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Hereditary sensory and autonomic neuropathies

Hereditary sensory and autonomic neuropathies
Literature review current through: Sep 2023.
This topic last updated: May 02, 2023.

INTRODUCTION — 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 [1]. 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 "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis" and "Neuropathies associated with hereditary disorders".)

OVERVIEW — 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 multiple types and subtypes, 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.

HSAN1 — 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 [3]. 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 [4,5].

Genetics — HSAN1 is genetically heterogeneous. Most cases show autosomal dominant inheritance. At least five genes have been implicated in the disorder [6].

HSAN1A is associated with several missense mutations in the SPTLC1 gene on chromosome 9q22.31 [7-9]. The gene encodes for serine palmitoyltransferase, long-chain base subunit-1, which is involved in the synthesis of sphingolipids. Variants of this gene are associated with the accumulation of neurotoxic deoxysphingolipid metabolites. These variants have also been shown to cause macular telangiectasia type 2 and juvenile amyotrophic lateral sclerosis [10-13]. Other SPTLC1 variants that vary from those that cause HSAN1A may disrupt the regulation of serine palmitoyltransferase, resulting in elevated levels of canonical sphingolipids.

HSAN1B, reported in a small number of families, is linked to chromosome location 3p24-p22 [14,15]. The clinical features include adult onset of cough, gastroesophageal reflux, and axonal neuropathy with distal sensory impairment.

HSAN1C is caused by missense mutations in the SPTLC2 gene on chromosome 14q24 [16,17]. Variants of the SPTLC2 gene have also been shown to cause macular telangiectasia type 2 [10].

HSN1D is caused by pathologic variants in the ATL1 gene on chromosome 14q [18]. The same gene is implicated as the cause of early-onset hereditary spastic paraplegia 3A [19].

HSN1E is caused by pathologic variants in the DNMT1 gene on chromosome 19p13.2 [20]. Onset occurs early in adulthood and is characterized by the triad of progressive dementia, hearing loss, and distal sensory neuropathy. Variable manifestations include myoclonic seizures, sleep disorders, narcolepsy, auditory or visual hallucinations, and renal failure [21].

HSN1F is caused by pathologic variants in the ATL3 gene [22]. The disorder predominantly affects the lower limbs. Distal sensory impairment becomes apparent by the third decade of life, resulting in painless ulceration of the feet with poor healing. This can progress to osteomyelitis, bone destruction, and amputation.

Clinical features — Symptom onset is usually during early adulthood, but ranges from early childhood until late adulthood. The core clinical features of HSAN1 are prominent sensory loss and a variable involvement of autonomic and motor systems. Sensory loss or sharp, brief leg pain typically is the initial symptom, followed by the development of motor weakness and foot ulcers caused by reduced sensation in the legs [23,24]. Complete sensation is lost with time, with the exception of facial sensation [25]. Involvement of the thinly myelinated A-delta and unmyelinated C-nerve fibers results in abnormal quantitative psychophysical testing to warm, cold, and pain sensation [1]. Motor findings, including pes cavus, peroneal muscle atrophy, and loss of reflexes, may be present, and bone necrosis and spontaneous distal amputation can occur [26].

Some patients with HSAN1 may also have macular telangiectasia characterized by progressive loss of central vision [10].

In detailed characterizations of families with SPTLC1 genetic variants, the following observations have been made [5,24]:

The mean age of onset was 29 years, but ranged from age 12 to 70. One individual at age 89 was unaffected. There was a statistically nonsignificant tendency for females compared with males to have a later mean age of onset (39 versus 25 years); females also tended to have less severe disease. There was considerable heterogeneity both within and between families regarding the clinical and electrophysiologic findings.

The most frequent presenting feature was decreased sensation in the feet. Limb pain, painless blisters, and foot ulcers were also common, as was severe shooting or burning limb pain. Symptom onset tended to follow a predictable sequence, beginning with sensory symptoms, and followed by weakness, ulcers, pain, and balance problems.

Sensory involvement was typically dissociated, with pain and temperature affected first and most severely, and light touch affected to a lesser degree. Vibration and joint position sense were affected later and much less than superficial sensation.

