Channel Mutation Implicated in Neuropathies

Mutations in the voltage-gated sodium channel Na_v1.7 appear to be the source of chronic pain in nearly 30% of patients with idiopathic small fiber neuropathy, according to a genetic and electrophysiological study of patients with the mutations.

Other gain-of-function mutations in the SCN9A gene that encodes Na_v1.7 have been known to cause inherited erythromelalgia and paroxysmal extreme pain disorder, but this is the first time that such mutations have been reported in patients with biopsy-proven idiopathic small fiber neuropathy (I-SFN), reported Dr. Catharina G. Faber of University Medical Centre Maastricht (Netherlands) and her colleagues (Ann. Neurol. 2011 May 20 [doi:10.1002/ana.22485]).

The researchers advised that SCN9A gene analysis might be considered for patients with small fiber neuropathy in whom other causes are excluded, particularly patients with younger ages of onset.

During 2006-2009, Dr. Faber and her coauthors assessed 248 patients who were 18 years and older with a suspected clinical diagnosis of SFN. A total of 185 patients had an underlying cause of SFN, and 19 were lost to follow-up or refused to participate. Inclusion and exclusion criteria were met by the remaining 44 patients. These patients had no identifiable underlying cause of SFN and had normal strength, tendon reflexes, vibration sense, and nerve conduction studies. They also had at least two neuropathic or autonomic symptoms.

Following skin biopsy and quantitative sensory testing (QST), 28 patients met criteria for I-SFN, which included reduced intraepidermal nerve fiber density and abnormal QST. All 28 patients were white.

Overall, 8 (29%) of the 28 patients with I-SFN had a missense mutation in the SCN9A gene. All patients were heterozygous for the mutation. No mutations were detected in SCN9A in 100 healthy control patients. Patients with SCN9A mutations were younger, albeit not significantly, than were the 20 patients without mutations (32.4 years vs. 42.7 years). No other clinical characteristics differed between the two groups.

All but two of the eight reported that their pain, which varied in intensity and quality from patient to patient, began in their distal extremities. Seven of the patients with mutations described autonomic problems.

Electrophysiological analyses of cultured dorsal root ganglion neurons that were transfected with the mutated sodium channels indicated that the mutations changed the function of the channel such that they conferred a hyperexcitable state to the neurons.

Dr. Faber and her associates wrote that the mutations in Na_v1.7 may trigger axonal degeneration because “sodium influx is known to impose an energetic load on neurons and neuronal processes, and increased activity of mutant Na_v1.7 channels would be expected to have an especially large effect on small-diameter intracutaneous axons.”

The research was supported by funds from the University Hospital Maastricht and the Rehabilitation Research Service and Medical Research Service of the U.S. Department of Veterans Affairs. The authors declared having no financial interests.

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A Little Less Idiopathic

Small fiber polyneuropathy (SFPN) is one of those common diseases that many have never heard of. Neurologists focus on diseases of myelinated axons, but most axons are unmyelinated and thinly myelinated “small fibers.” These tiny axons are invisible to light microscopy and conventional electrophysiology; thus, small fiber diseases remain largely unexplored. In addition, their cardinal symptom is chronic pain, a condition often avoided like a modern plague.

Two recent objective tests, neurodiagnostic skin biopsy and autonomic function testing, now facilitate the diagnosis of small fiber diseases (Neurology 2009;72:177-84) but do not identify their cause. Most SFPN is labeled “idiopathic,” which translates from Latin as “we are idiots” and translates for our patients as “no possibility of cure.” This study reports that a substantial minority of Dutch SFPN patients have gain-of-function mutations in a sodium channel enriched in small fibers. It will be important to replicate these findings because they come from a carefully selected subset of patients.

These findings remind us that a substantial portion of unexplained chronic pain is neurological, and that neurologists need to engage with such patients. If such mutations are common, testing may develop, along with family-planning questions. The patients will increasingly seek testing and treatment for SFPN, but few neurology groups are currently equipped to do this. Fortunately, any physician can perform skin biopsy and mail the punches to academic or commercial laboratories for analysis. Sodium channel blockers will be used more for treating SFPN and other neuropathic pain. Neurologists will need to learn to prescribe mexiletine and continuous subcutaneous lidocaine along with carbamazepine (Neurology 2004;62:218-25).

ANNE LOUISE OAKLANDER, M.D., directs Massachusetts General Hospital's neurodiagnostic skin biopsy laboratory. She investigates neurological causes of chronic pain and wrote her commentary upon request. She has no disclosures.

