Autosomal recessive cerebellar ataxia with late-onset spasticity is a GBA2-related spastic-ataxia disorder, overlapping spastic paraplegia 46 (SPG46). It is caused by biallelic GBA2 variants encoding the microsomal nonlysosomal glucosylceramidase that converts glucosylceramide to glucose and ceramide. Loss of GBA2 activity causes glucosylceramide accumulation and motor neuron and cerebellar dysfunction, producing a complex phenotype of cerebellar ataxia with spastic paraplegia, often with cerebellar and corpus callosum atrophy, cognitive impairment, cataract, and (in males) hypogonadism.
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name: Autosomal Recessive Cerebellar Ataxia With Late-Onset Spasticity
creation_date: "2026-06-13T00:00:00Z"
description: >-
Autosomal recessive cerebellar ataxia with late-onset spasticity is a GBA2-related
spastic-ataxia disorder, overlapping spastic paraplegia 46 (SPG46). It is caused by biallelic
GBA2 variants encoding the microsomal nonlysosomal glucosylceramidase that converts
glucosylceramide to glucose and ceramide. Loss of GBA2 activity causes glucosylceramide
accumulation and motor neuron and cerebellar dysfunction, producing a complex phenotype of
cerebellar ataxia with spastic paraplegia, often with cerebellar and corpus callosum atrophy,
cognitive impairment, cataract, and (in males) hypogonadism.
synonyms:
- GBA2-related spastic ataxia
- spastic paraplegia 46
- SPG46
- spastic ataxia, GBA2-related
category: Mendelian
disease_term:
preferred_term: autosomal recessive cerebellar ataxia with late-onset spasticity
term:
id: MONDO:0018129
label: autosomal recessive cerebellar ataxia with late-onset spasticity
mappings:
mondo_mappings:
- term:
id: MONDO:0018129
label: autosomal recessive cerebellar ataxia with late-onset spasticity
mapping_predicate: skos:exactMatch
mapping_source: MONDO
parents:
- Hereditary Ataxia
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Spastic paraplegia 46 refers to a locus mapped to chromosome 9 that accounts for\na complicated autosomal-recessive form of hereditary spastic paraplegia (HSP)"
explanation: The GBA2-related disorder (SPG46) is autosomal recessive.
pathophysiology:
- name: GBA2 Nonlysosomal Glucosylceramidase Deficiency
description: >-
Biallelic GBA2 variants reduce the microsomal nonlysosomal glucosylceramidase that converts
glucosylceramide to glucose and ceramide, impairing glucosylceramide turnover.
gene:
preferred_term: GBA2
term:
id: hgnc:18986
label: GBA2
biological_processes:
- preferred_term: glucosylceramide catabolic process
term:
id: GO:0006680
label: glucosylceramide catabolic process
modifier: DECREASED
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "GBA2 encodes a microsomal nonlysosomal glucosylceramidase that\ncatalyzes the conversion of glucosylceramide to free glucose and ceramide"
explanation: GBA2 is the nonlysosomal glucosylceramidase whose loss causes the disease.
downstream:
- target: Glucosylceramide Accumulation and Motor Neuron/Cerebellar Dysfunction
description: Reduced GBA2 activity impairs glucosylceramide turnover, injuring motor neurons and cerebellum.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Glucosylceramide Accumulation and Motor Neuron/Cerebellar Dysfunction
description: >-
Impaired glucosylceramide turnover injures corticospinal motor neurons and cerebellar
neurons, producing the combined spastic paraplegia and cerebellar ataxia with cerebellar
and corpus callosum atrophy.
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "various degrees of corpus callosum and\ncerebellar atrophy on brain imaging"
explanation: GBA2 loss produces cerebellar and corpus callosum atrophy reflecting neuronal injury.
downstream:
- target: Cerebellar ataxia
description: Cerebellar neuronal dysfunction manifests as the core ataxia phenotype.
causal_link_type: DIRECT
evidence:
- reference: PMID:38334933
reference_title: "Hereditary spastic paraparesis type 46 (SPG46): new GBA2 variants in a large Italian case series and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "recessive cerebellar ataxia or Marinesco-Sjögren Syndrome."
explanation: GBA2-related disease can present as recessive cerebellar ataxia.
- target: Spastic paraplegia
description: Motor-neuron and corticospinal-tract involvement manifests as spastic paraplegia.
causal_link_type: DIRECT
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a complicated autosomal-recessive form of hereditary spastic paraplegia (HSP)"
explanation: The causative GBA2 disorder is a complicated hereditary spastic paraplegia.
