Shinkarevsky Fleitman I, Nevo Y, Harel L, Amarilyo G, Dori A , et al.
Muscle & nerve •
Small-fiber neuropathy is rare in children. It has been associated with several autoimmune disorders, but there are no reports of an autoinflammatory etiology. The data of four children/adolescents presenting with erythromelalgia and neuropathic pain from 2014 to 2019 were collected retrospectively from the electronic database of a pediatric medical center. Results of clinical and/or electrophysiological evaluation excluded large nerve fiber involvement. Skin biopsy results confirmed small-fiber neuropathy. According to genetic analysis, two patients were heterozygous and one was homozygous for mutations in the familial Mediterranean fever (MEFV) gene. Behcet disease was diagnosed in the fourth patient. Treatment with anti-interleukin-1 agents, intravenous immunoglobulin, and glucocorticoids was beneficial. The diagnosis of small-fiber neuropathy should be considered in children/adolescents presenting with erythromelalgia. A thorough investigation is required to reveal the underlying disorder. Clinicians should be alert to the peripheral neurological manifestations of autoinflammatory syndromes because effective treatments are available.
Voltage-gated sodium channels play a pivotal role in pain transmission. They are widely expressed in nociceptive neurons, and participate in the generation of action potentials. Alteration in ionic conduction of these channels causes abnormal electrical firing, thus renders neurons hyperexcitable. So far, mutations in the Na(v)1.7 sodium channel, which is expressed in the dorsal root ganglia cells and sympathetic neurons, have been described to cause perturbations in pain sensation. Until recently, gain-of-function Na(v)1.7 mutations were known to cause two neuropathic pain syndromes: inherited erythromelalgia and paroxysmal extreme pain syndrome. These syndromes are inherited in a dominant trait; they usually begin in childhood or infancy, and are characterized by attacks of severe neuropathic pain accompanied with autonomic symptoms. Recently, small fiber neuropathy and chronic nonparoxysmal pain have been described in patients harboring gain-of-function mutations in Na(v)1.7 channel. Loss-of-function mutations in Na(v)1.7 are extremely rare, and invariably cause congenital inability to perceive pain.
Dabby R, Sadeh M, Gilad R, Lampl Y, Cohen S , et al.
Journal of the neurological sciences •
Gain-of-function mutations in the SCN9A gene (encoding to NaV1.7 voltage-gated sodium channel) cause two rare paroxysmal pain disorders: inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEDP). These phenotypes are characterized by episodic extreme localized pain with cutaneous autonomic signs. So far, no other phenotypes have been associated with mutation in the SCN9A gene. To investigate mutations in the SCN9A gene in patients with chronic non-paroxysmal neuropathic pain. 9 patients with chronic severe unexplained neuropathic pain. Of the nine patients one had predicted pathologic mutations in the SCN9A gene. This patient had a heterozygous change of n.4648 T-C in exon 27 resulting in a substitution of W1550R, a highly conserved amino acid, predicting damage in the transmembrane S2 region, repeat IV. This mutation was not found in 50 controls. SCN9A mutations cause pain syndromes other than IEM and PEPD. These mutations should be considered in patients with resistant unexplained chronic neuropathic pain.
Small-fiber neuropathy is often idiopathic and commonly follows a chronic course. Treatment is often effective in treating the core symptom of pain, but it has no effect on the pathologic process. We describe four patients with acute small-fiber neuropathy who responded dramatically to steroid therapy. All patients had acute onset neuropathic pain, normal nerve conduction studies, and evidence of small-fiber dysfunction in quantitative sensory testing and skin biopsy. Symptoms were distal and symmetrical in three patients and generalized in one patient. In two cases, the neuropathy presented as an erythromelalgia-like syndrome. Marked clinical improvement occurred 1-2 weeks after oral prednisone therapy was initiated. Three patients remained symptom free, and one patient experienced recurrence of neuropathy after prednisone was tapered.
