Hereditary Sensory And Autonomic Neuropathy Type Research Articles

Congenital Insensitivity TO Pain: A Case Report

Congenital insensitivity to pain or more scientifically Hereditary sensory and autonomic neuropathies (HSAN) is a rare genetic disorder which associates a sensory dysfunction with a varying degree of autonomic dysfunction. Due to the peripheral neuropathy, a decreased sensitivity or even complete anesthesia may be present resulting in, on the ophthalmological level, neurotrophic ulcers. We report the case of 2 sisters (JM and KM) presenting with HSAN with recurrent corneal ulcers. Unfortunately, genetic testing couldn’t be performed due to lack of means, but the clinical presentation and features were very favourable or even pathognomonic of this syndrome. The first cases or reported individuals presenting with congenital insensitivity to pain goes back to 1930’s. Five types of hereditary sensory and autonomic neuropathy have been identified according to age of onset of symptoms, clinical features and affected gene. HSAN type IV also known as congenital insensitivity to pain with anhidrosis (CIPA) is the second most common HSAN. It is caused by mutation in the NTRK1(Neurotrophic tyrosine kinase receptor type 1) (TRKA) gene located in chromosome 1 (1q21-q22). It is characterized by repetitive hyperthermic episodes in infancy, and mental retardation is usually present, as reported in our case. Clinical symptoms of pain insensitivity manifest as tongue, lip and fingers biting, and self-inflicted injuries. Congenital insensitivity to pain is a rare genetic syndrome characterized by an absence or an altered response to pain. Individuals with this syndrome can presented self-inflicted injuries and auto-mutilation leading in some cases to severe disabilities. Long-term visual prognosis in CIPA patients is not assessed and there’s an important lack of data regarding ocular manifestation of CIP syndrome.

Painless self-mutilation − A case of hereditary sensory autonomic neuropathy type 4

Children with hereditary sensory and autonomic neuropathy (HSAN) Type IV present with loss of pain and temperature sensation and anhidrosis. They may sometimes exhibit aggressive and self-mutilating behavior. We present here the case of a 5-year-old male child who presented with a history of self-mutilating behavior leading to ulcers over knees, elbows, toes and occiput, and amputation of index fingers of both hands. The patient had loss of temperature and pain sensation, but touch was normal. There was anhidrosis. Serum uric acid levels were normal. Histamine test was absent, and nerve studies showed decreased conduction velocity. A diagnosis of HSAN Type IV was made. This case is being presented as self-mutilation was the prominent complaint of the parents of the child. We also discuss the differences between HSAN Type IV and Lesch−Nyhan syndrome.

Hereditary Sensory and Autonomic Neuropathies: Adding More to the Classification.

Hereditary sensory and autonomic neuropathies (HSANs) are a clinically heterogeneous group of inherited neuropathies featuring prominent sensory and autonomic involvement. Classification of HSAN is based on mode of inheritance, genetic mutation, and phenotype. In this review, we discuss the recent additions to this classification and the important updates on management with a special focus on the recently investigated disease-modifying agents. In this past decade, three more HSAN types were added to the classification creating even more diversity in the genotype-phenotype. Clinical trials are underway for disease-modifying and symptomatic therapeutics, targeting mainly HSAN type III. Obtaining genetic testing leads to accurate diagnosis and guides focused management in the setting of such a diverse and continuously growing phenotype. It also increases the wealth of knowledge on HSAN pathophysiologies which paves the way toward development of targeted genetic treatments in the era of precision medicine.

Recessive mutations in the neuronal isoforms of DST, encoding dystonin, lead to abnormal actin cytoskeleton organization and HSAN type VI.

Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders, characterized by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. Several pathways have been implicated in the pathogenesis of neuronal degeneration in HSAN, while recent observations point to an emerging role of cytoskeleton organization and function. Here, we report novel biallelic mutations in the DST gene encoding dystonin, a large cytolinker protein of the plakin family, in an adult form of HSAN type VI. Affected individuals harbored the premature termination codon variant p.(Lys4330*) in trans with the p.(Ala203Glu) change affecting a highly conserved residue in an isoform-specific N-terminal region of dystonin. Functional studies showed defects in actin cytoskeleton organization and consequent delayed cell adhesion, spreading and migration, while recombinant p.Ala203Glu dystonin loses the ability to bind actin. Our data aid in the clinical and molecular delineation of HSAN-VI and suggest a central role for cell-motility and cytoskeletal defects in its pathogenesis possibly interfering with the neuronal outgrowth and guidance processes.

