Charlevoix-Saguenay spastic ataxia

Summary

Charlevoix-Saguenay spastic ataxia (MONDO:0010041) is a disease caused by SACS (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: SACS (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,733
• Phenotypes (HPO): 38
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	6-9 / 10 000	51.76	Specific population	Validated

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0000020	Urinary incontinence	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001317	Abnormal cerebellum morphology	Frequent (30-79%)
HP:0001320	Cerebellar vermis hypoplasia	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001634	Mitral valve prolapse	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0002073	Progressive cerebellar ataxia	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0007108	Demyelinating peripheral neuropathy	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0007361	Abnormality of the pons	Frequent (30-79%)
HP:0007922	Hypermyelinated retinal nerve fibers	Frequent (30-79%)
HP:0007979	Gaze-evoked horizontal nystagmus	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0011931	Abnormality of the cerebellar peduncle	Frequent (30-79%)
HP:0012104	Parietal cortical atrophy	Frequent (30-79%)
HP:0012896	Abnormal motor evoked potentials	Frequent (30-79%)
HP:0100702	Arachnoid cyst	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0001760	Abnormal foot morphology	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002066	Gait ataxia	Occasional (5-29%)
HP:0002080	Intention tremor	Occasional (5-29%)
HP:0002495	Impaired vibratory sensation	Occasional (5-29%)
HP:0003438	Absent Achilles reflex	Occasional (5-29%)
HP:0003693	Distal amyotrophy	Occasional (5-29%)
HP:0009027	Foot dorsiflexor weakness	Occasional (5-29%)
HP:0010830	Impaired tactile sensation	Occasional (5-29%)
HP:0000802	Impotence	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charlevoix-Saguenay spastic ataxia
Mondo ID	MONDO:0010041
MeSH	C536787
OMIM	270550
Orphanet	98
DOID	DOID:0050946
SNOMED CT	702445005
UMLS	C1849140
MedGen	338620
GARD	0004910
Is cancer (heuristic)	no

Also known as: ARSACS · autosomal recessive spastic ataxia type 6 · Charlevoix-Saguenay spastic ataxia · sacs · spastic ataxia Charlevoix-Saguenay type · spastic ataxia of Charlevoix-Saguenay · spastic ataxia, Charlevoix-Saguenay type · SPAX6

Data availability: 1,733 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › Charlevoix-Saguenay spastic ataxia

Related subtypes (28): infantile-onset autosomal recessive nonprogressive cerebellar ataxia, autosomal recessive spinocerebellar ataxia 7, autosomal recessive ataxia, Beauce type, RIDDLE syndrome, autosomal recessive ataxia due to ubiquinone deficiency, autosomal recessive spinocerebellar ataxia 10, ataxia with oculomotor apraxia type 3, autosomal recessive spinocerebellar ataxia 14, autosomal recessive spinocerebellar ataxia 16, Lichtenstein-Knorr syndrome, autosomal recessive spinocerebellar ataxia 20, spinocerebellar ataxia, autosomal recessive 22, spinocerebellar ataxia, autosomal recessive 24, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, autosomal recessive congenital cerebellar ataxia, autosomal recessive metabolic cerebellar ataxia, autosomal recessive degenerative and progressive cerebellar ataxia, autosomal recessive syndromic cerebellar ataxia, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy, spinocerebellar ataxia, autosomal recessive 29, spinocerebellar ataxia, autosomal recessive 30, spinocerebellar ataxia, autosomal recessive 31, spinocerebellar ataxia, autosomal recessive 27, spinocerebellar ataxia, autosomal recessive 28, spinocerebellar ataxia, autosomal recessive 25, spinocerebellar ataxia, autosomal recessive 26, spinocerebellar ataxia, autosomal recessive 32, spinocerebellar ataxia, autosomal recessive 33

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

600 retrieved; paginated sample, class counts are floors:

