Hereditary Sensory and Autonomic Neuropathy

Mendelian MONDO:0015364 Pathograph 15 Show in embeddings browser Peripheral Neuropathy

Hereditary sensory and autonomic neuropathy (HSAN), also called hereditary sensory neuropathy (HSN), is a genetically heterogeneous group of inherited peripheral neuropathies in which the primary lesion is degeneration or developmental failure of the sensory (dorsal root ganglion) and autonomic neurons, with relative sparing of the motor system. This is the sensory / autonomic counterpart of the motor-predominant Charcot-Marie-Tooth neuropathies: instead of distal motor weakness, the cardinal features are loss of pain, temperature, and touch sensation — frequently complicated by painless injuries, acral ulceration, and mutilation — together with autonomic dysfunction. HSAN is classified into numbered types by inheritance, age of onset, and gene. The forms curated here span the four principal mechanistic themes: neurotoxic deoxysphingolipid formation from gain-of-function serine palmitoyltransferase mutations (HSAN1 / SPTLC1, autosomal dominant, adult onset); failure of NGF-TrkA neurotrophic signaling that normally supports the development and survival of nociceptive and autonomic neurons (HSAN4 / NTRK1, the classic congenital insensitivity to pain with anhidrosis, and HSAN5 / NGF); deficiency of the Elongator complex from a tissue-specific splicing defect (HSAN3 / ELP1, familial dysautonomia / Riley-Day); and loss of the HSN2-dependent sensory-neuron maintenance function of WNK1 (HSAN2). Unlike the CMT compartments, HSAN is not modeled here as a length-dependent dying-back axonopathy conforming to the peripheral_axonal_degeneration module, because several forms arise from developmental neurotrophic failure and sensory / autonomic neuronopathy rather than distal axonal die-back.

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2
Inheritance
5
Pathophys.
6
Phenotypes
15
Pathograph
5
Genes
5
Medical Actions
5
Subtypes
3
References
👪

Inheritance

2
Autosomal Dominant HP:0000006
HSAN1 (SPTLC1) is inherited in an autosomal dominant manner, typically with adult onset.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:20504773 SUPPORT Human Clinical
"The autosomal dominant peripheral sensory neuropathy HSAN1 results from mutations in the LCB1 subunit of serine palmitoyltransferase (SPT)."
Documents autosomal dominant inheritance of HSAN1.
Autosomal Recessive HP:0000007
The congenital / early-onset HSAN forms — HSAN2 (WNK1/HSN2), HSAN3 (ELP1), HSAN4 (NTRK1), and HSAN5 (NGF) — are inherited in an autosomal recessive manner.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:8696348 SUPPORT Human Clinical
"Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is an autosomal-recessive disorder"
Documents autosomal recessive inheritance of the congenital HSAN forms (CIPA / HSAN4 shown).
PMID:20301359 SUPPORT Human Clinical
"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier"
GeneReviews (Familial Dysautonomia / HSAN3) gives the standard autosomal recessive recurrence risk (25% affected, 50% carrier per sib).
◆

Subtypes

5
HSAN1 (SPTLC1, autosomal dominant)
The most common autosomal dominant HSAN, adult-onset, caused by gain-of-function mutations in SPTLC1 (the LCB1 subunit of serine palmitoyltransferase) that generate neurotoxic 1-deoxysphingolipids. Distal sensory loss with painless ulcers and variable motor involvement.
Show evidence (1 reference)
PMID:20504773 SUPPORT Human Clinical
"The autosomal dominant peripheral sensory neuropathy HSAN1 results from mutations in the LCB1 subunit of serine palmitoyltransferase (SPT)."
Establishes SPTLC1 (LCB1 of serine palmitoyltransferase) mutations as the cause of autosomal dominant HSAN1.
HSAN2 (WNK1 / HSN2, autosomal recessive)
Autosomal recessive, early-onset HSAN with impairment of pain, temperature, and touch from reduction or loss of peripheral sensory neurons, caused by truncating mutations in HSN2 — a nervous-system-specific exon within the WNK1 gene.
Show evidence (1 reference)
PMID:15060842 SUPPORT Human Clinical
"Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons."
Establishes HSAN2 as an autosomal recessive sensory neuropathy; the HSN2 gene is a nervous-system-specific exon of WNK1.
HSAN3 / Familial Dysautonomia (ELP1 / IKBKAP, autosomal recessive)
Familial dysautonomia (Riley-Day syndrome), an autosomal recessive HSAN prevalent in the Ashkenazi Jewish population, caused by a tissue-specific splicing mutation in ELP1 (IKBKAP / IKAP), a subunit of the Elongator complex. Prominent autonomic dysfunction with sensory loss.
Show evidence (1 reference)
PMID:11179021 SUPPORT Human Clinical
"These findings demonstrate that mutations in the gene encoding IKAP are responsible for FD."
Establishes ELP1 (IKBKAP / IKAP) mutations as the cause of familial dysautonomia (HSAN3).
HSAN4 / CIPA (NTRK1, autosomal recessive)
Congenital insensitivity to pain with anhidrosis (CIPA), an autosomal recessive HSAN caused by mutations in NTRK1 (TrkA, the high-affinity NGF receptor). Absence of pain perception, anhidrosis, recurrent fever, self-mutilation, and intellectual disability.
Show evidence (1 reference)
PMID:8696348 SUPPORT Human Clinical
"Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans."
Establishes NTRK1 (TRKA) mutations as the cause of CIPA (HSAN4).
HSAN5 (NGF / NGFB, autosomal recessive)
Autosomal recessive HSAN caused by mutation in NGF (NGFB), the ligand of TrkA, producing loss of deep pain perception with severe reduction of unmyelinated small nerve fibers but largely preserved cognition.
Show evidence (1 reference)
PMID:14976160 SUPPORT Human Clinical
"revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype."
Establishes an NGF (NGFB) coding mutation as the cause of loss of pain perception (HSAN5).
⚙

