Hereditary Sensory Autonomic Neuropathy Type Research Articles

Case report: Hereditary sensory autonomic neuropathy presenting as bifid deformity to the tongue

Hereditary sensory autonomic neuropathy (HSAN) is a group of rare genetic disorders in which affected patients have a diminished capacity to feel pain. Patients with HSAN may present with a wide range of factitial injuries, where injury to the oral cavity may be an early presenting sign. While existing literature on HSAN is scant, many reports highlight the long-term outcomes that may include enucleation of eyes, amputation of fingers and limbs, and disfigurement of the tongue. This case describes a five-month-old female with repetitive injury to the tongue causing it to heal with a bifid deformity. The patient was later diagnosed with HSAN type 4. This case highlights the importance of recognition of extensive oral trauma as one of the early signs of HSAN that should provoke a timely referral for neurological assessment.

Single Center Experience of RETREG1-related Hereditary Sensory Autonomic Neuropathy in Turkey (P11-8.009)

<h3>Objective:</h3> To describe the clinical characteristics of patients with <i>RETREG1</i> mutations. <h3>Background:</h3> Homozygous loss-of-function mutations in <i>RETREG1</i> result in Hereditary Sensory Autonomic Neuropathy (HSAN) Type 2. Clinical features include variable autonomic disturbances and upper motor neuron features such as brisk tendon reflexes, spasticity, and Babinski sign. <h3>Design/Methods:</h3> Herein, we evaluated the clinical and genetic features of 6 patients from 3 unrelated families with <i>RETREG1</i> mutation at the Neuromuscular Unit of the Istanbul Faculty of Medicine, Istanbul University. <h3>Results:</h3> Four patients were male. The median age of onset was 7.0 ± 2.5 (between 2 and 9 years). Foot ulcerations were the presenting symptom in four patients and walking difficulties in two. All patients were born to consanguineous marriages. In a median disease duration of 23.0 ± 14.4 years, four patients had osteomyelitis, and two had toe amputations. Five patients had a history of painless fractures in different lower extremity bones. Four patients had autonomic nervous system symptoms such as excessive sweating, constipation and orthostatism. Neurological examination of all patients showed spasticity, and brisk tendon reflexes. Muscle weakness in the lower extremities was noted in five patients. Sensory examination showed stocking type hypoesthesia and diminished vibration sensation in all patients. Five patients had pes planus deformity. Nerve conduction studies showed axonal sensory neuropathy in four patients and sensory-motor in two. Two families had homozygous c.433C&gt;T (p.Gln145*), and one had c.826delA (p.S276VfsX8) pathogenic variants in the <i>RETREG1</i> gene. <h3>Conclusions:</h3> In our study, all patients showed signs and symptoms consistent with pain insensitivity. Although shadowed by marked sensory symptoms, motor signs, such as spasticity, and muscle weakness, were also noted in our patients. Considering the autosomal recessive inheritance, new cases with <i>RETREG1</i> mutation are likely to be reported from Turkey, a country with a high rate of consanguineous marriages. <b>Disclosure:</b> Arman Cakar has nothing to disclose. Ms. BAGIROVA has nothing to disclose. Dr. Durmus has nothing to disclose. Prof. UYGUNER has nothing to disclose. Dr. Parman has nothing to disclose.

Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease

ObjectivesThe non-essential amino acids serine, glycine, and alanine, as well as diverse sphingolipid species, are implicated in inherited neuro-retinal disorders and are metabolically linked by serine palmitoyltransferase (SPT), a key enzyme in membrane lipid biogenesis. To gain insight into the pathophysiological mechanisms linking these pathways to neuro-retinal diseases we compared patients diagnosed with two metabolically intertwined diseases: macular telangiectasia type II (MacTel), hereditary sensory autonomic neuropathy type 1 (HSAN1), or both. MethodsWe performed targeted metabolomic analyses of amino acids and broad sphingolipids in sera from a cohort of MacTel (205), HSAN1 (25) and Control (151) participants. ResultsMacTel patients exhibited broad alterations of amino acids, including changes in serine, glycine, alanine, glutamate, and branched-chain amino acids reminiscent of diabetes. MacTel patients had elevated 1-deoxysphingolipids but reduced levels of complex sphingolipids in circulation. A mouse model of retinopathy indicates dietary serine and glycine restriction can drive this depletion in complex sphingolipids. HSAN1 patients exhibited elevated serine, lower alanine, and a reduction in canonical ceramides and sphingomyelins compared to controls. Those patients diagnosed with both HSAN1 and MacTel showed the most significant decrease in circulating sphingomyelins. ConclusionsThese results highlight metabolic distinctions between MacTel and HSAN1, emphasize the importance of membrane lipids in the progression of MacTel, and suggest distinct therapeutic approaches for these two neurodegenerative diseases.

