Hereditary sensory and autonomic neuropathy type 1

Summary

Hereditary sensory and autonomic neuropathy type 1 (MONDO:0018213) is a disease (an umbrella term covering 6 Mondo subtypes) with 5 cohort genes and 2 clinical trials. Top therapeutic interventions include serine.

At a glance

• Prevalence: Unknown (Worldwide)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 5
• ClinVar variants: 423
• Phenotypes (HPO): 29
• Clinical trials: 2

Clinical features

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002141	Gait imbalance	Very frequent (80-99%)
HP:0002270	Abnormality of the autonomic nervous system	Very frequent (80-99%)
HP:0002936	Distal sensory impairment	Very frequent (80-99%)
HP:0007078	Decreased amplitude of sensory action potentials	Very frequent (80-99%)
HP:0031060	Impaired ability to dress oneself	Very frequent (80-99%)
HP:0000962	Hyperkeratosis	Frequent (30-79%)
HP:0001026	Penetrating foot ulcers	Frequent (30-79%)
HP:0001058	Poor wound healing	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0003376	Steppage gait	Frequent (30-79%)
HP:0006937	Impaired distal tactile sensation	Frequent (30-79%)
HP:0007021	Pain insensitivity	Frequent (30-79%)
HP:0007550	Hypohidrosis or hyperhidrosis	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0009763	Limb pain	Frequent (30-79%)
HP:0010829	Impaired temperature sensition	Frequent (30-79%)
HP:0010834	Trophic changes related to pain	Frequent (30-79%)
HP:0200042	Skin ulcer	Frequent (30-79%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002754	Osteomyelitis	Occasional (5-29%)
HP:0002756	Pathologic fracture	Occasional (5-29%)
HP:0002821	Neuropathic arthropathy	Occasional (5-29%)
HP:0003693	Distal amyotrophy	Occasional (5-29%)
HP:0007002	Motor axonal neuropathy	Occasional (5-29%)
HP:0012735	Cough	Occasional (5-29%)
HP:0100287	EMG: slow motor conduction	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary sensory and autonomic neuropathy type 1
Mondo ID	MONDO:0018213
Orphanet	36386
DOID	DOID:0070162
ICD-11	1989773046
SNOMED CT	397734008
UMLS	C0020071
MedGen	5645
GARD	0006635
NORD	1237
Is cancer (heuristic)	no

Also known as: hereditary sensory and autonomic neuropathy type I · hereditary sensory neuropathy type 1 · Hereditary Sensory Neuropathy Type I · HSAN 1 · HSAN1 · HSN1 · neuropathy hereditary sensory and autonomic type 1 · neuropathy hereditary sensory radicular, autosomal dominant

Data availability: 423 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › sensory peripheral neuropathy › hereditary sensory and autonomic neuropathy › hereditary sensory and autonomic neuropathy type 1

Related subtypes (12): polyneuropathy-hand defect syndrome, hereditary sensory and autonomic neuropathy type 4, neuropathy, hereditary sensory, atypical, X-linked hereditary sensory and autonomic neuropathy with hearing loss, hereditary sensory neuropathy X-linked, hereditary sensory and autonomic neuropathy type 5, hereditary sensory and autonomic neuropathy type 6, hereditary sensory and autonomic neuropathy type 7, congenital insensitivity to pain-hypohidrosis syndrome, congenital insensitivity to pain with hyperhidrosis, cold-induced sweating syndrome - hyperthermia spectrum, hereditary sensory and autonomic neuropathy type 2

Subtypes (6): neuropathy, hereditary sensory and autonomic, type 1A, neuropathy, hereditary sensory and autonomic, type 1C, neuropathy, hereditary sensory, type 1D, hereditary sensory neuropathy-deafness-dementia syndrome, neuropathy, hereditary sensory, type 1F, cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

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

423 retrieved; paginated sample, class counts are floors:

