Autosomal recessive cerebellar ataxia with late-onset spasticity

Summary

Autosomal recessive cerebellar ataxia with late-onset spasticity (MONDO:0018129) is a disease with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• Phenotypes (HPO): 26
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0002073	Progressive cerebellar ataxia	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0000570	Abnormal saccadic eye movements	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001348	Brisk reflexes	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0003477	Peripheral axonal neuropathy	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0010831	Impaired proprioception	Frequent (30-79%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002166	Impaired vibration sensation in the lower limbs	Occasional (5-29%)
HP:0002346	Head tremor	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003693	Distal amyotrophy	Occasional (5-29%)
HP:0004905	Low levels of vitamin A	Excluded (0%)
HP:0100513	Low levels of vitamin E	Excluded (0%)
HP:0001256	Intellectual disability, mild	Very rare (<1-4%)
HP:0002078	Truncal ataxia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive cerebellar ataxia with late-onset spasticity
Mondo ID	MONDO:0018129
Orphanet	352641
SNOMED CT	763348005
UMLS	C4706412
MedGen	1635411
GARD	0021525
Is cancer (heuristic)	no

Also known as: autosomal recessive cerebellar ataxia due to GBA2 deficiency

Data availability: 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › lysosomal lipid storage disorder › sphingolipidosis › autosomal recessive cerebellar ataxia with late-onset spasticity

Related subtypes (10): Niemann-Pick disease, Krabbe disease, sea-blue histiocyte syndrome, mucosulfatidosis, Fabry disease, gangliosidosis, Gaucher disease, metachromatic leukodystrophy, PSAP-related sphingolipidosis, ASAH1-related sphingolipidosis

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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	Supportive	Autosomal recessive	autosomal recessive cerebellar ataxia with late-onset spasticity	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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GBA2	HGNC:18986	ENSG00000070610	Q9HCG7	Non-lysosomal glucosylceramidase	gencc

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).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	12.0×	0.083

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

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
metanephros cortex	1
right hemisphere of cerebellum	1
small intestine Peyer’s patch	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GBA2	1,709

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GBA2	Q9HCG7	89.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycosphingolipid catabolism	1	292.8×	0.003	GBA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glucosylceramide catabolic process	1	5617.3×	0.001	GBA2
glycoside catabolic process	1	2808.7×	0.001	GBA2
regulation of membrane lipid distribution	1	2808.7×	0.001	GBA2
glycosphingolipid catabolic process	1	1532.0×	0.002	GBA2
glycolipid biosynthetic process	1	1404.3×	0.002	GBA2
regulation of microtubule polymerization	1	1123.5×	0.002	GBA2
bile acid metabolic process	1	991.3×	0.002	GBA2
central nervous system neuron development	1	802.5×	0.002	GBA2
regulation of actin filament polymerization	1	581.1×	0.002	GBA2
cholesterol metabolic process	1	195.9×	0.006	GBA2
carbohydrate metabolic process	1	135.9×	0.008	GBA2
central nervous system development	1	115.4×	0.009	GBA2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

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

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GBA2	3.2.1.45	glucosylceramidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford