Hereditary sensory and autonomic neuropathies
- Robert P Cruse, DO
Robert P Cruse, DO
- Assistant Professor
- University of Missouri College of Medicine
- Section Editors
- Douglas R Nordli, Jr, MD
Douglas R Nordli, Jr, MD
- Section Editor — Pediatric Neurology
- Chief of Neurology
- Children’s Hospital Los Angeles
- Vice Chair of Neurology
- USC Keck School of Medicine
- Helen V Firth, DM, FRCP, DCH
Helen V Firth, DM, FRCP, DCH
- Section Editor — Genetics
- Consultant Clinical Geneticist
- Addenbrooke's Hospital, Cambridge, UK
- Jeremy M Shefner, MD, PhD
Jeremy M Shefner, MD, PhD
- Section Editor — Neuromuscular Disease
- Professor and Chair of Neurology, Barrow Neurological Institute
- Professor of Neurology, University of Arizona, Phoenix
- Clinical Professor of Neurology, Creighton University
The hereditary peripheral neuropathies have been classified based upon clinical characteristics, mode of inheritance, electrophysiologic features, metabolic defect, and specific genetic markers. The Dyck classification developed in the 1970s helped to define specific types based upon clinical and electrophysiologic features . Many of the primary hereditary neuropathies were divided into motor-sensory and sensory-autonomic neuropathies.
The primary hereditary sensory and autonomic neuropathies are reviewed here. The primary hereditary motor sensory neuropathies and the disorders affecting both the central and peripheral nervous systems are discussed separately. (See "Overview of hereditary neuropathies" and "Hereditary primary motor sensory neuropathies, including Charcot-Marie-Tooth disease" and "Neuropathies associated with hereditary disorders".)
Hereditary sensory and autonomic neuropathies (HSANs) occur much less frequently than do the primary hereditary motor sensory neuropathies (HMSNs). The major feature of the HSANs is loss of large myelinated and unmyelinated fibers. They have been categorized into types one through five, although some children do not fit well into this classification (table 1) [1,2]. Our understanding of the basic genetic abnormalities in these diseases is substantially less than that of the hereditary motor sensory neuropathies.
Hereditary sensory and autonomic neuropathy type I (also known as hereditary sensory neuropathy type I and hereditary sensory radicular neuropathy) is the most common form of HSAN. It is characterized by progressive degeneration of dorsal root ganglion and motor neurons, leading to distal sensory loss and later distal muscle wasting and weakness and variable neural deafness [3,4].
Genetics — HSAN1 is genetically heterogeneous. Most cases show autosomal dominant inheritance. At least four genes have been implicated in the disorder, but most of the genetic loci are unknown .
- Dyck PJ. Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. In: Peripheral Neuropathy, Dyck PJ, Thomas PK, Griffin JW, Low PA (Eds), WB Saunders, Philadelphia 1993. Vol 2, p.1065.
- Thomas PK. Hereditary sensory neuropathies. Brain Pathol 1993; 3:157.
- Fitzpatrick DB, Hooper RE, Seife B. Hereditary deafness and sensory radicular neuropathy. Arch Otolaryngol 1976; 102:552.
- Houlden H, King R, Blake J, et al. Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I). Brain 2006; 129:411.
- Rotthier A, Baets J, De Vriendt E, et al. Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation. Brain 2009; 132:2699.
- Dawkins JL, Hulme DJ, Brahmbhatt SB, et al. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet 2001; 27:309.
- Bejaoui K, Wu C, Scheffler MD, et al. SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet 2001; 27:261.
- Klein CJ, Wu Y, Kruckeberg KE, et al. SPTLC1 and RAB7 mutation analysis in dominantly inherited and idiopathic sensory neuropathies. J Neurol Neurosurg Psychiatry 2005; 76:1022.
- Penno A, Reilly MM, Houlden H, et al. Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem 2010; 285:11178.
- Kok C, Kennerson ML, Spring PJ, et al. A locus for hereditary sensory neuropathy with cough and gastroesophageal reflux on chromosome 3p22-p24. Am J Hum Genet 2003; 73:632.
- Spring PJ, Kok C, Nicholson GA, 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.
- Rotthier A, Auer-Grumbach M, Janssens K, et al. Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am J Hum Genet 2010; 87:513.