Pathophysiology

5
Neurotoxic Deoxysphingolipid Formation
Gain-of-function mutations in SPTLC1 (HSAN1), the LCB1 subunit of serine palmitoyltransferase, shift the enzyme's substrate specificity so that it condenses alanine (instead of serine) with palmitoyl-CoA, generating atypical 1-deoxysphingolipids that are neurotoxic to sensory neurons and accumulate in patient serum.
Sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
SPTLC1 hgnc:11277 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPTLC1 (hgnc:11277). hgnc:11277 is a gene from the HUGO Gene Nomenclature Committee.
Sphingolipid biosynthetic process GO:0030148 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Sphingolipid biosynthetic process (GO:0030148). GO:0030148 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Sensory and Autonomic Neuron Degeneration Neurotoxic 1-deoxysphingolipids drive degeneration of sensory neurons in HSAN1.
Show evidence (1 reference)
PMID:20504773 SUPPORT Human Clinical
"Serum from patients and transgenic mice expressing a disease-causing mutation (C133W) contain elevated levels of 1-deoxysphinganine (1-deoxySa), which presumably arise from inappropriate condensation of alanine with palmitoyl-CoA."
Demonstrates accumulation of neurotoxic 1-deoxysphinganine from the SPTLC1 mutation, the HSAN1 mechanism.
Impaired NGF-TrkA Neurotrophic Signaling
Loss of signaling through the NGF-TrkA axis — from NTRK1 (TrkA receptor, HSAN4 / CIPA) or NGF (its ligand, HSAN5) mutations — removes the neurotrophic support that NGF provides for the development and survival of nociceptive sensory neurons and sympathetic (autonomic) neurons, so these populations fail to develop or are lost.
Sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology. Autonomic neuron CL:0000107 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Autonomic neuron (CL:0000107). CL:0000107 is a cell type from the Cell Ontology.
NTRK1 hgnc:8031 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NTRK1 (hgnc:8031). hgnc:8031 is a gene from the HUGO Gene Nomenclature Committee. NGF hgnc:7808 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NGF (hgnc:7808). hgnc:7808 is a gene from the HUGO Gene Nomenclature Committee.
Neurotrophin TRK receptor signaling pathway GO:0048011 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Neurotrophin TRK receptor signaling pathway (GO:0048011). GO:0048011 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Sensory and Autonomic Neuron Degeneration Failure of NGF-TrkA neurotrophic support causes loss of nociceptive and autonomic neurons in HSAN4 and HSAN5.
Show evidence (2 references)
PMID:8696348 SUPPORT Human Clinical
"Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons."
Establishes the NGF-TrkA neurotrophic role in sensory and sympathetic neuron survival that fails in HSAN4 / HSAN5.
PMID:14976160 SUPPORT Human Clinical
"A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients."
Documents loss of small sensory fibers resulting from defective NGF signaling in HSAN5.
Elongator Complex Deficiency
In familial dysautonomia (HSAN3), a tissue-specific splice-site mutation in ELP1 (IKBKAP / IKAP) causes skipping of exon 20 and a truncated protein, reducing functional ELP1 — a subunit of the Elongator complex required for tRNA wobble-uridine modification — most severely in neural tissue, impairing development and maintenance of sensory and autonomic neurons.
Sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology. Autonomic neuron CL:0000107 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Autonomic neuron (CL:0000107). CL:0000107 is a cell type from the Cell Ontology.
ELP1 hgnc:5959 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ELP1 (hgnc:5959). hgnc:5959 is a gene from the HUGO Gene Nomenclature Committee.
tRNA wobble uridine modification GO:0002098 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased tRNA wobble uridine modification (GO:0002098). GO:0002098 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Sensory and Autonomic Neuron Degeneration Neural-tissue-specific ELP1 deficiency impairs sensory and autonomic neuron development and maintenance in familial dysautonomia.
Show evidence (1 reference)
PMID:11179021 SUPPORT Human Clinical
"the RNA encoding the IkappaB kinase complex-associated protein (IKAP) lacks exon 20 and, as a result of a frameshift, encodes a truncated protein."
Establishes the tissue-specific splicing defect that reduces functional ELP1 (IKAP) in familial dysautonomia (HSAN3).
HSN2-Dependent Sensory Neuron Maintenance Failure
In HSAN2, truncating mutations in HSN2 — a single exon within the WNK1 gene, transcribed as a nervous-system-specific isoform — impair the development and/or maintenance of peripheral sensory neurons and their supporting Schwann cells, producing early-onset loss of pain, temperature, and touch.
Sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
WNK1 hgnc:14540 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves WNK1 (hgnc:14540). hgnc:14540 is a gene from the HUGO Gene Nomenclature Committee.
Neuron development GO:0048666 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Neuron development (GO:0048666). GO:0048666 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Sensory and Autonomic Neuron Degeneration Loss of HSN2/WNK1 sensory-neuron maintenance leads to reduction or absence of peripheral sensory neurons in HSAN2.
Show evidence (1 reference)
PMID:15060842 SUPPORT Human Clinical
"The HSN2 protein may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells."
Establishes the HSN2 (WNK1) role in sensory-neuron maintenance whose loss causes HSAN2.
Sensory and Autonomic Neuron Degeneration
The shared terminal node of HSAN. The diverse upstream lesions (deoxysphingolipid toxicity, NGF-TrkA neurotrophic failure, Elongator deficiency, HSN2/WNK1 maintenance loss) converge on reduction, loss, or developmental failure of peripheral sensory (dorsal root ganglion) and autonomic neurons — with prominent small-fiber involvement. The resulting deficit is sensory- and autonomic-predominant: impaired pain, temperature, and touch sensation (frequently with painless injuries and acral mutilation) and autonomic dysfunction, in contrast to the motor-predominant CMT compartments.
Sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology. Autonomic neuron CL:0000107 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Autonomic neuron (CL:0000107). CL:0000107 is a cell type from the Cell Ontology.
Neuron development GO:0048666 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Neuron development (GO:0048666). GO:0048666 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Pain Insensitivity
Distal Sensory Loss
Acral Ulceration
Autonomic Dysfunction
Self-Mutilation
Show evidence (1 reference)
PMID:15060842 SUPPORT Human Clinical
"impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons."
Supports the convergent sensory deficit from reduction or absence of peripheral sensory neurons in HSAN.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hereditary Sensory and Autonomic Neuropathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Integument 2
Acral Ulceration Skin ulcer HP:0200042 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skin ulcer (HP:0200042). HP:0200042 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301564 SUPPORT Human Clinical
"Loss of sensation can lead to painless injuries, which, if unrecognized, result in slow wound healing and subsequent osteomyelitis requiring distal amputations."
GeneReviews (SPTLC1-HSN1) documents painless injuries progressing to non-healing ulcers, osteomyelitis, and amputation — the acral-ulceration complication of HSAN sensory loss.
Anhidrosis HP:0000970 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anhidrosis (HP:0000970). HP:0000970 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8696348 SUPPORT Human Clinical
"Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans."
Links NGF-TRKA defects to impaired sweating (anhidrosis) in HSAN4 (CIPA).
Nervous System 4
Pain Insensitivity HP:0007021 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pain insensitivity (HP:0007021). HP:0007021 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8696348 SUPPORT Human Clinical
"Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating) and absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation."
Establishes absence of reaction to noxious stimuli (pain insensitivity) as a cardinal HSAN4 (CIPA) feature.
Distal Sensory Loss Distal sensory impairment HP:0002936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal sensory impairment (HP:0002936). HP:0002936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15060842 SUPPORT Human Clinical
"impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons."
Supports impairment of pain, temperature, and touch sensation as the core sensory deficit of HSAN.
Autonomic Dysfunction Abnormality of the autonomic nervous system HP:0002270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the autonomic nervous system (HP:0002270). HP:0002270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301359 SUPPORT Human Clinical
"Affected individuals have gastrointestinal dysfunction, autonomic crises (i.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and blood pressure instability."
GeneReviews (Familial Dysautonomia / HSAN3) enumerates the autonomic dysfunction — GI dysmotility, autonomic crises, blood-pressure instability, and thermoregulatory disturbance.
Self-Mutilation HP:0000742 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Self-mutilation (HP:0000742). HP:0000742 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8696348 SUPPORT Human Clinical
"absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation."
Documents self-mutilating behavior as a feature of HSAN4 (CIPA).
🧬

