Diagnosis of patients with clinical features suggestive of hereditary sensory and autonomic neuropathy, type I caused by variants in SPTLC1 and SPTLC2
Monitoring of patients with hereditary sensory and autonomic neuropathy, type I caused by variants in SPTLC1 and SPTLC2
Deoxysphingolipids (dSL) are elevated in patients with hereditary sensory and autonomic neuropathy type I (HSAN1) due to variants in SPTLC1 and SPTLC2, and measurement of dSL is useful to support a diagnosis of HSAN1.
Elevations in dSL may also be seen in patients with order disorders including type 2 diabetes mellitus, metabolic syndrome, mitochondrial disease, glycogen storage disease type I, and, possibly, disorders of serine biosynthesis.
Additional testing is required to determine the specific cause of elevated dSL.
Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)
Hereditary sensory and autonomic neuropathy, type I
HSAN1
dSLs
deoxysphingolipids
deoxySLs
dSLds
Serum
The following information is required for interpretation of results:
1. Patient's age
2. Reason for testing
3. Diabetic diagnosis
Patient Preparation: Fasting 8 hours
Collection Container/Tube:
Preferred: Serum gel
Acceptable: Red top
Submission Container/Tube: Plastic vial
Specimen Volume: 1 mL
1. Biochemical Genetics Patient Information (T602), see Special Instructions
2. If not ordering electronically, complete, print, and send a Biochemical Genetics Test Request (T798) with the specimen.
0.5 mL
Gross hemolysis | OK |
Gross lipemia | Reject |
Gross icterus | OK |
Specimen Type | Temperature | Time | Special Container |
---|---|---|---|
Serum | Frozen (preferred) | 90 days | |
Refrigerated | 24 hours |
Diagnosis of patients with clinical features suggestive of hereditary sensory and autonomic neuropathy, type I caused by variants in SPTLC1 and SPTLC2
Monitoring of patients with hereditary sensory and autonomic neuropathy, type I caused by variants in SPTLC1 and SPTLC2
Deoxysphingolipids (dSL) are elevated in patients with hereditary sensory and autonomic neuropathy type I (HSAN1) due to variants in SPTLC1 and SPTLC2, and measurement of dSL is useful to support a diagnosis of HSAN1.
Elevations in dSL may also be seen in patients with order disorders including type 2 diabetes mellitus, metabolic syndrome, mitochondrial disease, glycogen storage disease type I, and, possibly, disorders of serine biosynthesis.
Additional testing is required to determine the specific cause of elevated dSL.
Sphingolipids, a class of lipids derived from sphingosine, are essential components of plasma membranes and lipoproteins. They are synthesized from L-serine and palmitoyl-CoA by the enzyme serine palmitoyltransferase. Deoxysphingolipids (dSL) are atypical sphingolipids derived from the amino acids alanine or glycine instead of L-serine and cannot be degraded by normal catabolic pathways. Pathologically elevated dSL have been identified as potential biomarkers in a variety of conditions such as hereditary sensory and autonomic neuropathy type 1 (HSAN1), type 2 diabetes mellitus, metabolic syndrome, mitochondrial disease, glycogen storage disease type 1, and possibly disorders of serine biosynthesis.
Hereditary sensory and autonomic neuropathies are a group of clinically and genetically heterogeneous peripheral neuropathies. HSAN1 is inherited in an autosomal dominant fashion and is typically characterized by a later onset loss of pain and temperature sensation in the hands and feet, which can be accompanied by shooting pain attacks, lancinating pain, and skin ulcers predominantly affecting the lower limbs.
While variants in 5 different genes (SPTLC1, SPTLC2, ATL1, RAB7A and DNMT1) have been linked to HSAN1, the majority of variants are in SPTLC1 and SPTLC2, which encode 2 of 3 subunits of the serine palmitoyltransferase (SPT) enzyme. Variants in these 2 genes lead to a shift in SPT substrate specificity from L-serine to L-alanine, which ultimately produces 2 neurotoxic deoxysphingolipids, 1-deoxymethylsphinganine and 1-deoxysphinganine. The accumulation of these metabolites in the cells and serum of affected patients is thought to cause the clinical features associated with HSAN1. A recent clinical trial found that L-serine supplementation safely reduced levels of 1-deoxysphingolipids in humans and suggested that supplementation may offer a clinical benefit.(1)
Sphinganine: < or =18.0 ng/mL
1-deoxysphinganine: < or =0.25 ng/mL
1-deoxymethylsphinganine: < or =0.04 ng/mL
Sphingosine: < or =80.0 ng/mL
1-deoxysphingosine: < or =0.05 ng/mL
1-deoxymethylsphingosine: < or =0.09 ng/mL
Elevation of deoxysphingolipids may indicate hereditary sensory and autonomic neuropathy, type I caused by variants in SPTLC1 and SPTLC2.
Deoxysphingolipids may also be elevated in patients with other conditions such as type 2 diabetes mellitus, metabolic syndrome, mitochondrial disorders, glycogen storage disease type 1, and possibly disorders of serine biosynthesis.
This assay is not intended to but may detect neuropathies other than hereditary sensory and autonomic neuropathy, type I.
1. Fridman V, Suriyanarayanan S, Novak P, et al: Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1. Neurology. 2019 Jan 22;92(4):e359-e370. doi: 10.1212/WNL.0000000000006811
2. Astudillo L, Sabourdy F, Therville N, et al: Human genetic disorders of sphingolipid biosynthesis. J Inherit Metab Dis. 2015 Jan;38(1):65-76
3. Gable K, Gupta SD, Han G, Niranjanakumari S, Harmon JM, Dunn TM: A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity. J Biol Chem. 2010 Jul 23;285(30):22846-22852
4. Penno AK, Reilly MM, Houlden H, et al: Hereditary sensory neuropathy type I is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem. 2010 Apr 9;285(15):11178-11187
5. Lone MA, Santos T, Alecu I, Silva LC, Hornemann T: 1-Deoxysphingolipids. 2019 Apr;1864(4):512-521. doi: 10.1016/j.bbalip.2018.12.013
6. Ferreira CR, Goorden SMI, Soldatos A, et al: Deoxysphingolipid precursors indicate abnormal sphingolipid metabolism in individuals with primary and secondary disturbances of serine availability. Mol Genet Metab. 2018 Jul;124(3):204-209. doi: 10.1016/j.ymgme.2018.05.001
Internal standard is added to the serum. Sphingolipids and deoxysphingolipids are extracted from the serum prior to injection onto a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system. Following chromatographic isolation, the concentration is measured by MS/MS analysis in the selected reaction monitoring positive mode. The ratio of extracted peak area to internal standard is utilized to calculate the concentration of sphingolipid and deoxysphingolipid species in the sample.(Unpublished Mayo method)
Thursday
This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.
82542
Test Id | Test Order Name | Order LOINC Value |
---|---|---|
HSAN1 | Hereditary Sensory Neuropathy I, S | In Process |
Result Id | Test Result Name |
Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
|
---|---|---|
BG718 | Reason for Referral | 42349-1 |
BG719 | Diabetic diagnosis | In Process |
605993 | 1-deoxysphinganine | In Process |
605996 | 1-deoxysphingosine | In Process |
605994 | 1-deoxymethylsphinganine | In Process |
605997 | 1-deoxymethylsphingosine | In Process |
605992 | Sphinganine | In Process |
605995 | Sphingosine | In Process |
605998 | Interpretation (HSAN1) | 59462-2 |
605991 | Reviewed By | 18771-6 |