- Murphy SM, Ernst D, Wei Y, et al. Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2. Neurology 2013; 80:2106.
- Guelly C, Zhu PP, Leonardis L, et al. Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I. Am J Hum Genet 2011; 88:99.
- Namekawa M, Ribai P, Nelson I, et al. SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years. Neurology 2006; 66:112.
- Klein CJ, Botuyan MV, Wu Y, et al. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet 2011; 43:595.
- Baets J, Duan X, Wu Y, et al. Defects of mutant DNMT1 are linked to a spectrum of neurological disorders. Brain 2015; 138:845.
- Berginer V, Baruchin A, Ben-Yakar Y, Mahler D. Plantar ulcers in hereditary sensory neuropathy. A plea for conservative treatment. Int J Dermatol 1984; 23:664.
- Nance PW, Kirby RL. Rehabilitation of an adult with disabilities due to congenital sensory neuropathy. Arch Phys Med Rehabil 1985; 66:123.
- Teot L, Arnal F, Humeau C, et al. Ultrastructural aspects of nerves, bones, and vessels in hereditary sensory neuropathy. J Orthop Res 1985; 3:226.
- Nicholson GA. Hereditary sensory neuropathy type IA. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1390/ (Accessed on December 20, 2011).
- Gwathmey FW, House JH. Clinical manifestations of congenital insensitivity of the hand and classification of syndromes. J Hand Surg Am 1984; 9:863.
- Gable K, Gupta SD, Han G, et al. A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity. J Biol Chem 2010; 285:22846.
- Garofalo K, Penno A, Schmidt BP, et al. Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest 2011; 121:4735.
- Scherer SS. The debut of a rational treatment for an inherited neuropathy? J Clin Invest 2011; 121:4624.
- Kurth I. Hereditary sensory and autonomic neuropathy type II. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK49247/ (Accessed on December 08, 2011).
- Ferrière G, Guzzetta F, Kulakowski S, Evrard P. Nonprogressive type II hereditary sensory autonomic neuropathy: a homogeneous clinicopathologic entity. J Child Neurol 1992; 7:364.
- Ota M, Ellefson RD, Lambert EH, Dyck PJ. Hereditary sensory neuropathy, type II. Clinical, electrophysiologic, histologic, and biochemical studies of a Quebec kinship. Arch Neurol 1973; 29:23.
- Nukada H, Pollock M, Haas LF. The clinical spectrum and morphology of type II hereditary sensory neuropathy. Brain 1982; 105 (Pt 4):647.
- Berciano J, Combarros O, Figols J, et al. Hereditary motor and sensory neuropathy type II. Clinicopathological study of a family. Brain 1986; 109 ( Pt 5):897.
- Lafreniere RG, MacDonald ML, Dube MP, et al. Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates. Am J Hum Genet 2004; 74:1064.
- Shekarabi M, Girard N, Rivière JB, et al. Mutations in the nervous system--specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II. J Clin Invest 2008; 118:2496.
- Roddier K, Thomas T, Marleau G, et al. Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians. Neurology 2005; 64:1762.
- Kurth I, Pamminger T, Hennings JC, et al. Mutations in FAM134B, encoding a newly identified Golgi protein, cause severe sensory and autonomic neuropathy. Nat Genet 2009; 41:1179.
- Rivière JB, Ramalingam S, Lavastre V, et al. KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2. Am J Hum Genet 2011; 89:219.
- Erlich Y, Edvardson S, Hodges E, et al. Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis. Genome Res 2011; 21:658.
- Yuan J, Matsuura E, Higuchi Y, et al. Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation. Neurology 2013; 80:1641.
- Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature 2006; 444:894.
- Yang Y, Wang Y, Li S, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet 2004; 41:171.
- Fertleman CR, Baker MD, Parker KA, et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron 2006; 52:767.
- Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012; 71:26.
- RILEY CM, DAY RL. Central autonomic dysfunction with defective lacrimation; report of five cases. Pediatrics 1949; 3:468.
- Axelrod FB. Familial dysautonomia. Muscle Nerve 2004; 29:352.
- Elkayam L, Matalon A, Tseng CH, Axelrod F. Prevalence and severity of renal disease in familial dysautonomia. Am J Kidney Dis 2006; 48:780.
