The debut of a rational treatment for an inherited neuropathy?

Abstract

Hereditary neuropathies are common neurological conditions characterized by progressive loss of motor and/or sensory function. There are no effective treatments. Among the many causes of hereditary neuropathies are dominant mutations in serine palmitoyltransferase, long chain base subunit 1 (SPTLC1), which cause hereditary sensory and autonomic neuropathy type 1 (HSAN1). By incorporating L-alanine in place of L-serine, the mutant HSAN1–associated serine palmitoyltransferase generates deoxysphingolipids, which are thought to be neurotoxic. In this issue of the JCI, Garofalo and colleagues report that oral L-serine reverses the accumulation of deoxysphingolipids in humans with HSAN1 and in a transgenic mouse model. As oral L-serine reduces the severity of neuropathy in the mouse model of HSAN1, these data suggest a rational candidate therapy for this devastating condition.

Figure 1. The effects demyelination and axonal damage on myelinated axons.

(A) A single neuron and its axon, which has five myelin internodes that are separated by nodes of Ranvier. (B) In an inherited demyelinating neuropathy, two myelin internodes have been lost, leaving demyelinated segments that will usually be remyelinated. Even though demyelination is the primary pathology, axonal degeneration (see C) is a common, long-term consequence. (C) In an inherited axonal neuropathy, the distal part of the axon has degenerated (dashed region), and the myelin sheaths that formerly surrounded the degenerated region have disappeared as a secondary consequence of the axonal degeneration.

Figure 2. The effects of SPTLC1 mutations on the synthesis of sphinganine, 1-deoxysphinganine, and 1-deoxymethylsphinganine.

(A) SPTLC1, STPLC2, and SPTLC3 form serine palmitoyltransferase, which catalyzes the enzymatic condensation of l-serine and palmitoyl-CoA into sphinganine, a precursor of ceramide. Note that the intermediate, 3-ketosphinganine, is not shown. (B) In the case of SPTLC1 mutants associated with HSAN1, the serine palmitoyltransferase not only catalyzes the enzymatic condensation of l-serine and palmitoyl-CoA into sphinganine, but also catalyzes the enzymatic condensation of palmitoyl-CoA and both l-alanine and l-glycine to generate 1-deoxysphinganine and 1-deoxymethylsphinganine, respectively.