Genetic Small Fiber Sensory Neuropathy and Channelopathy

  • Rosario Privitera
  • Praveen AnandEmail author


Genetic neuropathies comprise a range of conditions which can include neuropathy as a predominant feature of the disease or as part of a multisystem disease. Small fiber sensory neuropathy and symptoms have been described in association with sodium channel mutations such as in the SCN9A, SCN10A, and SCN11A genes, which encode Nav1.7, Nav1.8, and Nav1.9 sodium channels, respectively. Erythromelalgia is an autosomal dominant painful condition characterized by redness of the skin and intermittent burning sensation of extremities, triggered by heat or exercise, and was shown to be related to mutations of Nav1.7. Paroxysmal extreme pain disorder (PEPD, first described as familial rectal pain) is an inherited syndrome with paroxysms of rectal, ocular, or submandibular pain with flushing, also linked to gain-of-function mutations of Nav1.7. In addition, SCN9A gene variants have been found in subjects of an idiopathic small fiber neuropathy (SFN) cohort. Predominant involvement of small nerve fibers has been documented in patients with Fabry disease, familial amyloid polyneuropathy (FAP), and Tangier’s disease. This chapter focuses on small fiber neuropathies and channelopathies with sensory symptoms, particularly pain, as the sole or primary feature.


Hereditary sensory and autonomic neuropathy (HSAN) Sodium channel mutations Erythromelalgia Paroxysmal extreme pain disorder Fabry disease Familial amyloid polyneuropathy Tangier’s disease 


  1. 1.
    Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol. 1981;10:222–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Auer-Grumbach M. Hereditary sensory and autonomic neuropathies. Handb Clin Neurol. 2013;115:893–906.PubMedCrossRefGoogle Scholar
  3. 3.
    Klein CJ, Wu Y, Kruckeberg KE, Hebbring SJ, Anderson SA, Cunningham JM, et al. SPTLC1 and RAB7 mutation analysis in dominantly inherited and idiopathic sensory neuropathies. J Neurol Neurosurg Psychiatry. 2005;76:1022–4.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Kurth I. Hereditary sensory and autonomic neuropathy type II. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle, WA: University of Washington; 1993.Google Scholar
  5. 5.
    Pinsky L, DiGeorge AM. Congenital familial sensory neuropathy with anhidrosis. J Pediatr. 1966;68:1–13.PubMedCrossRefGoogle Scholar
  6. 6.
    Axelrod FB. Familial dysautonomia. Muscle Nerve. 2004;29:352–63.PubMedCrossRefGoogle Scholar
  7. 7.
    Einarsdottir E, Carlsson A, Minde J, Toolanen G, Svensson O, Solders G, et al. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet. 2004;13:799–805.PubMedCrossRefGoogle Scholar
  8. 8.
    Zambelis T. Small fiber neuropathy in Charcot-Marie-Tooth disease. Acta Neurol Belg. 2009;109:294–7.PubMedGoogle Scholar
  9. 9.
    Mersiyanova IV, Perepelov AV, Polyakov AV, Sitnikov VF, Dadali EL, Opqrin AN, et al. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am J Hum Genet. 2000;67:37–46.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Bird TD. Charcot-marie-tooth neuropathy type 2. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle, WA: University of Washington; 1993.Google Scholar
  11. 11.
    Stevanin G, Dürr A, Brice A. Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology. Eur J Hum Genet. 2000;8:4–18.PubMedCrossRefGoogle Scholar
  12. 12.
    Spring PJ, Kok C, Nicholson GA, Ing AJ, Spies JM, Bassett ML, et al. Autosomal dominant hereditary sensory neuropathy with chronic cough and gastro-oesophageal reflux: clinical features in two families linked to chromosome 3p22-p24. Brain. 2005;128:2797–810.PubMedCrossRefGoogle Scholar
  13. 13.
    Margolis RL. The spinocerebellar ataxias: order emerges from chaos. Curr Neurol Neurosci Rep. 2002;2:447–56.PubMedCrossRefGoogle Scholar
  14. 14.
    Harding AE. Friedreich’s ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain. 1981;104:589–620.PubMedCrossRefGoogle Scholar
  15. 15.
    Hewer RL. Study of fatal cases of Friedreich’s ataxia. Br Med J. 1968;3:649–52.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Duman O, Uysal H, Skjei KL, Kizilay F, Karauzum S, Haspolat S. Sensorimotor polyneuropathy in patients with SMA type-1: electroneuromyographic findings. Muscle Nerve. 2013;48:117–21.PubMedCrossRefGoogle Scholar
  17. 17.
