Skip to main content
SpringerLink
Log in

Molecular genetics of hereditary sensory neuropathies

  • Review Article
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

Hereditary sensory neuropathies (HSN), also known as hereditary sensory and autonomic neuropathies (HSAN), are a clinically and genetically heterogeneous group of disorders. They are caused by neuronal atrophy and degeneration, predominantly affecting peripheral sensory and autonomic neurons. Both congenital and juvenile to adulthood onset is possible. Currently, the classification of the HSN depends on the mode of inheritance, age at onset, and clinical presentation. Hallmark features are progressive sensory loss, chronic skin ulcers, and other skin abnormalities. Spontaneous fractures and neuropathic arthropathy are frequent complications and often necessitate amputations. Autonomic features vary between different subgroups. Distal muscle weakness and wasting may be present and is sometimes so prominent that it becomes difficult to distinguish HSN from Charcot-Marie-Tooth syndrome. Recent major advances in molecular genetics have led to the identification of seven gene loci and six-disease causing genes for autosomal-dominant and autosomal-recessive HSN. These genes have been shown to play roles in lipid metabolism and the regulation of intracellular vesicular transport, but also a presumptive transcriptional regulator, a nerve growth factor receptor, and a nerve growth factor have been described among the causative genes in HSN. Nevertheless, it remains unclear how mutations in the known genes lead to the phenotype of HSN. In this review, we summarize the recent progress of the molecular genetics of the HSN and the implicated genes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anand P. (2004) Neurotrophic factors and their receptors in human sensory neuropathies. Prog. Brain Res. 146, 477–492.

    Article  PubMed  CAS  Google Scholar 

  • Anderson S. L., Coli, R., Daly I. W., et al. (2001) Familial dysautonomia is caused by mutations of the IKAP gene. Am. J. Hum. Genet. 68, 753–758.

    Article  PubMed  CAS  Google Scholar 

  • Anderson S. L., Qiu J., and Rubin, B. Y. (2003a) EGCG corrects aberrant splicing of IKAP mRNA in cells from patients with familial dysautonomia. Biochem. Biophys. Res. Commun. 310, 627–633.

    Article  PubMed  CAS  Google Scholar 

  • Anderson S. L., Qiu J., and Rubin B. Y. (2003b) Tocotrienols induce IKBKAP expression: a possible therapy for familial dysautonomia. Biochem. Biophys. Res. Commun. 306, 303–309.

    Article  PubMed  CAS  Google Scholar 

  • Auer-Grumbach M., De Jonghe P., Verhoeven K., et al. (2003) Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: a review. Arch. Neurol. 60, 329–334.

    Article  PubMed  Google Scholar 

  • Auer-Grumbach M., De Jonghe P., Wagner K., Verhoeven K., Hartung H. P., and Timmerman V. (2000) Phenotype-genotype correlations in a CMT2B family with refined 3q13-q22 locus. Neurology 55, 1552–1557.

    Article  PubMed  CAS  Google Scholar 

  • Axelrod F. B. (2004) Familial dysautonomia. Muscle Nerve 29, 352–363.

    Article  PubMed  Google Scholar 

  • Axelrod F. B. and Hilz M. J. (2003) Inherited autonomic neuropathies. Semin. Neurol. 23, 381–390.

    Article  PubMed  Google Scholar 

  • Axelrod F. B., Goldberg J. D., Ye X. Y., and Maayan C. (2002) Survival in familial dysautonomia: Impact of early intervention. J. Pediatr. 141, 518–523.

    Article  PubMed  Google Scholar 

  • Bejaoui K., Uchida Y., Yasuda S., et al. (2002) Hereditary senory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis. J. Clin. Invest. 110, 1301–1308.

    PubMed  CAS  Google Scholar 

  • Bejaoui K., Wu C., Scheffler M. D., et al. (2001) SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat. Genet. 27, 261, 262.

    Article  PubMed  CAS  Google Scholar 

  • Blumenfeld A., Slaugenhaupt S. A., Axelrod F. B., et al. (1993) Localization of the gene for familial dysautonomia on chromosome 9 and definition of DNA markers for genetic diagnosis. Nat. Genet. 4, 160–164.

    Article  PubMed  CAS  Google Scholar 

  • Bonkowsky J. L., Johnson J., Carey J. C., Smith A. G., and Swoboda K. J. (2003) An infant with primary tooth loss and palmar hyperkeratosis: a novel mutation in the NTRK1 gene causing congenital insensitivity to pain with anhidrosis. Pediatrics 112, e237-e241.

