The hereditary sensory and autonomic neuropathies (HSAN), which are also referred to as hereditary sensory neuropathies (HSN) in the absence of significant autonomic features, are a genetically and clinically heterogeneous group of disorders associated with sensory dysfunction. ... The hereditary sensory and autonomic neuropathies (HSAN), which are also referred to as hereditary sensory neuropathies (HSN) in the absence of significant autonomic features, are a genetically and clinically heterogeneous group of disorders associated with sensory dysfunction. HSAN1 is a dominantly inherited sensorimotor axonal neuropathy with onset in the first or second decades of life. - Genetic Heterogeneity of HSAN See also HSAN1C (613640), caused by mutation in the SPTLC2 gene on 14q24; HSN1D (613708), caused by mutation in the ATL1 gene (606439) on 14q; HSN1E (614116), caused by mutation in the DNMT1 gene (126375) on 19p13; HSAN2a (201300), caused by mutation in the HSN2 isoform of the WNK1 gene (605232) on 12p13; HSAN2B (613115), caused by mutation in the FAM134B gene (613114) on 5p15; HSN2C (614213), caused by mutation in the KIF1A gene (601255) on 2q37; HSAN3 (223900) caused by mutation in the IKBKAP gene (603722) on 9q31; HSAN4 (256800) caused by mutation in the NTRK1 gene (191315) on 1q21; HSAN5 (608654) caused by mutation in the NGFB gene (162030) on 1p13; HSAN6 (614653), caused by mutation in the DST gene (113810) on chromosome 6p; and HSAN7 (615548), caused by mutation in the SCN11A gene (604385) on chromosome 3p22. Adult-onset HSAN with anosmia (608720) is believed to be another distinct form of HSAN, and HSAN1B (608088) with cough and gastroesophageal reflux maps to chromosome 3p24-p22.
Hicks (1922) described an English family in which 10 members suffered from perforating ulcers of the feet, shooting pains, and deafness. Age of onset ranged from 15 to 36 years. Presentation was usually with a corn on a ... Hicks (1922) described an English family in which 10 members suffered from perforating ulcers of the feet, shooting pains, and deafness. Age of onset ranged from 15 to 36 years. Presentation was usually with a corn on a big toe followed by a painless ulcer with bony debris. Patients later experienced shooting pains similar to the lightning pains of tabes dorsalis and developed bilateral deafness progressing to total deafness over several years. Neurologic examination showed disappearance of ankle and knee jerks and absence of an extensor plantar response. There was loss of pain, touch, heat, and cold sensation over the feet, but sensation of the arms remained normal. Cranial nerves were normal, with the exception of the auditory nerve, pupils reacted normally, and there was no nystagmus. Hicks (1922) noted that although hereditary perforating ulcers of the feet had been reported in patients in the past, there had been no previous mention of accompanying deafness or shooting pains. Denny-Brown (1951) reported the clinical and autopsy findings of a 53-year-old woman who was a member of the family reported by Hicks (1922). When she was 22 years of age, an ulcer formed on her right great toe, requiring a year to heal. She subsequently suffered from recurrent ulceration, each episode lasting 6 to 9 months and sometimes extending to bone. In her early twenties, she first noticed shooting pains in her legs, sometimes in her arms. Deafness began at the age of 40 years and progressed to almost total deafness by 53 years of age. Neurologic examination at 53 years of age showed loss of all sensation in the lower legs, with loss of pain and temperature sensation in the thighs and hands. Autopsy showed a small brain and marked loss of ganglion cells in the sacral and lumbar dorsal root ganglia. Remaining ganglion cells showed proliferation of subcapsular dendrites and hyaline bodies, possibly representing an amyloid mass around capillaries. There were less severe changes in C-8 and T-1 ganglia. The affected families reported by Ervin and Sternbach (1960) and Silverman and Gilden (1959) appeared to show autosomal dominant inheritance. Mandell and Smith (1960) observed sensory radicular neuropathy in 3 generations of a family. Clinical features included neuropathic arthropathy, recurrent ulceration of the lower extremities, and signs of radicular sensory deficiency in both the upper and the lower extremities without any motor dysfunction. Dyck et al. (1965) described a family with sensory neuropathy accompanied by peroneal muscular