Hereditary spastic paraplegia 46

Summary

Hereditary spastic paraplegia 46 (MONDO:0013737) is a disease caused by GBA2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GBA2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 48
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0000518	Cataract	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002500	Abnormal cerebral white matter morphology	Frequent (30-79%)
HP:0007371	Corpus callosum atrophy	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0000789	Infertility	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002078	Truncal ataxia	Occasional (5-29%)
HP:0002136	Broad-based gait	Occasional (5-29%)
HP:0002346	Head tremor	Occasional (5-29%)
HP:0002464	Spastic dysarthria	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003477	Peripheral axonal neuropathy	Occasional (5-29%)
HP:0006938	Impaired vibration sensation at ankles	Occasional (5-29%)
HP:0006986	Upper limb spasticity	Occasional (5-29%)
HP:0007256	Abnormal pyramidal sign	Occasional (5-29%)
HP:0008003	Jerky ocular pursuit movements	Occasional (5-29%)
HP:0008734	Decreased testicular size	Occasional (5-29%)
HP:0012207	Reduced sperm motility	Occasional (5-29%)
HP:0012864	Abnormal sperm morphology	Occasional (5-29%)
HP:0012865	Sperm head anomaly	Occasional (5-29%)
HP:0100261	Abnormal tendon morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 46
Mondo ID	MONDO:0013737
OMIM	614409
Orphanet	320391
DOID	DOID:0110798
SNOMED CT	723822009
UMLS	C2828721
MedGen	473687
GARD	0017476
Is cancer (heuristic)	no

Also known as: autosomal recessive complex spastic paraplegia caused by mutation in GBA2 · autosomal recessive spastic paraplegia type 46 · GBA2 autosomal recessive complex spastic paraplegia · hereditary spastic paraplegia 46 · hereditary spastic paraplegia type 46 · spastic paraplegia 46, autosomal recessive · SPG46

Data availability: 48 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 46

Related subtypes (49): hereditary sensory and autonomic neuropathy with spastic paraplegia, hereditary spastic paraplegia 15, hereditary spastic paraplegia 23, spastic paraplegia-glaucoma-intellectual disability syndrome, Troyer syndrome, MASA syndrome, hereditary spastic paraplegia 11, hereditary spastic paraplegia 24, hereditary spastic paraplegia 25, hereditary spastic paraplegia 27, hereditary spastic paraplegia 26, spastic paraplegia, optic atropy, and neuropathy, hereditary spastic paraplegia 18, hereditary spastic paraplegia 32, spastic ataxia 2, hereditary spastic paraplegia 39, hereditary spastic paraplegia 45, hereditary spastic paraplegia 44, hereditary spastic paraplegia 53, hereditary spastic paraplegia 49, hereditary spastic paraplegia 54, hereditary spastic paraplegia 55, hereditary spastic paraplegia 43, hereditary spastic paraplegia 57, hereditary spastic paraplegia 64, hereditary spastic paraplegia 61, hereditary spastic paraplegia 63, glutamate pyruvate transaminase 2 deficiency, hereditary spastic paraplegia 74, autosomal recessive complex spastic paraplegia type 9B, hereditary spastic paraplegia 75, spastic paraplegia-severe developmental delay-epilepsy syndrome, autosomal recessive spastic paraplegia type 76, autosomal recessive spastic paraplegia type 78, autosomal dominant complex spastic paraplegia, maternally-inherited spastic paraplegia, fatty acid hydroxylase-associated neurodegeneration, autosomal recessive spastic paraplegia type 59, autosomal recessive spastic paraplegia type 60, autosomal recessive spastic paraplegia type 66, autosomal recessive spastic paraplegia type 67, autosomal recessive spastic paraplegia type 68, autosomal recessive spastic paraplegia type 69, autosomal recessive spastic paraplegia type 70, spastic paraplegia 84, autosomal recessive, spastic paraplegia 85, autosomal recessive, spastic paraplegia 86, autosomal recessive, kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

