hereditary sensory and autonomic neuropathies

Summary

Summary: A group of inherited disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and clinically by loss of sensation and autonomic dysfunction. There are five subtypes. Type I features autosomal dominant inheritance and distal sensory involvement. Type II is characterized by autosomal inheritance and distal and proximal sensory loss. Type III is DYSAUTONOMIA, FAMILIAL. Type IV features insensitivity to pain, heat intolerance, and mental deficiency. Type V is characterized by a selective loss of pain with intact light touch and vibratory sensation. (From Joynt, Clinical Neurology, 1995, Ch51, pp142-4)

Top Publications

  1. Nolano M, Crisci C, Santoro L, Barbieri F, Casale R, Kennedy W, et al. Absent innervation of skin and sweat glands in congenital insensitivity to pain with anhidrosis. Clin Neurophysiol. 2000;111:1596-601 pubmed
    ..A case of a 10-year-old girl with congenital insensitivity to pain with anhidrosis (CIPA) is reported...
  2. Bodzioch M, Lapicka K, Aslanidis C, Kacinski M, Schmitz G. Two novel mutant alleles of the gene encoding neurotrophic tyrosine kinase receptor type 1 (NTRK1) in a patient with congenital insensitivity to pain with anhidrosis: a splice junction mutation in intron 5 and cluster of four mutations in exon 15. Hum Mutat. 2001;17:72 pubmed
    ..Our report increases the spectrum of NTRK1 mutations in CIPA patients and describes an unusual case of a cluster of four mutations located close to each other in one exon...
  3. Bejaoui K, Wu C, Scheffler M, Haan G, Ashby P, Wu L, et al. SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet. 2001;27:261-2 pubmed
    ..1) genetically maps to human chromosome 9q22 (refs. 2-4). We report here that the gene encoding a subunit of serine palmitoyltransferase is located within the HSN1 locus, expressed in dorsal root ganglia (DRG) and mutated in HSN1...
  4. Dawkins J, Hulme D, Brahmbhatt S, Auer Grumbach M, Nicholson G. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet. 2001;27:309-12 pubmed
    ..Increased de novo ceramide synthesis triggers apoptosis and is associated with massive cell death during neural tube closure, raising the possibility that neural degeneration in HSN1 is due to ceramide-induced apoptotic cell death...
  5. Axelrod F, Gold von Simson G. Hereditary sensory and autonomic neuropathies: types II, III, and IV. Orphanet J Rare Dis. 2007;2:39 pubmed
    The hereditary sensory and autonomic neuropathies (HSAN) encompass a number of inherited disorders that are associated with sensory dysfunction (depressed reflexes, altered pain and temperature perception) and varying degrees of ..
  6. Rotthier A, Baets J, Timmerman V, Janssens K. Mechanisms of disease in hereditary sensory and autonomic neuropathies. Nat Rev Neurol. 2012;8:73-85 pubmed publisher
    b>Hereditary sensory and autonomic neuropathies (HSANs) are a clinically and genetically heterogeneous group of disorders of the PNS...
  7. Rotthier A, Baets J, De Vriendt E, Jacobs A, Auer Grumbach M, Levy N, et al. Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation. Brain. 2009;132:2699-711 pubmed publisher
    b>Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons...
  8. Verhoeven K, Coen K, De Vriendt E, Jacobs A, Van Gerwen V, Smouts I, et al. SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I. Neurology. 2004;62:1001-2 pubmed
    ..A novel missense mutation in exon 13 of the SPTLC1 gene (c.1160G-->C; p.G387A) in twin sisters with a severe HSN I phenotype is reported...
  9. Kok C, Kennerson M, Spring P, Ing A, Pollard J, Nicholson G. A locus for hereditary sensory neuropathy with cough and gastroesophageal reflux on chromosome 3p22-p24. Am J Hum Genet. 2003;73:632-7 pubmed
    ..A second family with a similar phenotype shares a different disease haplotype but segregates at the same locus. Extended haplotype analysis has refined the region to a 3.42-cM interval, flanked by markers D3S2336 and D3S1266...

More Information

Publications62

  1. Verpoorten N, Claeys K, Deprez L, Jacobs A, Van Gerwen V, Lagae L, et al. Novel frameshift and splice site mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with hereditary sensory neuropathy type IV. Neuromuscul Disord. 2006;16:19-25 pubmed
    ..NTRK1 mutations are only rarely reported in the European population. This report extends the spectrum of NTRK1 mutations observed in patients diagnosed with HSAN IV...