Congenital Insensitivity to Pain and Anhidrosis.

Hereditary sensory and autonomic neuropathy (HSAN) or hereditary sensory neuropathy has five different clinical subtypes. Congenital insensitivity to pain and anhidrosis (CIPA) is HSAN type IV. CIPA is a rare disease with an autosomal recessive inheritance. Recurrent episodes of fever, no sweating, insensitivity to pain, and self-injury are symptoms of CIPA. In addition, most patients suffering from CIPA experience mental retardation [1]. CIPA has been reported to occur with a genetic mutation of the neurotrophic tyrosine kinase 1 (NTRK1) gene [2]. This gene is encoded in the tyrosine kinase receptor, which is responsible for nerve growth factor. Thus, the signals for pain, heat, and cold cannot be transmitted to the brain. A previous study reported that approximately 20% of patients with CIPA die due to hyperpraxia before the age of 3 years [3]. Here, we report on a 33-month-old female with CIPA who presented with a pathognomonic clinical feature. This 33-month-old female child visited our department. Both her hands were crusted, with yellowish discharge, swelling, redness, and heating sensation on her right index finger (Fig. 1). On the X-ray, the distal phalanx of the right index finger had disappeared and the distal phalanx of the contralateral index finger was destructed (Fig. 2). The patient was diagnosed with cellulitis and osteomyelitis. She sucked and bit her fingers even though her fingers had a large number of open wounds. Therefore, we applied an elastic bandage on both of her hands in order to stop the sucking. Antibiotic treatment was also administered. During follow-up, swelling was observed on the left dorsum of the foot with no pain. She was diagnosed with a fracture of the first metatarsal bone (Fig. 3). She visited the orthopedic surgery department, and a splint was applied. Two days later, she was transferred to our department because of a splint sore. At this time, we realized that she could not feel the pain. She did not sweat easily and therefore had recurrent fever and did not wear clothes well for fever control. She had repeated oral ulcers and injuries to the hands and feet, such as contact burns. The Sequenced Language Scale for Infants showed delayed mental age at 13 months and low IQ at 66 points. Fig. 1 (A) Right hand. On the right index finger, an erythematous swelling was observed. There was yellowish discharge and a heating sensation. Further, multiple crusts and scars were observed. (B) Left hand. On the left hand, multiple crusts and scars were ... Fig. 2 X-ray of the right-hand oblique view. Distal phalangeal bone of the right index finger had disappeared. Fig. 3 X-ray of left foot. Fracture of the first metatarsal bone was observed. Because of the elastic bandage, the patient was no longer able to suck and bite her fingers. Thereafter, the symptoms (yellowish discharge, swelling, redness, and heating sensation) were relieved. The patient was discharged after a total hospital stay of 16 days. A weak steroid ointment was applied on her fingers. This ointment has a bitter taste; thus, the patient's sucking behavior decreased. The fracture of the first metatarsal bone healed with union achieved by maintaining the splint in place. The sore also healed with the dressing. We recommended nerve biopsy to confirm the diagnosis; however, the patient's parents did not give their consent for the procedure. CIPA is a rare disease with a short life expectancy. It is a hereditary disorder, but it could present with sporadic occurrence [4]. Specific treatment of CIPA is not known. Nevertheless, proper training is needed for prevention of injury. Patients suffering from CIPA usually visit the pediatrics department complaining of high fever. However, they may also visit a plastic surgeon due to recurrent wounds on the hands and feet. If the plastic surgeon is aware of CIPA, proper management could be administered in order to extend the patient's life expectancy.

Hereditary sensory and autonomic neuropathy types IV and V in Japan.