Motor signs were more severe than expected from the earlier descriptions of HSAN1, and autonomic symptoms scant. Severe and often early motor signs were seen in most of the affected family members. The proximal and distal weakness and wasting was the most prominent feature of the disease in some patients, leading in some to a misdiagnosis of Charcot-Marie-Tooth disease. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis".)

Nerve conduction studies most frequently showed an axonal motor and sensory peripheral neuropathy; sensory potentials were usually absent in the lower limbs but were often present and in some cases normal in the upper limbs. Motor conduction showed great variability, with velocities ranging from normal (≥50 m/s) through intermediate slowing (35 to 50 m/s) to unequivocal slowing in the demyelinating range (≤35 m/s). Conduction slowing, conduction block, and motor dispersion (all suggestive of demyelination) were seen in several subjects.

Needle electromyography of distal limb muscles showed moderate to severe chronic denervation.

Sural nerve biopsy and postmortem examination showed significant loss of myelinated axons, but there was scant evidence of demyelination. The dorsal spinal roots were mildly fibrotic while ventral roots were relatively well preserved.

Skin biopsies in adults showed loss of epidermal innervation at the distal leg with relative preservation at the thigh.

To summarize, the electrophysiologic studies showed a predominately axonal and sensory peripheral neuropathy, but a significant motor neuropathy was also present in most patients, and a minority had conduction studies suggestive of demyelination. Given the lack of significant demyelination on biopsy and postmortem samples, the authors speculated that abnormal axonal function and altered excitability rather than a defect of myelin itself may have been responsible for the motor slowing seen in these patients.

Thus, the diagnosis of HSAN1 secondary to SPTLC1 genetic variants should be considered in patients with a motor and sensory neuropathy, even in the presence of demyelinating features, particularly if there is marked sensory involvement and a family history [5].

Management of HSAN1 — No specific treatment exists for HSAN1. Management requires meticulous care of the distal limbs, which includes proper fit of shoes, prevention and treatment of callus formation, cleaning and protection of wounds, and avoidance of trauma to the hands and feet [27]. Chronic ulcerations and infections can lead to osteomyelitis and the need for surgical amputation [28]. Ankle-foot orthotics are used for foot drop and arthrodesis for Charcot arthropathy.

Experimental therapy — The hypothesis that HSAN1 is caused by the accumulation of neurotoxic sphingolipid metabolites suggests that interventions aimed at reducing the level of toxic metabolites may be beneficial. The SPTLC1 variants that cause HSAN1 are associated with reduced activity of the enzyme serine palmitoyltransferase, which catalyzes the condensation of L-serine and palmitoyl-CoA [11,16]. In addition, SPTLC1 variants result in reduced substrate specificity such that L-alanine and L-glycine are also condensed with palmitoyl-CoA [11,29], theoretically leading to formation of neurotoxic deoxysphingolipids.

One proposed intervention involves dietary supplementation with oral L-serine. In a mouse model of HSAN1, SPTLC1 variant mice placed on an L-serine enriched dieted demonstrated reduced deoxysphingolipid levels and improved performance on measures of motor and sensory neuropathy [30]. In addition, 14 patients with HSAN1 who received L-serine supplementation for 10 weeks showed reduced deoxysphingolipid levels. In a later controlled trial, 18 patients with HSAN1 were randomly assigned to oral L-serine supplementation or to placebo for the first year, followed by an open label extension phase for the second year [31]. Oral L-serine supplementation appeared safe and potentially effective at slowing disease progression; after one year, the L-serine group experienced improvement in Charcot-Marie-Tooth Neuropathy Score (a composite score based on patient symptoms, signs, and electrodiagnostic testing) relative to the placebo group (-1.5 units, 95% CI -2.8 to -0.1). There was also evidence of continued improvement in the second year of treatment (-0.77, 95% CI -1.67 to 0.13).

HSAN2 — The symptoms in hereditary sensory and autonomic neuropathy type 2 (HSAN2) are caused also by loss of pain, temperature, pressure, and touch sensation with large and small fiber sensory involvement [1,32]. Fractures and recurrent infections of the digits occur in early childhood, and mutilation of the fingers and toes occurs as the disease progresses. A stable, nonprogressive congenital form also has been recognized [33].