- target: Cerebellar atrophy
description: Cerebellar neuronal injury is visible as cerebellar atrophy on imaging.
causal_link_type: DIRECT
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "cerebellar atrophy on brain imaging."
explanation: Patient imaging documents cerebellar atrophy in the GBA2 disorder.
- target: Thin/atrophic corpus callosum
description: The same neurodegenerative process includes corpus-callosum atrophy.
causal_link_type: DIRECT
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypogonadism in males associated with various degrees of corpus callosum and"
explanation: Patient imaging documents corpus-callosum atrophy in the GBA2 disorder.
- target: Cognitive impairment
description: Complex GBA2-related neurodegeneration can include cognitive impairment.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The overall phenotype was a complex HSP with mental impairment, cataract, and"
explanation: The original report includes mental impairment as part of the GBA2 phenotype.
- target: Cataract
description: Cataract is part of the complex GBA2-associated phenotype, although the intermediate tissue mechanism is unresolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The overall phenotype was a complex HSP with mental impairment, cataract, and"
explanation: The original report includes cataract as part of the GBA2 phenotype.
- target: Hypogonadism
description: Male hypogonadism is part of the complex GBA2-associated phenotype, with unresolved intermediates.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypogonadism in males associated with various degrees of corpus callosum and"
explanation: The original report includes male hypogonadism in the GBA2 phenotype.
phenotypes:
- name: Cerebellar ataxia
description: Cerebellar ataxia, a core feature of the GBA2-related spastic-ataxia phenotype.
phenotype_term:
preferred_term: Ataxia
term:
id: HP:0001251
label: Ataxia
evidence:
- reference: PMID:38334933
reference_title: "Hereditary spastic paraparesis type 46 (SPG46): new GBA2 variants in a large Italian case series and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "different phenotypes like complicated HSP,\nrecessive cerebellar ataxia or Marinesco-Sj"
explanation: GBA2-related SPG46 can present as recessive cerebellar ataxia, a complex spastic-ataxia phenotype.
- name: Spastic paraplegia
description: Lower-limb spastic paraplegia from corticospinal tract degeneration.
phenotype_term:
preferred_term: Spastic paraplegia
term:
id: HP:0001258
label: Spastic paraplegia
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a complicated autosomal-recessive form of hereditary spastic paraplegia (HSP)"
explanation: The GBA2-related disorder is a complicated hereditary spastic paraplegia.
- name: Cerebellar atrophy
description: Cerebellar atrophy on brain imaging.
phenotype_term:
preferred_term: Cerebellar atrophy
term:
id: HP:0001272
label: Cerebellar atrophy
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "various degrees of corpus callosum and\ncerebellar atrophy on brain imaging"
explanation: Cerebellar atrophy is a characteristic neuroimaging finding.
- name: Thin/atrophic corpus callosum
description: Corpus callosum atrophy on brain imaging.
phenotype_term:
preferred_term: Corpus callosum atrophy
term:
id: HP:0007371
label: Corpus callosum atrophy
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "various degrees of corpus callosum and\ncerebellar atrophy on brain imaging"
explanation: Corpus callosum atrophy is part of the GBA2 neuroimaging signature.
- name: Cognitive impairment
description: Mental impairment / intellectual disability is part of the complex phenotype.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The overall phenotype was a complex HSP with mental impairment, cataract, and\nhypogonadism in males"
explanation: Mental impairment is part of the complex GBA2 phenotype.
- name: Cataract
description: Cataract is a recurrent extraneurological feature.
phenotype_term:
preferred_term: Cataract
term:
id: HP:0000518
label: Cataract
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The overall phenotype was a complex HSP with mental impairment, cataract, and\nhypogonadism in males"
explanation: Cataract is part of the complex GBA2 phenotype.
- name: Hypogonadism
description: Hypogonadism in affected males.
phenotype_term:
preferred_term: Hypogonadism
term:
id: HP:0000135
label: Hypogonadism
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "mental impairment, cataract, and\nhypogonadism in males"
explanation: Hypogonadism in males is part of the complex GBA2 phenotype.
- name: Peripheral neuropathy
description: >-
Peripheral neuropathy is frequent in the GBA2/SPG46 series (Cioffi 2024, 4/5 patients;
per-patient frequency in full text).
phenotype_term:
preferred_term: Peripheral neuropathy
term:
id: HP:0009830
label: Peripheral neuropathy
- name: Cerebral white matter abnormalities
description: >-
White matter abnormalities on neuroimaging are frequent in the GBA2/SPG46 series (Cioffi
2024, 4/5 patients; full-text data).
phenotype_term:
preferred_term: Cerebral white matter abnormality
term:
id: HP:0002500
label: Abnormal cerebral white matter morphology
genetic:
- name: GBA2 pathogenic variants
gene_term:
preferred_term: GBA2
term:
id: hgnc:18986
label: GBA2
association: Causative
notes: >-
Biallelic GBA2 variants (truncating and missense) cause the disorder; loss of GBA2
glucocerebrosidase activity is measurable in blood cells.