Hereditary sensory and autonomic neuropathy (HSAN) is a group of genetic disorders involving varying sensory and autonomic dysfunction. HSAN types IV and V are characterized by congenital generalized loss of pain and thermal sensation. HSAN type IV is additionally accompanied by decreased sweating and intellectual disability. From 2010 to 2013, we (members of the Japanese Research Group on Congenital Insensitivity to Pain) carried out research on HSAN types IV and V. Research by this group included epidemiological data, examination of clinical findings, solutions of disease etiology, investigation of complications and development of their management. Complications were categorized into musculoskeletal complications, oral/dental complications, dermal complications, ocular complications, complications resulting from impaired thermal control, anesthetic considerations, other complications possibly related to autonomic dysfunction, and abnormal mental development and behavior. Treatment and care for patients with HSAN types IV and V require a wide range of knowledge and experience, and a multidisciplinary team approach. Therefore, we produced the "Guideline of Total Management and Care for Congenital Insensitivity to Pain (Ver.1)" in 2012, to provide information for medical specialists based on our knowledge and experience. This guideline includes medical issues, as well as descriptions of social participation and welfare. This review outlines the situation of HSAN types IV and V in Japan, and the recommendations of treatment and care for patients, mostly based on research conducted by the Japanese Research Group.

She feels no pain: A child with congenital insensitivity to pain and anhidrosis

The hereditary sensory and autonomic neuropathies encompass a number of inherited disorders that are associated with sensory dysfunction and varying degree of autonomic dysfunction. Hereditary sensory and autonomic neuropathy (HSAN) with anhidrosis type IV is the second most common form of hereditary sensory neuropathy. We report here the youngest case diagnosed with HSAN type IV having all features of congenital insensitivity to pain and anhidrosis.

Insensibilité congénitale à la douleur, étude clinique et neurophysiologique chez 3 sœurs marocaines

Congenital insensitivity to pain is a rare hereditary sensory and autonomic neuropathy (HSAN). This disorder is an autosomal recessive condition: since 1996, mutations attributed to this entity have been found in the neurotrophin tyrosine-kinase gene receptor on chromosome 1. The authors report 3 cases of congenital insensitivity to pain. In these 3 sisters of consanguineous parents, the clinical investigation showed total absence of pain and temperature sensations with preservation of all other sensory modalities, mental retardation, but in contrast to HSAN type IV, there was no anhidrosis. The neurophysiological investigation revealed an isolated axonal sensory polyneuropathy in the 3 patients. The clinical and neurophysiological investigations were normal in both parents and the brother. The physiopathology of this entity is discussed. We suggest a particular form of HSAN type IV with preservation of transpiration or a new entity of congenital insensitivity to pain, which should be analyzed genetically.

Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation

To identify the clinical features of Japanese patients with suspected hereditary sensory and autonomic neuropathy (HSAN) on the basis of genetic diagnoses. On the basis of clinical, in vivo electrophysiologic, and pathologic findings, 9 Japanese patients with sensory and autonomic nervous dysfunctions were selected. Eleven known HSAN disease-causing genes and 5 related genes were screened using a next-generation sequencer. A homozygous mutation, c.3993delGinsTT, was identified in exon 22 of SCN9A from 2 patients/families. The clinical phenotype was characterized by adolescent or congenital onset with loss of pain and temperature sensation, autonomic nervous dysfunctions, hearing loss, and hyposmia. Subsequently, this mutation was discovered in one of patient 1's sisters, who also exhibited sensory and autonomic nervous system dysfunctions, with recurrent fractures being the most predominant feature. Nerve conduction studies revealed definite asymmetric sensory nerve involvement in patient 1. In addition, sural nerve pathologic findings showed loss of large myelinated fibers in patient 1, whereas the younger patient showed normal sural nerve pathology. We identified a novel homozygous mutation in SCN9A from 2 Japanese families with autosomal recessive HSAN. This loss-of-function SCN9A mutation results in disturbances in the sensory, olfactory, and autonomic nervous systems. We propose that SCN9A mutation results in the new entity of HSAN type IID, with additional symptoms including hyposmia, hearing loss, bone dysplasia, and hypogeusia.

