Intrafamilial phenotypic variability in B4GALNT1-related disorders: A sibling case report

Pathogenic variants in β-1,4-N-acetylgalactosaminyltransferase 1 (B4GALNT1) are primarily associated with hereditary spastic paraplegia type 26 (SPG26). In addition, these variants have been implicated in Charcot-Marie-Tooth disease, suggesting a broad phenotypic continuum involving both the central and peripheral nervous systems. Herein, we report a pair of siblings harboring novel compound heterozygous variants in B4GALNT1. Despite carrying identical variants, the sisters exhibited distinct clinical manifestations.

The proband, the younger sister (aged 13 years), presented with progressive lower-limb spasticity and muscle weakness. These symptoms prompted genetic testing, which identified compound heterozygous variants in B4GALNT1 and led to a diagnosis of SPG26. Genetic analysis of her elder sister confirmed the presence of the same variants; however, she did not exhibit spastic paraplegia. Instead, her primary clinical feature was intellectual disability (ID).

These cases illustrate the broad clinical spectrum of B4GALNT1-related disorders. Despite sharing identical pathogenic variants, the siblings demonstrated divergent phenotypes: one with typical spastic paraplegia and the other presenting primarily with ID. Given the absence of overt neurological deficits at the time of evaluation, the phenotype in the elder sister may represent a presymptomatic stage or a very mild manifestation of the disease. These findings suggest that B4GALNT1 variants should be considered in the differential diagnosis of unexplained ID, even when clear motor dysfunction is not yet apparent.