Sensory nerve action potentials are unobtainable with nerve conduction studies, while motor conduction velocity is only mildly slowed [34]. Sural nerve biopsy shows a marked decrease or absence of large and small myelinated fibers but only slight reduction of unmyelinated fibers [32,35,36].

Genetics — HSAN2 is transmitted as an autosomal recessive trait [32]. Subtypes with different genetic origins have been described.

HSAN2A is caused by variants in HSN2 gene, which is specific to the nervous system and located within exon 8 of the WNK1 gene on chromosome 12p13.33 [37,38]. This complex is referred to as the WNK1/HSN2 isoform. The apparently higher prevalence of HSAN2 in French Canadians is due to the presence of two distinct founder variants in the HSN2 gene [39].

HSAN2B is caused by loss-of-function pathologic variants in the FAM134B gene on chromosome 5p15.1 [40]. The phenotype of HSAN2B is similar to the progressive form of HSAN2A.

HSAN2C is caused by variants in the KIF1A gene on chromosome 2q37.3 that encodes for a kinesin family protein involved in axonal transport of synaptic vesicles [41]. The protein also interacts with the domain encoded by the HSN2 exon of the neuron-specific WNK1/HSN2 isoform. A variant in the KIF1A gene is implicated as the cause of hereditary spastic paraplegia 30 [42].

HSAN2D is caused by a loss-of-function pathologic variant in the SCN9A gene [43]. The phenotype involves congenital or adolescent onset with loss of pain and temperature sensation, autonomic dysfunction, hearing loss, and hyposmia. Loss-of-function SCN9A pathologic variants are also linked to channelopathy-associated insensitivity to pain [44]. Conversely, gain-of-function pathologic variants in SCN9A cause several disorders that result in excess pain, including primary erythromelalgia [45], paroxysmal extreme pain disorder [46], and small fiber neuropathy [47].

HSAN3 (FAMILIAL DYSAUTONOMIA) — Hereditary sensory and autonomic neuropathy type 3 (HSAN3) is more commonly known as familial dysautonomia or Riley-Day syndrome. This disorder is a progressive sensorimotor neuropathy, but sympathetic autonomic dysfunction is responsible for most clinical manifestations [48-50].

Episodes of dysautonomic crises occur in many patients, characterized by nausea and vomiting, and by symptoms of sympathetic storm with irritability, tachycardia, hypertension, facial flushing, bronchorrhea, and diminished oral coordination resulting in swallowing and speech dysfunction. These crises can be triggered by physical or emotional stress.

Additional autonomic symptoms include orthostatic hypotension, excessive salivation, gastrointestinal motility dysfunction, bladder dysfunction, decreased or absent tearing, pupil dilation, hypohidrosis and episodic hyperhidrosis (leading to defective temperature dysregulation), and blotchy skin.

Glomerulosclerosis and chronic kidney disease may develop, unrelated to autonomic dysfunction.

Neuropathic symptoms include loss of reflexes, hypotonia, and decreased perception of pain and temperature.

Additional clinical features include small stature, kyphoscoliosis, a smooth tongue that lacks fungiform papillae, recurrent aspiration or vomiting, multiple sites of skin trauma, dysarthria, intellectual disability, and emotional lability.

The respiratory, cardiovascular, and cerebrovascular responses to hypoxia are markedly diminished, but responses to hypercarbia remain intact [51].

Motor conduction velocity may be normal [52,53] or reduced [54,55]. Compound motor action potential amplitudes may also be reduced [54]. Sensory nerve action potentials are reduced or absent [53,54].

The disease affects central as well as peripheral myelin. With aging, dorsal column abnormalities are found on quantitative testing [56]. Sural nerve biopsy demonstrates severe loss of both myelinated and unmyelinated fibers smaller than 12 microns in diameter [57]. Histologic examination of sensory dorsal root ganglion shows a 50 percent reduction of neurons [55]. Both preganglionic and postganglionic sympathetic atrophy occur with preservation of parasympathetic ganglia [58].

Data from retrospective studies suggest that patients with familial dysautonomia have an increased incidence of neoplasia and an increased incidence of rhabdomyolysis compared with the general population [59,60].