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we identified\nfour different mutations in GBA2 (three truncating variants and one missense\nvariant)"
explanation: Biallelic GBA2 variants cosegregate with the disease.
diagnosis:
- name: GBA2 sequencing and enzyme activity
description: >-
Diagnosis rests on GBA2 molecular testing; reduced GBA2 glucocerebrosidase activity in
blood cells can support the diagnosis.
diagnosis_term:
preferred_term: genetic testing
term:
id: MAXO:0000127
label: genetic testing
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "no residual\nglucocerebrosidase activity of GBA2 could be evidenced in blood cells, opening\nthe way to a possible measurement of this enzyme activity in clinical practice"
explanation: Reduced GBA2 enzyme activity in blood cells is a usable diagnostic measure.
treatments:
- name: Supportive Care
description: >-
No disease-modifying therapy exists; management is supportive, including physiotherapy and
antispasticity measures, with management of cataract and endocrine features.
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:23332916
reference_title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a complicated autosomal-recessive form of hereditary spastic paraplegia (HSP)"
explanation: This is phenotype evidence (the complicated spastic-paraplegia/ataxia syndrome) motivating supportive/antispasticity management; no disease-modifying therapy exists.
references:
- reference: PMID:23332916
title: "Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia."
- reference: PMID:38334933
title: "Hereditary spastic paraparesis type 46 (SPG46): new GBA2 variants in a large Italian case series and review of the literature."
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Autosomal recessive cerebellar ataxia with late-onset spasticity (ARCA-LOS) is a Mendelian neurodegenerative spastic-ataxia phenotype on the ataxia–hereditary spastic paraplegia (HSP) continuum, strongly linked to biallelic loss-of-function or deleterious variants in GBA2 (glucosylceramidase beta 2), a non-lysosomal glucosylceramidase in sphingolipid metabolism. Across case series and mechanistic studies, the disorder is characterized by cerebellar ataxia plus corticospinal tract signs (spasticity, pyramidal weakness) with variable additional findings (neuropathy, cognitive involvement, cataracts, thin corpus callosum/white matter abnormalities, hypogonadism). Recent work (2022–2024) has expanded mechanistic understanding through patient-cell biochemistry, transcriptomics, and larger clinical series with enzymatic assays and imaging descriptions. (OpenTargets Search: Autosomal recessive cerebellar ataxia with spasticity,Hereditary spastic paraplegia type 46,SPG46,spastic ataxia-GBA2, martin2013lossoffunction pages 1-2, malekkou2018biochemicalcharacterizationof pages 1-3, kakouri2022transcriptomiccharacterizationof pages 1-2, cioffi2024hereditaryspasticparaparesis pages 1-2, cioffi2024hereditaryspasticparaparesis pages 4-7)
| 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 (kakouri2020analyzinggeneexpression pages 1-3, kakouri2022transcriptomiccharacterizationof pages 1-2, OpenTargets Search: Autosomal recessive cerebellar ataxia with spasticity,Hereditary spastic paraplegia type 46,SPG46,spastic ataxia-GBA2) | GBA2 is a non-lysosomal glucosylceramidase in sphingolipid metabolism; disease-associated dysfunction linked to altered glucosylceramide/ceramide handling (kakouri2022transcriptomiccharacterizationof pages 1-2, malekkou2018biochemicalcharacterizationof pages 1-3) | Open Targets disease-target association to GBA2 with literature PMID 23332917; MONDO mapping for the disease term (OpenTargets Search: Autosomal recessive cerebellar ataxia with spasticity,Hereditary spastic paraplegia type 46,SPG46,spastic ataxia-GBA2) | 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 (martin2013lossoffunction pages 1-2, cioffi2024hereditaryspasticparaparesis pages 1-2) | 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 (martin2013lossoffunction pages 1-2) | 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 (martin2013lossoffunction pages 1-2, cioffi2024hereditaryspasticparaparesis pages 1-2) | 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 (kakouri2020analyzinggeneexpression pages 1-3) | 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 (malekkou2018biochemicalcharacterizationof pages 1-3) | 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 (malekkou2018biochemicalcharacterizationof pages 1-3, kakouri2020analyzinggeneexpression pages 1-3) | 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 (kakouri2022transcriptomiccharacterizationof pages 1-2) | 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 (kakouri2022transcriptomiccharacterizationof pages 1-2) | Kakouri et al., 2022, Cell & Bioscience 12:29, DOI: 10.1186/s13578-022-00754-1 (kakouri2022transcriptomiccharacterizationof pages 1-2) | 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 (cioffi2024hereditaryspasticparaparesis pages 1-2) | GBA2 activity measurable in lymphoblasts/leucocytes; pathogenic mechanism linked to glucosylceramide accumulation and disturbed ganglioside/sphingolipid metabolism (cioffi2024hereditaryspasticparaparesis pages 1-2) | Cioffi et al., 2024, Neurogenetics 25:51-67, DOI: 10.1007/s10048-024-00749-9 (cioffi2024hereditaryspasticparaparesis pages 1-2) | 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.
