GAN – Giant Axonal Neuropathy 1

Autosomal recessive variants in the GAN gene underlie Giant Axonal Neuropathy 1 (MONDO:0009749), a rare neurodegenerative disorder with peripheral and central nervous system involvement. Clinically, affected individuals present in early childhood with gait disturbance, sensory impairment, scoliosis, and autonomic dysfunction, occasionally mimicking Charcot–Marie–Tooth disease.

In a large Japanese cohort of 3 315 inherited peripheral neuropathy patients screened by targeted NGS and WES, five probands from four unrelated families harbored seven biallelic GAN variants, including two novel pathogenic alleles (c.922G>T (p.Glu308Ter) and c.456dup (p.Ala153CysfsTer27)) (PMID:40668264). Additional case series identified two siblings with a homozygous AluYa5 insertion (c.1657ALUYa5ins (p.Thr553_Pro597del)) in India (PMID:18595793) and three Iranian patients with a novel nonsense variant c.1162del (p.Leu388Ter) and a missense c.370T>A (p.Phe124Ile) (PMID:36866531).

The variant spectrum includes four loss-of-function alleles—c.280C>T (p.Gln94Ter) (PMID:16565160), c.922G>T (p.Glu308Ter), c.456dup (p.Ala153CysfsTer27), c.1162del (p.Leu388Ter)—one missense (c.370T>A (p.Phe124Ile)), and one in-frame Alu insertion (c.1657ALUYa5ins (p.Thr553_Pro597del)). No recurrent or founder variants have been reported to date.

Segregation analysis demonstrated co-segregation of pathogenic alleles in four additional affected relatives across Iranian and Indian families, confirming autosomal recessive inheritance (affected relatives = 4). Functional studies in GAN knockout mice showed progressive neurological phenotypes, MAP8 accumulation, ubiquitin–proteasome dysfunction, and impaired axonal transport replicating human disease (PMID:16565160). Complementary human cell models reveal that O-linked β-N-acetylglucosamine modification at Ser272 and Thr277 is critical for gigaxonin-mediated intermediate filament turnover, linking metabolism to disease mechanisms (PMID:31944090).

No conflicting evidence disputing GAN’s role in Giant Axonal Neuropathy has been reported. Integration of genetic and experimental data supports a loss-of-function mechanism with defective ubiquitin-mediated degradation of cytoskeletal proteins and impaired axonal transport. Systematic screening for GAN variants is recommended in pediatric-onset CMT presentations, even without classical frizzy hair or central signs.

Key Take-home: Autosomal recessive GAN loss-of-function variants cause Giant Axonal Neuropathy 1 with early-onset sensorimotor neuropathy; genetic testing and functional studies inform diagnosis and therapeutic development.

References

• Journal of neurology • 2025 • Charcot-Marie-Tooth-like presentation in giant axonal neuropathy: clinical variability and prevalence in a large Japanese case series. PMID:40668264
• 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 medical genetics • 2008 • Clinical, pathological and molecular findings in two siblings with giant axonal neuropathy (GAN): report from India. PMID:18595793
• Molecular genetics & genomic medicine • 2023 • Expanding the genetic spectrum of giant axonal neuropathy: Two novel variants in Iranian families. PMID:36866531
• JCI insight • 2020 • Gigaxonin glycosylation regulates intermediate filament turnover and may impact giant axonal neuropathy etiology or treatment. PMID:31944090

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