atrophy and pes cavus. Campbell and Hoffman (1964) and DeLeon (1969) also reported cases in which amyotrophy was a feature. Using a cholinesterase technique on skin biopsies from the pad of the great toe of affected persons, Dyck et al. (1965) found normal numbers of Meissner corpuscles in a 14-year-old boy with early signs suggestive of the disorder, but no corpuscles in a 37-year-old man and a 28-year-old woman with well-developed disease. Dyck et al. (1983) noted that 'burning feet' may be the only manifestation of dominantly inherited sensory neuropathy. The symptoms are ameliorated by cold and aggravated by heat. Restless legs and lancinating pain are other presentations of the disorder, which often resulted in severe distal sensory loss, mutilating acropathy, and neurotrophic arthropathy. In a detailed clinical study of a patient with HSN1, including audiometric testing, autonomic functions, electromyography, transcranial magnetic stimulation, and brain imaging, Hageman et al. (1992) determined that there were no signs of central nervous system involvement and stated that HSN1 is a disorder of the dorsal root ganglia and peripheral nerves. Wallace (1968, 1970) studied an extensively affected Australian kindred. In a study of this kindred and 3 other Australian kindreds with HSAN1, Nicholson et al. (1996) found that a typical history included lightning pains, painless skin injuries and ulceration, and signs including distal sensory loss to sharp, hot, and cold sensation, with loss of distal reflexes and distal muscle wasting. Nerve conduction velocities showed an axonal neuropathy, particularly of the lower limbs. Dubourg et al. (2000) reported a French family with autosomal dominant hereditary sensory neuropathy suggestive of linkage to chromosome 9q. Mean age at onset was 34 years. All patients presented with distal sensory loss and distal muscle weakness of both the upper and lower limbs. Four patients had foot ulcerations, and 3 patients had hyperhidrosis. Motor nerve conduction velocities were normal or mildly decreased, consistent with an axonal neuropathy. Sensory nerve action potentials were either reduced or could not be recorded. - Clinical Variability Rotthier et al. (2009) reported a French Gypsy patient with an unusually severe form of HSAN1. The patient had congenital onset, insensitivity to pain with eschar and foot ulceration, pes cavus/equinovarus, vocal cord paralysis, and gastroesophageal reflux. The patient also had severe growth and mental retardation, microcephaly, hypotonia, amyotrophy, and respiratory insufficiency. Nerve conduction studies showed absent sensory and motor responses in the upper and lower limbs. Genetic analysis identified a de novo heterozygous mutation in the SPTLC1 gene (S331F; 605712.0005). The phenotype expanded the clinical spectrum of HSAN1.
In all affected members of 11 HSN1 families, Dawkins et al. (2001) identified mutations in the SPTLC1 gene (C133Y, 605712.0001; C133W, 605712.0002; V144D, 605712.0003). Bejaoui et al. (2001) independently identified 2 of the same SPTLC1 mutations in 2 ... In all affected members of 11 HSN1 families, Dawkins et al. (2001) identified mutations in the SPTLC1 gene (C133Y, 605712.0001; C133W, 605712.0002; V144D, 605712.0003). Bejaoui et al. (2001) independently identified 2 of the same SPTLC1 mutations in 2 unrelated families with HSN1. In twin sisters with HSN1 from a Belgian family originally reported by Montanini (1958), Verhoeven et al. (2004) identified a mutation in the SPTLC1 gene (G387A; 605712.0004). The findings of Hornemann et al. (2009) cast doubt on the pathogenicity of the G387A mutation. By in vitro functional expression assays in HEK293 cells, Hornemann et al. (2009) found that none of the 4 SPTLC1 mutations, C133Y, C133W, V144D, or G387A, interfered with formation of the SPT complex. The first 3 mutant proteins resulted in 40 to 50% decreased SPT activity, but the G387A protein showed no effect on SPT activity. Further studies showed that the G387A protein could rescue a SPTLC1-deficient cell line. Finally, Hornemann et al. (2009) identified an unaffected woman who was homozygous for the G387A mutation, suggesting that it is not pathogenic. Hornemann et al. (2009) postulated that the G387A variant, and perhaps the other 3 SPTLC1 variants previously associated with HSN1, may not be directly disease-causing, but rather have an indirect or bystander effect by increasing the risk for HSN1 in conjunction with another mutation.