IKAP expression levels modulate disease severity in a mouse model of familial dysautonomia

Hereditary sensory and autonomic neuropathies (HSANs) encompass a group of genetically inherited disorders characterized by sensory and autonomic dysfunctions. Familial dysautonomia (FD), also known as HSAN type III, is an autosomal recessive disorder that affects 1/3600 live births in the Ashkenazi Jewish population. The disease is caused by abnormal development and progressive degeneration of the sensory and autonomic nervous systems and is inevitably fatal, with only 50% of patients reaching the age of 40. FD is caused by a mutation in intron 20 of the Ikbkap gene that results in severe reduction in the expression of its encoded protein, inhibitor of kappaB kinase complex-associated protein (IKAP). Although the mutation that causes FD was identified in 2001, so far there is no appropriate animal model that recapitulates the disorder. Here, we report the generation and characterization of the first mouse models for FD that recapitulate the molecular and pathological features of the disease. Important for therapeutic interventions is also our finding that a slight increase in IKAP levels is enough to ameliorate the phenotype and increase the life span. Understanding the mechanisms underlying FD will provide insights for potential new therapeutic interventions not only for FD, but also for other peripheral neuropathies.

Association of osteonecrosis and peripheral neuropathy in HIV-1-infected patients

Atraumatic osteonecrosis affects about 1% of HIV-infected persons when asymptomatic and about 5% when symptomatic [1]. Two clinical circumstances suggest that nerve growth factor (NGF) might be involved in the excessive prevalence. First, patients with hereditary sensory and autonomic neuropathy (HSAN) have a remarkable (5–23%) prevalence of osteonecrosis [2–5]; the genetic basis of HSAN type 4B is missense mutations in the trkA receptor for NGF [6,7]. Second, 16 patients who received a monoclonal antibody that blocks interaction of NGF with its receptor, developed osteonecrosis [8]. Moreover, NGF is both osteogenic [9] and angiogenic through upregulation of vascular endothelial growth factor (VEGF) [10]. The above circumstances suggested the hypothesis that HIV-infected persons with osteonecrosis might have more peripheral neuropathy than those without osteonecrosis and that impaired actions of NGF and, probably, of VEGF might contribute to the excess of osteonecrosis. We identified 106 patients with osteonecrosis among 11 506 HIV-infected persons; characteristics of these 106 individuals have been presented [11]. The diagnosis of peripheral neuropathy was taken from the electronic medical record (EMR). This was the only basis for that diagnosis in the 11 400 patients without osteonecrosis. For the 106 patients with osteonecrosis, we also required written documentation of symptoms and signs confirming the diagnosis of peripheral neuropathy. Unilateral symptoms or symptoms confined to the upper limbs were not accepted. Symptoms were generally recorded as burning, pain or numbness, or a combination of these, in the feet. Signs typically included impairment of pin-prick, light touch or vibratory, sensations in the toes or feet, and impairment or loss of tendo-Achilles reflexes. The diagnosis of diabetes mellitus required the use of antidiabetic medication, fasting blood glucose of more than 125 mg/dl on two separate occasions or glycated hemoglobin more than 6.4%. The diagnosis of alcohol abuse was taken from the EMR. Pharmacy records were reviewed for the use, before the diagnosis of peripheral neuropathy, of zalcitabine (ddC), didanosine (ddI) or stavudine (d4T). Statistical analyses used χ2 or Fisher's exact tests. Significance was two-tailed. Among the 106 patients with osteonecrosis, there were 44 diagnosed with peripheral neuropathy involving the lower limbs. We excluded 13 of these for various reasons. Peripheral neuropathy in the remaining 31 (29.2%) of the 106 osteonecrotic patients was 1.8-fold more frequent than in the 1856 (16.2%) of the 11 400 without osteonecrosis (odds ratio 2.1, 95% confidence interval 1.4–3.2, P < 0.0003). We did not seek written documentation confirming the diagnoses of peripheral neuropathy for the 1856 without osteonecrosis; were that number reduced, by a factor of 13/44, in order to provide the same proportion of excluded patients as in those with osteonecrosis, then the 31 (29.2%) of 106 would be compared with 1308 (11.5%) of 11 400 (P < 0.0001), a 2.5-fold difference. In the following analyses, group 1 comprises the 31 patients with peripheral neuropathy before osteonecrosis and group 2 excludes four with unobtainable records and comprises the 71 with osteonecrosis either without peripheral neuropathy or with peripheral neuropathy diagnosed after osteonecrosis. ddC, ddI or d4T were used by 90.3% of group 1 and by 69.0% of group 2 (P = 0.02). Diabetes mellitus was present before the diagnoses of peripheral neuropathy in 9.7% of group 1 and in 15.5% of group 2 (P = 0.54). Alcohol abuse was present before the diagnoses of osteonecrosis in 16.1% of group 1 and in 11.3% of group 2 (P = 0.53). The above data confirm that HIV-infected persons with osteonecrosis have between 1.8-fold and 2.6-fold more peripheral neuropathy than those without osteonecrosis and support the inference that low levels of NGF could be among the biological underpinnings of osteonecrosis. Antibodies against NGF impair nerve function and, in a clinical trial, resulted in osteonecrosis [8]. Low levels of NGF were seen in a group of 131 HIV-infected patients [12], and have been described in patients with diabetic peripheral neuropathy [13]. NGF recognizes a variety of ligands relevant to bone regeneration, including VEGF receptors and receptors on osteoblasts. The role of reduced levels of VEGF in the pathogenesis of osteonecrosis is shown by the observation of osteonecrosis in some patients given a monoclonal antibody against VEGF [14]. Corticosteroids and alcohol abuse, which together are associated with 90% of cases of atraumatic osteonecrosis of the femoral head [15], are both associated with low levels of VEGF [16–20]. In summary, excessive peripheral neuropathy in patients with osteonecrosis not only suggests that NGF and VEGF contribute to the pathogenesis, but also supports the hypothesis that impaired regenerative capacity of osteoblasts, imposed by these cytokines, is responsible for the excess of osteonecrosis in HIV-infected patients. Acknowledgements Conflicts of interest There are no conflicts of interest.