- Bernardi L, Hilz M, Stemper B, et al. Respiratory and cerebrovascular responses to hypoxia and hypercapnia in familial dysautonomia. Am J Respir Crit Care Med 2003; 167:141.
- Brown JC, Johns RJ. Nerve conduction in familial dysautonomia (Riley-Day syndrome). JAMA 1967; 201:200.
- Nordborg C, Conradi N, Sourander P, Westerberg B. A new type of non-progressive sensory neuropathy in children with atypical dysautonomia. Acta Neuropathol 1981; 55:135.
- Kuhlenbäumer G, Young P, Hünermund G, et al. Clinical features and molecular genetics of hereditary peripheral neuropathies. J Neurol 2002; 249:1629.
- Aguayo AJ, Nair CP, Bray GM. Peripheral nerve abnormalities in the Riley-Day syndrome. Findings in a sural nerve biopsy. Arch Neurol 1971; 24:106.
- Pearson J, Pytel BA. Quantitative studies of sympathetic ganglia and spinal cord intermedio-lateral gray columns in familial dysautonomia. J Neurol Sci 1978; 39:47.
- Jaradeh SS. Hereditary neuropathies. J Clin Neuromuscul Dis 2003; 5:72.
- Pearson J, Pytel B. Quantitative studies of ciliary and sphenopalatine ganglia in familial dysautonomia. J Neurol Sci 1978; 39:123.
- Gold-von Simson G, Romanos-Sirakis E, Maayan C, Axelrod FB. Neoplasia in familial dysautonomia: a 20-year review in a young patient population. J Pediatr 2009; 155:934.
- Palma JA, Roda R, Norcliffe-Kaufmann L, Kaufmann H. Increased frequency of rhabdomyolysis in familial dysautonomia. Muscle Nerve 2015; 52:887.
- Shohat M, Halpern GJ. Familial dysautonomia. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1180/ (Accessed on December 08, 2011).
- Maayan C, Kaplan E, Shachar S, et al. Incidence of familial dysautonomia in Israel 1977-1981. Clin Genet 1987; 32:106.
- Klebanoff MA, Neff JM. Familial dysautonomia associated with recurrent osteomyelitis in a non-Jewish girl. J Pediatr 1980; 96:75.
- Levine SL, Manniello RL, Farrell PM. Familial dysautonomia: unusual presentation in an infant of non-Jewish ancestry. J Pediatr 1977; 90:79.
- Mehta K. Familial dysautonomia in a Hindu boy. Am J Dis Child 1978; 132:719.
- Slaugenhaupt SA, Blumenfeld A, Gill SP, et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 2001; 68:598.
- Anderson SL, Coli R, Daly IW, et al. Familial dysautonomia is caused by mutations of the IKAP gene. Am J Hum Genet 2001; 68:753.
- Nelson Textbook of Pediatrics, 15th ed, Behrman RE, Kliegman RM, Marvin AM (Eds), WB Saunders, Philadelphia 1996. Vol 1760.
- Axelrod FB. Familial dysautonomia: a review of the current pharmacological treatments. Expert Opin Pharmacother 2005; 6:561.
- Giarraffa P, Berger KI, Chaikin AA, et al. Assessing efficacy of high-frequency chest wall oscillation in patients with familial dysautonomia. Chest 2005; 128:3377.
- Tutaj M, Marthol H, Berlin D, et al. Effect of physical countermaneuvers on orthostatic hypotension in familial dysautonomia. J Neurol 2006; 253:65.
- Axelrod FB, Krey L, Glickstein JS, et al. Preliminary observations on the use of midodrine in treating orthostatic hypotension in familial dysautonomia. J Auton Nerv Syst 1995; 55:29.
- Axelrod FB, Goldberg JD, Rolnitzky L, et al. Fludrocortisone in patients with familial dysautonomia--assessing effect on clinical parameters and gene expression. Clin Auton Res 2005; 15:284.
- Gold-von Simson G, Rutkowski M, Berlin D, Axelrod FB. Pacemakers in patients with familial dysautonomia--a review of experience with 20 patients. Clin Auton Res 2005; 15:15.