  2. Verhoeven K, Timmerman V, Mauko B, Pieber T, De Jonghe P, Auer Grumbach M. Recent advances in hereditary sensory and autonomic neuropathies. Curr Opin Neurol. 2006;19:474-80 pubmed
    This review summarizes the genetic advances of hereditary sensory neuropathies and hereditary sensory and autonomic neuropathies, and provides information on phenotype-genotype correlation and on possible underlying pathomechanisms.
  3. Indo Y. Nerve growth factor, interoception, and sympathetic neuron: lesson from congenital insensitivity to pain with anhidrosis. Auton Neurosci. 2009;147:3-8 pubmed publisher
    ..Thus, NGF-dependent neurons play a crucial role in emotional experiences and decision-making processes. Prospective studies focused on these neurons might provide further insights into the neural basis of human emotion and feeling...
  4. Houlden H, King R, Muddle J, Warner T, Reilly M, Orrell R, et al. A novel RAB7 mutation associated with ulcero-mutilating neuropathy. Ann Neurol. 2004;56:586-90 pubmed
    ..The mutation is situated adjacent to a previously identified valine to methionine mutation at codon 162, implying a hotspot for mutations in the highly conserved C terminus of RAB7...
  5. Eichler F, Hornemann T, McCampbell A, Kuljis D, Penno A, Vardeh D, et al. Overexpression of the wild-type SPT1 subunit lowers desoxysphingolipid levels and rescues the phenotype of HSAN1. J Neurosci. 2009;29:14646-51 pubmed publisher
    ..This observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite...
  6. Covaceuszach S, Capsoni S, Marinelli S, Pavone F, Ceci M, Ugolini G, et al. In vitro receptor binding properties of a "painless" NGF mutein, linked to hereditary sensory autonomic neuropathy type V. Biochem Biophys Res Commun. 2010;391:824-9 pubmed publisher
    ..These results provide a basis for elucidating the mechanisms underlying the clinical manifestations of HSAN V patients, and provide a basis for the development of "painless" hNGF molecules with therapeutic potential...
  7. Murphy S, Ernst D, Wei Y, Laura M, Liu Y, Polke J, et al. Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2. Neurology. 2013;80:2106-11 pubmed publisher
    ..To describe the clinical and neurophysiologic phenotype of a family with hereditary sensory and autonomic neuropathy type 1 (HSANI) due to a novel mutation in SPTLC2 and to characterize the biochemical properties of this mutation...
  8. Auer Grumbach M, Bode H, Pieber T, Schabhüttl M, Fischer D, Seidl R, et al. Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype. Eur J Med Genet. 2013;56:266-9 pubmed publisher
    ..In contrast to other HSN patients reported so far, our findings strongly indicate that mutations at amino acid position Ser331 of the SPTLC1 gene lead to a distinct syndrome...
  9. Li M, Liang J, Sun Z, Zhang H, Yao Z. Novel nonsense and frameshift NTRK1 gene mutations in Chinese patients with congenital insensitivity to pain with anhidrosis. Genet Mol Res. 2012;11:2156-62 pubmed publisher
    ..Thirty-four among the 62 mutations (55%) are located within the tyrosine kinase domain of the NTRK1 protein. We concluded that the tyrosine kinase domain is a hot spot for mutations...
  10. Bellone E, Rodolico C, Toscano A, Di Maria E, Cassandrini D, Pizzuti A, et al. A family with autosomal dominant mutilating neuropathy not linked to either Charcot-Marie-Tooth disease type 2B (CMT2B) or hereditary sensory neuropathy type I (HSN I) loci. Neuromuscul Disord. 2002;12:286-91 pubmed
  11. Houlden H, King R, Hashemi Nejad A, Wood N, Mathias C, Reilly M, et al. A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V. Ann Neurol. 2001;49:521-5 pubmed
    ..Mutations in this gene are known to be responsible for HSAN IV (congenital insensitivity to pain with anhidrosis). The two disorders are therefore likely to be allelic...
  12. Houlden H, King R, Blake J, Groves M, Love S, Woodward C, et al. Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I). Brain. 2006;129:411-25 pubmed
  13. Axelrod F. Hereditary sensory and autonomic neuropathies. Familial dysautonomia and other HSANs. Clin Auton Res. 2002;12 Suppl 1:I2-14 pubmed
  14. Dedov V, Dedova I, Merrill A, Nicholson G. Activity of partially inhibited serine palmitoyltransferase is sufficient for normal sphingolipid metabolism and viability of HSN1 patient cells. Biochim Biophys Acta. 2004;1688:168-75 pubmed
  15. Tomioka T, Awaya Y, Nihei K, Sekiyama H, Sawamura S, Hanaoka K. Anesthesia for patients with congenital insensitivity to pain and anhidrosis: a questionnaire study in Japan. Anesth Analg. 2002;94:271-4, table of contents pubmed
    ..Therefore, patients with CIPA can be safely managed with anesthesia...