The NGF R100W Mutation, Associated with Hereditary Sensory Autonomic Neuropathy Type V, Specifically Affects the Binding Energetic Landscapes of NGF and of Its Precursor proNGF and p75NTR.

Nerve Growth Factor (NGF), the prototype of the neurotrophin family, stimulates morphological differentiation and regulates neuronal gene expression by binding to TrkA and p75NTR receptors. It plays a critical role in maintaining the function and phenotype of peripheral sensory and sympathetic neurons and in mediating pain transmission and perception during adulthood. A point mutation in the NGFB gene (leading to the amino acid substitution R100W) is responsible for Hereditary Sensory and Autonomic Neuropathy type V (HSAN V), leading to a congenital pain insensitivity with no clear cognitive impairments, but with alterations in the NGF/proNGF balance. The available crystal structures of the p75NTR/NGF and 2p75NTR/proNGF complexes offer a starting point for Molecular Dynamics (MD) simulations in order to capture the impact of the R100W mutation on their binding energetic landscapes and to unveil the molecular determinants that trigger their different physiological and pathological outcomes. The present in silico studies highlight that the stability and the binding energetic fingerprints in the 2p75NTR/proNGF complex is not affected by R100W mutation, which on the contrary, deeply affects the energetic landscape, and thus the stability in the p75NTR/NGF complex. Overall, these findings present insights into the structural basis of the molecular mechanisms beyond the clinical manifestations of HSAN V patients.

Hereditary Sensory and Autonomic Neuropathy Type II in Two Brothers, a Close Differential of Leprosy

Hereditary sensory autonomic neuropathy (HSAN) falls under heritable neuropathies and is often misdiagnosed as leprosy leading to physical, emotional and financial burden to patients and their families. It presents as sensory and autonomic dysfunction leading to recurrent skin ulcers, scars, deformities of anaesthetic areas, Charcot joints, and decreased sweating. We report similar findings in an 11-year-old boy and his 10-year-old brother, in the form of ulcer, multiple healed scars and amputation of toes with reduced perception of touch, pain, temperature and vibration. No peripheral nerves were thickened, motor examination was within normal limits along with negative slit skin smear. Nerve conduction study revealed sensory polyneuropathy. X-ray of ankle joint showed degenerative changes. A diagnosis of HSAN type II with Charcot joint was made highlighting the importance of clinical history taking and physical examination. Parents were counselled regarding the management.

Oral Manifestation of Autoimmune Connective Tissue Disease in a 5 Year Old Patient: A Case report

One of the leading causes of morbidity among children includes Connective Tissue Disorders (CTD). Early diagnosis and prompt treatment of any CTD would help identify the associated disorders and is beneficial in preventing severe complications at a later age. Non-specific clinical presentations have made it challenging for both medical and dental practitioners in diagnosing and treating CTDs. Oral manifestations of systemic diseases help in the early diagnosis of certain diseases. Hence it is extremely important for dentists to carefully observe the patient complaints and define the diagnosis. The present case report identifies a CTD condition in a 5-year-old patient, with Hereditary sensory autonomic neuropathy type IV (HSAN -IV).

Hereditary Sensory and Autonomic Neuropathy Type VIII: Congenital Insensitivity to Pain with Anhidrosis.