- Norcliffe-Kaufmann L, Martinez J, Axelrod F, Kaufmann H. Hyperdopaminergic crises in familial dysautonomia: a randomized trial of carbidopa. Neurology 2013; 80:1611.
- Axelrod FB, Berlin D. Pregabalin: a new approach to treatment of the dysautonomic crisis. Pediatrics 2009; 124:743.
- Eng CM, Slaugenhaupt SA, Blumenfeld A, et al. Prenatal diagnosis of familial dysautonomia by analysis of linked CA-repeat polymorphisms on chromosome 9q31-q33. Am J Med Genet 1995; 59:349.
- Oddoux C, Reich E, Axelrod F, et al. Prenatal diagnostic testing for familial dysautonomia using linked genetic markers. Prenat Diagn 1995; 15:817.
- Blumenfeld A, Slaugenhaupt SA, Liebert CB, et al. Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31. Am J Hum Genet 1999; 64:1110.
- Lerner BH. When diseases disappear--the case of familial dysautonomia. N Engl J Med 2009; 361:1622.
- Rosemberg S, Marie SK, Kliemann S. Congenital insensitivity to pain with anhidrosis (hereditary sensory and autonomic neuropathy type IV). Pediatr Neurol 1994; 11:50.
- Indo Y, Tsuruta M, Hayashida Y, et al. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet 1996; 13:485.
- Greco A, Villa R, Fusetti L, et al. The Gly571Arg mutation, associated with the autonomic and sensory disorder congenital insensitivity to pain with anhidrosis, causes the inactivation of the NTRK1/nerve growth factor receptor. J Cell Physiol 2000; 182:127.
- Indo Y, Mardy S, Tsuruta M, et al. Structure and organization of the human TRKA gene encoding a high affinity receptor for nerve growth factor. Jpn J Hum Genet 1997; 42:343.
- Shatzky S, Moses S, Levy J, et al. Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies. Am J Med Genet 2000; 92:353.
- Dyck PJ, Mellinger JF, Reagan TJ, et al. Not 'indifference to pain' but varieties of hereditary sensory and autonomic neuropathy. Brain 1983; 106 (Pt 2):373.
- Carvalho OP, Thornton GK, Hertecant J, et al. A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy. J Med Genet 2011; 48:131.
- Einarsdottir E, Carlsson A, Minde J, et al. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum Mol Genet 2004; 13:799.
- Edvardson S, Cinnamon Y, Jalas C, et al. Hereditary sensory autonomic neuropathy caused by a mutation in dystonin. Ann Neurol 2012; 71:569.
- Cavanagh NP, Eames RA, Galvin RJ, et al. Hereditary sensory neuropathy with spastic paraplegia. Brain 1979; 102:79.
- Bouhouche A, Benomar A, Bouslam N, et al. Autosomal recessive mutilating sensory neuropathy with spastic paraplegia maps to chromosome 5p15.31-14.1. Eur J Hum Genet 2006; 14:249.
- Axelrod FB, Pearson J, Tepperberg J, Ackerman BD. Congenital sensory neuropathy with skeletal dysplasia. J Pediatr 1983; 102:727.
- Donaghy M, Hakin RN, Bamford JM, et al. Hereditary sensory neuropathy with neurotrophic keratitis. Description of an autosomal recessive disorder with a selective reduction of small myelinated nerve fibres and a discussion of the classification of the hereditary sensory neuropathies. Brain 1987; 110 ( Pt 3):563.
- Liberfarb RM, Jackson AH, Eavey RD, Robb RM. Unique hereditary sensory and autonomic neuropathy with growth hormone deficiency. J Child Neurol 1993; 8:271.
- Quinlivan R, Robb S, Hughes RA, et al. Congenital sensory neuropathy in association with ichthyosis and anterior chamber cleavage syndrome. Neuromuscul Disord 1993; 3:217.
- Linssen WH, Van den Bent MJ, Brunner HG, Poels PJ. Deafness, sensory neuropathy, and ovarian dysgenesis: a new syndrome or a broader spectrum of Perrault syndrome? Am J Med Genet 1994; 51:81.
- Johnsen SD, Johnson PC, Stein SR. Familial sensory autonomic neuropathy with arthropathy in Navajo children. Neurology 1993; 43:1120.