  16. Rotthier A, Penno A, Rautenstrauss B, Auer Grumbach M, Stettner G, Asselbergh B, et al. Characterization of two mutations in the SPTLC1 subunit of serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathy type I. Hum Mutat. 2011;32:E2211-25 pubmed publisher
  17. Hilz M. Assessment and evaluation of hereditary sensory and autonomic neuropathies with autonomic and neurophysiological examinations. Clin Auton Res. 2002;12 Suppl 1:I33-43 pubmed
    The five different types of the rare hereditary sensory and autonomic neuropathies (HSAN) are classified by their mode of inheritance, pathology, natural history, biochemical, neurophysiologic and autonomic abnormalities...
  18. Minde J, Andersson T, Fulford M, Aguirre M, Nennesmo I, Remahl I, et al. A novel NGFB point mutation: a phenotype study of heterozygous patients. J Neurol Neurosurg Psychiatry. 2009;80:188-95 pubmed publisher
    ..The homozygous genotype gives disabling symptoms. The purpose of the present study was to evaluate the symptoms in heterozygous patients...
  19. Rotthier A, Auer Grumbach M, Janssens K, Baets J, Penno A, Almeida Souza L, et al. Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am J Hum Genet. 2010;87:513-22 pubmed publisher
    ..We further show that HSAN-I is consistently associated with an increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I...
  20. Guelly C, Zhu P, Leonardis L, Papić L, Zidar J, Schabhüttl M, 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;88:99-105 pubmed publisher
    ..196G>C [p.Glu66Gln] and c.976 delG [p.Val326TrpfsX8]). This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders...
  21. Miura Y, Mardy S, Awaya Y, Nihei K, Endo F, Matsuda I, et al. Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families. Hum Genet. 2000;106:116-24 pubmed
  22. McCormick J, Ellison D. The WNKs: atypical protein kinases with pleiotropic actions. Physiol Rev. 2011;91:177-219 pubmed publisher
    ..Next, consequences of these effects on integrated physiological function are outlined. Finally, we discuss the known and putative pathophysiological relevance of the WNKs...
  23. Axelrod F, Chelimsky G, Weese Mayer D. Pediatric autonomic disorders. Pediatrics. 2006;118:309-21 pubmed
    ..To illustrate further the breadth and complexities of autonomic dysfunction, some pediatric disorders are described, concentrating on those that present at birth or appear in early childhood...
  24. Hornemann T, Penno A, Richard S, Nicholson G, van Dijk F, Rotthier A, et al. A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated. Neurogenetics. 2009;10:135-43 pubmed publisher
    ..These findings were genetically confirmed by the identification of a nuclear HSAN family which showed segregation of the G387A variant as a non-synonymous SNP...
  25. Lee S, Lee J, Lee M, Kim J, Ki C. Clinical and genetic analysis of Korean patients with congenital insensitivity to pain with anhidrosis. Muscle Nerve. 2009;40:855-9 pubmed publisher
    ..This study extends the spectrum of mutations in the NTRK1 gene and confirms that Korean patients with CIPA have the same genetic background as other ethnicities...
  26. Gable K, Gupta S, Han G, Niranjanakumari S, Harmon J, Dunn T. A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity. J Biol Chem. 2010;285:22846-52 pubmed publisher
    ..GADD153 was also elevated in cells treated with 1-deoxySa. Taken together, these data indicate that the HSAN1 mutations perturb the active site of SPT resulting in a gain of function that is responsible for the HSAN1 phenotype...
  27. Gable K, Han G, Monaghan E, Bacikova D, Natarajan M, Williams R, et al. 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. 2002;277:10194-200 pubmed
  28. Lafreniere R, MacDonald M, Dube M, MacFarlane J, O Driscoll M, Brais B, 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;74:1064-73 pubmed
    ..The HSN2 protein may play a role in the development and/or maintenance of peripheral sensory neurons or their supporting Schwann cells...
  29. Hojo K, Kawamata T, Tanaka C, Maeda K. Inflammatory glial activation in the brain of a patient with hereditary sensory neuropathy type 1 with deafness and dementia. Neurosci Lett. 2004;367:340-3 pubmed
    ..These results indicate that the widespread neuronal degeneration may be accelerated by inflammatory processes including glial activation in the brain of a patient with HSN-1 associated with deafness and dementia...
