MCID: ERY029
MIFTS: 43

Erythermalgia, Primary

Categories: Genetic diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Erythermalgia, Primary

MalaCards integrated aliases for Erythermalgia, Primary:

Name: Erythermalgia, Primary 54 13
Small Fiber Neuropathy 54 24 25 29 69
Primary Erythermalgia 56 71 69
Sfnp 24 25
Small Nerve Fiber Neuropathy 25
Perythm 71
Sfn 25

Characteristics:

Orphanet epidemiological data:

56
primary erythermalgia
Inheritance: Autosomal dominant; Prevalence: <1/1000000 (Worldwide); Age of onset: Childhood;

OMIM:

54
Inheritance:
autosomal dominant

Miscellaneous:
relief is achieved by cooling or by elevating the extremities
disorder may progress to involve a larger body area
onset usually in childhood or adolescence
adult-onset is referred to as small fiber neuropathy


HPO:

32
erythermalgia, primary:
Inheritance autosomal dominant inheritance
Onset and clinical course juvenile onset


Classifications:

Orphanet: 56  
Rare neurological diseases


Summaries for Erythermalgia, Primary

OMIM : 54
'Primary erythermalgia' is an autosomal dominant disorder characterized by childhood or adolescent onset of episodic symmetrical red congestion, vasodilatation, and burning pain of the feet and lower legs provoked by exercise, long standing, and exposure to warmth. Relief is obtained with cold (Michiels et al., 2005). The severity of the disorder may progress with age, and symptoms may extend over a larger body area, such as over the ankles and lower legs, and become constant (Mandell et al., 1977). Waxman and Dib-Hajj (2005) provided a review of primary erythermalgia. Although 'primary' or 'familial erythromelalgia' are sometimes used as alternative terms for primary erythermalgia (Waxman and Dib-Hajj, 2005), secondary erythromelalgia is a distinct acquired disorder associated with thrombocythemia or myeloproliferative disorders. It has relatively late onset and symptoms are caused by platelet aggregation in end-arteriolar circulation, leading to ischemia and symptoms (Michiels and van Joost, 1990). Treatment with aspirin, which irreversibly inhibits platelet cyclooxygenase activity, affords relief from acquired erythromelalgia (Michiels et al., 1984; Drenth et al., 1996). Similarly, acquired erythromelalgia vanishes with lowering the platelet count to normal with chemotherapy (Michiels et al., 1985). Van Genderen et al. (1993) emphasized the distinction between hereditary erythermalgia and acquired erythromelalgia. In primary erythermalgia, the burning pain, redness, and warmth of feet and lower legs, with relative sparing of the toes, are easily provoked by warmth and exercise. In contrast, in acquired erythromelalgia the burning pain and red congestion preferentially involves one or more toes or fingers or sole of the forefoot (Michiels and van Joost, 1990). Van Genderen et al. (1993) noted that 3 of the 5 patients reported by Smith and Allen (1938) were not consistent with the diagnosis of primary erythromelalgia because the symptoms were relieved promptly by aspirin, consistent with acquired erythromelalgia. (133020)

MalaCards based summary : Erythermalgia, Primary, also known as small fiber neuropathy, is related to sodium channelopathy-related small fiber neuropathy and breast cancer, and has symptoms including diarrhea, palpitations and constipation. An important gene associated with Erythermalgia, Primary is SCN9A (Sodium Voltage-Gated Channel Alpha Subunit 9), and among its related pathways/superpathways are Activation of cAMP-Dependent PKA and Developmental Biology. The drug Pharmaceutical Solutions has been mentioned in the context of this disorder. Affiliated tissues include skin and eye, and related phenotype is integument.

UniProtKB/Swiss-Prot : 71 Primary erythermalgia: Autosomal dominant disease characterized by recurrent episodes of severe pain associated with redness and warmth in the feet or hands.

Genetics Home Reference : 25 Small fiber neuropathy is a condition characterized by severe pain attacks that typically begin in the feet or hands. As a person ages, the pain attacks can affect other regions. Some people initially experience a more generalized, whole-body pain. The attacks usually consist of pain described as stabbing or burning, or abnormal skin sensations such as tingling or itchiness. In some individuals, the pain is more severe during times of rest or at night. The signs and symptoms of small fiber neuropathy usually begin in adolescence to mid-adulthood.