    Farrar MA, Kiernan MC. The genetics of spinal muscular atrophy: progress and challenges. Neurotherapeutics. 2015;12:290–302.PubMedCrossRefGoogle Scholar
  18. 18.
    Klein CJ, Duan X, Shy ME. Inherited neuropathies: clinical overview and update. Muscle Nerve. 2013;48:604–22.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Lewis RA, Sumner AJ. The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies. Neurology. 1982;32:592–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Lewis RA, Sumner AJ, Shy ME. Electrophysiological features of inherited demyelinating neuropathies: a reappraisal in the era of molecular diagnosis. Muscle Nerve. 2000;23:1472–87.PubMedCrossRefGoogle Scholar
  21. 21.
    Dyck PJ, Karnes JL, Lambert EH. Longitudinal study of neuropathic deficits and nerve conduction abnormalities in hereditary motor and sensory neuropathy type 1. Neurology. 1989;39:1302–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Hilz MJ, Axelrod FB. Quantitative sensory testing of thermal and vibratory perception in familial dysautonomia. Clin Auton Res. 2000;10:177–83.PubMedCrossRefGoogle Scholar
  23. 23.
    McDonnell A, Schulman B, Ali Z, Dib-Hajj SD, Brock F, Cobain S, et al. Inherited erythromelalgia due to mutations in SCN9A: natural history, clinical phenotype and somatosensory profile. Brain. 2016;139:1052–65.PubMedCrossRefGoogle Scholar
  24. 24.
    Knowles CH, Scott SM, Wellmer A, Misra VP, Pilot MA, Williams NS, et al. Sensory and autonomic neuropathy in patients with idiopathic slow-transit constipation. Br J Surg. 1999;86:54–60.PubMedCrossRefGoogle Scholar
  25. 25.
    González-Duarte A, Lem-Carrillo M, Cárdenas-Soto K. Description of transthyretin S50A, S52P and G47A mutations in familial amyloidosis polyneuropathy. Amyloid. 2013;20:221–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Hansen N, Kahn AK, Zeller D, Katsarava Z, Sommer C, Űçeyler N. Amplitudes of pain-related evoked potentials are useful to detect small fiber involvement in painful mixed fiber neuropathies in addition to quantitative sensory testing – an electrophysiological study. Front Neurol. 2015;6:244.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Valeriani M, Mariotti P, Le Pera D, Restuccia D, De Armas L, Maiese T, et al. Functional assessment of A delta and C fibers in patients with Fabry’s disease. Muscle Nerve. 2004;30:708–13.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Wood JN, Boorman JP, Okuse K, Baker MD. Voltage-gated sodium channels and pain pathways. J Neurobiol. 2004;61:55–71.PubMedCrossRefGoogle Scholar
  29. 29.
    Catterall WA. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron. 2000;26:13–25.PubMedCrossRefGoogle Scholar
  30. 30.
    Cummins TR, Sheets PL, Waxman SG. The roles of sodium channels in nociception: implications for mechanisms of pain. Pain. 2007;131:243–57.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Beneng K, Renton T, Yilmaz Z, Yiangou Y, Anand P. Sodium channel Nav 1.7 immunoreactivity in painful human dental pulp and burning mouth syndrome. BMC Neurosci. 2010;11:71.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Nassar MA, Stirling LC, Forlani G, Baker MD, Mathews EA, Dickenson AH, et al. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc Natl Acad Sci U S A. 2004;101:12706–11.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Black JA, Liu S, Tanaka M, Cummins TR, Waxman SG. Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain. 2004;108:237–47.PubMedCrossRefGoogle Scholar
  34. 34.
    Payne CE, Brown AR, Theile JW, Loucif AJ, Alexandrou AJ, Fuller MD, et al. A novel selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability. Br J Pharmacol. 2015;172:2654–70.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Hoeijmakers JGJ, Merkies ISJ, Gerrits MM, Waxman SG, Faber CG, et al. Genetic aspects of sodium channelopathy in small fiber neuropathy. Clin Genet. 2012;82:351–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Devor M. Sodium channels and mechanisms of neuropathic pain. J Pain. 2006;7:S3–S12.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Levinson SR, Luo S, Henry MA. The role of sodium channels in chronic pain. Muscle Nerve. 2012;46:155–65.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Coward K, Plumpton C, Facer P, Birch R, Caristedt T, Tate S, et al. Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain. 2000;85:41–50.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Bucknill AT, Coward K, Plumpton C, Tate S, Bountra C, Birch R, et al. Nerve fibers in lumbar spine structures and injured spinal roots express the sensory neuron-specific sodium channels SNS/PN3 and NaN/SNS2. Spine. 2002;27:135–40.PubMedCrossRefGoogle Scholar
  40. 40.
