Clinical and molecular characterization of giant axonal neuropathy due to a homozygous c.851 + 1G>A variant in GAN: A case report and literature review.

BACKGROUND: Giant Axonal Neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder caused by biallelic pathogenic variants in the GAN gene, which encodes gigaxonin. The disease typically begins in childhood and is characterized by muscle weakness, gait disturbances, peripheral neuropathy, and distinctive kinky hair. CASE DESCRIPTION: We report the clinical, radiological, and molecular findings of a 7-year-old Mexican girl from Jalisco, Mexico, born to consanguineous parents, who presented with global developmental delay and absence of independent ambulation by age of seven. Additional features included kinky hair, broad forehead, blepharoptosis, depressed nasal bridge with a bulbous tip, high-arched palate, micrognathia, and generalized joint hyperlaxity. Given the phenotypic overlap with Noonan syndrome, PTPN11 Sanger sequencing was initially performed, followed by a RASopathy gene panel; both analyses yielded negative results. RESULTS: Whole-exome sequencing identified a homozygous splice-site variant in GAN c.851 + 1 G>A, which was confirmed by Sanger sequencing. Both parents were heterozygous carriers, consistent with parental consanguinity. According to ACMG/AMP guidelines (PVS1, PM2, PM3), the variant was classified as pathogenic. Additional studies, including brain magnetic resonance imaging, revealed peridentate hyperintensities compatible with gliosis or hypomyelination. CONCLUSION: The integration of clinical features, neuroimaging findings, and molecular analysis confirmed the diagnosis of giant axonal neuropathy type 1. This case underscores the clinical relevance of whole-exome sequencing in patients with overlapping syndromic features. Notably, the GAN c.851 + 1 G>A variant has previously been reported in at least five homozygous patients of Mexican ancestry, supporting a possible founder effect in this population.