Genetic Associations

5
SPTLC1 (Causal)
Gene: SPTLC1 hgnc:11277 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SPTLC1 (hgnc:11277). hgnc:11277 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:20504773 SUPPORT Human Clinical
"The autosomal dominant peripheral sensory neuropathy HSAN1 results from mutations in the LCB1 subunit of serine palmitoyltransferase (SPT)."
Establishes SPTLC1 as the HSAN1 gene.
WNK1 (Causal)
Gene: WNK1 (HSN2 exon) hgnc:14540 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is WNK1 (HSN2 exon), annotated with WNK1 (hgnc:14540). hgnc:14540 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:15060842 SUPPORT Human Clinical
"consists of a single exon located within intron 8 of the PRKWNK1 gene and is transcribed from the same strand."
Establishes HSN2 as an exon within WNK1 (PRKWNK1), the HSAN2 gene.
ELP1 (Causal)
Gene: ELP1 hgnc:5959 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ELP1 (hgnc:5959). hgnc:5959 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:11179021 SUPPORT Human Clinical
"These findings demonstrate that mutations in the gene encoding IKAP are responsible for FD."
Establishes ELP1 (IKAP) as the familial dysautonomia (HSAN3) gene.
NTRK1 (Causal)
Gene: NTRK1 hgnc:8031 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NTRK1 (hgnc:8031). hgnc:8031 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:8696348 SUPPORT Human Clinical
"Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans."
Establishes NTRK1 (TRKA) as the CIPA / HSAN4 gene.
NGF (Causal)
Gene: NGF hgnc:7808 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NGF (hgnc:7808). hgnc:7808 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:14976160 SUPPORT Human Clinical
"revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype."
Establishes NGF (NGFB) as the HSAN5 gene.
💊