    Coward K, Aitken A, Powell A, Plumpton C, Birch R, Tate S, et al. Plasticity of TTX-sensitive sodium channels PN1 and brain III in injured human nerves. Neuroreport. 2001;12:495–500.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Coward K, Jowett A, Plumpton C, Powell A, Birch R, Tate S, et al. Sodium channel beta1 and beta2 subunits parallel SNS/PN3 alpha-subunit changes in injured human sensory neurons. Neuroreport. 2001;12:483–8.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Drenth JPH, Waxman SG. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J Clin Invest. 2007;117:3603–9.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Faber CG, Hoeijmakers JGJ, Ahn HS Cheng X, Han C, Choi JS, et al. Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012;71:26–39.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Faber CG, Lauria G, Merkies ISJ, Cheng X, Han C, Ahn HS, et al. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A. 2012;109:19444–9.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Huang J, Han C, Estacion M, Vasylyev D, Hoeijmakers JG, Gerrits MM, et al. Gain-of-function mutations in sodium channel Nav1.9 in painful neuropathy. Brain. 2014;137:1627–42.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    England JD, Happel LT, Kline DG, Gamboni F, Thouron CL, Liu ZP, et al. Sodium channel accumulation in humans with painful neuromas. Neurology. 1996;47:272–6.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Black JA, Nikolajsen L, Kroner K, Jensen TS, Waxman SG, et al. Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann Neurol. 2008;64:644–53.PubMedCrossRefGoogle Scholar
  48. 48.
    Tanaka BS, Nguyen PT, Zhou EY, Yang Y, Yarov-Yarovoy V, Dib-Haji SD, et al. Gain-of-function mutation of a voltage-gated sodium channel Nav1.7 associated with peripheral pain and impaired limb development. J Biol Chem. 2017;292:9262–72.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Yang Y, Wang Y, Li S, Xu Z, Li H, Ma L, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet. 2004;41:171–4.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Han C, Lampert A, Rush AM, Dib-Haji SD, Wang X, Yang Y, et al. Temperature dependence of erythromelalgia mutation L858F in sodium channel Nav1.7. Mol Pain. 2007;3:3.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Harty TP, Dib-Hajj SD, Tyrrell L, Blackman R, Hisama FM, Rose JB, et al. Nav1.7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons. J Neurosci. 2006;26:12566–75.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Michiels JJ, te Morsche RHM, Jansen JBMJ, Drenth JPH. Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Nav1.7. Arch Neurol. 2005;62:1587–90.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Choi J-S, Dib-Hajj SD, Waxman SG. Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy. Neurology. 2006;67:1563–7.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Lampert A, Dib-Hajj SD, Tyrrell L, Waxman SG. Size matters: erythromelalgia mutation S241T in Nav1.7 alters channel gating. J Biol Chem. 2006;281:36029–35.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Lee MJ, Yu HS, Hsieh ST, Stephenson DA, Lu CJ, Yang CC, et al. Characterization of a familial case with primary erythromelalgia from Taiwan. J Neurol. 2007;254:210–4.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Zhang LL, Lin ZM, Ma ZH, Xu Z, Yang YL, Yang Y. Mutation hotspots of SCN9A in primary erythermalgia. Br J Dermatol. 2007;156:767–9.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Han C, Rush AM, Dib-Hajj SD, Li S, Xu Z, Wang Y, et al. Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7. Ann Neurol. 2006;59:553–8.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Wu B, Zhang Y, Tang H, Yang M, Long H, Shi G, et al. A novel SCN9A mutation (F826Y) in primary erythromelalgia alters the excitability of Nav1.7. Curr Mol Med. 2017;17:450–7.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Drenth JP, Finley WH, Breedveld GJ, Testers L, Michiels JJ, Guillet G, et al. The primary erythermalgia-susceptibility gene is located on chromosome 2q31-32. Am J Hum Genet. 2001;68:1277–82.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Hisama FM, Dib-Hajj SD, Waxman SG. SCN9A-related inherited erythromelalgia. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle, WA: University of Washington; 1993.Google Scholar
  61. 61.