Genetics — Familial dysautonomia (HSAN3) is transmitted as an autosomal recessive trait and is mainly seen in children of Ashkenazi Jewish decent [61]. The carrier frequency is 1 in 30, and the incidence is approximately 1 in 3700 live births [62]. Only a few non-Jewish children have been described [63-65].

The causative gene is located on chromosome 9q31 and encodes for a truncated form of I kappa B kinase complex-associated protein (IKBKAP) [66,67]. How this leads to the clinical manifestations of HSAN3 is not clear, but tissue-specific expression of the defective IKBKAP gene may be involved [66].

Diagnosis — Genetic evaluation is sensitive and specific for the diagnosis of HSAN3 and the most reliable way to make the diagnosis. No other specific diagnostic test exists, although the following tests are suggestive:

Intradermal histamine may produce a wheal but no flare or pain at the injection site. Histamine should be used at a 1:1000 dilution in adolescents, while a 1:10,000 dilution should be used in infants [68].

Urine excretion of vanillylmandelic acid excretion may be diminished, and excretion of homovanillic acid increased.

Methacholine (2.5 percent) administration into the conjunctival sac produces no response in normal children, but induces pupillary constriction in children with familial dysautonomia.

Blood pressure responses are exaggerated following intravenous norepinephrine, and methacholine infusion generates an increased hypotensive response.

Management — No specific treatment exists for familial dysautonomia (HSAN3). Supportive care and symptomatic therapies are the mainstay of management [61,69]:

Vomiting and dysautonomic crisis may require intravenous fluids to prevent dehydration. Diazepam, clonidine, pregabalin, or a peripheral decarboxylase inhibitor such as carbidopa may be helpful to control symptoms. (See 'Dysautonomic crisis' below.)

Nutrition, airway protection, and avoidance of aspiration are important, particularly during infancy.

Gastroesophageal reflux management includes upright positioning during feeding, prokinetic agents (eg, bethanechol), H2 antagonists, and gastrostomy with or with fundoplication.

For patients with chronic lung disease from recurrent aspiration pneumonia, daily chest physiotherapy (ie, nebulizers, bronchodilators, postural drainage) is suggested. High frequency chest wall oscillation was beneficial in one report [70].

Orthostatic hypotension can be treated with elastic stockings, leg exercises, and physical maneuvers such as squatting and bending forward [71]. Fludrocortisone and midodrine can alleviate orthostatic symptoms and may help prolong survival [72,73]. Carbidopa can blunt spikes in systolic blood pressure and reduce blood pressure variability [74]. (See "Treatment of orthostatic and postprandial hypotension".)

For patients with bradyarrhythmia and/or syncope, a pacemaker may be protective [75].

Corneal scarring is a risk due to decreased corneal sensation and diminished tearing. Artificial tear solutions that contain methylcellulose can be given three to six times daily. Other measures include maintenance of normal hydration, moisture chamber spectacle attachments, and soft contact lenses. Tarsorrhaphy is an option if conservative measures fail.

A yearly spine examination is suggested to evaluate for kyphoscoliosis; some patients may benefit from spinal fusion.

Patients are at risk for decubitus ulcers due to decreased pain sensitivity. Awareness of pressure points is needed when fitting orthopedic devices.

Exercise may be helpful to correct or prevent contractures.

Dysautonomic crisis — To control vomiting and dysautonomic crisis, some experts treat with intravenous or rectal diazepam (0.2 mg/kg every three hours); oral clonidine (0.005 to 0.01 mg/kg daily in three or four divided doses) is another option [69]. Clonidine may be increased gradually up to 0.025 mg/kg per day in four divided doses, with a maximum total dose of 0.9 mg/day.

Findings from a small trial suggest that carbidopa is effective as an antiemetic for adolescents and adults with HSAN3 and severe nausea and retching that is refractory to treatment with benzodiazepines and clonidine [76]. During an open label titration phase, carbidopa was started at 12 mg daily and the dose was increased every other day in 25 mg increments up to a total of 600 mg daily given in three divided doses. The dose was adjusted for children weighing <50 kg, using the formula (weight x 2) percent of an adult dose for children ≤30 kg, and (weight + 30) percent of adult dose for children 31 to 49 kg. During the double-blind crossover phase, patients reported significantly less nausea and retching while on carbidopa (average daily dose 480 mg) than on placebo.