“Spastic ataxia (SA)” is commonly used as the umbrella clinical concept for disorders overlapping cerebellar ataxia and spastic paraplegia. A representative definition from recent mechanistic work states: “Spastic ataxia (SA) is a group of rare neurodegenerative diseases, characterized by mixed features of generalized ataxia and spasticity.” (Published 2020-09-14; Int J Mol Sci; URL https://doi.org/10.3390/ijms21186722) (kakouri2020analyzinggeneexpression pages 1-3)
Within this clinical space, ARCA-LOS corresponds to a specific ontology entity in Open Targets: MONDO_0018129 (“autosomal recessive cerebellar ataxia with late-onset spasticity”) with a curated disease–target association to GBA2 supported by PubMed literature (PMID 23332917) (OpenTargets Search: Autosomal recessive cerebellar ataxia with spasticity,Hereditary spastic paraplegia type 46,SPG46,spastic ataxia-GBA2).
The retrieved literature uses partially overlapping disease labels for GBA2-related disease: * Spastic ataxia (SA) (kakouri2020analyzinggeneexpression pages 1-3, kakouri2022transcriptomiccharacterizationof pages 1-2) * SPG46 / Hereditary spastic paraparesis (paraplegia) type 46 (martin2013lossoffunction pages 1-2, cioffi2024hereditaryspasticparaparesis pages 1-2) * “Autosomal recessive cerebellar ataxia with spasticity” (as part of the SPG46/ARCA spectrum) (cioffi2024hereditaryspasticparaparesis pages 1-2, cioffi2024hereditaryspasticparaparesis pages 4-7)
The information summarized here is derived from: * Aggregated disease-level resources: Open Targets MONDO mapping and gene association (OpenTargets Search: Autosomal recessive cerebellar ataxia with spasticity,Hereditary spastic paraplegia type 46,SPG46,spastic ataxia-GBA2) * Primary human genetics and case series: Martin 2013 (SPG46), Cioffi 2024 (Italian series) (martin2013lossoffunction pages 1-2, cioffi2024hereditaryspasticparaparesis pages 1-2, cioffi2024hereditaryspasticparaparesis pages 4-7) * Patient-derived cell studies: Malekkou 2018 (LCL biochemistry), Kakouri 2022 (RNA-seq on patient-derived cell types) (malekkou2018biochemicalcharacterizationof pages 1-3, kakouri2022transcriptomiccharacterizationof pages 1-2) * Natural history/registry trials and rehabilitation trials in related spastic ataxias: ClinicalTrials.gov records (NCT04297891 chunk 1, NCT05768750 chunk 1, NCT06261424 chunk 3)
Genetic (Mendelian, autosomal recessive): GBA2 * A core mechanistic/genetic statement from Am J Hum Genet (2013-02-07) reports: “Spastic paraplegia 46 refers to a locus mapped to chromosome 9 that accounts for a complicated autosomal-recessive form of hereditary spastic paraplegia (HSP). With next-generation sequencing in three independent families, we identified four different mutations in GBA2…” (URL https://doi.org/10.1016/j.ajhg.2012.11.021) (martin2013lossoffunction pages 1-2) * A 2024 review/case series similarly states: “SPG46 is a rare, early-onset and autosomal recessive HSP, linked to biallelic GBA2 mutations.” (Published online 2024-02-09; Neurogenetics; URL https://doi.org/10.1007/s10048-024-00749-9) (cioffi2024hereditaryspasticparaparesis pages 1-2)
For this Mendelian condition, the dominant risk factor is biallelic pathogenic GBA2 variation. Non-genetic risk factors were not identified in the retrieved sources.
No protective factors or gene–environment interactions were identified in the retrieved sources.
A broad clinical description of spastic ataxia notes: “Their main characteristics include gait ataxia, spasticity, and weakness in the limbs.” (Kakouri 2020; Int J Mol Sci; 2020-09-14; https://doi.org/10.3390/ijms21186722) (kakouri2020analyzinggeneexpression pages 1-3)
Additional features reported as potentially present include: “neuropathy, pyramidal and extrapyramidal involvement, oculomotor abnormalities, cognitive involvement, seizures, retinopathy, and hypogonadism” (kakouri2020analyzinggeneexpression pages 1-3).
