INT81955

Context Info Confidence 0.70 First Reported 1999 Last Reported 2010 Negated 0 Speculated 0 Reported most in Body Documents 12 Total Number 14 Disease Relevance 10.25 Pain Relevance 3.12

small molecule metabolic process (SPTLC1) endoplasmic reticulum (SPTLC1) biosynthetic process (SPTLC1) transferase activity, transferring acyl groups (SPTLC1)

Anatomy Link Frequency sympathetic 2 skin 1 SPTLC1 (Homo sapiens) SPTLC1 - V144D (1)

Pain Link Frequency Relevance Heat Hsan 388 100.00 lancinating pain 5 97.32 Nerve growth factor 2 96.60 unmyelinated 16 90.80 imagery 9 86.68 Pain 37 85.20 Action potential 3 84.12 hyperpathia 1 63.08 ischemia 3 36.88 Neuropathic pain 3 25.36

Disease Link Frequency Relevance Heat Hereditary Sensory And Autonomic Neuropathies 489 100.00 Neuropathic Pain 114 100.00 Foot Deformities 4 97.96 Diabetes Mellitus 108 97.92 Peripheral Neuropathy 7 97.76 Pain 41 97.32 Familial Dysautonomia 30 97.16 Spontaneous Fractures 8 96.72 Disease 111 96.68 Osteomyelitis 9 94.88

Sentences Mentioned In

Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

All mutations which have been identified as a cause of HSN I are summarised in the Mutation Database of Inherited Peripheral Neuropathies [20].

Positive_regulation (cause) of HSN associated with peripheral neuropathy and hsan

1) Confidence 0.70 Published 2008 Journal Orphanet J Rare Dis Section Body Doc Link PMC2311280 Disease Relevance 0.64 Pain Relevance 0.41

Large families in which mutations in SPTLC1 and RAB7 are excluded can be used for genome wide linkage studies to detect a novel HSN I locus or to confirm linkage to the third known HSN I locus (i.e. the HSN IB locus).

Positive_regulation (mutations) of SPTLC1 associated with hsan

2) Confidence 0.50 Published 2008 Journal Orphanet J Rare Dis Section Body Doc Link PMC2311280 Disease Relevance 1.47 Pain Relevance 1.15

Despite the late onset of the disease, the progressive course, and the lancinating pain, the terminal features of this patient, which involved a selective loss of myelinated fibers and widespread sensory loss, seem to be symptomatic of HSAN II, the progressive form of autosomal recessive sensory neuropathy, and emphasize the clinical heterogeneity of HSAN.

Positive_regulation (symptomatic) of HSAN associated with pain, neuropathic pain, lancinating pain, hereditary sensory and autonomic neuropathies and disease

3) Confidence 0.50 Published 2003 Journal Clin Neurol Neurosurg Section Abstract Doc Link 12860510 Disease Relevance 0.85 Pain Relevance 0.18

HSAN IV is caused by mutations in the NTRK1 (TRKA) gene that is located on chromosome 1 (1q21-q22).

Positive_regulation (caused) of HSAN associated with hereditary sensory and autonomic neuropathies

4) Confidence 0.45 Published 2007 Journal Orphanet J Rare Dis Section Body Doc Link PMC2098750 Disease Relevance 0.67 Pain Relevance 0.04

The C133W and V144D SPTLC1 mutations were originally suggested to increase the serine palmitoyltransferase function with higher levels of glycosyl ceramide compared to controls behaving as gain of function mutations [13].

Positive_regulation (increase) of SPTLC1 (V144D)

5) Confidence 0.44 Published 2008 Journal Orphanet J Rare Dis Section Body Doc Link PMC2311280 Disease Relevance 0.44 Pain Relevance 0.29

Foot deformity promotes ulcerations and skin changes such as hyperkeratosis at pressure points, which is also often prominent in HSN I.

Positive_regulation (prominent) of HSN in skin associated with foot deformities and hsan

6) Confidence 0.44 Published 2008 Journal Orphanet J Rare Dis Section Body Doc Link PMC2311280 Disease Relevance 2.00 Pain Relevance 0.38

Comparing the kinetics between mutant and wildtype SPT showed that both forms have similar Km's for serine and alanine but that Vmax for alanine is greatly increased in the HSAN1 mutants [12].

Positive_regulation (increased) of HSAN1

7) Confidence 0.17 Published 2010 Journal Lipids Health Dis Section Body Doc Link PMC2931514 Disease Relevance 0.81 Pain Relevance 0.09

HSN1 is caused by mutations in the gene, encoding the long chain base 1 of serine palmitoyltransferase (SPT) [Nat.

Positive_regulation (caused) of HSN1

8) Confidence 0.17 Published 2004 Journal Biochim. Biophys. Acta Section Abstract Doc Link 14990347 Disease Relevance 0.30 Pain Relevance 0.10

The inherited neuropathy HSAN1 is caused by a pathological overproduction of DSBs due to several missense mutations in SPT [4].

Positive_regulation (caused) of HSAN1 associated with neuropathic pain

9) Confidence 0.16 Published 2010 Journal Lipids Health Dis Section Body Doc Link PMC2931514 Disease Relevance 0.98 Pain Relevance 0.15

This promiscuous activity is greatly increased in the case of the sensory neuropathy HSAN1, and pathologically elevated DSB levels have been identified as the cause of this disease.

Positive_regulation (increased) of HSAN1 associated with neuropathic pain and disease

10) Confidence 0.14 Published 2010 Journal Lipids Health Dis Section Abstract Doc Link PMC2931514 Disease Relevance 0.73 Pain Relevance 0

This observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite.

Positive_regulation (result) of HSAN1

11) Confidence 0.13 Published 2009 Journal J. Neurosci. Section Abstract Doc Link 19923297 Disease Relevance 0.43 Pain Relevance 0.06

CONCLUSION: SSR provides another parameter to improve differentiation of HSAN III from HSAN IV, and also gives us additional information regarding sympathetic sudomotor fiber function in these developmental diseases.

Positive_regulation (differentiation) of HSAN in sympathetic

12) Confidence 0.06 Published 1999 Journal Neurology Section Body Doc Link 10331694 Disease Relevance 0 Pain Relevance 0

CONCLUSION: SSR provides another parameter to improve differentiation of HSAN III from HSAN IV, and also gives us additional information regarding sympathetic sudomotor fiber function in these developmental diseases.

Positive_regulation (differentiation) of HSAN in sympathetic

13) Confidence 0.06 Published 1999 Journal Neurology Section Body Doc Link 10331694 Disease Relevance 0 Pain Relevance 0

Mutations in this gene are known to be responsible for HSAN IV (congenital insensitivity to pain with anhidrosis).

Positive_regulation (responsible) of HSAN associated with hereditary sensory and autonomic neuropathies and hsan

14) Confidence 0.03 Published 2001 Journal Ann. Neurol. Section Abstract Doc Link 11310631 Disease Relevance 0.93 Pain Relevance 0.27

General Comments

This test has worked.