In a case series, treatment with pregabalin was associated with improvement in nausea and symptoms of dysautonomic crisis in 13 of 15 patients, most of whom were maintained on their pre-study regimen of a benzodiazepine and/or clonidine [77]. Pregabalin was started at 25 to 50 mg twice daily and gradually titrated over one month to benefit or a maximum total daily dose of 6 mg/kg; weight-based dosing was used because the subjects were small in stature, with average weight of approximately 42 kg.

As noted earlier, intravenous fluids are used to prevent dehydration with vomiting crises.

Prenatal screening — Issues related to prenatal screening in Ashkenazi Jews are discussed separately. (See "Preconception and prenatal carrier screening for genetic disorders more common in people of Ashkenazi Jewish descent and others with a family history of these disorders".)

Pre-implantation and prenatal diagnosis of familial dysautonomia (HSAN3) is possible if the familial pathologic variant has been identified. Since the advent of prenatal screening for the gene linked to familial dysautonomia in 2001, the incidence of newborns with the disease has markedly declined in the United States [78].

HSAN4 — Hereditary sensory and autonomic neuropathy type 4 (HSAN4), also called congenital insensitivity to pain with anhidrosis (CIPA), is an autosomal recessive disorder. Symptoms begin early in infancy and prominent features include [79]:

Profound loss of pain sensitivity, leading to injuries, self-mutilation, and osteomyelitis. Loss of oral sensation leads to mutilation of the face and mouth.

Defects in thermoregulation and anhidrosis, leading to episodic hyperthermia that can be associated with seizures.

Mild to moderate intellectual disability; in addition, microcephaly often is present.

Tearing is preserved, and fungiform papillae are present on the tongue; both serve to differentiate HSAN4 from the Riley-Day syndrome (HSAN3). Up to 20 percent of patients die from hyperpyrexia by three years of age [79].

Neuropathologic findings include a marked reduction in sural nerve size and a severe reduction in unmyelinated and small myelinated fibers in peripheral nerves.

HSAN4 has been linked to variants within the tyrosinase-kinase domain of the NTRK1 gene on chromosome 1q23.1, which encodes one of the receptors for the nerve growth factor [80,81]. These pathologic variants cause inactivation of the receptor, producing a loss of function effect [82]. Nerve growth factor normally induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons [83]. It is likely that another gene also is involved. In a series of nine unrelated consanguineous families, the disease was not linked to the NTRK1 gene in one family [84].

HSAN5 — Patients with hereditary sensory and autonomic neuropathy type 5 (HSAN5) have loss of pain and temperature sensation, but other sensation is preserved [85]. Muscle strength, reflexes, and nerve conduction studies are normal. However, one report of a single consanguineous family noted additional manifestations including mild intellectual disability, anhidrosis, and chronic immunodeficiency [86].

Sural nerve biopsy shows absence of the small myelinated fibers, with preservation of the large fibers. Inheritance is autosomal recessive. HSAN5 appears to be caused by variants in the nerve growth factor beta (NGFB) gene on chromosome 1p13.2 [86,87].

HSAN6 — Hereditary sensory and autonomic neuropathy type 6 (HSAN6) is a severe autosomal recessive disorder characterized by neonatal hypotonia, respiratory and feeding difficulties, and lack of psychomotor development [88]. Autonomic abnormalities include labile cardiovascular function, lack of corneal reflexes leading to corneal scarring, and areflexia. HSAN6 is caused by a pathologic variant in the dystonin (DST) gene, leading to abnormal actin cytoskeleton organization and affecting neuronal outgrowth [89].

HSAN7 — The clinical course of patients with hereditary sensory and autonomic neuropathy type 7 (HSAN7) is remarkable for a congenital inability to experience pain [90,91]. This results in self-mutilation, slow wound healing, and multiple painless bone fractures. The few reported patients also had gastrointestinal dysmotility, mild muscle weakness, and delayed motor development. The disorder is caused by a variant in the SCN11A gene, which encodes a voltage-gated sodium channel that is expressed mainly in nociceptive neurons.

