibility for emerging gene therapy trials.

Key Take-home: Biallelic loss-of-function variants in GAN cause definitive autosomal recessive Giant Axonal Neuropathy; comprehensive sequencing and CNV analysis of GAN is clinically indicated in early-onset axonal neuropathy with frizzy hair.

References

• Neurogenetics • 1997 • Homozygosity mapping of giant axonal neuropathy gene to chromosome 16q24.1 PMID:10732815
• Journal of child neurology • 2009 • Clinical and genetic studies in a Chinese family with giant axonal neuropathy. PMID:19295179
• Journal of neurology, neurosurgery, and psychiatry • 2005 • Giant axonal neuropathy: clinical and genetic study in six cases. PMID:15897506
• Human molecular genetics • 2006 • Gene targeting of GAN in mouse causes a toxic accumulation of microtubule-associated protein 8 and impaired retrograde axonal transport. PMID:16565160
• European journal of paediatric neurology • 2013 • Giant axonal neuropathy caused by compound heterozygosity for a maternally inherited microdeletion and a paternal mutation within the GAN gene. PMID:23332420

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