Medical Actions

5
Wound and Skin Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Meticulous foot and skin care, protective footwear, and early treatment of injuries to prevent the acral ulceration and mutilation that follow unperceived trauma.
Autonomic Supportive Management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Supportive management of autonomic dysfunction (e.g., blood-pressure lability, temperature dysregulation, and dysautonomic crises), especially in familial dysautonomia.
Symptomatic Neuropathic Pain and Orthopedic Management
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Symptomatic care for the sensorimotor complications: ankle-foot orthoses for foot drop, arthrodesis for Charcot (neuropathic) joints, and neuropathic-pain pharmacotherapy (pregabalin, carbamazepine, gabapentin, or amitriptyline).
Show evidence (1 reference)
PMID:20301564 SUPPORT Other
"ankle/foot orthotics for foot drop; arthrodesis for Charcot joints; pregabalin, carbamazepine, gabapentin, or amitriptyline"
GeneReviews (SPTLC1-HSN1) management recommendations for foot drop, Charcot joints, and neuropathic pain.
Avoidance of Chronic Opioid Use
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Chronic opioid therapy is discouraged because HSAN is a lifelong disorder and long-term opioid use carries dependence and diminishing-benefit risks in this setting.
Show evidence (1 reference)
PMID:20301564 SUPPORT Other
"Agents/circumstances to avoid: Opiates as SPTLC1-related HSN is a chronic disorder."
GeneReviews (SPTLC1-HSN1) lists opiates among agents/circumstances to avoid given the chronicity of the disorder.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling for affected individuals and families, addressing the dominant (HSAN1) and recessive (HSAN2-5) inheritance patterns and, for HSAN3, Ashkenazi Jewish carrier screening.
🔬

Diagnosis

1
Molecular Genetic Testing
Diagnosis of each HSAN subtype is established in a proband with suggestive clinical findings (sensory-predominant neuropathy ± autonomic involvement) by identifying the subtype-specific pathogenic variant(s) on molecular genetic testing — biallelic for the recessive forms (e.g. NTRK1 in HSAN4/CIPA), a heterozygous variant for dominant HSAN1 (SPTLC1).
Molecular confirmation of the causal gene is the diagnostic standard across HSAN subtypes.
Show evidence (1 reference)
PMID:20301726 SUPPORT Other
"The diagnosis of NTRK1-CIPA is established in a proband with suggestive clinical findings and biallelic pathogenic variants in NTRK1 identified by molecular genetic testing."
GeneReviews (NTRK1-CIPA / HSAN4) states the molecular-genetic diagnostic criterion — the model for confirmatory diagnosis across the HSAN subtypes.
{ }