HSAN8 — Hereditary sensory and autonomic neuropathy type 8 (HSAN8) is an autosomal recessive disorder characterized by insensitivity to pain [92]. This may lead to self-mutilation behavior, soft-tissue injuries, and premature tooth loss [93]. Affected infants present with lip and tongue ulcerations, lack of corneal reflexes leading to corneal scarring, and a predilection for skin infections. Associated autonomic features include hypohidrosis and reduced tear production. The disorder is caused by variants in the PRDM12 gene, which helps regulate the development of nociceptors [94].

Genetic variants in the PRDM12 gene are also implicated in the midface toddler excoriation syndrome (MiTES), a disorder characterized by recurrent wounds around the eyes and nose from habitual scratching [95,96]. (See "Skin picking (excoriation) disorder and related disorders", section on 'Primary skin disorders'.)

UNCLASSIFIED — Several reported cases of hereditary sensory neuropathy in children do not fit into the current classification. They include:

Spastic paraplegia with ulcerations of the hands and feet associated with CCT5 gene variants [97,98].

Congenital sensory neuropathy with skeletal dysplasia [99].

Hereditary sensory neuropathy with neurotrophic keratitis [100], which may be a variant of HSAN5.

Congenital sensory polyneuropathy with growth hormone deficiency [101].

Sensory neuropathy with ichthyosis and anterior chamber syndrome [102].

Deafness, sensory neuropathy, and ovarian dysgenesis [103], which may be a variant of gonadal dysgenesis, XX type, with deafness.

Navajo familial neurogenic arthropathy [104], which may be a variant of Navajo neurohepatopathy related to variants in the MPV17 gene.

SUMMARY

Classification – The major feature of the hereditary sensory and autonomic neuropathies (HSANs) is loss of large myelinated and unmyelinated fibers. They have been categorized into several distinct subtypes based on clinical features and underlying genetic causes (table 1). (See 'Overview' above.)

HSAN1 – HSAN1 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 to distal muscle wasting and weakness. The core clinical features of HSAN1 are prominent sensory loss and a variable involvement of autonomic and motor systems. Some affected families have hearing loss and dementia. Inheritance is autosomal dominant. At least four genetic subtypes are known. (See 'HSAN1' above.)

HSAN2 – HSAN2 is caused also by loss of pain, temperature, pressure and touch sensation with large and small fiber sensory involvement. Inheritance is autosomal recessive, and at least three genetic subtypes are described. (See 'HSAN2' above.)

HSAN3 – HSAN3 is more commonly known as familial dysautonomia. This disorder is a progressive sensorimotor neuropathy, but sympathetic autonomic dysfunction is responsible for most clinical manifestations. It is transmitted as an autosomal recessive trait and is essentially limited to children of Ashkenazi Jewish decent. (See 'HSAN3 (Familial dysautonomia)' above.)

HSAN4 – HSAN4, also called congenital insensitivity to pain with anhidrosis (CIPA), is an autosomal recessive disorder. Patients with HSAN4 have a profound loss of pain sensitivity, leading to injuries, self-mutilation, and osteomyelitis as well as defects in thermoregulation, seizures, and mild to moderate intellectual disability. (See 'HSAN4' above.)

HSAN5 – HSAN5 is an autosomal recessive disorder characterized by loss of pain and temperature sensation, but other sensation is preserved. (See 'HSAN5' above.)

HSAN6 – HSAN6 is a severe autosomal recessive disorder characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities. (See 'HSAN6' above.)

HSAN7 – HSAN7 is characterized by a congenital inability to experience pain. This results in self-mutilation, slow wound healing, multiple painless bone fractures, gastrointestinal dysmotility, mild muscle weakness, and delayed motor development. (See 'HSAN7' above.)

HSAN8 – HSAN8 is an uncommon autosomal recessive disorder in infants and children characterized by insensitivity to pain that may lead to self-mutilation behavior, soft-tissue injuries, and premature tooth loss. (See 'HSAN8' above.)

Unclassified types – Some cases of hereditary sensory neuropathy in children do not fit into the current classification. (See 'Unclassified' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert P Cruse, DO, who contributed to earlier versions of this topic review.

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Topic 6227 Version 25.0

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