Related Diseases for Erythermalgia, Primary

Diseases related to Erythermalgia, Primary via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 53)
id Related Disease Score Top Affiliating Genes
1 sodium channelopathy-related small fiber neuropathy 12.0
2 breast cancer 11.4
3 popliteal pterygium syndrome 1 10.8
4 limbal stem cell deficiency 10.8
5 colloid carcinoma of the pancreas 10.8
6 cocoon syndrome 10.8
7 microphthalmia, isolated 1 10.8
8 neuropathy 10.7
9 burns 10.0
10 fabry disease 9.9
11 pancreatic ductal adenocarcinoma 9.9
12 choroiditis 9.8
13 complex regional pain syndrome 9.8
14 neuronitis 9.8
15 vasculitis 9.8
16 tooth disease 9.8
17 erythromelalgia 9.8
18 wilson disease 9.8
19 dysautonomia 9.8
20 reflex sympathetic dystrophy 9.8
21 charcot-marie-tooth disease 9.8
22 cerebritis 9.8
23 thrombosis 9.8
24 cerebral sinovenous thrombosis 9.8
25 diabetic neuropathy 9.7
26 burning mouth syndrome 9.7
27 obesity 9.7
28 wrinkles 9.7
29 alcohol dependence 9.7
30 restless legs syndrome 9.7
31 celiac disease 9.7
32 fragile x-associated tremor/ataxia syndrome 9.7
33 multiple myeloma 9.7
34 rabies 9.7
35 ataxia 9.7
36 autonomic dysfunction 9.7
37 charcot-marie-tooth disease, type 1a 9.7
38 lyme disease 9.7
39 chagas disease 9.7
40 tremor 9.7
41 ehlers-danlos syndrome, hypermobility type 9.7
42 porphyria 9.7
43 ehlers-danlos syndrome 9.7
44 polyneuropathy 9.7
45 hypothyroidism 9.7
46 waardenburg's syndrome 9.4 SCN10A SCN9A
47 benign familial infantile epilepsy 9.4 SCN11A SCN9A
48 spinal canal intradural extramedullary neoplasm 9.3 SCN11A SCN9A
49 congenital absence of both lower leg and foot, bilateral 9.1 SCN10A SCN11A SCN9A
50 paroxysmal extreme pain disorder 9.0 SCN10A SCN11A SCN9A

Graphical network of the top 20 diseases related to Erythermalgia, Primary:



Diseases related to Erythermalgia, Primary

Symptoms & Phenotypes for Erythermalgia, Primary

Symptoms via clinical synopsis from OMIM:

54

Abdomen- Gastroin testinal:
diarrhea
constipation

Cardiovascular- Heart:
palpitations

Head And Neck- Mouth:
dry mouth

Head And Neck- Face:
jaw pain

Muscle Soft Tissue:
muscle pain
myalgias
swelling of the affected areas

Head And Neck- Eyes:
blurred vision
dry eyes

Skin Nails & Hair- Skin:
hyperhidrosis
reddish or purplish skin discoloration, episodic, associated with pain
decreased intraepithelial nerve fiber density

Neurologic- Peripheral Nervous System:
burning pain, episodic, typically in the distal extremities, particularly the hands and feet (bilateral, symmetric), triggered by warm stimuli, exercise, standing
itching
impaired distal temperature sensation
hypoesthesia over affected areas
autonomic dysfunction (in some patients)


Clinical features from OMIM:

133020

Human phenotypes related to Erythermalgia, Primary:

32 (show all 10)
id Description HPO Frequency HPO Source Accession
1 diarrhea 32 HP:0002014
2 palpitations 32 HP:0001962
3 constipation 32 HP:0002019
4 myalgia 32 HP:0003326
5 blurred vision 32 HP:0000622
6 hyperhidrosis 32 HP:0000975
7 xerostomia 32 HP:0000217
8 dysautonomia 32 occasional (7.5%) HP:0002459
9 pain 32 HP:0012531
10 abnormality of the musculature 32 HP:0003011

UMLS symptoms related to Erythermalgia, Primary:


constipation, diarrhea, pruritus, myalgia, jaw pain, dryness of eye, blurred vision, neuralgia