Source YAML

click to show 
name: Hereditary Sensory and Autonomic Neuropathy
creation_date: "2026-07-31T00:00:00Z"
category: Mendelian
description: >-
  Hereditary sensory and autonomic neuropathy (HSAN), also called hereditary
  sensory neuropathy (HSN), is a genetically heterogeneous group of inherited
  peripheral neuropathies in which the primary lesion is degeneration or
  developmental failure of the sensory (dorsal root ganglion) and autonomic
  neurons, with relative sparing of the motor system. This is the sensory /
  autonomic counterpart of the motor-predominant Charcot-Marie-Tooth
  neuropathies: instead of distal motor weakness, the cardinal features are loss
  of pain, temperature, and touch sensation — frequently complicated by painless
  injuries, acral ulceration, and mutilation — together with autonomic
  dysfunction. HSAN is classified into numbered types by inheritance, age of
  onset, and gene. The forms curated here span the four principal mechanistic
  themes: neurotoxic deoxysphingolipid formation from gain-of-function serine
  palmitoyltransferase mutations (HSAN1 / SPTLC1, autosomal dominant, adult
  onset); failure of NGF-TrkA neurotrophic signaling that normally supports the
  development and survival of nociceptive and autonomic neurons (HSAN4 / NTRK1,
  the classic congenital insensitivity to pain with anhidrosis, and HSAN5 / NGF);
  deficiency of the Elongator complex from a tissue-specific splicing defect
  (HSAN3 / ELP1, familial dysautonomia / Riley-Day); and loss of the
  HSN2-dependent sensory-neuron maintenance function of WNK1 (HSAN2). Unlike the
  CMT compartments, HSAN is not modeled here as a length-dependent dying-back
  axonopathy conforming to the peripheral_axonal_degeneration module, because
  several forms arise from developmental neurotrophic failure and sensory /
  autonomic neuronopathy rather than distal axonal die-back.
disease_term:
  preferred_term: Hereditary sensory and autonomic neuropathy (HSAN)
  term:
    id: MONDO:0015364
    label: hereditary sensory and autonomic neuropathy
parents:
- Peripheral Neuropathy
has_subtypes:
- name: HSAN1
  display_name: HSAN1 (SPTLC1, autosomal dominant)
  description: >-
    The most common autosomal dominant HSAN, adult-onset, caused by
    gain-of-function mutations in SPTLC1 (the LCB1 subunit of serine
    palmitoyltransferase) that generate neurotoxic 1-deoxysphingolipids.
    Distal sensory loss with painless ulcers and variable motor involvement.
  evidence:
  - reference: PMID:20504773
    reference_title: "A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autosomal dominant peripheral sensory neuropathy HSAN1 results from mutations in the LCB1 subunit of serine palmitoyltransferase (SPT)."
    explanation: Establishes SPTLC1 (LCB1 of serine palmitoyltransferase) mutations as the cause of autosomal dominant HSAN1.
- name: HSAN2
  display_name: HSAN2 (WNK1 / HSN2, autosomal recessive)
  description: >-
    Autosomal recessive, early-onset HSAN with impairment of pain, temperature,
    and touch from reduction or loss of peripheral sensory neurons, caused by
    truncating mutations in HSN2 — a nervous-system-specific exon within the
    WNK1 gene.
  evidence:
  - reference: PMID:15060842
    reference_title: "Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder characterized by impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons."
    explanation: Establishes HSAN2 as an autosomal recessive sensory neuropathy; the HSN2 gene is a nervous-system-specific exon of WNK1.
- name: HSAN3
  display_name: HSAN3 / Familial Dysautonomia (ELP1 / IKBKAP, autosomal recessive)
  description: >-
    Familial dysautonomia (Riley-Day syndrome), an autosomal recessive HSAN
    prevalent in the Ashkenazi Jewish population, caused by a tissue-specific
    splicing mutation in ELP1 (IKBKAP / IKAP), a subunit of the Elongator
    complex. Prominent autonomic dysfunction with sensory loss.
  evidence:
  - reference: PMID:11179021
    reference_title: "Familial dysautonomia is caused by mutations of the IKAP gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings demonstrate that mutations in the gene encoding IKAP are responsible for FD."
    explanation: Establishes ELP1 (IKBKAP / IKAP) mutations as the cause of familial dysautonomia (HSAN3).
- name: HSAN4
  display_name: HSAN4 / CIPA (NTRK1, autosomal recessive)
  description: >-
    Congenital insensitivity to pain with anhidrosis (CIPA), an autosomal
    recessive HSAN caused by mutations in NTRK1 (TrkA, the high-affinity NGF
    receptor). Absence of pain perception, anhidrosis, recurrent fever,
    self-mutilation, and intellectual disability.
  evidence:
  - reference: PMID:8696348
    reference_title: "Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans."
    explanation: Establishes NTRK1 (TRKA) mutations as the cause of CIPA (HSAN4).
- name: HSAN5
  display_name: HSAN5 (NGF / NGFB, autosomal recessive)
  description: >-
    Autosomal recessive HSAN caused by mutation in NGF (NGFB), the ligand of
    TrkA, producing loss of deep pain perception with severe reduction of
    unmyelinated small nerve fibers but largely preserved cognition.
  evidence:
  - reference: PMID:14976160
    reference_title: "A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype."
    explanation: Establishes an NGF (NGFB) coding mutation as the cause of loss of pain perception (HSAN5).
pathophysiology:
- name: Neurotoxic Deoxysphingolipid Formation
  description: >-
    Gain-of-function mutations in SPTLC1 (HSAN1), the LCB1 subunit of serine
    palmitoyltransferase, shift the enzyme's substrate specificity so that it
    condenses alanine (instead of serine) with palmitoyl-CoA, generating atypical
    1-deoxysphingolipids that are neurotoxic to sensory neurons and accumulate in
    patient serum.
  cell_types:
  - preferred_term: Sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  biological_processes:
  - preferred_term: Sphingolipid biosynthetic process
    term:
      id: GO:0030148
      label: sphingolipid biosynthetic process
    modifier: ABNORMAL
  genes:
  - preferred_term: SPTLC1
    term:
      id: hgnc:11277
      label: SPTLC1