    Low SA, Robbins W, Tawfik VL. Complex management of a patient with refractory primary erythromelalgia lacking a SCN9A mutation. J Pain Res. 2017;10:973–7.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Cook-Norris RH, Tollefson MM, Cruz-Inigo AE, Sandroni P, Davis MD, Davis DM. Pediatric erythromelalgia: a retrospective review of 32 cases evaluated at Mayo Clinic over a 37-year period. J Am Acad Dermatol. 2012;66:416–23.PubMedCrossRefGoogle Scholar
  63. 63.
    Estacion M, Dib-Hajj SD, Benke PJ, Te Morsche RH, Eastman EM, Macala LJ, et al. Nav1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders. J Neurosci. 2008;28:11079–88.PubMedCrossRefGoogle Scholar
  64. 64.
    Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. Sodium channels in normal and pathological pain. Annu Rev Neurosci. 2010;33:325–47.PubMedCrossRefGoogle Scholar
  65. 65.
    Han C, Dib-Hajj SD, Lin Z, Eastman EM, Tyrrell L, Cao X, et al. Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation. Brain. 2009;132:1711–22.PubMedCrossRefGoogle Scholar
  66. 66.
    Van Genderen PJ, Michiels JJ, Drenth JP. Hereditary erythermalgia and acquired erythromelalgia. Am J Med Genet. 1993;45:530–2.PubMedCrossRefGoogle Scholar
  67. 67.
    Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci U S A. 2006;103:8245–50.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Cummins TR, Dib-Hajj SD, Waxman SG. Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. J Neurosci. 2004;24:8232–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Davis MDP, Sandroni P, Rooke TW, Low PA. Erythromelalgia: vasculopathy, neuropathy, or both? A prospective study of vascular and neurophysiologic studies in erythromelalgia. Arch Dermatol. 2003;139:1337–43.PubMedCrossRefGoogle Scholar
  70. 70.
    Drenth JP, Vuzevski V, Van Joost T, Casteels-Van Daele M, Vermylen J, Michiels JJ. Cutaneous pathology in primary erythermalgia. Am J Dermatopathol. 1996;18:30–4.PubMedCrossRefGoogle Scholar
  71. 71.
    Anand P, Privitera R, Yiangou Y, Donatien P, Birch R, Misra P. Trench foot or non-freezing cold injury as a painful vaso-neuropathy: clinical and skin biopsy assessments. Front Neurol. 2017;8:514.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Mantyh WG, Dyck PJB, Dyck PJ, Engelstad JK, Litchy WJ, Sandroni P, et al. Epidermal nerve fiber quantification in patients with erythromelalgia. JAMA Dermatol. 2017;153:162–7.CrossRefGoogle Scholar
  73. 73.
    Davis MDP, Weenig RH, Genebriera J, Wendelschafer-Crabb G, Kennedy WR, Sandroni P. Histopathologic findings in primary erythromelalgia are nonspecific: special studies show a decrease in small nerve fiber density. J Am Acad Dermatol. 2006;55:519–22.PubMedCrossRefGoogle Scholar
  74. 74.
    Fischer TZ, Gilmore ES, Estacion M, Eastman E, Taylor S, Melanson M, et al. A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia. Ann Neurol. 2009;65:733–41.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Choi J-S, Zhang L, Dib-Hajj SD, Han C, Tyrrell L, Lin Z, et al. Mexiletine-responsive erythromelalgia due to a new Nav1.7 mutation showing use-dependent current fall-off. Exp Neurol. 2009;216:383–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron. 2006;52:767–74.PubMedCrossRefGoogle Scholar
  77. 77.
    Hayden R, Grossman M. Rectal, ocular, and submaxillary pain; a familial autonomic disorder related to proctalgia fugaz: report of a family. AMA J Dis Child. 1959;97:479–82.PubMedCrossRefGoogle Scholar
  78. 78.
    Fertleman CR, Ferrie CD. What’s in a name-familial rectal pain syndrome becomes paroxysmal extreme pain disorder. J Neurol Neurosurg Psychiatry. 2006;77:1294–5.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Bednarek N, Arbuès AS, Motte J, Sabouraud P, Plouin P, Morville P. Familial rectal pain: a familial autonomic disorder as a cause of paroxysmal attacks in the newborn baby. Epileptic Disord. 2005;7:360–2.PubMedGoogle Scholar
  80. 80.
    Hayden R. Rectal, ocular, and submaxillary pain. AMA Am J Dis Child. 1959;97:479.CrossRefGoogle Scholar
  81. 81.