In GBA2-related SPG46, the phenotype is frequently “complex” HSP. The 2013 report describes the overall phenotype as: “a complex HSP with mental impairment, cataract, and hypogonadism in males associated with various degrees of corpus callosum and cerebellar atrophy on brain imaging.” (martin2013lossoffunction pages 1-2)
In a multicenter Italian case series (n=5) of SPG46 with biallelic GBA2 variants, key summary statistics included: * Mean onset: 6.8 years * Mean disease duration/progression: 32 years * Mean age at last exam: 38.6 years * Core findings (counts): spasticity 5/5, cerebellar syndrome 4/5, peripheral neuropathy 4/5, bilateral cataracts 4/5; imaging white matter abnormalities 4/5, thin corpus callosum 2/5 (cioffi2024hereditaryspasticparaparesis pages 2-4, cioffi2024hereditaryspasticparaparesis pages 4-7)
Based on the clinical descriptions in the retrieved sources: * Cerebellar ataxia — HP:0001251 * Spasticity — HP:0001257 * Gait ataxia — HP:0002066 * Pyramidal weakness — HP:0002493 * Peripheral neuropathy — HP:0009830 * Cognitive impairment / intellectual disability — HP:0100543 / HP:0001249 * Cataract — HP:0000518 * Hypogonadism (male) — HP:0000026 * Thin corpus callosum — HP:0002079 * White matter abnormalities — HP:0002500 * Oculomotor abnormality / gaze palsy — HP:0000602
(These HPO identifiers are provided as ontology suggestions; the underlying phenotypes are supported by the cited sources.) (kakouri2020analyzinggeneexpression pages 1-3, martin2013lossoffunction pages 1-2, cioffi2024hereditaryspasticparaparesis pages 1-2, cioffi2024hereditaryspasticparaparesis pages 4-7)
Formal QoL instruments specific to GBA2/SPG46 were not identified in the retrieved papers. However, recent spastic ataxia natural history efforts explicitly incorporate PROMIS domains (“physical function”, “social roles and activities”) to quantify functional impact longitudinally (NCT04297891; first posted 2020-03-06; updated 2022-05-18) (NCT04297891 chunk 2).
Martin et al., 2013 (Am J Hum Genet; 2013-02-07) * Missense variant example: c.1888C>T (p.Arg630Trp) (martin2013lossoffunction pages 1-2)
Cioffi et al., 2024 (Neurogenetics; published online 2024-02-09) * Previously reported variants in their series/literature context: c.472G>A (p.Gly158Arg); c.2063G>A (p.Cys688Thr) (cioffi2024hereditaryspasticparaparesis pages 4-7) * New variants (examples in the excerpt): c.1786G>T (p.Gly596Trp) (homozygous) and truncating variants including p.Gln674 and p.Trp551** as part of compound heterozygous genotypes (cioffi2024hereditaryspasticparaparesis pages 4-7)
Cypriot family (patient-cell functional work) * c.1780G>C (p.Asp594His) identified as causal in a consanguineous family with spastic ataxia and used for downstream mechanistic studies (kakouri2020analyzinggeneexpression pages 1-3, kakouri2022transcriptomiccharacterizationof pages 1-2, malekkou2018biochemicalcharacterizationof pages 1-3)
Across the retrieved sources, pathogenicity is frequently consistent with loss of function (LoF): * Martin 2013: “three truncating variants and one missense variant” with absent residual GBA2 activity in blood cells for a homozygous missense case; the paper frames the mechanism as “Loss of Function of Glucocerebrosidase GBA2…” (martin2013lossoffunction pages 1-2) * Malekkou 2018: the c.1780G>C variant leads to markedly reduced enzyme activity and substrate accumulation (malekkou2018biochemicalcharacterizationof pages 1-3)
Detailed allele frequencies from gnomAD/1000G were not present in the retrieved excerpts. However, Martin 2013 reports absence of c.1888C>T in 1,038 control chromosomes and ~6,500 exomes (Exome Variant Server) (martin2013lossoffunction pages 1-2).
No modifier genes or epigenetic/chromosomal mechanisms were identified in the retrieved sources.
No environmental, lifestyle, or infectious triggers were reported in the retrieved sources; this appears primarily a genetic neurodegenerative disorder in the available evidence.