MGI Mouse Phenotypes related to Erythermalgia, Primary:

44
id Description MGI Source Accession Score Top Affiliating Genes
1 integument MP:0010771 8.8 SCN10A SCN11A SCN9A

Drugs & Therapeutics for Erythermalgia, Primary

Drugs for Erythermalgia, Primary (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):


id Name Status Phase Clinical Trials Cas Number PubChem Id
1 Pharmaceutical Solutions Phase 2

Interventional clinical trials:


id Name Status NCT ID Phase Drugs
1 Phase 2a, Exploratory Study to Evaluate the Safety, Efficacy, Tolerability and Pharmacokinetics of XPF-002 in Patients With Primary/Inherited Erythromelalgia Completed NCT01486446 Phase 1, Phase 2 XPF-002;Placebo
2 Study of XPF-001 in the Treatment of Pain From Primary/Inherited Erythromelalgia (IEM) Completed NCT01090622 Phase 1, Phase 2 XPF-001;Placebo
3 A Phase 2a Study of BIIB074 in the Treatment of Erythromelalgia Completed NCT02917187 Phase 2 BIIB074;Placebo
4 Evaluation Of The Efficacy And Safety Of Single Doses Of PF-05089771 In Patients With Primary (Inherited) Erythromelalgia Completed NCT01769274 Phase 2 PF-05089771;Placebo

Search NIH Clinical Center for Erythermalgia, Primary

Genetic Tests for Erythermalgia, Primary

Genetic tests related to Erythermalgia, Primary:

id Genetic test Affiliating Genes
1 Small Fiber Neuropathy 29 24 SCN9A

Anatomical Context for Erythermalgia, Primary

MalaCards organs/tissues related to Erythermalgia, Primary:

39
Skin, Eye

Publications for Erythermalgia, Primary

Variations for Erythermalgia, Primary

UniProtKB/Swiss-Prot genetic disease variations for Erythermalgia, Primary:

71 (show all 11)
id Symbol AA change Variation ID SNP ID
1 SCN9A p.Ile859Thr VAR_019947 rs80356474
2 SCN9A p.Leu869His VAR_019948 rs80356475
3 SCN9A p.Ser241Thr VAR_032014 rs80356470
4 SCN9A p.Phe1460Val VAR_032019 rs80356478
5 SCN9A p.Gln10Arg VAR_064595 rs267607030
6 SCN9A p.Phe216Ser VAR_064598 rs80356469
7 SCN9A p.Asn395Lys VAR_064600 rs80356471
8 SCN9A p.Glu406Lys VAR_064601
9 SCN9A p.Leu869Phe VAR_064609 rs80356476
10 SCN9A p.Ala1643Glu VAR_072280 rs879253994
11 SCN9A p.Ala1643Thr VAR_072281

ClinVar genetic disease variations for Erythermalgia, Primary:

6 (show all 11)
id Gene Variation Type Significance SNP ID Assembly Location
1 SCN9A NM_002977.3(SCN9A): c.2573T> A (p.Leu858His) single nucleotide variant Pathogenic rs80356475 GRCh37 Chromosome 2, 167133761: 167133761
2 SCN9A NM_002977.3(SCN9A): c.2543T> C (p.Ile848Thr) single nucleotide variant Pathogenic rs80356474 GRCh37 Chromosome 2, 167133791: 167133791
3 SCN9A NM_002977.3(SCN9A): c.721T> A (p.Ser241Thr) single nucleotide variant Pathogenic rs80356470 GRCh37 Chromosome 2, 167159780: 167159780
4 SCN9A NM_002977.3(SCN9A): c.4345T> G (p.Phe1449Val) single nucleotide variant Pathogenic rs80356478 GRCh37 Chromosome 2, 167083097: 167083097
5 SCN9A NM_002977.3(SCN9A): c.2572C> T (p.Leu858Phe) single nucleotide variant Pathogenic rs80356476 GRCh37 Chromosome 2, 167133762: 167133762
6 SCN9A NM_002977.3(SCN9A): c.647T> C (p.Phe216Ser) single nucleotide variant Pathogenic rs80356469 GRCh37 Chromosome 2, 167160789: 167160789
7 SCN9A NM_002977.3(SCN9A): c.2468T> G (p.Leu823Arg) single nucleotide variant Pathogenic rs80356473 GRCh38 Chromosome 2, 166278156: 166278156
8 SCN9A NM_002977.3(SCN9A): c.1185C> A (p.Asn395Lys) single nucleotide variant Pathogenic rs80356471 GRCh37 Chromosome 2, 167145076: 167145076
9 SCN9A NM_002977.3(SCN9A): c.2587G> C (p.Ala863Pro) single nucleotide variant Pathogenic rs80356477 GRCh37 Chromosome 2, 167133747: 167133747
10 SCN9A NM_002977.3(SCN9A): c.406A> G (p.Ile136Val) single nucleotide variant Pathogenic rs80356468 GRCh37 Chromosome 2, 167163081: 167163081
11 SCN9A NM_002977.3(SCN9A): c.1867G> A (p.Asp623Asn) single nucleotide variant Pathogenic rs200398202 GRCh37 Chromosome 2, 167141070: 167141070

