The Debut of a Rational Treatment for an Inherited Neuropathy?

The debut of a rational treatment for an inherited neuropathy? Steven S. Scherer J Clin Invest. 2011;121(12):4624-4627. https://doi.org/10.1172/JCI60511. Commentary 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. Find the latest version: https://jci.me/60511/pdf commentaries The debut of a rational treatment for an inherited neuropathy? Steven S. Scherer Department of Neurology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. Hereditary neuropathies are common neurological conditions characterized cause CMT (4), and many more remain to by progressive loss of motor and/or sensory function. There are no effective be discovered. The demyelinating forms are treatments. Among the many causes of hereditary neuropathies are dominant the most common, and the genetic causes mutations in serine palmitoyltransferase, long chain base subunit 1 (SPTLC1), of most of these conditions have been dis- which cause hereditary sensory and autonomic neuropathy type 1 (HSAN1). covered (5, 6). Even though some of the By incorporating L-alanine in place of L-serine, the mutant HSAN1–associated genes associated with demyelinating forms serine palmitoyltransferase generates deoxysphingolipids, which are thought of CMT are expressed in other cell types, to be neurotoxic. In this issue of the JCI, Garofalo and colleagues report that the primary abnormality — demyelination oral L-serine reverses the accumulation of deoxysphingolipids in humans with — is caused by effects of the mutations in HSAN1 and in a transgenic mouse model. As oral L-serine reduces the severity myelinating Schwann cells (7). The axonal of neuropathy in the mouse model of HSAN1, these data suggest a rational forms of CMT are less common, and their candidate therapy for this devastating condition. genetic causes remain unknown for the majority of affected patients (5, 6). In most The peripheral nerves are the specialized long, but a one-meter-long motor axon cases, expression of the mutant gene in the conduits for the axons that connect the that innervates the foot presents formi- affected neurons likely produces an axonal brain and spinal cord to the rest of the dable challenges. Its cell body in the spinal neuropathy, but this has been experimen- body. Their functions are well understood cord not only synthesizes all of the axonal tally demonstrated for only a few kinds. (1). Motor axons conduct action poten- components, it transports them down What both demyelinating and axonal forms tials from the brain and spinal cord to the axon, a journey that can take up to a of CMT share in common is their tendency skeletal muscles; sensory axons conduct in year. In addition, the axon requires ATP to cause a progressive axonal degeneration, the opposite direction. All volitional move- to maintain its ion gradients and cellular beginning with the longest axons (Figure 1, ments and sensations depend on the proper integrity, and this must be locally supplied B and C). The demyelinating forms of CMT functioning of motor and sensory axons. all along its length. typically affect all myelinated sensory and Axons are elegantly adapted for their nor- motor axons and spare unmyelinated axons mal functions (Figure 1A and ref. 1). Their HSAN1, one of many hereditary (largely sensory and autonomic axons), cell membrane contains a repertoire of ion peripheral neuropathies whereas the axonal forms of CMT typically channels that generate and propagate action Damage to peripheral axons that impairs affect both myelinated and unmyelinated potentials. In addition, axons larger than their function results in peripheral neu- axons. Some axonal forms, however, chiefly 1 μm in diameter are myelinated by glial ropathy. Since each peripheral nerve serves affect either motor axons (called heredi- cells (Schwann cells and oligodendrocytes in a specific part of the body and contains the tary motor neuropathies) or sensory axons the peripheral and central nervous systems, appropriate axons for that body part, the (called hereditary sensory and autonomic respectively). Myelin sheaths form segments array of symptoms exhibited by individuals neuropathies [HSANs]), including the called internodes around individual axons with peripheral neuropathy varies widely. unmyelinated ones. that are separated by thin gaps (approximate- There are also numerous kinds of periph- Missense mutations in either serine pal- ly 1 μm in length) known as nodes of Ranvier. eral neuropathy, and these can be divided mitoyltransferase, long chain base subunit 1 By both reducing the internodal capacitance into those that are inherited and those that (SPTLC1) (8, 9) or SPTLC2 (10) — which and clustering the appropriate ion channels are acquired. encode two of the three subunits of the (2), myelination restricts ionic conductance Hereditary peripheral neuropathies are enzyme serine palmitoyltransferase — cause to nodes of Ranvier, enabling action poten- usually called Charcot-Marie-Tooth disease HSAN type 1 (HSAN1), a rare and clinically tials to jump from node to node (saltatory (CMT), in honor of the physicians who first distinct form of dominantly inherited CMT. conduction), which is faster and energetically described them. CMT is a common disease, HSAN1 is in fact a misnomer because motor cheaper than continuous conduction. affecting approximately 1 in 2,500 people axons are typically affected and autonomic Their length makes axons vulnerable to (3). Patients are classified according to the defects are sparse (11). Most patients iden- disease. Compared with more colossal ver- pattern of inheritance, the degree of clinical tified to date have a C133W mutation in tebrates, the human leg is not particularly severity, the cell type that is primarily affect- SPTLC1 and share a common haplotype, and ed (myelin sheath or axon/neuron), and — in thus a common ancestor (12). These patients cases in which neurons are the main affect- most frequently present with decreased sen- Conflict of interest: The author has declared that no conflict of interest exists. ed cell type — the kind of peripheral neu- sation in the feet, as well as painless blisters Citation for this article: J Clin Invest. 2011; ron affected (sensory, motor, and/or auto- and ulcers. However, positive sensory symp- 121(12):4624–4627. doi:10.1172/JCI60511. nomic). Mutations in more than 30 genes toms, including shooting and burning pain, 4624 The Journal of Clinical Investigation http://www.jci.org Volume 121 Number 12 December 2011 commentaries 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, leav- ing 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 dis- tal part of the axon has degenerated (dashed region), and the myelin sheaths that formerly surrounded the degenerated region have dis- appeared as a secondary consequence of the axonal degeneration. are also common. Regardless of the initial respectively (Figure 2B and refs. 13, 14). er sensory thresholds than did untreated symptoms, the loss of sensation, especially Because they can neither be converted into transgenic mice, and the unmyelinated and pain, leads to the horrible complications of complex sphingolipids nor degraded by the myelinated axons in the sciatic nerve tended unheeded infections and painless ulcers that classical catabolic pathways, deoxysphin- to have smaller diameters (16). It remains to can result in amputations of the affected golipids accumulate in cells transfected to be rigorously shown, however, that L-alanine extremities (11). express the SPTLC1 mutations associated exacerbates axonal loss (which should be Despite the discrete phenotype arising as with HSAN1, in transformed lymphoblasts age and length dependent). Conversely, a result of these dominant SPTLC1 muta- from patients with HSAN1, in tissues and even more importantly, Garofalo et tions associated with HSAN1, many cell (including peripheral nerves) of mice that al. found that oral supplementation with types, including neurons, express SPTLC1 express the C133W SPTLC1 mutation as a L-serine improved the neuropathy of C133W and SPTLC2 and the enzyme that they transgene, and in the plasma of patients transgenic mice (16). Mice treated between form. Serine palmitoyltransferase con- with HSAN1 (13–15). These data have led 2 and 12 months of age had better rotarod denses L-serine with palmitoyl-CoA to to the

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