177 likely pathogenic, 139 conflicting classifications of pathogenicity, 104 uncertain significance, 78 pathogenic/likely pathogenic, 44 likely benign, 37 pathogenic, 17 benign/likely benign, 3 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
3236305	Single allele	LOC130009365	Pathogenic	criteria provided, single submitter
2081622	NM_014363.6(SACS):c.24G>A (p.Trp8Ter)	LOC130009366	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2761875	NM_014363.6(SACS):c.44_45del (p.Pro15fs)	LOC130009366	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236270	Single allele	LOC130009366	Pathogenic	criteria provided, single submitter
1027860	NM_014363.6(SACS):c.8716C>T (p.Arg2906Ter)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069256	NM_014363.6(SACS):c.12536del (p.Gly4179fs)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069976	NM_014363.6(SACS):c.11109del (p.Cys3704fs)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070056	NM_014363.6(SACS):c.12106A>T (p.Arg4036Ter)	SACS	Pathogenic	criteria provided, multiple submitters, no conflicts
1071138	NM_014363.6(SACS):c.11136del (p.Pro3713_Leu3714insTer)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074005	NM_014363.6(SACS):c.5008_5011del (p.Tyr1670fs)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075545	NM_014363.6(SACS):c.1769_1770del (p.Val590fs)	SACS	Pathogenic	criteria provided, multiple submitters, no conflicts
1098922	NM_014363.6(SACS):c.3281dup (p.Asn1094fs)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1098923	NM_014363.6(SACS):c.9866C>G (p.Ser3289Ter)	SACS	Pathogenic	criteria provided, multiple submitters, no conflicts
1098924	NM_014363.6(SACS):c.8132C>A (p.Ser2711Ter)	SACS	Pathogenic	criteria provided, single submitter
1175062	NM_014363.6(SACS):c.13176C>G (p.Tyr4392Ter)	SACS	Pathogenic	criteria provided, multiple submitters, no conflicts
1202576	NM_014363.6(SACS):c.4756_4760del (p.Asn1586fs)	SACS	Pathogenic	criteria provided, multiple submitters, no conflicts
1297504	NM_014363.6(SACS):c.1925del (p.Gly642fs)	SACS	Pathogenic	criteria provided, single submitter
1323550	NM_014363.6(SACS):c.7110C>G (p.Tyr2370Ter)	SACS	Pathogenic	criteria provided, single submitter
1331499	NM_014363.6(SACS):c.6837dup (p.Glu2280fs)	SACS	Pathogenic	criteria provided, multiple submitters, no conflicts
1331579	NM_014363.6(SACS):c.6186dup (p.Pro2063fs)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343106	NM_014363.6(SACS):c.3836G>A (p.Trp1279Ter)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343983	NM_014363.6(SACS):c.237dup (p.Ser80fs)	SACS	Pathogenic	criteria provided, multiple submitters, no conflicts
1344003	NM_014363.6(SACS):c.8584A>T (p.Lys2862Ter)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1344007	NM_014363.6(SACS):c.9119dup (p.Asn3040fs)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1367088	NM_014363.6(SACS):c.470_471del (p.Tyr157fs)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1374280	NM_014363.6(SACS):c.1627del (p.Val543fs)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1395285	NM_014363.6(SACS):c.5440_5449del (p.Glu1814fs)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1395488	NM_014363.6(SACS):c.7080_7084del (p.His2362fs)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1413253	NM_014363.6(SACS):c.8955del (p.His2986fs)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1424932	NM_014363.6(SACS):c.2987T>G (p.Leu996Ter)	SACS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
SACS	Definitive	Autosomal recessive	Charlevoix-Saguenay spastic ataxia	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SACS	Orphanet:98	Autosomal recessive spastic ataxia of Charlevoix-Saguenay

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
SACS	HGNC:10519	ENSG00000151835	Q9NZJ4	Sacsin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SACS	Sacsin	Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SACS	Other/Unknown	no		Ubiquitin-like_dom, DnaJ_domain, HEPN_dom

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
Brodmann (1909) area 23	1
frontal pole	1
middle frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SACS	286	ubiquitous	marker	Brodmann (1909) area 23, middle frontal gyrus, frontal pole

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SACS	1,441

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SACS	Q9NZJ4	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
negative regulation of inclusion body assembly	1	1685.2×	0.001	SACS
protein folding	1	103.4×	0.010	SACS

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SACS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	1	SACS

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SACS	0	—

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
NCT06596850	Not specified	NOT_YET_RECRUITING	Wheelchair Skills Training for People with ARSACS and DM1