Recurrent Fatal Necrotizing Fasciitis due to &lt;i&gt;Streptococcus pyogenes&lt;/i&gt; in a Child with Hereditary Sensory and Automic Neuropathy Type IV

Although necrotizing fasciitis (NF) is a rapidly progressive infection, recurrent NF is very rare. Herein we report a rare case of recurrent NF due to Streptococcus pyogenes. A 12-year-old female with hereditary sensory and autonomic neuropathy (HSAN) type IV presented with fever and swelling on her left knee. NF was diagnosed and she was treated successfully. Two years later she was readmitted with NF of the right knee and limb. Despite treatment, progressive tissue necrosis developed and proximal femur amputation was performed. Eight months following the second attack she was readmitted with NF of her left knee and her entire leg. Despite a wide surgical debridement and antibiotic treatment, the clinical status of the patient failed to improve and she subsequently died. Although many conditions have been reported to be predisposing factors for NF, this is the first report of an association between HSAN type IV and recurrent NF due to S. pyogenes. We recommend antibiotic prophylaxis for patients with NF due to S. pyogenes, especially for those with predisposing factors.

Peripheral Arthropathy in Hereditary Sensory and Autonomic Neuropathy Types III and IV

To determine the features of the underlying destructive arthropathy in the peripheral joints of children with hereditary sensory and autonomic neuropathy (HSAN) type III and to compare and contrast this to the arthropathy noted in HSAN type IV, as both groups experience decreased pain perception. From a database of 547 patients with HSAN type III and 32 patients with HSAN type IV, we performed a retrospective chart review and radiographic analysis of all patients who presented with joint swelling and deformity. Underlying joint pathology was classified as either osteonecrosis or Charcot arthropathy. In the HSAN type III population, 44 (8%; 22 males and 22 females) of the 547 patients had clinical evidence of arthropathy. In 42 patients, 48 joints demonstrated radiographic evidence of osteonecrosis; 45 (94%) of the 48 joints with osteonecrosis occurred in the lower extremity. In each case of osteonecrosis of the knee (n = 19), isolated involvement of the lateral distal femoral condyle was seen consisting of varying sizes of posterolateral osteochondral fragmentation. In the 32 patients comprising the HSAN type IV population, 18 (56%) were found to have radiographic findings consistent with Charcot arthropathy in a total of 30 affected joints. One patient demonstrated Charcot arthropathy of the spine and subsequent progressive spondylolisthesis. Nine patients (12 joints) also demonstrated osteomyelitis. In patients with HSAN type III, osteonecrosis is the initial lesion preceding destructive arthropathy. Osteonecrosis and osteochondral fragmentation were always isolated at the lateral distal femoral condyle in the knee. This pathology may be amenable to surgical reconstruction and fixation to stabilize the knee and prevent further degeneration. Hereditary sensory and autonomic neuropathy type IV was most commonly associated with Charcot arthropathy or joint subluxation and dislocation. Late secondary changes at the articular surface may make radiographic distinction difficult. Charcot arthropathy affected both sides of the involved joint with evidence of collapse and fragmentation. With osteonecrosis, the articular process was found to be more focal.

