Hereditary sensory and autonomic neuropathy with spastic paraplegia

Summary

Hereditary sensory and autonomic neuropathy with spastic paraplegia (MONDO:0009748) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 312
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001258	Spastic paraplegia	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0003409	Distal sensory impairment of all modalities	Very frequent (80-99%)
HP:0007328	Impaired pain sensation	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0012332	Abnormal autonomic nervous system physiology	Very frequent (80-99%)
HP:0200042	Skin ulcer	Very frequent (80-99%)
HP:0002143	Abnormality of the spinal cord	Frequent (30-79%)
HP:0002169	Clonus	Frequent (30-79%)
HP:0003390	Sensory axonal neuropathy	Frequent (30-79%)
HP:0003431	Decreased motor nerve conduction velocity	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0007020	Progressive spastic paraplegia	Frequent (30-79%)
HP:0006121	Acral ulceration	Occasional (5-29%)
HP:0001886	Foot osteomyelitis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary sensory and autonomic neuropathy with spastic paraplegia
Mondo ID	MONDO:0009748
MeSH	C564948
OMIM	256840
Orphanet	139578
DOID	DOID:0061188
ICD-11	813709854
SNOMED CT	717827000
UMLS	C1850395
MedGen	342492
GARD	0016959
Is cancer (heuristic)	no

Also known as: hereditary sensory and autonomic neuropathy with spastic paraplegia · HSAN with spastic paraplegia

Data availability: 312 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary sensory and autonomic neuropathy with spastic paraplegia

Related subtypes (49): 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 46, 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

312 retrieved; paginated sample, class counts are floors:

164 uncertain significance, 101 likely benign, 37 benign, 8 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1802575	NM_012073.5(CCT5):c.670C>G (p.Leu224Val)	CCT5	Likely pathogenic	criteria provided, single submitter
1402611	NM_012073.5(CCT5):c.10A>G (p.Met4Val)	CCT5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1675971	NM_012073.5(CCT5):c.759T>C (p.Cys253=)	CCT5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
465410	NM_012073.5(CCT5):c.954C>T (p.Asn318=)	CCT5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
695832	NM_012073.5(CCT5):c.166+8del	CCT5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903671	NM_012073.5(CCT5):c.1075G>A (p.Val359Ile)	CCT5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906045	NM_012073.5(CCT5):c.331+14A>T	CCT5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906106	NM_012073.5(CCT5):c.1425C>T (p.Thr475=)	CCT5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907058	NM_012073.5(CCT5):c.531-13G>T	CCT5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1021115	NM_012073.5(CCT5):c.1229G>A (p.Arg410Gln)	CCT5	Uncertain significance	criteria provided, single submitter
1030217	NM_012073.5(CCT5):c.664A>T (p.Thr222Ser)	CCT5	Uncertain significance	criteria provided, single submitter
1037636	NM_012073.5(CCT5):c.1378A>G (p.Met460Val)	CCT5	Uncertain significance	criteria provided, single submitter
1039017	NM_012073.5(CCT5):c.271A>G (p.Met91Val)	CCT5	Uncertain significance	criteria provided, single submitter
1046675	NM_012073.5(CCT5):c.1078C>A (p.Gln360Lys)	CCT5	Uncertain significance	criteria provided, single submitter
1054922	NM_012073.5(CCT5):c.610G>A (p.Val204Ile)	CCT5	Uncertain significance	criteria provided, single submitter
1060642	NM_012073.5(CCT5):c.1250G>A (p.Arg417His)	CCT5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1061893	NM_012073.5(CCT5):c.1499-10T>G	CCT5	Uncertain significance	criteria provided, single submitter
1327	NM_012073.5(CCT5):c.440A>G (p.His147Arg)	CCT5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1357641	NM_012073.5(CCT5):c.1A>T (p.Met1Leu)	CCT5	Uncertain significance	criteria provided, single submitter
1363311	NM_012073.5(CCT5):c.548G>A (p.Arg183Gln)	CCT5	Uncertain significance	criteria provided, single submitter
1375154	NM_012073.5(CCT5):c.1549A>G (p.Ile517Val)	CCT5	Uncertain significance	criteria provided, single submitter
1380103	NM_012073.5(CCT5):c.1123G>A (p.Glu375Lys)	CCT5	Uncertain significance	criteria provided, single submitter
1401115	NM_012073.5(CCT5):c.85A>C (p.Met29Leu)	CCT5	Uncertain significance	criteria provided, single submitter
1403452	NM_012073.5(CCT5):c.531-3C>T	CCT5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1407767	NM_012073.5(CCT5):c.122C>G (p.Ala41Gly)	CCT5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1441920	NM_012073.5(CCT5):c.1199G>T (p.Arg400Leu)	CCT5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1445881	NM_012073.5(CCT5):c.1391A>G (p.Glu464Gly)	CCT5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1476830	NM_012073.5(CCT5):c.577G>A (p.Val193Ile)	CCT5	Uncertain significance	criteria provided, single submitter
1517172	NM_012073.5(CCT5):c.1379T>C (p.Met460Thr)	CCT5	Uncertain significance	criteria provided, single submitter
1719185	NM_012073.5(CCT5):c.694A>G (p.Lys232Glu)	CCT5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
CCT5	Supportive	Autosomal recessive	hereditary sensory and autonomic neuropathy with spastic paraplegia	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CCT5	Orphanet:139578	Mutilating hereditary sensory neuropathy with spastic paraplegia

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
CCT5	HGNC:1618	ENSG00000150753	P48643	T-complex protein 1 subunit epsilon	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CCT5	T-complex protein 1 subunit epsilon	Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of actin, tubulin and other proteins upon ATP hydrolysis.

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)
CCT5	Enzyme (other)	yes	3.6.4.B10	Chaperonin_TCP-1_CS, Cpn60/GroEL/TCP-1, Chap_CCT_epsi

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
adrenal tissue	1
endometrium epithelium	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CCT5	298	ubiquitous	marker	primordial germ cell in gonad, endometrium epithelium, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCT5	6,388

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCT5	P48643	69

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Folding of actin by CCT/TriC	1	1142.0×	0.005	CCT5
BBSome-mediated cargo-targeting to cilium	1	496.5×	0.005	CCT5
Formation of tubulin folding intermediates by CCT/TriC	1	423.0×	0.005	CCT5
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	407.9×	0.005	CCT5
Prefoldin mediated transfer of substrate to CCT/TriC	1	393.8×	0.005	CCT5
Chaperonin-mediated protein folding	1	300.5×	0.005	CCT5
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding	1	300.5×	0.005	CCT5
Association of TriC/CCT with target proteins during biosynthesis	1	292.8×	0.005	CCT5
Protein folding	1	259.6×	0.005	CCT5
Cargo trafficking to the periciliary membrane	1	248.3×	0.005	CCT5
Cilium Assembly	1	108.8×	0.011	CCT5
Organelle biogenesis and maintenance	1	66.0×	0.016	CCT5
Metabolism of proteins	1	12.4×	0.081	CCT5

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
positive regulation of telomerase RNA localization to Cajal body	1	1872.4×	0.002	CCT5
positive regulation of protein localization to Cajal body	1	1685.2×	0.002	CCT5
positive regulation of telomere maintenance via telomerase	1	732.7×	0.003	CCT5
binding of sperm to zona pellucida	1	421.3×	0.004	CCT5
response to virus	1	144.0×	0.010	CCT5
protein folding	1	103.4×	0.011	CCT5
protein stabilization	1	66.9×	0.015	CCT5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CCT5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CCT5	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CCT5	3.6.4.B10

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	1	CCT5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
CCT5	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.