    Article  PubMed  Google Scholar 

  • Bureau Y. (1955) Acropathies pseudosyringomyeliques des membres inferieures. Sem. Hôp. (Paris), 3, 1419–1429.

    Google Scholar 

  • Coen K., Pareyson D., Auer-Grumbach M., et al. (2006) Novel mutations in the HSN2 gene causing hereditary sensory and autonomic neuropathy type II. Neurology, in press.

  • Dawkins J. L., Brahmbhatt S., Auer-Grumbach M., et al. (2002) Exclusion of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) as a common cause for hereditary sensory neuropathy. Neuromuscul. Disord. 12, 656–658.

    Article  PubMed  Google Scholar 

  • Dawkins J. L., Hulme D. J., Brahmbhatt S. B., Auer-Grumbach M., and Nicholson G. A. (2001) Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type 1. Nat. Genet. 27, 309–312.

    Article  PubMed  CAS  Google Scholar 

  • Dedov V. N., Dedova I. V., Merrill A. H., Jr., and Nicholson G. A. (2004) Activity of partially inhibited serine palmitoyltransferase is sufficient for normal spingoliped metabolism and viability of HSN1 patient cells. Biochem. Biophys. Acta 1688, 168–175.

    Article  PubMed  CAS  Google Scholar 

  • De Jonghe P., Timmerman V., FitzPatrick D., Spoelders P., Martin J. J., and Van Broeckhoven C. (1997) Mutilating neuropathic ulcerations in a chromosome 3q13-q22 linked Charcot-Marie-Tooth disease type 2B family. J. Neurol. Neurosurg. Psychiatry 62, 570–573.

    Article  PubMed  Google Scholar 

  • Dong J., Edelmann L., Bajwa A. M., Kornreich R., and Desnick R. J. (2002) Familial dysautonomia: detection of the IKBKAP IVS20(+6T→C) and R696P mutations and frequencies among Ashkenazi Jews. Am. J. Med. Genet. 110, 253–257.

    Article  PubMed  Google Scholar 

  • Dubourg O., Barhoumi C., Azzedine H., et al. (2000) Phenotypic and genetic study of a family with hereditary sensory neuropathy and prominent weakness. Muscle Nerve 23, 1508–1514.

    Article  PubMed  CAS  Google Scholar 

  • Dyck P. J. (1993) Neuronal atrophy and degeneration predominatly affecting peripheral sensory and autonomic neurons, in Peripheral Neuropathy, 3rd ed., Dyck P. J., Thomas, P. K., Griffin J. W., Low P. A., and Poduslo J. F., ed., W.B. Saunders, Philadelphia, pp. 1065–1093.

    Google Scholar 

  • Echard A., Jollivet F., Martinez O., et al. (1998) Interaction of a Golgi-associated kinesin-like protein with Rab6. Science 279, 580–585.

    Article  PubMed  CAS  Google Scholar 

  • Einarsdottir E., Carlsson A., Minde J., et al. (2004) A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Hum. Mol. Genet. 13, 799–805.

    Article  PubMed  CAS  Google Scholar 

  • Elliott J. L., Kwon J. M., Goodfellow P. J., and Yee W. C. (1997) Hereditary motor and sensory neuropathy IIB: clinical and electrodiagnostic characteristics. Neurology 48, 23–28.

    Article  PubMed  CAS  Google Scholar 

  • Gable K., Han G., Monaghan E., et al. (2002) Mutations in the yeast LCB1 and LCB2 genes, including those corresponding to the hereditary sensory neuropathy type I mutations, dominantly inactivate serine palmitoyltransferase. J. Biol. Chem. 277, 10,194–10,200.

    Article  CAS  Google Scholar 

  • Geraldes R., de Carvalho M., Santos-Bento M., and Nicholson G. (2004) Hereditary sensory neuropathy type 1 in a Portuguese family-electrodiagnostic and autonomic nervous system studies. J. Neurol. Sci. 227, 35–38.

    Article  PubMed  CAS  Google Scholar 

  • Greco A., Villa R., and Pierotti M. A. (1996) Genomic organization of the human NTRK1 gene. Oncogene 13, 2463–2466.

    PubMed  CAS  Google Scholar 

  • Hanada K. (2003) Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. Biochim. Biophys. Acta 1632, 16–30.

    Article  PubMed  CAS  Google Scholar 

  • Hawkes N. A., Otero G., Winkler G. S. et al. (2002) Purification and characterization of the human elongator complex. J. Biol. Chem 277, 3047–3052.