    Fertleman CR, Ferrie CD, Aicardi J, Bednarek NA, Eeg-Olofsson O, Elmslie FV, et al. Paroxysmal extreme pain disorder (previously familial rectal pain syndrome). Neurology. 2007;69:586–95.PubMedCrossRefGoogle Scholar
  82. 82.
    Yiangou Y, Facer P, Chessell IP, Bountra C, Chan C, Fertleman C, et al. Voltage-gated ion channel Nav1.7 innervation in patients with idiopathic rectal hypersensitivity and paroxysmal extreme pain disorder (familial rectal pain). Neurosci Lett. 2007;427:77–82.PubMedCrossRefGoogle Scholar
  83. 83.
    Chan CLH, Facer P, Davis JB, Smith JB, Egerton J, Bountra C, et al. Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet. 2003;361:385–91.PubMedCrossRefGoogle Scholar
  84. 84.
    Suter MR. What are the treatment options for paroxysmal extreme pain disorder? Pain Manag. 2015;5:229–32.PubMedCrossRefGoogle Scholar
  85. 85.
    Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444:894–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Goldberg YP, MacFarlane J, MacDonald ML, Thompson J, Dube MP, Mattice M, et al. Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet. 2007;71:311–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Ahmad S, Dahllund L, Eriksson AB, Hellgren D, Karlsson U, Lund PE, et al. A stop codon mutation in SCN9A causes lack of pain sensation. Hum Mol Genet. 2007;16:2114–21.PubMedCrossRefGoogle Scholar
  88. 88.
    Nilsen KB, Nicholas AK, Woods CG, Mellgren SI, Nebuchennykh M, Aasly J. Two novel SCN9A mutations causing insensitivity to pain. Pain. 2009;143:155–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Silverman FN, Gilden JJ. Congenital insensitivity to pain: a neurologic syndrome with bizarre skeletal lesions. Radiology. 1959;72:176–90.PubMedCrossRefGoogle Scholar
  90. 90.
    Schiffmann R, Ries M. Fabry disease: a disorder of childhood onset. Pediatr Neurol. 2016;64:10–20.PubMedCrossRefGoogle Scholar
  91. 91.
    Ries M, Ramaswami U, Parini R, Lindblad B, Whybra C, Willers I, et al. The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents. Eur J Pediatr. 2003;162:767–72.PubMedCrossRefGoogle Scholar
  92. 92.
    Arends M, Körver S, Hughes DA, Mehta A, Hollak CEM, Biegstraaten M. Phenotype, disease severity and pain are major determinants of quality of life in Fabry disease: results from a large multicenter cohort study. J Inherit Metab Dis. 2018;41:141–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest. 2004;34:236–42.PubMedCrossRefGoogle Scholar
  94. 94.
    Smid BE, van der Tol L, Biegstraaten M, Linthorst GE, Hollak CE, Poorthuis BJ. Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease. J Med Genet. 2015;52:262–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Laney DA, Peck DS, Atherton AM, Manwaring LP, Christensen KM, Shankar SP, et al. Fabry disease in infancy and early childhood: a systematic literature review. Genet Med. 2015;17:323–30.PubMedCrossRefGoogle Scholar
  96. 96.
    Hoffmann B, Beck M, Sunder-Plassmann G, Borsini W, Ricci R, Mehta A, et al. Nature and prevalence of pain in Fabry disease and its response to enzyme replacement therapy-a retrospective analysis from the Fabry Outcome Survey. Clin J Pain. 2007;23:535–42.PubMedCrossRefGoogle Scholar
  97. 97.
    MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38:750–60.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet. 2001;38:769–75.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Üçeyler N, Ganendiran S, Kramer D, Sommer C. Characterization of pain in Fabry disease. Clin J Pain. 2014;30:915–20.PubMedCrossRefGoogle Scholar
  100. 100.
    Gomes I, Nora DB, Becker J, Ehlers JA, Schwartz IV, Giugliani R, et al. Nerve conduction studies, electromyography and sympathetic skin response in Fabry’s disease. J Neurol Sci. 2003;214:21–5.PubMedCrossRefGoogle Scholar
  101. 101.
    Dütsch M, Marthol H, Stemper B, Brys M, Haendl T, Hilz MJ. Small fiber dysfunction predominates in Fabry neuropathy. J Clin Neurophysiol. 2002;19:575–86.PubMedCrossRefGoogle Scholar
  102. 102.