48 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 13 pathogenic, 10 likely pathogenic, 7 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2173795	NM_020944.3(GBA2):c.1361_1362del (p.Glu454fs)	CREB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572509	NM_020944.3(GBA2):c.1602C>A (p.Tyr534Ter)	GBA2	Pathogenic	criteria provided, single submitter
3068747	NM_020944.3(GBA2):c.1720C>T (p.Arg574Ter)	GBA2	Pathogenic	criteria provided, multiple submitters, no conflicts
3148838	NM_020944.3(GBA2):c.1351C>T (p.Arg451Ter)	GBA2	Pathogenic	criteria provided, single submitter
3775633	NM_020944.3(GBA2):c.2025del (p.Tyr676fs)	GBA2	Pathogenic	criteria provided, single submitter
41485	NM_020944.3(GBA2):c.1888C>T (p.Arg630Trp)	GBA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
41486	NM_020944.3(GBA2):c.700C>T (p.Arg234Ter)	GBA2	Pathogenic	criteria provided, multiple submitters, no conflicts
41488	NM_020944.3(GBA2):c.1471_1474dup (p.Thr492fs)	GBA2	Pathogenic	no assertion criteria provided
41489	NM_020944.3(GBA2):c.1018C>T (p.Arg340Ter)	GBA2	Pathogenic	criteria provided, multiple submitters, no conflicts
41490	NM_020944.3(GBA2):c.2618G>A (p.Arg873His)	GBA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4526006	NM_020944.3(GBA2):c.323_327del (p.Leu108fs)	GBA2	Pathogenic	criteria provided, single submitter
567447	NM_020944.3(GBA2):c.2202del (p.Tyr735fs)	GBA2	Pathogenic	criteria provided, multiple submitters, no conflicts
638293	NM_020944.3(GBA2):c.363C>A (p.Tyr121Ter)	GBA2	Pathogenic	criteria provided, single submitter
638294	NM_020944.3(GBA2):c.518G>A (p.Trp173Ter)	GBA2	Pathogenic	criteria provided, single submitter
989141	NM_020944.3(GBA2):c.2166_2176del (p.Gly722_Gln723insTer)	GBA2	Pathogenic	criteria provided, single submitter
989142	NM_020944.3(GBA2):c.2248_2249del (p.Met750fs)	GBA2	Pathogenic	criteria provided, single submitter
1802259	NM_020944.3(GBA2):c.2506-2A>G	GBA2	Likely pathogenic	criteria provided, single submitter
2440428	NM_020944.3(GBA2):c.2608C>T (p.Arg870Ter)	GBA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2574041	NM_020944.3(GBA2):c.715dup (p.Tyr239fs)	GBA2	Likely pathogenic	criteria provided, single submitter
3256771	NM_020944.3(GBA2):c.1255T>G (p.Phe419Val)	GBA2	Likely pathogenic	no assertion criteria provided
3896872	NM_020944.3(GBA2):c.812_813del (p.Phe271fs)	GBA2	Likely pathogenic	criteria provided, single submitter
4849435	NM_020944.3(GBA2):c.1410-1G>A	GBA2	Likely pathogenic	criteria provided, single submitter
4849457	NM_020944.3(GBA2):c.261dup (p.Ile88fs)	GBA2	Likely pathogenic	criteria provided, single submitter
92166	NM_020944.3(GBA2):c.1780G>C (p.Asp594His)	GBA2	Likely pathogenic	criteria provided, single submitter
992195	NM_020944.3(GBA2):c.1582+2T>G	GBA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
992263	NM_020944.3(GBA2):c.451+1G>A	GBA2	Likely pathogenic	criteria provided, single submitter
999107	NM_001958.5(EEF1A2):c.305T>C (p.Met102Thr)	EEF1A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191235	NM_020944.3(GBA2):c.2548C>T (p.Arg850Cys)	GBA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
241329	NM_020944.3(GBA2):c.1552C>T (p.Arg518Trp)	GBA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2585505	NM_020944.3(GBA2):c.2617C>T (p.Arg873Cys)	GBA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GBA2	Definitive	Autosomal recessive	hereditary spastic paraplegia 46	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GBA2	Orphanet:320391	Autosomal recessive spastic paraplegia type 46
GBA2	Orphanet:352641	Autosomal recessive cerebellar ataxia with late-onset spasticity
EEF1A2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
EEF1A2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GBA2	HGNC:18986	ENSG00000070610	Q9HCG7	Non-lysosomal glucosylceramidase	gencc,clinvar
CREB3	HGNC:2347	ENSG00000107175	O43889	Cyclic AMP-responsive element-binding protein 3	clinvar
EEF1A2	HGNC:3192	ENSG00000101210	Q05639	Elongation factor 1-alpha 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GBA2	Non-lysosomal glucosylceramidase	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).
CREB3	Cyclic AMP-responsive element-binding protein 3	Endoplasmic reticulum (ER)-bound sequence-specific transcription factor that directly binds DNA and activates transcription.
EEF1A2	Elongation factor 1-alpha 2	Translation elongation factor that catalyzes the GTP-dependent binding of aminoacyl-tRNA (aa-tRNA) to the A-site of ribosomes during the elongation phase of protein synthesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GBA2	Enzyme (other)	yes	3.2.1.45	GH116_catalytic, 6-hairpin_glycosidase_sf, 6hp_glycosidase-like_sf
CREB3	Other/Unknown	no		bZIP, bZIP_sf, CREB_ATF_subfamily
EEF1A2	Other/Unknown	no		T_Tr_GTP-bd_dom, EFTu-like_2, Transl_elong_EF1A_euk/arc