  30. Verpoorten N, De Jonghe P, Timmerman V. Disease mechanisms in hereditary sensory and autonomic neuropathies. Neurobiol Dis. 2006;21:247-55 pubmed
    ..In contrast, sensory abnormalities predominate or are exclusively present in hereditary sensory and autonomic neuropathies (HSAN)...
  31. Geraldes R, de Carvalho M, Santos Bento M, Nicholson G. Hereditary sensory neuropathy type 1 in a Portuguese family-electrodiagnostic and autonomic nervous system studies. J Neurol Sci. 2004;227:35-8 pubmed
    ..This report documents the lesion of the motor nerve fibers in this disease, as well as the preservation of the autonomic nervous system function, therefore suggesting that HSNA is an inappropriate name for this disorder...
  32. Houlden H, Blake J, Reilly M. Hereditary sensory neuropathies. Curr Opin Neurol. 2004;17:569-77 pubmed
    The hereditary sensory neuropathies, also known as the hereditary sensory and autonomic neuropathies, are a clinically and genetically heterogeneous group of disorders...
  33. Bouhouche A, Benomar A, Bouslam N, Ouazzani R, Chkili T, Yahyaoui M. Autosomal recessive mutilating sensory neuropathy with spastic paraplegia maps to chromosome 5p15.31-14.1. Eur J Hum Genet. 2006;14:249-52 pubmed
    ..92 was obtained for all markers located in this candidate interval. This study establishes the presence of a locus for autosomal recessive mutilating sensory neuropathy with spastic paraplegia on chromosome 5p15.31-14.1...
  34. Potulska Chromik A, Kabzinska D, Lipowska M, Kostera Pruszczyk A, Kochanski A. A novel homozygous mutation in the WNK1/HSN2 gene causing hereditary sensory neuropathy type 2. Acta Biochim Pol. 2012;59:413-5 pubmed
    ..To the best of our knowledge this is the first genetically proven case of hereditary sensory and autonomic neuropathy type 2 originating from East Europe...
  35. Indo Y. Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. Hum Mutat. 2001;18:462-71 pubmed
    ..Further, molecular pathology of CIPA would provide unique opportunities to explore critical roles of the autonomic sympathetic nervous system as well as peripheral sensory nervous system that transmit noxious stimuli in humans...
  36. Hanada K. Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. Biochim Biophys Acta. 2003;1632:16-30 pubmed
    ..Specific missense mutations in the human LCB1 gene cause hereditary sensory neuropathy type I, an autosomal dominantly inherited disease, and these mutations confer dominant-negative effects on SPT activity...
  37. de Andrade D, Baudic S, Attal N, Rodrigues C, Caramelli P, Lino A, et al. Beyond neuropathy in hereditary sensory and autonomic neuropathy type V: cognitive evaluation. Eur J Neurol. 2008;15:712-9 pubmed publisher
    ..HSAN type V is usually reported not to cause mental retardation or cognitive decline. However, a structured assessment of the cognitive profile of these patients has never been made...
  38. Coen K, Pareyson D, Auer Grumbach M, Buyse G, Goemans N, Claeys K, et al. Novel mutations in the HSN2 gene causing hereditary sensory and autonomic neuropathy type II. Neurology. 2006;66:748-51 pubmed
    ..Genotype-phenotype correlations indicated that HSN2 mutations are associated with an early childhood onset of a predominantly sensory neuropathy, complicated by acromutilations in both upper and lower limbs...
  39. Bonkowsky J, Johnson J, Carey J, Smith A, Swoboda K. An infant with primary tooth loss and palmar hyperkeratosis: a novel mutation in the NTRK1 gene causing congenital insensitivity to pain with anhidrosis. Pediatrics. 2003;112:e237-41 pubmed
    ..Immunohistochemistry of skin biopsy specimens, together with routine nerve conduction studies, can provide quick and reliable confirmation if CIPA is clinically suspected...
  40. Tuysuz B, Bayrakli F, DiLuna M, Bilguvar K, Bayri Y, Yalcinkaya C, et al. Novel NTRK1 mutations cause hereditary sensory and autonomic neuropathy type IV: demonstration of a founder mutation in the Turkish population. Neurogenetics. 2008;9:119-25 pubmed publisher
    ..This report broadens the spectrum of mutations in NTRK1 that cause HSAN IV and demonstrates a founder mutation in the Turkish population...
  41. Minde J, Toolanen G, Andersson T, Nennesmo I, Remahl I, Svensson O, et al. Familial insensitivity to pain (HSAN V) and a mutation in the NGFB gene. A neurophysiological and pathological study. Muscle Nerve. 2004;30:752-60 pubmed
    ..The three most severely affected cases were all born to consanguineous parents, and were homozygotes for the causal genetic mutation. Treatment of these patients is discussed...
