Pain Mechanisms and Treatments (60)
Botulinum Toxin and Related Neurological Disorders (42)
Hereditary Neurological Disorders (36)
Ion channel regulation and function (24)
Peripheral Neuropathies and Disorders (22)
Sopacua M, Hoeijmakers JGJ, van der Kooi AJ, Merkies ISJ, Faber CG
Molecular genetics & genomic medicine •
Voltage-gated sodium channels are essential for the generation and conduction of electrical impulses in excitable cells. Sodium channel Na 1.7, encoded by the SCN9A-gene, has been of special interest in the last decades because missense gain-of-function mutations have been linked to a spectrum of neuropathic pain conditions, including inherited erythermalgia (IEM), paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy (SFN). In this case report, we present a 61-year-old woman who was referred to our tertiary referral center in a standard day care setting with suspicion of SFN. We performed additional investigations: skin biopsy to determine the intra-epidermal nerve fiber density (IENFD), quantitative sensory testing (QST), and blood examination (including DNA analysis) for possible underlying conditions. The patient showed a clinical picture that fulfilled the criteria of IEM, PEPD, and SFN. DNA analysis revealed the heterozygous variant c.554G > A in the SCN9A-gene (OMIM 603415). This variant has already been described in all three human pain conditions separately, but never in one patient having symptoms of all three conditions. Because its pathogenicity has never been functionally confirmed, the variant is classified as a variance of unknown significance (VUS)/risk factor. This suggests that another genetic and/or environmental substrate plays a role in the development of neuropathic conditions like described. We have described this as the SCN9A-pain triangle phenomenon. Treatment should focus on pain management, genetic counseling, and improving/maintaining quality of life by treating symptoms and, if indicated, starting a rehabilitation program.
Eijkenboom I, Sopacua M, Hoeijmakers JGJ, de Greef BTA, Lindsey P , et al.
Journal of neurology, neurosurgery, and psychiatry •
Neuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of , and variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening. Between September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for , and variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared. Among 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for 3.7% (n=42/1139) for and 2.9% (n=33/1139) for . Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants. (Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of and should be considered in patients with pure SFN, independently of clinical features or underlying conditions.
Hoeijmakers JG, Faber CG, Miedema CJ, Merkies IS, Vles JS
Pediatrics •
Small fiber neuropathy (SFN) is a debilitating condition that often leads to pain and autonomic dysfunction. In the last few decades, SFN has been gaining more attention, particularly in adults. However, literature about SFN in children remains limited. The present article reports the cases of 2 adolescent girls diagnosed with SFN. The first patient (14 years of age) complained about painful itch and tingling in her legs, as well as dysautonomia symptoms for years. She also reported a red/purple-type discoloration of her legs aggravated by warmth and standing, compatible with erythromelalgia. The diagnosis of SFN was confirmed by a reduced intraepidermal nerve fiber density (IENFD) in skin biopsy sample. No underlying conditions were found. Symptomatic neuropathic pain treatment was started with moderate effect. The second patient (16 years of age) developed painful sensations in both feet and hands 6 weeks after an ICU admission for diabetic ketoacidosis, which included dysautonomia symptoms. She also exhibited some signs of erythromelalgia. The patient was diagnosed with predominant SFN (abnormal IENFD and quantitative sensory testing) as well as minor large nerve fiber involvement. Treatment with duloxetine, combined with a rehabilitation program, resulted in a marked improvement in her daily functioning. Although the SFN diagnosis in these 2 cases could be established according to the definition of SFN used in adults, additional diagnostic tools are needed that may be more appropriate for children. Additional information about the course of SFN in children may result in better treatment options.
Brouwer BA, Merkies IS, Gerrits MM, Waxman SG, Hoeijmakers JG , et al.
Journal of the peripheral nervous system : JPNS •
Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (Aδ and C) fibers. Voltage-gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where NaV 1.7, NaV 1.8, and NaV 1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed. The human genetic pain conditions inherited erythromelalgia and paroxysmal extreme pain disorder were the first to be linked to gain-of-function SCN9A mutations. Recent studies have expanded this spectrum with gain-of-function SCN9A mutations in patients with small fiber neuropathy and in a new syndrome of pain, dysautonomia, and small hands and small feet (acromesomelia). In addition, painful neuropathies have been recently linked to SCN10A mutations. Patch-clamp studies have shown that the effect of SCN9A mutations is dependent upon the cell-type background. The functional effects of a mutation in dorsal root ganglion (DRG) neurons and sympathetic neuron cells may differ per mutation, reflecting the pattern of expression of autonomic symptoms in patients with painful neuropathies who carry the mutation in question. Peripheral neuropathies may not always be length-dependent, as demonstrated in patients with initial facial and scalp pain symptoms with SCN9A mutations showing hyperexcitability in both trigeminal ganglion and DRG neurons. There is some evidence suggesting that gain-of-function SCN9A mutations can lead to degeneration of peripheral axons. This review will focus on the emerging role of sodium channelopathies in painful peripheral neuropathies, which could serve as a basis for novel therapeutic strategies.
Estacion M, Han C, Choi JS, Hoeijmakers JG, Lauria G , et al.
Molecular pain •
Sodium channel NaV1.7 is preferentially expressed within dorsal root ganglia (DRG), trigeminal ganglia and sympathetic ganglion neurons and their fine-diamter axons, where it acts as a threshold channel, amplifying stimuli such as generator potentials in nociceptors. Gain-of-function mutations and variants (single amino acid substitutions) of NaV1.7 have been linked to three pain syndromes: Inherited Erythromelalgia (IEM), Paroxysmal Extreme Pain Disorder (PEPD), and Small Fiber Neuropathy (SFN). IEM is characterized clinically by burning pain and redness that is usually focused on the distal extremities, precipitated by mild warmth and relieved by cooling, and is caused by mutations that hyperpolarize activation, slow deactivation, and enhance the channel ramp response. PEPD is characterized by perirectal, periocular or perimandibular pain, often triggered by defecation or lower body stimulation, and is caused by mutations that severely impair fast-inactivation. SFN presents a clinical picture dominated by neuropathic pain and autonomic symptoms; gain-of-function variants have been reported to be present in approximately 30% of patients with biopsy-confirmed idiopathic SFN, and functional testing has shown altered fast-inactivation, slow-inactivation or resurgent current. In this paper we describe three patients who house the NaV1.7/I228M variant. We have used clinical assessment of patients, quantitative sensory testing and skin biopsy to study these patients, including two siblings in one family, in whom genomic screening demonstrated the I228M NaV1.7 variant. Electrophysiology (voltage-clamp and current-clamp) was used to test functional effects of the variant channel. We report three different clinical presentations of the I228M NaV1.7 variant: presentation with severe facial pain, presentation with distal (feet, hands) pain, and presentation with scalp discomfort in three patients housing this NaV1.7 variant, two of which are from a single family. We also demonstrate that the NaV1.7/I228M variant impairs slow-inactivation, and produces hyperexcitability in both trigeminal ganglion and DRG neurons. Our results demonstrate intra- and interfamily phenotypic diversity in pain syndromes produced by a gain-of-function variant of NaV1.7.