Nicholson et al. (2001) found that 3 Australian families of English extraction and 3 English families had the same SPTLC1 mutation (605712.0002), the same chromosome 9 haplotype, and the same phenotype. They therefore concluded that the Australian and ... Nicholson et al. (2001) found that 3 Australian families of English extraction and 3 English families had the same SPTLC1 mutation (605712.0002), the same chromosome 9 haplotype, and the same phenotype. They therefore concluded that the Australian and English families had the same founder who, on the basis of historical information, lived in southern England before 1800. The phenotype caused by this mutation is the same as that in the English families of Campbell and Hoffman (1964) and possibly in the original English family of Hicks (1922).
The clinical diagnosis of hereditary sensory neuropathy type IA (HSN1A) is based on presence of the following:...
DiagnosisClinical DiagnosisThe clinical diagnosis of hereditary sensory neuropathy type IA (HSN1A) is based on presence of the following:Sensory loss that is more severe than in other motor and sensory neuropathies Commonly, foot ulcers; shooting pains may be a distinctive but variable feature. An axonal neuropathy resembling Charcot-Marie-Tooth Neuropathy Type 2 (CMT2), resulting in distal muscle weakness and, in advanced stages, proximal weakness Family history consistent with autosomal dominant inheritance Sensorineural hearing loss (variably present) Electrophysiology is initially normal and is not useful for early detection [Author, personal observation]. Sensory nerve action potentials are reduced only late in the disease. Motor nerve conduction velocities are normal until motor action potential amplitudes become reduced. Motor nerve conduction velocities are mildly slowed and motor action potentials are reduced in advanced cases. Sural nerve biopsy shows axonal degeneration with loss of both small and large fibers. These findings are nonspecific and not diagnostic. Molecular Genetic TestingGene. SPTLC1 is the only gene in which mutations are currently known to cause HSN1A [Bejaoui et al 2001, Dawkins et al 2001]. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Hereditary Sensory Neuropathy Type IAView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1, 2Test AvailabilityPositive Family HistoryNegative Family HistorySPTLC1Sequence analysis of select exons Sequence variants 3 in exon 5 (incl. p.Cys133Tyr, p.Cys133Trp) and exon 6 (p.Val144Asp) 47 families (86%) N/AClinical Sequence analysisSequence variants 3 including the known mutations p.Cys133Tyr, p.Cys133Trp, and p.Val144AspN/A10 families (10%)1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Houlden et al [2006], Personal communication 3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 4. Bejaoui et al [2001], Dawkins et al [2001]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband Clinical examination Molecular genetic testing of SPTLC1 may begin with sequence analysis of exons 5 and 6. If no disease causing mutation is identified, further sequence analysis of SPTLC1 may be considered. However, only mutations affecting the SPT active site and the SPTLC2 subunit of the SPT dimer cause the phenotype. Note: Sural nerve biopsy is not used for diagnosis.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in SPTLC1.
Hereditary sensory neuropathy type IA (HSN1A) is usually first noticed when painless injuries appear. Onset ranges from the teens to the sixth decade. Later, positive sensory phenomena occur (numbness, paresthesia, burning, and shooting pains). Shooting pains may be a distinctive but variable feature of HSN1. ...