  downstream:
  - target: Sensory and Autonomic Neuron Degeneration
    description: >-
      Neurotoxic 1-deoxysphingolipids drive degeneration of sensory neurons in
      HSAN1.
  evidence:
  - reference: PMID:20504773
    reference_title: "A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum from patients and transgenic mice expressing a disease-causing mutation (C133W) contain elevated levels of 1-deoxysphinganine (1-deoxySa), which presumably arise from inappropriate condensation of alanine with palmitoyl-CoA."
    explanation: Demonstrates accumulation of neurotoxic 1-deoxysphinganine from the SPTLC1 mutation, the HSAN1 mechanism.
- name: Impaired NGF-TrkA Neurotrophic Signaling
  description: >-
    Loss of signaling through the NGF-TrkA axis — from NTRK1 (TrkA receptor,
    HSAN4 / CIPA) or NGF (its ligand, HSAN5) mutations — removes the
    neurotrophic support that NGF provides for the development and survival of
    nociceptive sensory neurons and sympathetic (autonomic) neurons, so these
    populations fail to develop or are lost.
  cell_types:
  - preferred_term: Sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  - preferred_term: Autonomic neuron
    term:
      id: CL:0000107
      label: autonomic neuron
  biological_processes:
  - preferred_term: Neurotrophin TRK receptor signaling pathway
    term:
      id: GO:0048011
      label: neurotrophin TRK receptor signaling pathway
    modifier: DECREASED
  genes:
  - preferred_term: NTRK1
    term:
      id: hgnc:8031
      label: NTRK1
  - preferred_term: NGF
    term:
      id: hgnc:7808
      label: NGF
  downstream:
  - target: Sensory and Autonomic Neuron Degeneration
    description: >-
      Failure of NGF-TrkA neurotrophic support causes loss of nociceptive and
      autonomic neurons in HSAN4 and HSAN5.
  evidence:
  - reference: PMID:8696348
    reference_title: "Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons."
    explanation: Establishes the NGF-TrkA neurotrophic role in sensory and sympathetic neuron survival that fails in HSAN4 / HSAN5.
  - reference: PMID:14976160
    reference_title: "A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients."
    explanation: Documents loss of small sensory fibers resulting from defective NGF signaling in HSAN5.
- name: Elongator Complex Deficiency
  description: >-
    In familial dysautonomia (HSAN3), a tissue-specific splice-site mutation in
    ELP1 (IKBKAP / IKAP) causes skipping of exon 20 and a truncated protein,
    reducing functional ELP1 — a subunit of the Elongator complex required for
    tRNA wobble-uridine modification — most severely in neural tissue, impairing
    development and maintenance of sensory and autonomic neurons.
  cell_types:
  - preferred_term: Sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  - preferred_term: Autonomic neuron
    term:
      id: CL:0000107
      label: autonomic neuron
  biological_processes:
  - preferred_term: tRNA wobble uridine modification
    term:
      id: GO:0002098
      label: tRNA wobble uridine modification
    modifier: DECREASED
  genes:
  - preferred_term: ELP1
    term:
      id: hgnc:5959
      label: ELP1
  downstream:
  - target: Sensory and Autonomic Neuron Degeneration
    description: >-
      Neural-tissue-specific ELP1 deficiency impairs sensory and autonomic
      neuron development and maintenance in familial dysautonomia.
  evidence:
  - reference: PMID:11179021
    reference_title: "Familial dysautonomia is caused by mutations of the IKAP gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the RNA encoding the IkappaB kinase complex-associated protein (IKAP) lacks exon 20 and, as a result of a frameshift, encodes a truncated protein."
    explanation: Establishes the tissue-specific splicing defect that reduces functional ELP1 (IKAP) in familial dysautonomia (HSAN3).
- name: HSN2-Dependent Sensory Neuron Maintenance Failure
  description: >-
    In HSAN2, truncating mutations in HSN2 — a single exon within the WNK1 gene,
    transcribed as a nervous-system-specific isoform — impair the development
    and/or maintenance of peripheral sensory neurons and their supporting Schwann
    cells, producing early-onset loss of pain, temperature, and touch.
  cell_types:
  - preferred_term: Sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  biological_processes:
  - preferred_term: Neuron development
    term:
      id: GO:0048666
      label: neuron development
    modifier: ABNORMAL
  genes:
  - preferred_term: WNK1
    term:
      id: hgnc:14540
      label: WNK1
  downstream:
  - target: Sensory and Autonomic Neuron Degeneration
    description: >-
      Loss of HSN2/WNK1 sensory-neuron maintenance leads to reduction or absence
      of peripheral sensory neurons in HSAN2.
  evidence:
  - reference: PMID:15060842
    reference_title: "Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The HSN2 protein may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells."
    explanation: Establishes the HSN2 (WNK1) role in sensory-neuron maintenance whose loss causes HSAN2.
- name: Sensory and Autonomic Neuron Degeneration
  description: >-
    The shared terminal node of HSAN. The diverse upstream lesions (deoxysphingolipid
    toxicity, NGF-TrkA neurotrophic failure, Elongator deficiency, HSN2/WNK1
    maintenance loss) converge on reduction, loss, or developmental failure of
    peripheral sensory (dorsal root ganglion) and autonomic neurons — with
    prominent small-fiber involvement. The resulting deficit is sensory- and
    autonomic-predominant: impaired pain, temperature, and touch sensation
    (frequently with painless injuries and acral mutilation) and autonomic
    dysfunction, in contrast to the motor-predominant CMT compartments.
  cell_types:
  - preferred_term: Sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  - preferred_term: Autonomic neuron
    term:
      id: CL:0000107
      label: autonomic neuron
  biological_processes:
  - preferred_term: Neuron development
    term:
      id: GO:0048666
      label: neuron development
    modifier: ABNORMAL
  downstream:
  - target: Pain Insensitivity
  - target: Distal Sensory Loss