Expression for Erythermalgia, Primary

Search GEO for disease gene expression data for Erythermalgia, Primary.

Pathways for Erythermalgia, Primary

Pathways related to Erythermalgia, Primary according to GeneCards Suite gene sharing:

id Super pathways Score Top Affiliating Genes
1
Show member pathways
12.89 SCN10A SCN11A SCN9A
2
Show member pathways
12.82 SCN10A SCN11A SCN9A
3
Show member pathways
12.34 SCN10A SCN11A SCN9A
4
Show member pathways
12.27 SCN10A SCN11A SCN9A
5
Show member pathways
12.09 SCN10A SCN11A SCN9A
6 11.94 SCN10A SCN11A SCN9A
7
Show member pathways
11.43 SCN10A SCN11A SCN9A
8
Show member pathways
11.01 SCN10A SCN11A SCN9A
9 10.28 SCN10A SCN11A SCN9A

GO Terms for Erythermalgia, Primary

Cellular components related to Erythermalgia, Primary according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 voltage-gated sodium channel complex GO:0001518 8.8 SCN10A SCN11A SCN9A

Biological processes related to Erythermalgia, Primary according to GeneCards Suite gene sharing:

(show all 11)
id Name GO ID Score Top Affiliating Genes
1 transport GO:0006810 9.67 SCN10A SCN11A SCN9A
2 ion transport GO:0006811 9.63 SCN10A SCN11A SCN9A
3 transmembrane transport GO:0055085 9.58 SCN10A SCN11A SCN9A
4 regulation of ion transmembrane transport GO:0034765 9.54 SCN10A SCN11A SCN9A
5 sodium ion transport GO:0006814 9.5 SCN10A SCN11A SCN9A
6 ion transmembrane transport GO:0034220 9.48 SCN11A SCN9A
7 sensory perception of pain GO:0019233 9.43 SCN10A SCN9A
8 sodium ion transmembrane transport GO:0035725 9.43 SCN10A SCN11A SCN9A
9 regulation of postsynaptic membrane potential GO:0060078 9.33 SCN10A SCN11A SCN9A
10 neuronal action potential GO:0019228 9.13 SCN10A SCN11A SCN9A
11 membrane depolarization during action potential GO:0086010 8.8 SCN10A SCN11A SCN9A

Molecular functions related to Erythermalgia, Primary according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 voltage-gated ion channel activity GO:0005244 9.43 SCN10A SCN11A SCN9A
2 ion channel activity GO:0005216 9.33 SCN10A SCN11A SCN9A
3 sodium channel activity GO:0005272 9.13 SCN10A SCN11A SCN9A
4 voltage-gated sodium channel activity GO:0005248 8.8 SCN10A SCN11A SCN9A

Sources for Erythermalgia, Primary

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
16 ExPASy
18 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 MedGen
42 MeSH
43 MESH via Orphanet
44 MGI
46 NCI
47 NCIt
48 NDF-RT
51 NINDS
52 Novoseek
54 OMIM
55 OMIM via Orphanet
59 PubMed
60 QIAGEN
65 SNOMED-CT via HPO
66 SNOMED-CT via Orphanet
67 TGDB
68 Tocris
69 UMLS
70 UMLS via Orphanet
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