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	1
right hemisphere of cerebellum	1
small intestine Peyer’s patch	1
adenohypophysis	1
popliteal artery	1
right testis	1
apex of heart	1
gastrocnemius	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GBA2	248	ubiquitous	marker	metanephros cortex, right hemisphere of cerebellum, small intestine Peyer’s patch
CREB3	276	ubiquitous	marker	adenohypophysis, popliteal artery, right testis
EEF1A2	247	ubiquitous	marker	gastrocnemius, apex of heart, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CREB3	1,969
GBA2	1,709
EEF1A2	745

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EEF1A2	Q05639	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GBA2	Q9HCG7	89.77
CREB3	O43889	61.35

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
CREB3 factors activate genes	1	423.0×	0.007	CREB3
Glycosphingolipid catabolism	1	97.6×	0.011	GBA2
Eukaryotic Translation Elongation	1	92.8×	0.011	EEF1A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of deacetylase activity	1	5617.3×	0.003	CREB3
positive regulation of lipid kinase activity	1	5617.3×	0.003	EEF1A2
glucosylceramide catabolic process	1	1872.4×	0.005	GBA2
release from viral latency	1	1872.4×	0.005	CREB3
regulation of chaperone-mediated autophagy	1	1123.5×	0.005	EEF1A2
glycoside catabolic process	1	936.2×	0.005	GBA2
regulation of membrane lipid distribution	1	936.2×	0.005	GBA2
glycosphingolipid catabolic process	1	510.7×	0.008	GBA2
glycolipid biosynthetic process	1	468.1×	0.008	GBA2
translational elongation	1	401.2×	0.008	EEF1A2
regulation of microtubule polymerization	1	374.5×	0.008	GBA2
bile acid metabolic process	1	330.4×	0.008	GBA2
induction of positive chemotaxis	1	330.4×	0.008	CREB3
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1	280.9×	0.008	CREB3
central nervous system neuron development	1	267.5×	0.008	GBA2
positive regulation of monocyte chemotaxis	1	267.5×	0.008	CREB3
integrated stress response signaling	1	234.1×	0.009	CREB3
regulation of actin filament polymerization	1	193.7×	0.009	GBA2
positive regulation of calcium ion transport	1	193.7×	0.009	CREB3
endoplasmic reticulum unfolded protein response	1	98.5×	0.017	CREB3
negative regulation of cell cycle	1	96.8×	0.017	CREB3
DNA-templated transcription	1	74.9×	0.020	CREB3
regulation of cell growth	1	73.9×	0.020	CREB3
cholesterol metabolic process	1	65.3×	0.022	GBA2
carbohydrate metabolic process	1	45.3×	0.029	GBA2
chemotaxis	1	45.3×	0.029	CREB3
central nervous system development	1	38.5×	0.032	GBA2
regulation of cell population proliferation	1	38.5×	0.032	CREB3
translation	1	34.2×	0.035	EEF1A2
regulation of apoptotic process	1	27.8×	0.041	CREB3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GBA2	MIGLUSTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GBA2	6	4
CREB3	0	0
EEF1A2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGLUSTAT	4	GBA2
MIGALASTAT	4	GBA2
LUCERASTAT	3	GBA2
AFEGOSTAT	2	GBA2
DUVOGLUSTAT	2	GBA2
NIZUBAGLUSTAT	2	GBA2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GBA2	38	Binding:38
EEF1A2	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GBA2	3.2.1.45	glucosylceramidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

6 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MIGLUSTAT	4	GBA2
MIGALASTAT	4	GBA2
LUCERASTAT	3	GBA2
AFEGOSTAT	2	GBA2
DUVOGLUSTAT	2	GBA2
NIZUBAGLUSTAT	2	GBA2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GBA2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CREB3, EEF1A2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CREB3	0	—
EEF1A2	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.