Natural HistoryHereditary sensory neuropathy type IA (HSN1A) is usually first noticed when painless injuries appear. Onset ranges from the teens to the sixth decade. Later, positive sensory phenomena occur (numbness, paresthesia, burning, and shooting pains). Shooting pains may be a distinctive but variable feature of HSN1. If the sensory loss is unheeded, chronic ulcerations of the extremities may lead to osteomyelitis and require amputations. Neuropathic joints are common.Weakness commences in the distal lower limbs, followed by the distal upper limbs and in severe cases, proximal upper- and lower-limb girdle muscles. Distal muscle weakness and wasting is present in all advanced cases. The weakness of ankle flexors produces a floppy, flipper-like foot rather than pes cavus. A few instances of early severe motor involvement have been reported [Houlden et al 2006].Older affected individuals may require wheelchairs for mobility.Retained and even brisk proximal reflexes in some affected individuals may indicate some upper motor neuron involvement. Corticospinal degeneration was not observed in an autopsied case with a known SPTLC1 mutation, but data are limited.Sensorineural hearing loss is variable. When present, its onset is in middle to late adulthood. Rarely, pupillary abnormalities termed "tonic pupils" or pseudo-Argyll-Robertson pupils (i.e., those not associated with syphilis) are present.Visceral autonomic features are rare [Nicholson, unpublished data], with abdominal pain, diarrhea, and weight loss reported in some individuals in one family only [Houlden et al 2006].Neuropathology. The disease process affects the axons and cell bodies of dorsal root ganglia neurons and motor neurons in the anterior horns of the spinal cord. Studies show a distal axonal degeneration with loss of unmyelinated, small myelinated, and large myelinated fibers with decreasing severity in that order proceeding to ganglion cell loss [Houlden et al 2006]. See review in Thomas [1993].
Dominant forms of hereditary sensory neuropathy (HSN) are genetically heterogeneous:...
Differential DiagnosisDominant forms of hereditary sensory neuropathy (HSN) are genetically heterogeneous:HSAN1B (OMIM 608088), a dominantly inherited sensory neuropathy without foot ulcers but with cough and gastroesophageal reflux disease, maps to chromosome 3p24-p22 [Kok et al 2003].Mutations in subunit 2 of the dimer SPTLC2 on chromosome 14q24 cause a neuropathy that is phenotypically similar to HSN1A but without autonomic signs. This condition is designated HSAN1C in OMIM (613640). HSN1D (OMIM 613708) is caused by mutation in ATL1 (OMIM 606439) on 14q. Hereditary sensory neuropathy with dementia and hearing loss (HSN1E), a late-onset mild sensory neuropathy associated with ataxia and deafness, is caused by mutations in DNMT1 [Klein et al 2011]. The families with a dominantly inherited sensory neuropathy that is not linked to chromosome 9 [Auer-Grumbach et al 2000, Bellone et al 2002] do not have shooting pains. Families with CMT2 and foot ulcers (CMT2B) mapping to chromosome 3 are described by Kwon et al [1995]. A mutation in RAB7 is causative [Verhoeven et al 2003]. Some families do not link to either the chromosome 9 or the chromosome 3 locus [Auer-Grumbach et al 2003]. Disorders with similar phenotypes are CMT2, particularly CMT2B, which is a motor and sensory neuropathy with severe sensory loss and foot ulcers but no shooting pains. The p.Thr124Met mutation of MPZ, which encodes the myelin protein zero protein, is associated with a phenotype almost identical to HSN1A, with severe sensory loss, shooting pains, and occasional pseudo Argyl-Robertson pupils but no ulcerations [De Jonghe et al 1999].Painful diabetic neuropathy may have a similar phenotype but usually lacks a family history of neuropathy. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with hereditary sensory neuropathy type IA, the following assessments are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with hereditary sensory neuropathy type IA, the following assessments are recommended:Feet, ankles, and hands re the condition of the skinJoints for evidence of Charcot joints StrengthLoss of sweating and compensatory patchy hyperhydrosisMedical genetics consultationTreatment of ManifestationsWounds on neuropathic limbs heal if they are clean and protected and the limb is rested. Principles of treatment are the same as for leprosy surgery; see Warren & Nade [1999].Foot drop can be treated with ankle/foot orthotics (AFOs), but these need sleeving with stockings or some form of second skin to prevent skin abrasion. Charcot joints may require arthrodesis.Shooting pains are difficult to treat and only partial relief can be obtained with carbamazepine, gabapentin, or amitryptiline, or a combination of an antiepileptic and an antidepressant. Opiates are contraindicated as HSN1A is a chronic disorder.Prevention of Secondary ComplicationsFoot ulcers are frequently caused by breakdown of callus. Therefore, it is important to prevent callus formation by removing sources of pressure and to treat existing callus by softening the skin. Routine foot care by a diabetic clinic or by a podiatrist instructed to treat as for a diabetic foot is recommended.Burns can be prevented by using gloves as needed (e.g., during cooking).A diabetic education clinic is an excellent source of advice regarding skin care.SurveillanceFeet should be inspected at least daily for injuries or sources of wear. Agents/Circumstances to AvoidOpiates are contraindicated as this is a chronic disorder. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationPenno et al [2010] found that HSN1A-causing mutations in SPTLC1 result in decreased specificity of the active site of the enzyme, allowing alanine and glycine into the active site and producing neurotoxic sphingoid bases. The finding suggests that HSN1A is caused by these toxic products and opens an avenue for possible (at present, experimental) therapeutic approaches. Addition of serine to the diet of an HSN1 animal model and to 14 humans with HSN1 was effective in reducing plasma levels of the toxic deoxysphingolipids [Garofalo et al 2011].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Hereditary Sensory Neuropathy Type IA: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSPTLC19q22.31Serine palmitoyltransferase 1IPN Mutations, SPTLC1 SPTLC1 @ LOVD SPTLC1 homepage - Leiden Muscular Dystrophy pagesSPTLC1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Hereditary Sensory Neuropathy Type IA (View All in OMIM) View in own window 162400NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IA; HSAN1A 605712SERINE PALMITOYLTRANSFERASE, LONG-CHAIN BASE SUBUNIT 1; SPTLC1Molecular Genetic Pathogenesis Raised levels of toxic deoxy-sphingoid bases (DSBs) 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine have recently been reported in HSN1A plasma [Penno et al 2010]. Overexpression of the wild type allele in a mouse model of HSN1A has reversed the phenotype [Eichler et al 2009]. This finding opens the prospect of possible treatments aimed at reducing the levels of these metabolites. Normal allelic variants. No normal allelic variants have been identified in the coding region. Pathologic allelic variants. The most common mutation, p.Cys133Trp in exon 5, was found in English and Canadian families and in US and Australian families of English origin [Bejaoui et al 2001, Dawkins et al 2001]. Another mutation affecting the same codon, p.Cys133Tyr, was described in two families of Austrian and German origin [Bejaoui et al 2001, Dawkins et al 2001]. The mutation p.Val144Asp in exon 6 was found in two Australian families of English and Scottish origins. These three mutations result in significant amino acid changes likely to have functional or structural effects. An apparent de novo mutation in exon 13, p.Gly387Ala, was identified in two sisters of Belgian origin [Verhoeven et al 2004]. Mutations in the active sites of the SPTLC1 and SPTLC2 subunits cause altered substrate specificity allowing alanine and glycine to be incorporated into new toxic sphingolipids which cannot be degraded, leading to the accumulation of the toxic lipids 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine. Table 2. Selected SPTLC1 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencesc.399T>Gp.Cys133TrpNM_006415.2 NP_006406.1 c.398G>Ap.Cys133Tyrc.431T>Ap.Val144Aspc.1160G>Cp.Gly387AlaSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).Normal gene product. The serine palmitoyltransferase light chain 1 has 473 amino acids. Abnormal gene product. Expression of the mutant gene product has not been investigated.