217 uncertain significance, 157 likely benign, 19 conflicting classifications of pathogenicity, 15 benign/likely benign, 7 benign, 4 pathogenic, 2 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
372788	NM_006415.4(SPTLC1):c.992C>A (p.Ser331Tyr)	SPTLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
456600	NM_006415.4(SPTLC1):c.1015G>T (p.Ala339Ser)	SPTLC1	Pathogenic	criteria provided, single submitter
4800	NM_006415.4(SPTLC1):c.398G>A (p.Cys133Tyr)	SPTLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
4801	NM_006415.4(SPTLC1):c.431T>A (p.Val144Asp)	SPTLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4803	NM_006415.4(SPTLC1):c.399T>G (p.Cys133Trp)	SPTLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
802489	NM_006415.4(SPTLC1):c.112CTT[1] (p.Leu39del)	SPTLC1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1917874	NM_006415.4(SPTLC1):c.398G>T (p.Cys133Phe)	SPTLC1	Likely pathogenic	criteria provided, single submitter
209194	NM_006415.4(SPTLC1):c.1072G>C (p.Glu358Gln)	SPTLC1	Likely pathogenic	criteria provided, single submitter
1021849	NM_006415.4(SPTLC1):c.367G>A (p.Ala123Thr)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1042690	NM_006415.4(SPTLC1):c.1393A>G (p.Lys465Glu)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1205559	NM_006415.4(SPTLC1):c.1288C>T (p.Arg430Cys)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1405754	NM_006415.4(SPTLC1):c.940A>G (p.Ile314Val)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234709	NM_006415.4(SPTLC1):c.208G>T (p.Val70Phe)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234762	NM_006415.4(SPTLC1):c.784A>G (p.Lys262Glu)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
367549	NM_006415.4(SPTLC1):c.640A>G (p.Met214Val)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
367552	NM_006415.4(SPTLC1):c.58-9C>T	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
380134	NM_006415.4(SPTLC1):c.1329-9T>C	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
388906	NM_006415.4(SPTLC1):c.1402G>T (p.Ala468Ser)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
449988	NM_006415.4(SPTLC1):c.120C>G (p.Phe40Leu)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
456599	NM_006415.4(SPTLC1):c.1012T>A (p.Ser338Thr)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
526705	NM_006415.4(SPTLC1):c.1213C>T (p.Arg405Cys)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
526710	NM_006415.4(SPTLC1):c.929C>G (p.Ala310Gly)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
651220	NM_006415.4(SPTLC1):c.1168C>T (p.Leu390Phe)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
657595	NM_006415.4(SPTLC1):c.707G>C (p.Arg236Pro)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
704277	NM_006415.4(SPTLC1):c.388G>T (p.Val130Leu)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
732005	NM_006415.4(SPTLC1):c.1111G>A (p.Gly371Arg)	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
860758	NM_006415.4(SPTLC1):c.165+4C>T	SPTLC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1373353	NC_000009.11:g.(?94794747)(95527026_?)del	ASPN	Uncertain significance	criteria provided, single submitter
1002990	NM_006415.4(SPTLC1):c.985-3C>T	SPTLC1	Uncertain significance	criteria provided, single submitter
1008500	NM_006415.4(SPTLC1):c.1259T>G (p.Met420Arg)	SPTLC1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 27 · Orphanet: 6 · 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
ATL1	Definitive	Autosomal dominant	neuropathy, hereditary sensory, type 1D	10
SPTLC2	Definitive	Autosomal dominant	neuropathy, hereditary sensory and autonomic, type 1C	6
ATL3	Strong	Autosomal dominant	neuropathy, hereditary sensory, type 1F	5
SPTLC1	Strong	Autosomal dominant	neuropathy, hereditary sensory and autonomic, type 1A	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPTLC1	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
SPTLC1	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1
ATL1	Orphanet:100984	Autosomal dominant spastic paraplegia type 3
ATL1	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1
SPTLC2	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1
ATL3	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPTLC1	HGNC:11277	ENSG00000090054	O15269	Serine palmitoyltransferase 1	gencc,clinvar
ATL1	HGNC:11231	ENSG00000198513	Q8WXF7	Atlastin-1	gencc
SPTLC2	HGNC:11278	ENSG00000100596	O15270	Serine palmitoyltransferase 2	gencc
ATL3	HGNC:24526	ENSG00000184743	Q6DD88	Atlastin-3	gencc
ASPN	HGNC:14872	ENSG00000106819	Q9BXN1	Asporin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPTLC1	Serine palmitoyltransferase 1	Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-…
ATL1	Atlastin-1	Atlastin-1 (ATL1) is a membrane-anchored GTPase that mediates the GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network.
SPTLC2	Serine palmitoyltransferase 2	Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-…
ATL3	Atlastin-3	Atlastin-3 (ATL3) is a membrane-anchored GTPase that mediates the GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network.
ASPN	Asporin	Negatively regulates periodontal ligament (PDL) differentiation and mineralization to ensure that the PDL is not ossified and to maintain homeostasis of the tooth-supporting system.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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)	2	4.8×	0.117
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPTLC1	Enzyme (other)	yes	2.3.1.50	Aminotransferase_I/II_large, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small
ATL1	Other/Unknown	no		Guanylate-bd_N, P-loop_NTPase, G_GB1_RHD3_dom
SPTLC2	Enzyme (other)	yes	2.3.1.50	Aminotrans_II_pyridoxalP_BS, Aminotransferase_I/II_large, PyrdxlP-dep_Trfase_major
ATL3	Other/Unknown	no		Guanylate-bd/ATL_C, Guanylate-bd_N, P-loop_NTPase
ASPN	Other/Unknown	no		LRRNT, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of esophagus	1
esophagus squamous epithelium	1
oral cavity	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
corpus callosum	1
inferior vagus X ganglion	1
medial globus pallidus	1
layer of synovial tissue	1
saphenous vein	1
upper arm skin	1
periodontal ligament	1
synovial joint	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPTLC1	300	ubiquitous	marker	esophagus squamous epithelium, oral cavity, epithelium of esophagus
ATL1	241	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, endothelial cell
SPTLC2	274	ubiquitous	marker	corpus callosum, inferior vagus X ganglion, medial globus pallidus
ATL3	255	ubiquitous	marker	upper arm skin, saphenous vein, layer of synovial tissue
ASPN	243	broad	marker	tendon of biceps brachii, synovial joint, periodontal ligament