    Luciano CA, Russell JW, Banerjee TK, Quirk JM, Scott LJ, Dambrosia JM, et al. Physiological characterization of neuropathy in Fabry’s disease. Muscle Nerve. 2002;26:622–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Akpinar ÇK, Türker H, Bayrak O, Cengiz N. Electroneuromyographic features in fabry disease: a retrospective review. Arch Neuropsychiatr. 2015;52:258–62.CrossRefGoogle Scholar
  104. 104.
    Low M, Nicholls K, Tubridy N, Hand P, Velakoulis D, Kiers L, et al. Neurology of Fabry disease. Intern Med J. 2007;37:436–47.PubMedCrossRefGoogle Scholar
  105. 105.
    Scott LJ, Griffin JW, Luciano C, Barton NW, Banerjee T, Crawford T, et al. Quantitative analysis of epidermal innervation in Fabry disease. Neurology. 1999;52:1249–54.PubMedCrossRefGoogle Scholar
  106. 106.
    Torvin Møller A, Winther Bach F, Feldt-Rasmussen U, Rasmussen A, Hasholt L, Lan H, et al. Functional and structural nerve fiber findings in heterozygote patients with Fabry disease. Pain. 2009;145:237–45.PubMedCrossRefGoogle Scholar
  107. 107.
    Laaksonen SM, Röyttä M, Jääskeläinen SK, Kantola I, Penttinen M, Falck B. Neuropathic symptoms and findings in women with Fabry disease. Clin Neurophysiol. 2008;119:1365–72.PubMedCrossRefGoogle Scholar
  108. 108.
    Liguori R, Di Stasi V, Bugiardini E, Mignani R, Burlina A, Borsini W, et al. Small fiber neuropathy in female patients with Fabry disease. Muscle Nerve. 2010;41:409–12.PubMedCrossRefGoogle Scholar
  109. 109.
    Planté-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol. 2011;10:1086–97.PubMedCrossRefGoogle Scholar
  110. 110.
    Wallace MR, Naylor SL, Kluve-Beckerman B, Long GL, McDonald L, Shows TB, et al. Localization of the human prealbumin gene to chromosome 18. Biochem Biophys Res Commun. 1985;129:753–8.PubMedCrossRefGoogle Scholar
  111. 111.
    Suanprasert N, Berk JL, Benson MD, Dyck PJ, Klein CJ, Gollob JA, et al. Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials. J Neurol Sci. 2014;344:121–8.PubMedCrossRefGoogle Scholar
  112. 112.
    Kim DH, Zeldenrust SR, Low PA, Dyck PJ. Quantitative sensation and autonomic test abnormalities in transthyretin amyloidosis polyneuropathy. Muscle Nerve. 2009;40:363–70.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Shin SC, Robinson-Papp J. Amyloid neuropathies. Mt Sinai J Med. 2012;79:733–48.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Carr AS, Pelayo-Negro AL, Evans MR, Laurà M, Blake J, Stancanelli C, et al. A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK. J Neurol Neurosurg Psychiatry. 2016;87:620–7.PubMedCrossRefGoogle Scholar
  115. 115.
    Per H, Canpolat M, Bayram AK, Ulgen E, Baran B, Kardas F, et al. Clinical, electrodiagnostic, and genetic features of Tangier disease in an adolescent girl with presentation of peripheral neuropathy. Neuropediatrics. 2015;46:420–3.PubMedCrossRefGoogle Scholar
  116. 116.
    Bracco G, Dotti G, Levis F, David E, Saracco G, Rizzetto M, et al. Familial high-density lipoprotein deficiency (Tangier disease): the third italian case. J Inherit Metab Dis. 1988;11:155–7.PubMedCrossRefGoogle Scholar
  117. 117.
    Hoffman HN, Fredrickson DS. Tangier disease (familial high density lipoprotein deficiency). Clinical and genetic features in two adults. Am J Med. 1965;39:582–93.PubMedCrossRefGoogle Scholar
  118. 118.
    Puntoni M, Sbrana F, Bigazzi F, Sampietro T. Tangier disease: epidemiology, pathophysiology, and management. Am J Cardiovasc Drugs. 2012;12:303–11.PubMedCrossRefGoogle Scholar
  119. 119.
    Zyss J, Béhin A, Couvert P, Bouhour F, Sassolas A, Kolev I, et al. Clinical and electrophysiological characteristics of neuropathy associated with Tangier disease. J Neurol. 2012;259:1222–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Peripheral Neuropathy Unit, Centre for Clinical Translation, Division of Brain SciencesImperial College London, Hammersmith HospitalLondonUK

Personalised recommendations