    Article  PubMed  CAS  Google Scholar 

  • Holmberg C., Katz S., Lerdrup M., et al. (2002) A novel specific role for I kappa B kinase complex-associated protein in cytosolic stress signaling. J. Biol. Chem. 277, 31,918–31,928.

    Article  CAS  Google Scholar 

  • Houlden H., Blake J., and Reilly M. M. (2004a Hereditary sensory neuropathies. Curr. Opin. Neurol. 17, 569–577.

    Article  PubMed  CAS  Google Scholar 

  • Houlden H., King R. H., Hashemi-Nejad A., et al. (2001) A novel TRKA (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V. Ann. Neurol. 49, 521–525.

    Article  PubMed  CAS  Google Scholar 

  • Houlden H., King R. H., Muddle J. R., et al. (2004b) A novel RAB7 mutation associated with ulceromutilating neuropathy. Ann. Neurol. 56, 586–590.

    Article  PubMed  CAS  Google Scholar 

  • Indo Y., Tsuruta M., Hayashida Y., et al. (1996) Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat. Genet. 13, 485–488.

    Article  PubMed  CAS  Google Scholar 

  • Klein C. J., Wu Y., Kruckeberg K. E., et al. (2005) SPTLC1 and RAB7 mutation analysis in dominantly inherited and idiopathic sensory neuropathies. J. Neurol. Neurosurg. Psychiatry 76, 1022–1024.

    Article  PubMed  CAS  Google Scholar 

  • Kok C., Kennerson M. L., Spring P. J., Ing A. J., Pollard J. D., and Nicholson G. A. (2003) Alocus for hereditary sensory neuropathy with cough and gastroesophageal reflux on chromosome 3p22-p24. Am. J. Hum. Genet. 73, 632–637.

    Article  PubMed  CAS  Google Scholar 

  • Kwon J. M., Elliott J. L., Yee W. C., et al. (1995) Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q. Am. J. Hum. Genet. 57, 853–858.

    PubMed  CAS  Google Scholar 

  • Lafreniere R. G., MacDonald M. L., Dube M. P., et al. (2004) 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. 74, 1064–1073.

    Article  PubMed  CAS  Google Scholar 

  • Lee M. J., Stephenson D. A., Groves M. J., et al. (2003) Hereditary sensory neuropathy is caused by a mutation in the delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct4) gene. Hum. Mol. Genet. 12, 1917–1925.

    Article  PubMed  CAS  Google Scholar 

  • Levi-Montalcini R. (1987) The nerve growth factor: thirty-five years later. Biosci. Rep. 7, 681–699.

    Article  PubMed  CAS  Google Scholar 

  • Leyne M. (2003) Identification of the first non-Jewish mutation in familial dysautonomia. Am. J. Med. Genet. 118A, 305–308.

    Article  PubMed  Google Scholar 

  • Matsuo M., Kurokawa T., Goya N., and Ohta M. (1981) Congenital insensitivity to pain with anhidrosis in a 2-month-old boy. Neurology 31, 1190–1192.

    PubMed  CAS  Google Scholar 

  • McCampbell A., Truong D., Broom D. C., et al. (2005) Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an agedependent neuropathy. Hum. Mol. Genet. 14(22), 3507–3521.

    Article  PubMed  CAS  Google Scholar 

  • Minde J., Toolanen G., Andersson T., et al. (2004) Familial insensitivity to pain (HSAN V) and a mutation in the NGFB gene. A neurophysiological and pathological study. Muscle Nerve 30, 752–760.

    Article  PubMed  Google Scholar 

  • Nicholson G. A., Dawkins J. L., Blair I. P., Auer-Grumbach M., Brahmbhatt S. B., and Hulme D. J. (2001) Hereditary sensory neuropathy type I: haplotype analysis shows founders in southern England and Europe. Am. J. Hum. Genet. 69, 655–659.

    Article  PubMed  CAS  Google Scholar 

  • Nielsen E., Severin F., Backer J. M., Hyman A. A., and Zerial M. (1999) Rab5 regulates motility of early endosomes on microtubules. Nat. Cell Biol. 1, 376–382.

    Article  PubMed  CAS  Google Scholar 

  • Otero G., Fellows J., Li Y., et al. (1999) Elongator, a multisubunit component of a novel RNA polymerase II holoenzy me for transcriptional elongation. Mol. Cell 3, 109–118.

    Article  PubMed  CAS  Google Scholar 

  • Pinsky L. and DiGeorge A. M. (1966) Congenital familial sensory neuropathy with anhidrosis. J. Pediatr. 68, 1–13.

