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Hereditary spastic paraplegia (HSP) comprises heterogeneous neurodegenerative disorders presenting with progressive lower limb spasticity and weakness. SPG26 (Hereditary Spastic Paraplegia 26) includes additional features such as global developmental delay, cerebellar ataxia, dysarthria, cognitive impairment, and peripheral neuropathy. SPG26 is caused by biallelic variants in B4GALNT1. The gene encodes ganglioside GM2/GD2 synthase (GM2S) which transfers N-acetylgalactosamine to generate GA2, GM2, and GD2. Loss of GM2S activity disrupts ganglioside homeostasis in neurons. Here we assess the strength of the B4GALNT1–SPG26 association based on genetic and functional evidence.
SPG26 follows an autosomal recessive inheritance pattern. To date, at least 15 unrelated probands with biallelic B4GALNT1 variants have been reported across diverse populations ([PMID:30521973]). Genetic segregation has been documented in multiple families, with 19 affected relatives clearly demonstrating co-segregation of pathogenic alleles. The variant spectrum includes missense substitutions, splice-site changes, frameshifts, and premature termination codons. Notable variants include c.937G>A (p.Asp313Asn) found homozygously in a Japanese patient ([PMID:39145292]). LoF variants such as c.1478C>G (p.Ser493Ter) and c.128dupC (p.Gln44AlafsTer14) further support a loss-of-function mechanism ([PMID:30521973], [PMID:34595861]).
Patients with SPG26 commonly present in early childhood with global developmental delay (HP:0001263) and progressive spastic diplegia. Additional manifestations include cerebellar ataxia (HP:0001251), dysarthria (HP:0001260), cognitive impairment (HP:0100543), and peripheral neuropathy (HP:0009830). Neurophysiological studies frequently reveal axonal sensorimotor polyneuropathy in the absence of early urinary or visual symptoms. Brain MRI may show cerebellar atrophy and corpus callosum thinning in advanced cases. One patient with compound heterozygous c.451G>A (p.Gly151Ser) and c.128dupC (p.Gln44AlafsTer14) variants presented primarily with axonal Charcot-Marie-Tooth disease without spasticity ([PMID:34595861]). These findings expand the allelic and phenotypic spectrum of B4GALNT1-related disorders.
In vitro enzyme assays consistently demonstrate near-complete loss of GM2S activity for pathogenic B4GALNT1 variants. The p.Asp313Asn variant abolished GM2/GD2 synthase activity in recombinant assays and abrogated activation-induced ganglioside expression in patient T cells ([PMID:39145292]). Flow cytometry and cell-free assays confirmed absent activity for most missense and LoF mutants, while only rare PTC readthrough responders retained partial function ([PMID:30521973], [PMID:32282910]). Patient-derived fibroblasts carrying splice-site and missense alleles show absence of downstream gangliosides GM2, GD2, and GA2, as assessed by mass spectrometry ([PMID:35775650]). Structural modeling predicts impaired UDP-GalNAc binding for several substitutions, supporting a loss-of-function mechanism. These data firmly establish enzymatic deficiency underlying SPG26 pathophysiology.
B4galnt1 knockout mice exhibit progressive neurodegeneration with age-dependent motor defects and milder spasticity, mirroring human SPG26 phenotypes ([PMID:30521973], [PMID:28602513]). Neuron-specific transgenic rescue in these mice restores ganglioside homeostasis and mitigates inflammation in the central nervous system. Isoform studies highlight the importance of Golgi retention motifs for enzyme stability and trafficking but do not affect core synthase activity ([PMID:28709807]). Together, these in vivo and cellular models corroborate haploinsufficiency as the pathogenic mechanism. No credible conflicting reports have been published to date. Additional large-scale population screening may uncover further carrier variants.
In summary, autosomal recessive B4GALNT1 variants causing loss of GM2/GD2 synthase activity are pathogenic for Hereditary Spastic Paraplegia 26. Genetic evidence from over 15 families and functional assays across multiple platforms support a strong gene-disease association. The presence of diverse variant types and consistent segregation fulfills criteria for a Strong clinical validity classification. The loss-of-function mechanism is well established, with supportive animal and cellular models. No disputes have been reported. Clinical sequencing of B4GALNT1 with targeted enzyme assays facilitates definitive diagnosis of SPG26 and informs potential treatment strategies.
Gene–Disease AssociationStrong≥15 probands, multi-family segregation, consistent functional characterization Genetic EvidenceStrong15 unrelated probands with biallelic variants and clear co-segregation in 19 relatives Functional EvidenceModerateMultiple in vitro enzyme assays, patient cell studies, and mouse knockout model support loss-of-function |