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPTLC1	3,288
SPTLC2	2,335
ASPN	2,075
ATL3	1,536
ATL1	1,206

Intra-cohort edges

A	B	Sources
SPTLC1	SPTLC2	intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPTLC1	O15269	17
SPTLC2	O15270	17
ATL1	Q8WXF7	14
ATL3	Q6DD88	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ASPN	Q9BXN1	85.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 5 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
Sphingolipid de novo biosynthesis	2	190.3×	2e-04	SPTLC1, SPTLC2
Sphingolipid metabolism	2	112.0×	3e-04	SPTLC1, SPTLC2
Metabolism of lipids	2	21.0×	0.006	SPTLC1, SPTLC2
ECM proteoglycans	1	50.1×	0.025	ASPN
Metabolism	2	7.7×	0.025	SPTLC1, SPTLC2
Extracellular matrix organization	1	21.0×	0.047	ASPN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sphinganine biosynthetic process	2	3370.4×	1e-06	SPTLC1, SPTLC2
endoplasmic reticulum membrane fusion	2	1348.2×	4e-06	ATL1, ATL3
positive regulation of lipophagy	2	1348.2×	4e-06	SPTLC1, SPTLC2
endoplasmic reticulum tubular network membrane organization	2	842.6×	9e-06	ATL1, ATL3
sphingomyelin biosynthetic process	2	561.7×	2e-05	SPTLC1, SPTLC2
sphingosine biosynthetic process	2	421.3×	3e-05	SPTLC1, SPTLC2
endoplasmic reticulum organization	2	168.5×	1e-04	ATL1, ATL3
ceramide biosynthetic process	2	168.5×	1e-04	SPTLC1, SPTLC2
sphingolipid biosynthetic process	2	143.4×	2e-04	SPTLC1, SPTLC2
regulation of fat cell apoptotic process	1	3370.4×	5e-04	SPTLC1
negative regulation of tooth mineralization	1	1685.2×	1e-03	ASPN
protein homooligomerization	2	48.9×	1e-03	ATL1, ATL3
response to fluoride	1	1123.5×	0.001	ASPN
sphingolipid metabolic process	1	198.3×	0.006	SPTLC1
adipose tissue development	1	80.2×	0.015	SPTLC2
bone mineralization	1	54.4×	0.021	ASPN
negative regulation of transforming growth factor beta receptor signaling pathway	1	34.8×	0.030	ASPN
axonogenesis	1	32.1×	0.031	ATL1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 3 of 5 evidence-associated genes (60%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SPTLC1	0	0
ATL1	0	0
SPTLC2	0	0
ATL3	0	0
ASPN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
SPTLC1	4	Binding:4
SPTLC2	4	Binding:4
ATL3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SPTLC1	2.3.1.50	serine C-palmitoyltransferase
SPTLC2	2.3.1.50	serine C-palmitoyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	2	SPTLC1, SPTLC2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	ATL1, ATL3, ASPN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPTLC1	4	—
ATL1	0	—
SPTLC2	4	—
ATL3	1	—
ASPN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01733407	PHASE1/PHASE2	COMPLETED	L-Serine Supplementation in Hereditary Sensory Neuropathy Type 1
NCT06113055	PHASE2	UNKNOWN	Hereditary Sensory Neuropathy Serine Trial

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SERINE	3	2