Beyond neuropathy in hereditary sensory and autonomic neuropathy type V: cognitive evaluation

Hereditary sensory and autonomic neuropathy (HSAN) type V is a very rare disorder. It is characterized by the absence of thermal and mechanical pain perception caused by decreased number of small diameter neurons in peripheral nerves. Recent genetic studies have pointed out the aetiological role of nerve growth factor beta, which is also involved in the development of the autonomic nervous system and cholinergic pathways in the brain. 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. We performed a throughout evaluation of four HSAN type V patients and compared their performance with 37 normal individuals. Our patients showed no cognitive deficits, not even mild ones. Although newer mutations on this and related disorders are continuously described, their clinical characterization has been restricted to the peripheral aspects of these conditions. A broader characterization of this rare disorder may contribute to better understand the mechanisms of the nociceptive and cognitive aspects of pain.

Hereditary sensory and autonomic neuropathies: types II, III, and IV

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 autonomic dysfunction (gastroesophageal reflux, postural hypotention, excessive sweating). Subsequent to the numerical classification of four distinct forms of HSAN that was proposed by Dyck and Ohta, additional entities continue to be described, so that identification and classification are ongoing. As a group, the HSAN are rare diseases that affect both sexes. HSAN III is almost exclusive to individuals of Eastern European Jewish extraction, with incidence of 1 per 3600 live births. Several hundred cases with HSAN IV have been reported. The worldwide prevalence of HSAN type II is very low. This review focuses on the description of three of the disorders, HSAN II through IV, that are characterized by autosomal recessive inheritance and onset at birth. These three forms of HSAN have been the most intensively studied, especially familial dysautonomia (Riley-Day syndrome or HSAN III), which is often used as a prototype for comparison to the other HSAN. Each HSAN disorder is likely caused by different genetic errors that affect specific aspects of small fiber neurodevelopment, which result in variable phenotypic expression. As genetic tests are routinely used for diagnostic confirmation of HSAN III only, other means of differentiating between the disorders is necessary. Diagnosis is based on the clinical features, the degree of both sensory and autonomic dysfunction, and biochemical evaluations, with pathologic examinations serving to further confirm differences. Treatments for all these disorders are supportive.

Novel mutation in the HSN2 gene in a Korean patient with hereditary sensory and autonomic neuropathy type 2

Hereditary sensory and autonomic neuropathies (HSAN) are a group of clinically and genetically heterogeneous disorders that are associated with sensory dysfunction. Among these, HSAN type 2 (HSAN2; MIM 201300) is a rare recessive disease that is characterized by an early age of onset with distal and proximal sensory loss, dysfunction of the autonomic nervous system, loss of the tendon reflex, the presence of various mutilations, and the slow progression of the disease over time. The authors report a Korean patient with the clinical features of HSAN2, who was compound heterozygous for two loss-of-function mutations in the HSN2 gene: c.217C > T (Gln73X) and c.1134_1135insT (Asp379fsX1). The Gln73X mutation was a novel mutation while the Asp379fsX1 mutation has recently been reported in a Japanese patient with HSAN2. These results expanded the spectrum of mutations of the HSN2 gene by identifying a novel truncating mutation in a Korean patient and further support the hypothesis that HSN2 is a causative gene for HSAN2.

