GBA2 – SPG46-related Hereditary Spastic Paraplegia

Hereditary spastic paraplegia 46 (SPG46) is an autosomal recessive neurodegenerative disorder characterized by progressive lower‐limb spasticity, pyramidal weakness, cerebellar ataxia, thin corpus callosum, congenital cataracts, dysarthria and urinary disturbances. GBA2 encodes a microsomal non‐lysosomal glucosylceramidase that hydrolyzes glucosylceramide to ceramide and glucose. Loss‐of‐function mutations in GBA2 disrupt ceramide metabolism, leading to axonal degeneration of upper motor neurons in SPG46.

Initial genetic evidence came from three independent families in which four distinct GBA2 truncating or splice‐site variants cosegregated with a complex spastic paraplegia phenotype and were absent in controls (PMID:23332916). Enzyme assays in patient blood cells showed complete abrogation of GBA2 activity. Subsequent zebrafish morpholino knockdown of gba2 orthologues reproduced motor defects and axonal shortening, which were rescued by wild-type but not mutant human GBA2 mRNA (PMID:23332916).

A single Japanese patient was later reported with a novel homozygous missense variant c.1838A>G (p.Asp613Gly) in exon 12 of GBA2, presenting with spasticity, ataxia, dysarthria, pollakisuria and thin corpus callosum on MRI (PMID:32280793). Her clinical features matched the SPG46 spectrum and supported autosomal recessive inheritance of a deleterious missense allele.

A multi‐centre cohort from Italy described five unrelated SPG46 probands harbouring five novel bi-allelic GBA2 mutations, expanding the allelic series and noting upper gaze palsy and movement disorders in addition to classic spastic paraplegia (PMID:38334933). To date, ~30 families worldwide have been documented with biallelic GBA2 variants causing SPG46, underscoring its global prevalence.

The mutation spectrum includes missense, nonsense, splice‐site, frameshift and deep‐intronic alleles. Functional characterization of ten GBA2 mutants in transfected cells demonstrated complete loss of enzymatic activity for both nonsense and missense variants (e.g., p.Asp594His), indicating a loss-of-function mechanism (PMID:26220345).

Mechanistic studies reveal that GBA2 deficiency leads to glucosylceramide accumulation, altered sphingolipid signaling, impaired neurite outgrowth and disrupted F-actin dynamics in neuronal models (PMID:30662006). Mouse GBA2 knockout models exhibit variable locomotor phenotypes, highlighting species-specific differences but supporting a conserved role in motor neuron integrity.

No studies to date refute the GBA2–SPG46 association. Collectively, genetic and experimental data establish GBA2 loss-of-function as the cause of SPG46. Key take-home: GBA2 genetic testing informs diagnosis of autosomal recessive SPG46 and may guide future therapeutic development targeting sphingolipid metabolism.

References

• eNeurologicalSci • 2020 • A novel mutation in the GBA2 gene in a Japanese patient with SPG46: A case report. [PMID:32280793]
• American Journal of Human Genetics • 2013 • Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. [PMID:23332916]
• Journal Unknown • Year Unknown • Five SPG46 patients harbouring novel GBA2 mutations in Italy. [PMID:38334933]
• Biochemical and Biophysical Research Communications • 2015 • Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46). [PMID:26220345]
• The Journal of Biological Chemistry • 2019 • Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations. [PMID:30662006]

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