  - target: Acral Ulceration
  - target: Autonomic Dysfunction
  - target: Self-Mutilation
  evidence:
  - reference: PMID:15060842
    reference_title: "Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons."
    explanation: Supports the convergent sensory deficit from reduction or absence of peripheral sensory neurons in HSAN.
phenotypes:
- category: Neurologic
  name: Pain Insensitivity
  diagnostic: true
  description: >-
    Reduced or absent perception of noxious (painful) stimuli, the cardinal
    feature of HSAN, leading to painless injuries.
  phenotype_term:
    preferred_term: Pain insensitivity
    term:
      id: HP:0007021
      label: Pain insensitivity
  evidence:
  - reference: PMID:8696348
    reference_title: "Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating) and absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation."
    explanation: Establishes absence of reaction to noxious stimuli (pain insensitivity) as a cardinal HSAN4 (CIPA) feature.
- category: Neurologic
  name: Distal Sensory Loss
  phenotype_term:
    preferred_term: Distal sensory impairment
    term:
      id: HP:0002936
      label: Distal sensory impairment
  evidence:
  - reference: PMID:15060842
    reference_title: "Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impairment of pain, temperature, and touch sensation owing to reduction or absence of peripheral sensory neurons."
    explanation: Supports impairment of pain, temperature, and touch sensation as the core sensory deficit of HSAN.
- category: Integumentary
  name: Acral Ulceration
  description: >-
    Painless ulcers of the feet and hands resulting from unperceived repetitive
    injury, a common and disabling complication of the sensory loss in HSAN.
  phenotype_term:
    preferred_term: Skin ulcer
    term:
      id: HP:0200042
      label: Skin ulcer
  evidence:
  - reference: PMID:20301564
    reference_title: "SPTLC1-Related Hereditary Sensory Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss of sensation can lead to painless injuries, which, if unrecognized, result in slow wound healing and subsequent osteomyelitis requiring distal amputations."
    explanation: GeneReviews (SPTLC1-HSN1) documents painless injuries progressing to non-healing ulcers, osteomyelitis, and amputation — the acral-ulceration complication of HSAN sensory loss.
- category: Neurologic
  name: Autonomic Dysfunction
  description: >-
    Dysregulation of autonomic function (e.g., abnormal sweating, blood-pressure
    and gastrointestinal control, and autonomic crises), most prominent in
    familial dysautonomia (HSAN3).
  phenotype_term:
    preferred_term: Abnormality of the autonomic nervous system
    term:
      id: HP:0002270
      label: Abnormality of the autonomic nervous system
  evidence:
  - reference: PMID:20301359
    reference_title: "Familial Dysautonomia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals have gastrointestinal dysfunction, autonomic crises (i.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and blood pressure instability."
    explanation: GeneReviews (Familial Dysautonomia / HSAN3) enumerates the autonomic dysfunction — GI dysmotility, autonomic crises, blood-pressure instability, and thermoregulatory disturbance.
- category: Integumentary
  name: Anhidrosis
  subtype: HSAN4
  description: >-
    Absence of sweating, a defining feature of HSAN4 (CIPA) reflecting the loss
    of NGF-TrkA-dependent sympathetic innervation of sweat glands.
  phenotype_term:
    preferred_term: Anhidrosis
    term:
      id: HP:0000970
      label: Anhidrosis
  evidence:
  - reference: PMID:8696348
    reference_title: "Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans."
    explanation: Links NGF-TRKA defects to impaired sweating (anhidrosis) in HSAN4 (CIPA).
- category: Neurologic
  name: Self-Mutilation
  description: >-
    Self-injurious behavior and acral mutilation arising from the absence of
    protective pain sensation, characteristic of the congenital HSAN forms.
  phenotype_term:
    preferred_term: Self-mutilation
    term:
      id: HP:0000742
      label: Self-mutilation
  evidence:
  - reference: PMID:8696348
    reference_title: "Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation."
    explanation: Documents self-mutilating behavior as a feature of HSAN4 (CIPA).
genetic:
- name: SPTLC1
  gene_term:
    preferred_term: SPTLC1
    term:
      id: hgnc:11277
      label: SPTLC1
  association: Causal
  subtype: HSAN1
  notes: >-
    LCB1 subunit of serine palmitoyltransferase; gain-of-function mutations cause
    autosomal dominant HSAN1 via neurotoxic 1-deoxysphingolipids.
  evidence:
  - reference: PMID:20504773
    reference_title: "A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autosomal dominant peripheral sensory neuropathy HSAN1 results from mutations in the LCB1 subunit of serine palmitoyltransferase (SPT)."
    explanation: Establishes SPTLC1 as the HSAN1 gene.
- name: WNK1
  gene_term:
    preferred_term: WNK1 (HSN2 exon)
    term:
      id: hgnc:14540
      label: WNK1
  association: Causal
  subtype: HSAN2
  notes: >-
    HSAN2 is caused by truncating mutations in HSN2, a nervous-system-specific
    single exon located within intron 8 of the WNK1 (PRKWNK1) gene.
  evidence:
  - reference: PMID:15060842
    reference_title: "Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "consists of a single exon located within intron 8 of the PRKWNK1 gene and is transcribed from the same strand."
    explanation: Establishes HSN2 as an exon within WNK1 (PRKWNK1), the HSAN2 gene.
- name: ELP1
  gene_term:
    preferred_term: ELP1
    term:
      id: hgnc:5959
      label: ELP1
  association: Causal
  subtype: HSAN3
  notes: >-
    ELP1 (IKBKAP / IKAP), an Elongator-complex subunit; a tissue-specific splice
    mutation causes familial dysautonomia (HSAN3), common in Ashkenazi Jews.
  evidence:
  - reference: PMID:11179021
    reference_title: "Familial dysautonomia is caused by mutations of the IKAP gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings demonstrate that mutations in the gene encoding IKAP are responsible for FD."
