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hereditary spastic paraplegia 46 - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

hereditary spastic paraplegia 46

MONDO:0013737

Also known as:GBA2 autosomal recessive complex spastic paraplegiaSPG46autosomal recessive complex spastic paraplegia caused by mutation in GBA2

Overview

A rare, complex type of hereditary spastic paraplegia characterized by an onset, in infancy or childhood, of the typical signs of spastic paraplegia (i.e. spastic gait and weakness of the lower limbs) associated with a variety of additional manifestations including upper limb spasticity and weakness, pseudobulbar dysarthria, bladder dysfunction, cerebellar ataxia, cataracts, and cognitive impairment that can progress to dementia. Brain imaging may show thinning of the corpus callosum and mild atrophy of the cerebrum and cerebellum. SPG46 is due to mutations in the GBA2 gene (9p13.2) encoding non-lysosomal glucosylceramidase.

GeneticsAutosomal recessive · GBA2 (chr 9)

OnsetCONGENITAL

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

Features include always present findings: Shrinkage of the cerebellum (cerebellar atrophy), Lower limb spasticity, Lower limb muscle weakness, and Overactive reflexes (hyperreflexia) and others; and very common findings: Cataract and Pes cavus. 33 total HPO annotations.

Organ System	Phenotype Count	Example Features
Brain and nerves	16	Spastic gait, Lower limb spasticity, Mental deterioration

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

GBA2 encodes glucosylceramidase beta 2 (927 aa). Non-lysosomal glucosylceramidase that catalyzes the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine) to free glucose and ceramides (such as N-acylsphing-4-enine). Highest expression in Brain Cerebellum (137.0 TPM) and Brain Cerebellar Hemisphere (119.2 TPM).

Hereditary spastic paraplegia 46 is associated with mutations in the GBA2 gene on chromosome 9.

GBA2 is classified as a druggable target (Druggable Genome and Enzyme categories) with score 0.0.

Diagnosis

Genetic testing for GBA2 is available. Testing is considered confirmatory for diagnosis.

Prognosis

Phenotype severity distribution: 10 always present features, 2 very common features, 2 common features.

Estimated prevalence: <1 in 1,000,000 (VERY_RARE).

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

No clinical trials have been registered for hereditary spastic paraplegia 46.

19 publications have been identified in PubMed for hereditary spastic paraplegia 46. Research spans Case Report / Case Series (42%), Epidemiology / Natural History (26%), and Review / Meta-Analysis (16%).

Research Type	Count	% of Total
Patient case studies	8	42%

Data assembled from 6 of 12 sources · Last updated Sep 20, 2026, 3:04 PM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:614409

Orphanet

European rare disease database

Orphanet:320391

GARD

Genetic and Rare Diseases Info Center

GARD:17476

Questions for Your Care Team

→Should my partner and I meet with a genetic counselor to discuss carrier status and family planning?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

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Kisho

hereditary spastic paraplegia 46

Overview

Clinical Presentation

Genetic Landscape

Diagnosis

Prognosis

Research Landscape

Medical References

External Resources

OMIM

Orphanet

GARD

Questions for Your Care Team

Questions for Your Care Team

Explore clinical features

Recent Publications

hereditary spastic paraplegia 46

Overview

Clinical Presentation

Genetic Landscape

Diagnosis

Prognosis

Research Landscape

Medical References

External Resources

OMIM

Orphanet

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

Explore clinical features

Recent Publications