A key mechanistic statement from Malekkou 2018 (2018-10-10; Int J Mol Sci) is: * “The GBA2 gene encodes the non-lysosomal glucosylceramidase (NLGase), an enzyme that catalyzes the conversion of glucosylceramide (GlcCer) to ceramide and glucose.” (https://doi.org/10.3390/ijms19103099) (malekkou2018biochemicalcharacterizationof pages 1-3)
This aligns with Martin 2013’s description that GBA2 “catalyzes the conversion of glucosylceramide to free glucose and ceramide” and emphasizes a lipid/ceramide axis in motor neuron pathology (martin2013lossoffunction pages 1-2).
In lymphoblastoid cell lines from patients homozygous for c.1780G>C (p.Asp594His), Malekkou 2018 reports: * “the mutation strongly reduce NLGase activity both intracellularly and at the plasma membrane level” * “a two-fold increase of GlcCer content” * “the activity of GCase was three-fold higher in LCLs derived from patients compared to controls” * concluding: “loss of function with abolishment of the enzymatic activity and accumulation of GlcCer accompanied by a compensatory increase in GCase.” (malekkou2018biochemicalcharacterizationof pages 1-3)
Kakouri 2022 performed RNA-seq in LCLs, fibroblasts, and iPSC-derived neurons from patients homozygous for c.1780G>C and reports: * “a total of 5217 genes with significantly altered expression” * enriched pathways including “oxidative stress, neuroinflammation, sphingolipid signaling and metabolism, PI3K-Akt and MAPK signaling pathways.” (Published 2022-03-??; Cell & Bioscience; https://doi.org/10.1186/s13578-022-00754-1) (kakouri2022transcriptomiccharacterizationof pages 1-2)
Martin 2013 provides functional model evidence: zebrafish knockdown of the GBA2 ortholog caused abnormal motor behavior and motoneuron axonal defects, rescued by wild-type but not mutant human mRNA (martin2013lossoffunction pages 1-2). This supports a causal chain: GBA2 LoF → altered ceramide/GlcCer handling → neuronal (motoneuron/corticospinal) structural/functional defects → spasticity and ataxia phenotypes (martin2013lossoffunction pages 1-2, malekkou2018biochemicalcharacterizationof pages 1-3).
Cell types (CL suggestions based on affected systems described): * Purkinje cell — CL:0000121 (cerebellar involvement implied; not directly proven in the excerpts) * Upper motor neuron / corticospinal neuron — (CL term depends on chosen ontology slice; suggested due to HSP hallmark “upper motor neurons”) (cioffi2024hereditaryspasticparaparesis pages 1-2) * Motor neuron — CL:0000100 (supported by zebrafish motoneuron phenotype) (martin2013lossoffunction pages 1-2)
The disorder primarily affects the nervous system, especially long motor pathways and cerebellar circuits.
Kakouri 2020 notes the affected structures can include “the cerebellum, the corpus callosum, the pyramidal track, as well as the spinocerebellar tract and/or the sensory tracts of the spinal cord.” (kakouri2020analyzinggeneexpression pages 1-3)
SPG46 imaging in Martin 2013 includes “corpus callosum and cerebellar atrophy” (martin2013lossoffunction pages 1-2). The 2024 series reports frequent white matter abnormalities and thin corpus callosum (cioffi2024hereditaryspasticparaparesis pages 4-7).
There is phenotypic heterogeneity in age at onset across labels (spastic ataxia vs SPG46 series): * Kakouri 2022 states spastic ataxias are “characterized by an early age of onset, usually before the age of 20 years.” (kakouri2022transcriptomiccharacterizationof pages 1-2) * Cioffi 2024 SPG46 series: mean onset 6.8 years with one congenital case (cioffi2024hereditaryspasticparaparesis pages 2-4, cioffi2024hereditaryspasticparaparesis pages 4-7)
Because the target disease label includes “late-onset spasticity,” an important interpretation is that spasticity may appear later than cerebellar features, but the retrieved excerpts did not provide a formal staging model for this timing.
The Italian SPG46 cohort had a slowly progressive course with mean disease duration 32 years (cioffi2024hereditaryspasticparaparesis pages 2-4, cioffi2024hereditaryspasticparaparesis pages 4-7).
Autosomal recessive inheritance is consistently reported: * “complicated autosomal-recessive form” (Martin 2013) (martin2013lossoffunction pages 1-2) * “autosomal recessive HSP, linked to biallelic GBA2 mutations” (Cioffi 2024) (cioffi2024hereditaryspasticparaparesis pages 1-2)
No prevalence/incidence for ARCA-LOS specifically was found in the retrieved sources.
However, Cioffi 2024 provides literature-based counts: * “About thirty families” and “62 patients… described worldwide” (cioffi2024hereditaryspasticparaparesis pages 1-2) * A broader literature summary in the same work notes “67 cases from 36 families” (cioffi2024hereditaryspasticparaparesis pages 4-7)
The same review also notes an apparent higher prevalence in Mediterranean countries (qualitative) (cioffi2024hereditaryspasticparaparesis pages 4-7).