    explanation: Establishes ELP1 (IKAP) as the familial dysautonomia (HSAN3) gene.
- name: NTRK1
  gene_term:
    preferred_term: NTRK1
    term:
      id: hgnc:8031
      label: NTRK1
  association: Causal
  subtype: HSAN4
  notes: >-
    NTRK1 (TrkA), the high-affinity NGF receptor tyrosine kinase; recessive
    mutations cause CIPA (HSAN4).
  evidence:
  - reference: PMID:8696348
    reference_title: "Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans."
    explanation: Establishes NTRK1 (TRKA) as the CIPA / HSAN4 gene.
- name: NGF
  gene_term:
    preferred_term: NGF
    term:
      id: hgnc:7808
      label: NGF
  association: Causal
  subtype: HSAN5
  notes: >-
    NGF (NGFB), the TrkA ligand; recessive mutation causes HSAN5 with loss of
    deep pain perception and small-fiber loss.
  evidence:
  - reference: PMID:14976160
    reference_title: "A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype."
    explanation: Establishes NGF (NGFB) as the HSAN5 gene.
inheritance:
- name: Autosomal Dominant
  description: >-
    HSAN1 (SPTLC1) is inherited in an autosomal dominant manner, typically with
    adult onset.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20504773
    reference_title: "A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autosomal dominant peripheral sensory neuropathy HSAN1 results from mutations in the LCB1 subunit of serine palmitoyltransferase (SPT)."
    explanation: Documents autosomal dominant inheritance of HSAN1.
- name: Autosomal Recessive
  description: >-
    The congenital / early-onset HSAN forms — HSAN2 (WNK1/HSN2), HSAN3 (ELP1),
    HSAN4 (NTRK1), and HSAN5 (NGF) — are inherited in an autosomal recessive
    manner.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:8696348
    reference_title: "Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is an autosomal-recessive disorder"
    explanation: Documents autosomal recessive inheritance of the congenital HSAN forms (CIPA / HSAN4 shown).
  - reference: PMID:20301359
    reference_title: "Familial Dysautonomia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier"
    explanation: GeneReviews (Familial Dysautonomia / HSAN3) gives the standard autosomal recessive recurrence risk (25% affected, 50% carrier per sib).
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Diagnosis of each HSAN subtype is established in a proband with suggestive
    clinical findings (sensory-predominant neuropathy ± autonomic involvement) by
    identifying the subtype-specific pathogenic variant(s) on molecular genetic
    testing — biallelic for the recessive forms (e.g. NTRK1 in HSAN4/CIPA), a
    heterozygous variant for dominant HSAN1 (SPTLC1).
  notes: Molecular confirmation of the causal gene is the diagnostic standard across HSAN subtypes.
  evidence:
  - reference: PMID:20301726
    reference_title: "NTRK1 Congenital Insensitivity to Pain with Anhidrosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of NTRK1-CIPA is established in a proband with suggestive clinical findings and biallelic pathogenic variants in NTRK1 identified by molecular genetic testing."
    explanation: GeneReviews (NTRK1-CIPA / HSAN4) states the molecular-genetic diagnostic criterion — the model for confirmatory diagnosis across the HSAN subtypes.
treatments:
- name: Wound and Skin Care
  description: >-
    Meticulous foot and skin care, protective footwear, and early treatment of
    injuries to prevent the acral ulceration and mutilation that follow
    unperceived trauma.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Autonomic Supportive Management
  description: >-
    Supportive management of autonomic dysfunction (e.g., blood-pressure
    lability, temperature dysregulation, and dysautonomic crises), especially in
    familial dysautonomia.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Symptomatic Neuropathic Pain and Orthopedic Management
  description: >-
    Symptomatic care for the sensorimotor complications: ankle-foot orthoses for
    foot drop, arthrodesis for Charcot (neuropathic) joints, and neuropathic-pain
    pharmacotherapy (pregabalin, carbamazepine, gabapentin, or amitriptyline).
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:20301564
    reference_title: "SPTLC1-Related Hereditary Sensory Neuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ankle/foot orthotics for foot drop; arthrodesis for Charcot joints; pregabalin, carbamazepine, gabapentin, or amitriptyline"
    explanation: GeneReviews (SPTLC1-HSN1) management recommendations for foot drop, Charcot joints, and neuropathic pain.
- name: Avoidance of Chronic Opioid Use
  description: >-
    Chronic opioid therapy is discouraged because HSAN is a lifelong disorder and
    long-term opioid use carries dependence and diminishing-benefit risks in this
    setting.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301564
    reference_title: "SPTLC1-Related Hereditary Sensory Neuropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Agents/circumstances to avoid: Opiates as SPTLC1-related HSN is a chronic disorder."
    explanation: GeneReviews (SPTLC1-HSN1) lists opiates among agents/circumstances to avoid given the chronicity of the disorder.
- name: Genetic Counseling
  description: >-
    Counseling for affected individuals and families, addressing the dominant
    (HSAN1) and recessive (HSAN2-5) inheritance patterns and, for HSAN3,
    Ashkenazi Jewish carrier screening.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
references:
- reference: PMID:20301564
  title: "SPTLC1-Related Hereditary Sensory Neuropathy."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301359
  title: "Familial Dysautonomia."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301726
  title: "NTRK1 Congenital Insensitivity to Pain with Anhidrosis."
  tags:
  - GeneReviews
  findings: []
datasets: []
📚

References & Deep Research

References

3
PMID:20301564
SPTLC1-Related Hereditary Sensory Neuropathy.
No top-level findings curated for this source.
PMID:20301359
Familial Dysautonomia.
No top-level findings curated for this source.
PMID:20301726
NTRK1 Congenital Insensitivity to Pain with Anhidrosis.
No top-level findings curated for this source.