Hereditary sensory and autonomic neuropathy type I (HSAN1) is characterized by early sensory involvement affecting pain and temperature due to a length-dependent axonal neuropathy. There are frequent positive sensory symptoms of severe shooting or burning pain in the limbs and an early but transient period of hyperpathia in some patients. Due to profound sensory impairment, many affected individuals develop neuropathic ulcers and Charcot joints requiring amputation. There is prominent and often early motor involvement in most patients. Autopsy reports from HSAN1 patients show pronounced degeneration of dorsal root ganglion cells with depletion of myelinated axons in peripheral nerve. Loss of unmyelinated axons is present but reported to be less severe.
HSAN1 is caused by several missense mutations in the SPTLC1 and SPTLC2 gene encoding two out of three subunits of the enzyme serine palmitoyltransferase (SPT). No mutations in the third SPT subunit (SPTLC3) have yet been associated with HSAN1. SPT catalyzes the first and rate limiting step in the de novo synthesis of sphingolipids, namely the condensation of L-serine and palmitoyl-CoA. The reaction product, 3-ketosphinganine, is quickly converted to sphinganine (SA) which is subsequently N-acylated to dihydro-ceramide and finally converted to ceramide. Complex sphingolipids are generated by adding various head groups to the C1 hydroxyl group of ceramide.
To date, five SPTLC1 mutations, C133W, C133Y, V144D, S331F and A352V, have been conclusively linked to HSAN1. A common feature of all HSAN1 mutants is a reduced in vitro activity of the enzyme, as measured by the incorporation of labeled L- serine. Besides this reduced reactivity with its canonical substrate L-serine it appears that the mutant SPT has a promiscuously increased reactivity with L-alanine and partly also glycine as alternative substrates. This results in the formation of an atypical class of deoxy-sphingolipids (dSL’s) which are composed either of deoxysphinganine (doxSA) when alanine or deoxymethylsphinganine (doxmethSA) when glycine is used by SPT (Figure 1).
Like regular sphingolipids deoxy-sphingolipids are also N-acetylated. However, dSL’s lack the C1 hydroxyl group of ceramides and are, therefore, not converted to complex sphingolipids like phospho -or glycosphingolipids nor degraded by the classical catabolic pathway which requires the formation of the catabolic intermediate sphingosine-1-phosphate (S1P). Deoxy-sphingolipids were found to be highly elevated in cells expressing the mutant forms of SPT but also in plasma of HSAN1 patients and in mice bearing a transgene expressing mutant SPTLC1. These observations led to the hypothesis that an altered substrate selectivity of the mutant SPT is the underlying key to the pathophysiology of HSAN1.
Our research is currently focused on treating this disorder with L-serine supplementation. Our studies in culture, mice and humans have indicated that supplementation can rapidly lower the levels of dSL’s. Below is a figure reporting our findings in a 12 week pilot study with 14 human patients:
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