Diagnosis relies on recognition of combined cerebellar and pyramidal signs (ataxia + spasticity) and evaluation for additional multisystem signs (neuropathy, cataracts, cognitive changes), supported by imaging and genetic testing (kakouri2020analyzinggeneexpression pages 1-3, martin2013lossoffunction pages 1-2, cioffi2024hereditaryspasticparaparesis pages 1-2).
Reported imaging findings across SPG46 include: * corpus callosum involvement / thin corpus callosum * cerebellar atrophy * white matter abnormalities
These are specifically mentioned in Martin 2013 (“corpus callosum and cerebellar atrophy”) and in Cioffi 2024 (WMA and TCC frequencies in their cohort) (martin2013lossoffunction pages 1-2, cioffi2024hereditaryspasticparaparesis pages 4-7).
A prominent diagnostic biomarker is measured GBA2 enzymatic activity.
Martin 2013 emphasizes feasibility of clinical enzyme measurement: “The missense variant was also found at the homozygous state in a simplex subject in whom no residual glucocerebrosidase activity of GBA2 could be evidenced in blood cells, opening the way to a possible measurement of this enzyme activity in clinical practice.” (martin2013lossoffunction pages 1-2)
Cioffi 2024 provides an explicit leukocyte assay approach and values, including proband activities as low as 0.01 nmol/mg vs control mean 3.9 nmol/mg (ref 2.5–5.3), and stresses diagnostic usefulness of enzyme testing (cioffi2024hereditaryspasticparaparesis pages 2-4, cioffi2024hereditaryspasticparaparesis pages 4-7).
The available evidence supports the utility of multi-gene panels/exome sequencing in spastic-ataxia phenotypes (implied by targeted sequencing approaches and exome usage in Martin 2013 and modern cohort screening in Cioffi 2024) (martin2013lossoffunction pages 1-2, cioffi2024hereditaryspasticparaparesis pages 1-2).
The retrieved sources did not provide a structured differential diagnosis list specific to ARCA-LOS; however, they note that spastic ataxia can be caused by many genes (e.g., SACS, FXN, SPG7, POLR3A, NKX6-2, GBA2) (kakouri2020analyzinggeneexpression pages 1-3).
No survival statistics were identified. Available evidence supports chronic, slowly progressive disability in long-duration cohorts (e.g., mean disease duration ~32 years in one SPG46 cohort) (cioffi2024hereditaryspasticparaparesis pages 4-7).
No established disease-modifying therapy for GBA2-related ARCA-LOS/SPG46 was identified in the retrieved sources.
Although not specific to GBA2/SPG46, spastic ataxia rehabilitation trials and natural history efforts provide practical implementation templates for similar phenotypes:
Natural history / trial readiness platform * NCT04297891 “Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias” (first posted 2020-03-06; last update 2022-05-18; start 2020-09-01; primary completion estimated 2024-06) includes standardized ataxia/spasticity scales (SARA, SPRS), PROMIS PROs, biosampling, multi-omics, and multimodal MRI; also includes digital monitoring via mHealth/wearables (NCT04297891 chunk 1, NCT04297891 chunk 2).
Rehabilitation / functional interventions * NCT05768750 (submitted 2023-03-03; start 2022-12-01; estimated completion 2024-12-01) tests a pragmatic 12-week home-based rehabilitation program in ARSACS with balance and spasticity measures (Modified Ashworth Scale) and feasibility/acceptability assessments (NCT05768750 chunk 1, NCT05768750 chunk 2). * NCT06261424 (2024 record) evaluates supervised rehabilitation in spastic ataxias (explicitly ARSACS or SPG7), incorporating objective biomechanical/physiologic endpoints (surface EMG, instrumented gait metrics) and health-economic evaluation (NCT06261424 chunk 3).
These programs are directly relevant to real-world care for spastic-ataxia phenotypes (including GBA2-related disease) because they operationalize measurable outcomes (SARA/SPRS, gait speed, balance tests, spasticity scales) and scalable delivery models (home programs with tele-follow-ups). (NCT05768750 chunk 1, NCT06261424 chunk 3)
Primary prevention is not applicable in the usual sense for a recessive genetic disorder; prevention is primarily reproductive and family-risk management: * Carrier testing and cascade testing in affected families (supported by the AR inheritance evidence base) (martin2013lossoffunction pages 1-2, cioffi2024hereditaryspasticparaparesis pages 1-2) * Genetic counseling for recurrence risk and reproductive options
No vaccination or environmental prevention strategies were identified.