Mutations in the voltage-gated sodium channel Na_v1.7 appear to be the source of chronic pain in nearly 30% of patients with idiopathic small fiber neuropathy, according to a genetic and electrophysiological study of patients with the mutations.

Other gain-of-function mutations in the SCN9A gene that encodes Na_v1.7 have been known to cause inherited erythromelalgia and paroxysmal extreme pain disorder, but this is the first time that such mutations have been reported in patients with biopsy-proven idiopathic small fiber neuropathy (I-SFN), reported Dr. Catharina G. Faber of University Medical Centre Maastricht (Netherlands) and her colleagues (Ann. Neurol. 2011 May 20 [doi:10.1002/ana.22485]).

The researchers advised that SCN9A gene analysis might be considered for patients with small fiber neuropathy in whom other causes are excluded, particularly patients with younger ages of onset.

During 2006-2009, Dr. Faber and her coauthors assessed 248 patients who were 18 years and older with a suspected clinical diagnosis of SFN. A total of 185 patients had an underlying cause of SFN, and 19 were lost to follow-up or refused to participate. Inclusion and exclusion criteria were met by the remaining 44 patients. These patients had no identifiable underlying cause of SFN and had normal strength, tendon reflexes, vibration sense, and nerve conduction studies. They also had at least two neuropathic or autonomic symptoms.

Following skin biopsy and quantitative sensory testing (QST), 28 patients met criteria for I-SFN, which included reduced intraepidermal nerve fiber density and abnormal QST. All 28 patients were white.

Overall, 8 (29%) of the 28 patients with I-SFN had a missense mutation in the SCN9A gene. All patients were heterozygous for the mutation. No mutations were detected in SCN9A in 100 healthy control patients. Patients with SCN9A mutations were younger, albeit not significantly, than were the 20 patients without mutations (32.4 years vs. 42.7 years). No other clinical characteristics differed between the two groups.

All but two of the eight reported that their pain, which varied in intensity and quality from patient to patient, began in their distal extremities. Seven of the patients with mutations described autonomic problems.

Electrophysiological analyses of cultured dorsal root ganglion neurons that were transfected with the mutated sodium channels indicated that the mutations changed the function of the channel such that they conferred a hyperexcitable state to the neurons.

Dr. Faber and her associates wrote that the mutations in Na_v1.7 may trigger axonal degeneration because “sodium influx is known to impose an energetic load on neurons and neuronal processes, and increased activity of mutant Na_v1.7 channels would be expected to have an especially large effect on small-diameter intracutaneous axons.”

The research was supported by funds from the University Hospital Maastricht and the Rehabilitation Research Service and Medical Research Service of the U.S. Department of Veterans Affairs. The authors declared having no financial interests.

View on the News

A Little Less Idiopathic

Small fiber polyneuropathy (SFPN) is one of those common diseases that many have never heard of. Neurologists focus on diseases of myelinated axons, but most axons are unmyelinated and thinly myelinated “small fibers.” These tiny axons are invisible to light microscopy and conventional electrophysiology; thus, small fiber diseases remain largely unexplored. In addition, their cardinal symptom is chronic pain, a condition often avoided like a modern plague.

Two recent objective tests, neurodiagnostic skin biopsy and autonomic function testing, now facilitate the diagnosis of small fiber diseases (Neurology 2009;72:177-84) but do not identify their cause. Most SFPN is labeled “idiopathic,” which translates from Latin as “we are idiots” and translates for our patients as “no possibility of cure.” This study reports that a substantial minority of Dutch SFPN patients have gain-of-function mutations in a sodium channel enriched in small fibers. It will be important to replicate these findings because they come from a carefully selected subset of patients.

These findings remind us that a substantial portion of unexplained chronic pain is neurological, and that neurologists need to engage with such patients. If such mutations are common, testing may develop, along with family-planning questions. The patients will increasingly seek testing and treatment for SFPN, but few neurology groups are currently equipped to do this. Fortunately, any physician can perform skin biopsy and mail the punches to academic or commercial laboratories for analysis. Sodium channel blockers will be used more for treating SFPN and other neuropathic pain. Neurologists will need to learn to prescribe mexiletine and continuous subcutaneous lidocaine along with carbamazepine (Neurology 2004;62:218-25).

ANNE LOUISE OAKLANDER, M.D., directs Massachusetts General Hospital's neurodiagnostic skin biopsy laboratory. She investigates neurological causes of chronic pain and wrote her commentary upon request. She has no disclosures.