Tension-type headache as the unique pain experience of a patient with congenital insensitivity to pain

Congenital insensitivity to pain (CIP) is a rare clinical syndrome characterized by dramatic impairment of pain perception since birth and is generally caused by a hereditary sensory and autonomic neuropathy (HSAN) with loss of the small-calibre, nociceptive nerve fibres. We report the case of a 32-year-old woman with CIP and a presumptive diagnosis of HSAN type V, who experienced physical pain for the first and unique time in her life shortly after the sudden loss of her brother. This patient had sustained innumerable painless injuries during childhood, including bone fractures and severe burns. The only pain she ever felt consisted in an intense headache, which took place in a context of strong emotional overload and anxiety, 3 weeks after her younger brother died suddenly in a car accident. The description of this inaugural episode of headache fulfilled the diagnostic criteria of episodic tension-type headache. This case strongly suggests that the transcription of the grief of bereavement into physical pain may sometimes occur independently of the peripheral mechanisms of nociception and despite the lack of previous pain experience. In the light of recent experimental data showing that the same neural mechanisms that regulate physical pain may also control the expression of separation distress and the feeling of social exclusion, this unique case helps to better understand why some patients may feel physically hurt after the loss of someone they love.

Assessment and evaluation of hereditary sensory and autonomic neuropathies with autonomic and neurophysiological examinations.

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. Clinically, the different types of HSANs can be identified by a detailed history and examination and 'bedside' tests of sympathetic or parasympathetic function such as active standing, metronomic breathing or the Valsalva maneuver, sensory and motor nerve conduction studies, quantitative sensory testing of thermal and vibratory perception, and the analysis of sudomotor function by recordings of the sympathetic skin response (SSR) or the sweat output during quantitative sudomotor axon reflex testing (QSART). The slowly progressive, symmetrical HSAN type I manifests between the second and fourth decade with ulcers or mutilations of the lower extremities, low normal sensory and motor nerve conduction velocities, but abnormal warm, cold and heat pain perception and distal anhidrosis. In HSAN type II, symptoms occur already in infancy, trophic alterations affect fingers and toes. There are acral anhidrosis and various autonomic dysfunctions such as tonic pupils, eating and swallowing difficulties, constipation, episodic fever, profound hypotonia and episodes of apnea. Sensory perception is severely impaired and accounts for elevated vibratory but also thermal perception thresholds. Sensory nerve conduction is highly abnormal while motor nerve conduction studies are almost normal. Type III, the autosomal recessive familial dysautonomia (FD), is the most common of the HSANs. FD is characterized by pronounced autonomic, primarily sympathetic dysregulation with severe orthostatic hypotension, repeated episodes of autonomic crises with excessive arterial hypertension, profuse sweating, skin blotching, puffy hands and behavioral abnormalities. FD manifests only in children of Ashkenazi Jewish ancestry. Cardinal findings are diminished deep tendon reflexes, absence of overflow tears, absence of fungi-form papillae of the tongue and of axon flare response following intradermal histamine injection. Thermal and vibratory testing show pronounced impairment of temperature and pain but also of vibratory perception. Children with HSAN IV, 'congenital insensitivity to pain with anhidrosis' experience repeated episodes of high fevers during high environmental temperature due to anhidrosis. The anhidrosis of the hyperkeratotic skin accounts for absence of the SSR or lack of sweat output during QSART. The patients' insensitivity to superficial as well as deep, visceral pain can be demonstrated e. g. by quantitative heat pain testing. Patients develop severe mutilations e. g. of the tip of their tongue, they might have severe burn injuries and multiple, unnoticed fractures with neuropathic joints. Children with the very rare HSAN type V respond normally to tactile, vibratory or thermal stimuli, but have a selective loss of pain perception with otherwise normal neurological examination. Painful stimuli reveal no signs of discomfort.

Two Brothers with a Variant of Hereditary Sensory Neuropathy

We report two brothers with the clinical symptoms and neuropathological findings of hereditary sensory and autonomic neuropathy (HSAN) type IV but with normal sweating function and absence of recurrent fever. We propose that our patients may have a lower degree of expression of the genetic defect underlying HSAN type IV or that they represent a separate genetic entity.