No naturally occurring non-human disease analogous to ARCA-LOS due to GBA2 was identified in the retrieved sources.
Martin 2013 provides direct model-organism evidence that reduced GBA2 function causes motor neuron defects, including abnormal motor behavior and motoneuron axonal shortening/branching, and rescue with wild-type human mRNA (martin2013lossoffunction pages 1-2).
Malekkou 2018 notes that GBA2-knockout mice can show non-neurologic phenotypes (e.g., male infertility) and do not necessarily reproduce the neurologic phenotype despite brain GlcCer accumulation, highlighting model limitations; in contrast, zebrafish knockdown shows motor neuron defects (malekkou2018biochemicalcharacterizationof pages 1-3).
References
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(kakouri2022transcriptomiccharacterizationof pages 1-2): Andrea C. Kakouri, Christina Votsi, Anastasis Oulas, Paschalis Nicolaou, Massimo Aureli, Giulia Lunghi, Maura Samarani, Giacomo M. Compagnoni, Sabrina Salani, Alessio Di Fonzo, Thalis Christophides, George A. Tanteles, Eleni Zamba-Papanicolaou, Marios Pantzaris, George M. Spyrou, and Kyproula Christodoulou. Transcriptomic characterization of tissues from patients and subsequent pathway analyses reveal biological pathways that are implicated in spastic ataxia. Cell & Bioscience, Mar 2022. URL: https://doi.org/10.1186/s13578-022-00754-1, doi:10.1186/s13578-022-00754-1. This article has 3 citations and is from a peer-reviewed journal.
(cioffi2024hereditaryspasticparaparesis pages 1-2): Ettore Cioffi, Gianluca Coppola, Olimpia Musumeci, Salvatore Gallone, Gabriella Silvestri, Salvatore Rossi, Fiorella Piemonte, Jessica D’Amico, Alessandra Tessa, Filippo Maria Santorelli, and Carlo Casali. Hereditary spastic paraparesis type 46 (spg46): new gba2 variants in a large italian case series and review of the literature. Neurogenetics, 25:51-67, Feb 2024. URL: https://doi.org/10.1007/s10048-024-00749-9, doi:10.1007/s10048-024-00749-9. This article has 1 citations and is from a peer-reviewed journal.
(cioffi2024hereditaryspasticparaparesis pages 4-7): Ettore Cioffi, Gianluca Coppola, Olimpia Musumeci, Salvatore Gallone, Gabriella Silvestri, Salvatore Rossi, Fiorella Piemonte, Jessica D’Amico, Alessandra Tessa, Filippo Maria Santorelli, and Carlo Casali. Hereditary spastic paraparesis type 46 (spg46): new gba2 variants in a large italian case series and review of the literature. Neurogenetics, 25:51-67, Feb 2024. URL: https://doi.org/10.1007/s10048-024-00749-9, doi:10.1007/s10048-024-00749-9. This article has 1 citations and is from a peer-reviewed journal.
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(NCT04297891 chunk 1): Dr. Rebecca Schule. Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias. Dr. Rebecca Schule. 2020. ClinicalTrials.gov Identifier: NCT04297891
(NCT05768750 chunk 1): Cynthia Gagnon. A Home-based Rehabilitation in ARSACS. Université de Sherbrooke. 2022. ClinicalTrials.gov Identifier: NCT05768750
(NCT06261424 chunk 3): Elise Duchesne. Effects of a Supervised Rehabilitation Program on Disease Severity in Spastic Ataxias. Laval University. 2024. ClinicalTrials.gov Identifier: NCT06261424
(cioffi2024hereditaryspasticparaparesis pages 2-4): Ettore Cioffi, Gianluca Coppola, Olimpia Musumeci, Salvatore Gallone, Gabriella Silvestri, Salvatore Rossi, Fiorella Piemonte, Jessica D’Amico, Alessandra Tessa, Filippo Maria Santorelli, and Carlo Casali. Hereditary spastic paraparesis type 46 (spg46): new gba2 variants in a large italian case series and review of the literature. Neurogenetics, 25:51-67, Feb 2024. URL: https://doi.org/10.1007/s10048-024-00749-9, doi:10.1007/s10048-024-00749-9. This article has 1 citations and is from a peer-reviewed journal.
(NCT04297891 chunk 2): Dr. Rebecca Schule. Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias. Dr. Rebecca Schule. 2020. ClinicalTrials.gov Identifier: NCT04297891
(NCT05768750 chunk 2): Cynthia Gagnon. A Home-based Rehabilitation in ARSACS. Université de Sherbrooke. 2022. ClinicalTrials.gov Identifier: NCT05768750