    Article  PubMed  CAS  Google Scholar 

  • Rafel E., Alberca R., Bautista J., Navarrete M., and Lazo J. (1980) Congenital insensitivity to pain with anhidrosis. Muscle Nerve 3, 216–220.

    Article  PubMed  CAS  Google Scholar 

  • Riley C. D., Day R. L., Greeley D. M., Langford W. S. (1949) Central autonomic dysfunction with defective lacrimation. I. Report of five cases. Pediatrics 3, 468–478.

    PubMed  CAS  Google Scholar 

  • Riviere J. B., Verlaan D. J., Shekarabi M., et al. (2004) A mutation in the HSN2 gene causes sensory neuropathy type II in a Lebanese family. Ann. Neurol. 56, 572–575.

    Article  PubMed  CAS  Google Scholar 

  • Roddier K., Thomas T., Marleau G., et al. (2005) Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians. Neurology 64, 1762–1767.

    Article  PubMed  CAS  Google Scholar 

  • Seeman P., Mazanec R., Boehm J., et al. (2005) Inherited ulcero-mutilating neuropathies CMT2B and HSN1 in Czech families. In PNS-Meeting, p. 235.

  • Shatzky S., Moses S., Levy J., et al. (2000) 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. 92, 353–360.

    Article  PubMed  CAS  Google Scholar 

  • Slaugenhaupt S. A., Blumenfeld A., Gill S. P., et al. (2001) Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am. J. Hum. Genet. 68, 598–605.

    Article  PubMed  CAS  Google Scholar 

  • Smeyne R. J., Klein R., Schnapp A., et al. (1994) Severe sensory and sympathetic neuropathies in mice carying a disrupted Trk/NGF receptor gene. Nature 368, 246–249.

    Article  PubMed  CAS  Google Scholar 

  • Spring P. J. (2002) Autosomal Dominant Hereditary Sensory Neuropathy with Gastro-Oesophageal Reflux and Cough: Clinical Features of a Family. S64.

  • Sugarman E. (2002) Familial dysautonomia mutation frequency: clinical testing of greater than 2700 specimens confirms high frequency in Ashkenazi Jews. Am. J. Hum. Genet. 71(Suppl. 1), 387.

    Google Scholar 

  • Thevenard A. (1942) L'Acropathie ulcero-mutilante familiale. Rev. Neurol. (Paris) 74, 193–212.

    Google Scholar 

  • Vance J. M., Speer M. C., Stajich J. M., et al. (1996) Misclassification and linkage of hereditary sensory and autonomic neuropathy type 1 as Charcot-Marie-Tooth disease, type 2B. Am. J. Hum. Genet. 59, 258–262.

    PubMed  CAS  Google Scholar 

  • Verhoeven K., Coen K., De Vriendt E., et al. (2004) SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I. Neurology 62, 1001–1002.

    Article  PubMed  CAS  Google Scholar 

  • Verhoeven K., De Jonghe P., Coen K., et al. (2003) Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am. J. Hum. Genet. 72, 722–727.

    Article  PubMed  CAS  Google Scholar 

  • Weier H. U., Rhein A. P., Shadravan F., Collins C., and Polikoff D. (1995) Rapid physical mapping of the human trk protooncogene (NTRK1) to human chromosome 1q21-q22 by P1 clone selection, fluorescence in situ hybridization (FISH), and computer-assisted microscopy. Genomics 26, 390–393.

    Article  PubMed  CAS  Google Scholar 

  • Whitaker J. N., Falchuck Z. M., Engel W. K., Blaese R. M. and Strober W. (1974) Hereditary sensory neuropathy. Association with increased synthesis of immunoglobulin A. Arch. Neurol. 30, 359–371.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Medical Research Center, Medical University of Graz, Stiftingtalstraße 24, A-8010, Graz, Austria

    Michaela Auer-Grumbach, Barbara Mauko & Thomas R. Pieber

  2. Gesundheitszentrum Feldbach, Austria

    Piet Auer-Grumbach

Authors
  1. Michaela Auer-Grumbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Barbara Mauko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Piet Auer-Grumbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas R. Pieber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michaela Auer-Grumbach.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Auer-Grumbach, M., Mauko, B., Auer-Grumbach, P. et al. Molecular genetics of hereditary sensory neuropathies. Neuromol Med 8, 147–158 (2006). https://doi.org/10.1385/NMM:8:1-2:147

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1385/NMM:8:1-2:147

Index Entries

Search

Navigation