| Disease term | MONDO ID | Primary causal gene | Inheritance | Core phenotype | Notable lab/biochemical findings | Key supporting publications | Evidence type |
|---|---|---|---|---|---|---|---|
| Autosomal recessive cerebellar ataxia with late-onset spasticity | MONDO_0018129 | **GBA2** (ENSG00000070610) | Autosomal recessive | Spastic ataxia with overlap of cerebellar ataxia and spastic paraplegia; gait ataxia, limb spasticity/weakness; variable neuropathy and additional neurologic/extraneurologic features (pqac-00000007, pqac-00000008, pqac-00000012) | GBA2 is a non-lysosomal glucosylceramidase in sphingolipid metabolism; disease-associated dysfunction linked to altered glucosylceramide/ceramide handling (pqac-00000008, pqac-00000010) | Open Targets disease-target association to GBA2 with literature PMID 23332917; MONDO mapping for the disease term (pqac-00000012) | Human disease ontology / disease-target association |
| SPG46 (hereditary spastic paraplegia type 46) | MONDO_0018129* | **GBA2** (ENSG00000070610) | Autosomal recessive | Complex HSP phenotype with spastic paraplegia, cerebellar atrophy/ataxia, mental impairment, cataract, hypogonadism in males; variable corpus callosum and cerebellar atrophy on imaging (pqac-00000009, pqac-00000011) | Missense example **c.1888C>T (p.Arg630Trp)** with absent residual GBA2 activity in blood cells in one homozygous subject; GBA2 catalyzes glucosylceramide to glucose + ceramide (pqac-00000009) | Martin et al., 2013, *Am J Hum Genet* 92:238-244, DOI: 10.1016/j.ajhg.2012.11.021; Cioffi et al., 2024, *Neurogenetics* 25:51-67, DOI: 10.1007/s10048-024-00749-9 (pqac-00000009, pqac-00000011) | Human genetics, enzyme assay, zebrafish functional model |
| Spastic ataxia (GBA2-associated; Cypriot family) | MONDO_0018129* | **GBA2** (ENSG00000070610) | Autosomal recessive | Mixed cerebellar ataxia and spasticity; main features include gait ataxia, spasticity, limb weakness; can include neuropathy, pyramidal/extrapyramidal signs, oculomotor abnormalities, cognitive involvement, seizures, retinopathy, hypogonadism (pqac-00000007) | Homozygous **c.1780G>C (p.Asp594His)** causes marked reduction/abolishment of non-lysosomal glucosylceramidase activity, ~2-fold increased glucosylceramide in patient LCLs, and ~3-fold compensatory increase in lysosomal GBA activity (pqac-00000010) | Malekkou et al., 2018, *Int J Mol Sci* 19:3099, DOI: 10.3390/ijms19103099; Kakouri et al., 2020, *Int J Mol Sci* 21:6722, DOI: 10.3390/ijms21186722 (pqac-00000010, pqac-00000007) | Human clinical report, patient-derived lymphoblastoid cells, pathway analysis |
| GBA2-associated spastic ataxia transcriptomic model | MONDO_0018129* | **GBA2** (ENSG00000070610) | Autosomal recessive | SA tissues/cells from patients with homozygous **c.1780G>C** used to study disease mechanisms; symptoms framed as overlap between ataxia and spastic paraplegia (pqac-00000008) | RNA-seq across LCLs, fibroblasts, and iPSC-derived neurons found **5217** significantly altered genes; implicated oxidative stress, neuroinflammation, sphingolipid signaling/metabolism, PI3K-Akt, and MAPK pathways (pqac-00000008) | Kakouri et al., 2022, *Cell & Bioscience* 12:29, DOI: 10.1186/s13578-022-00754-1 (pqac-00000008) | Patient cells, iPSC-derived neurons, transcriptomics |
| SPG46 / GBA2 literature synthesis | MONDO_0018129* | **GBA2** (ENSG00000070610) | Autosomal recessive | Review notes ~30 families and 62 patients reported worldwide; phenotypes span complicated HSP, recessive cerebellar ataxia, and Marinesco-Sjögren-like syndrome; notable features include upper gaze palsy and movement disorders (pqac-00000011) | GBA2 activity measurable in lymphoblasts/leucocytes; pathogenic mechanism linked to glucosylceramide accumulation and disturbed ganglioside/sphingolipid metabolism (pqac-00000011) | Cioffi et al., 2024, *Neurogenetics* 25:51-67, DOI: 10.1007/s10048-024-00749-9 (pqac-00000011) | Human case series and literature review |


*Table: This table summarizes the disease labels, ontology mapping, causal gene, phenotype, biochemical findings, and supporting studies for GBA2-associated autosomal recessive spastic ataxia/SPG46. It is useful for quickly aligning nomenclature across disease resources and the core human/mechanistic evidence base.*