  42. Dawkins J, Brahmbhatt S, Auer Grumbach M, Wagner K, Hartung H, Verhoeven K, et al. Exclusion of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) as a common cause for hereditary sensory neuropathy. Neuromuscul Disord. 2002;12:656-8 pubmed
    ..No mutations in the SPTLC2 gene were found in any family. These results suggest that SPTLC2 mutations are not a common cause for genetic sensory neuropathies...
  43. Dubourg O, Barhoumi C, Azzedine H, Birouk N, Brice A, Bouche P, et al. Phenotypic and genetic study of a family with hereditary sensory neuropathy and prominent weakness. Muscle Nerve. 2000;23:1508-14 pubmed
    ..Results of linkage analysis excluded the Charcot-Marie-Tooth 2A (CMT2A) and CMT2B loci and suggested the possibility of a linkage to HSAN-I locus on 9q22.1-q22.3...
  44. Nicholson G, Dawkins J, Blair I, Auer Grumbach M, Brahmbhatt S, Hulme D. Hereditary sensory neuropathy type I: haplotype analysis shows founders in southern England and Europe. Am J Hum Genet. 2001;69:655-9 pubmed
    ..The sensorimotor neuropathy phenotype caused by the 399T-->G SPTLC1 mutation is the same as that reported by Campbell and Hoffman and, possibly, the same as that originally described by Hicks...
  45. Indo Y, Mardy S, Miura Y, Moosa A, Ismail E, Toscano E, et al. Congenital insensitivity to pain with anhidrosis (CIPA): novel mutations of the TRKA (NTRK1) gene, a putative uniparental disomy, and a linkage of the mutant TRKA and PKLR genes in a family with CIPA and pyruvate kinase deficiency. Hum Mutat. 2001;18:308-18 pubmed
    ..All these data further support findings that TRKA defects can cause CIPA in various ethnic groups. This will aid in diagnosis and genetic counseling of this painless but severe genetic disorder...
  46. Spring P, Kok C, Nicholson G, Ing A, Spies J, Bassett M, 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 pubmed
    ..These families represent a genetically novel variant of HSN I, with a distinctive cough owing to involvement of the upper aerodigestive tract...
  47. Bejaoui K, Uchida Y, Yasuda S, Ho M, Nishijima M, Brown R, et al. Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis. J Clin Invest. 2002;110:1301-8 pubmed
    ..These results indicate that the HSN1-associated mutations in LCB1 confer dominant negative effects on the SPT enzyme...
  48. Auer Grumbach M. Hereditary sensory neuropathies. Drugs Today (Barc). 2004;40:385-94 pubmed
    ..They will also be the basis for functional studies in the future...
  49. Rivière J, Ramalingam S, Lavastre V, Shekarabi M, Holbert S, Lafontaine J, et al. KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2. Am J Hum Genet. 2011;89:219-30 pubmed publisher
    ..This study provides additional insights into the molecular pathogenesis of HSANII and highlights the potential biological relevance of alternative splicing in the peripheral sensory nervous system...
  50. Garofalo K, Penno A, Schmidt B, Lee H, Frosch M, von Eckardstein A, 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;121:4735-45 pubmed publisher
    ..These observations support the hypothesis that an altered substrate selectivity of the mutant SPT is key to the pathophysiology of HSAN1 and raise the prospect of l-serine supplementation as a first treatment option for this disorder...
  51. Huehne K, Zweier C, Raab K, Odent S, Bonnaure Mallet M, Sixou J, et al. Novel missense, insertion and deletion mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with congenital insensitivity to pain with anhidrosis. Neuromuscul Disord. 2008;18:159-66 pubmed
    ..7335164-7336545del), a homozygous insertion c.722_723insC in exon 7 and two compound heterozygous mutations (p.Q558X+p.L717R). The less typical patient as well as one HSAN IV patient revealed no NTRK1 mutation...
  52. Penno A, Reilly M, Houlden H, Laura M, Rentsch K, Niederkofler V, et al. Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem. 2010;285:11178-87 pubmed publisher
    ..Based on these observations, we conclude that HSAN1 is caused by a gain of function mutation, which results in the formation of two atypical and neurotoxic sphingolipid metabolites...
  53. Bertorini T, Narayanaswami P, Rashed H. Charcot-Marie-Tooth disease (hereditary motor sensory neuropathies) and hereditary sensory and autonomic neuropathies. Neurologist. 2004;10:327-37 pubmed
    ..These disorders can also have variable phenotypes due to dysfunction of peripheral nerve axons or their myelin due to the genetic defects that affect the formation of specific nerve proteins...