Mutations in the voltage-gated sodium channel Na_v1.7 appear to be the source of chronic pain in nearly 30% of patients with idiopathic small fiber neuropathy, according to a genetic and electrophysiological study of patients with the mutations.

Other gain-of-function mutations in the SCN9A gene that encodes Na_v1.7 have been known to cause inherited erythromelalgia and paroxysmal extreme pain disorder, but this is the first time that such mutations have been reported in patients with biopsy-proven idiopathic small fiber neuropathy (I-SFN), reported Dr. Catharina G. Faber of University Medical Centre Maastricht (Netherlands) and her colleagues (Ann. Neurol. 2011 May 20 [doi:10.1002/ana.22485]).

The researchers advised that SCN9A gene analysis might be considered for patients with small fiber neuropathy in whom other causes are excluded, particularly patients with younger ages of onset.

During 2006-2009, Dr. Faber and her coauthors assessed 248 patients who were 18 years and older with a suspected clinical diagnosis of SFN. A total of 185 patients had an underlying cause of SFN, and 19 were lost to follow-up or refused to participate. Inclusion and exclusion criteria were met by the remaining 44 patients. These patients had no identifiable underlying cause of SFN and had normal strength, tendon reflexes, vibration sense, and nerve conduction studies. They also had at least two neuropathic or autonomic symptoms.

Following skin biopsy and quantitative sensory testing (QST), 28 patients met criteria for I-SFN, which included reduced intraepidermal nerve fiber density and abnormal QST. All 28 patients were white.

Overall, 8 (29%) of the 28 patients with I-SFN had a missense mutation in the SCN9A gene. All patients were heterozygous for the mutation. No mutations were detected in SCN9A in 100 healthy control patients. Patients with SCN9A mutations were younger, albeit not significantly, than were the 20 patients without mutations (32.4 years vs. 42.7 years). No other clinical characteristics differed between the two groups.

All but two of the eight reported that their pain, which varied in intensity and quality from patient to patient, began in their distal extremities. Seven of the patients with mutations described autonomic problems.

Electrophysiological analyses of cultured dorsal root ganglion neurons that were transfected with the mutated sodium channels indicated that the mutations changed the function of the channel such that they conferred a hyperexcitable state to the neurons.

Dr. Faber and her associates wrote that the mutations in Na_v1.7 may trigger axonal degeneration because “sodium influx is known to impose an energetic load on neurons and neuronal processes, and increased activity of mutant Na_v1.7 channels would be expected to have an especially large effect on small-diameter intracutaneous axons.”

The research was supported by funds from the University Hospital Maastricht and the Rehabilitation Research Service and Medical Research Service of the U.S. Department of Veterans Affairs. The authors declared having no financial interests.

View on the News

A Little Less Idiopathic

Small fiber polyneuropathy (SFPN) is one of those common diseases that many have never heard of. Neurologists focus on diseases of myelinated axons, but most axons are unmyelinated and thinly myelinated “small fibers.” These tiny axons are invisible to light microscopy and conventional electrophysiology; thus, small fiber diseases remain largely unexplored. In addition, their cardinal symptom is chronic pain, a condition often avoided like a modern plague.

Two recent objective tests, neurodiagnostic skin biopsy and autonomic function testing, now facilitate the diagnosis of small fiber diseases (Neurology 2009;72:177-84) but do not identify their cause. Most SFPN is labeled “idiopathic,” which translates from Latin as “we are idiots” and translates for our patients as “no possibility of cure.” This study reports that a substantial minority of Dutch SFPN patients have gain-of-function mutations in a sodium channel enriched in small fibers. It will be important to replicate these findings because they come from a carefully selected subset of patients.

These findings remind us that a substantial portion of unexplained chronic pain is neurological, and that neurologists need to engage with such patients. If such mutations are common, testing may develop, along with family-planning questions. The patients will increasingly seek testing and treatment for SFPN, but few neurology groups are currently equipped to do this. Fortunately, any physician can perform skin biopsy and mail the punches to academic or commercial laboratories for analysis. Sodium channel blockers will be used more for treating SFPN and other neuropathic pain. Neurologists will need to learn to prescribe mexiletine and continuous subcutaneous lidocaine along with carbamazepine (Neurology 2004;62:218-25).

ANNE LOUISE OAKLANDER, M.D., directs Massachusetts General Hospital's neurodiagnostic skin biopsy laboratory. She investigates neurological causes of chronic pain and wrote her commentary upon request. She has no disclosures.