Hereditary sensory autonomic neuropathy type VIII (HSAN VIII) is a rare genetic disorder that characterized by insensitivity to pain, anhidrosis, self-mutilation, and absence of corneal reflex. We here report a 2-year-old female child presented with corneal opacity and was diagnosed HSAN VIII by its typical clinical features confirmed by gene analysis revealing the presence of homozygous mutation in the PRDM12 gene. Case Summary A 2-year-old female child was presented with complaint of corneal opacity in both eyes noticed 4 months ago [Figure 1a]. The mother also complained of missing both upper and lower front teeth [Figure 1b]. Frequent history of trauma either unknown or self-mutilated without any sign of discomfort was revealed. No lacrimation during cry, lack of sweating with dry skin, and recurrent episodes of unexplained fever were also noticed [Figure 1c]. She was the only child of consanguineous marriage with no similar disease in the family. General examination revealed evidence of mutilation such as multiple scars, well-defined nontender ulcers over face and limbs, and shortening of distal phalanges [Figure 1d-f]. Ocular examination showed absence of corneal sensation with corneal scar. Neurologic examination found generalized absence of pain and temperature perception with loss of reflexes. Gene analysis revealed the presence of homozygous mutation in the PRDM12 gene confirming the diagnosis of HSAN VIII.Figure 1: Composite picture depicting various manifestations of a child with hereditary sensory and autonomic neuropathy type VIII: (a) bilateral corneal scarring, (b) missing upper and lower front teeth, (c) dry skin, (d) painless ulcer on the right ankle, and (e and f) mutilated distal phalanges of hand and feetHSAN type VIII comprises a group of genetic disorders involving sensory and autonomic dysfunctions, described as a rare autosomal recessive disorder caused by homozygous mutation in the PRDM12 gene on chromosome 9q34.[12] It is characterized by insensitivity to pain and thermal stimuli, altered sweat and tear formation, self-mutilation behavior, absence of the corneal reflex resulting in corneal scarring and presence of repeated infections of the skin and bone that are also common [Table 1].[34] The diagnosis of HSAN is challenging due to its rarity and lack of simple diagnostic tests. The affected persons are vulnerable to severe complications and self-mutilation. Therefore, early identification and appropriate management are necessary to avoid severe injuries and its consequences.[5]Table 1: Reported cases of hereditary sensory autonomic neuropathy type VIII (HSAN VIII)Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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.

FIRST REPORTED CASE OF MAJEED SYNDROME FROM PAKISTAN

Majeed syndrome, characterized by chronic recurrent multifocal osteomyelitis and congenital dyserythropoeitic anemia, is a rare disease reported in children. We report a case of Majeed Syndrome in a 9-year-old boy, born of consanguineous marriage reporting to us for treatment of anemia, requiring blood transfusion. He underwent below-knee-amputation due to unresolving recurrent osteomyelitis at multiple sites. There was history of pain insensitivity and fever during hot weather as well. His interleukin-6 levels were raised. This is the first case of Majeed Syndrome from Pakistan and first in the world with Hereditary Sensory Autonomic Neuropathy type 4 as an associated feature.

Two Case Reports of Hereditary Sensory Autonomic Neuropathy Type IV

Hereditary Sensory Autonomic Neuropathy type IV (HSAN-IV), previously known as congenital insensitivity to pain and anhidrosis (CIPA), is an uncommon condition that presents in infancy with repeated episodes of fever, loss of pain sensations and self-mutilation. We are reporting two patients from two different families. Both patients had history of recurrent fever, anhidrosis, and pain insensitivity and self-mutilation behavior. Both had delayed motor developmental milestones with cognitive impairment. Clinical diagnosis of HSAN type IV was made on the basis of history, clinical examination and excluding other possible causes. Diagnosis of this rare disease is commonly delayed and patients ultimately develop complications. As there is no definitive treatment, these patients and their families should receive proper education and counselling for rehabilitation

Mechanisms of L-Serine-Mediated Neuroprotection Include Selective Activation of Lysosomal Cathepsins B and L.

L-serine is a naturally occurring dietary amino acid that has recently received renewed attention as a potential therapy for the treatment of amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), hereditary sensory autonomic neuropathy type I (HSAN1), and sleep induction and maintenance. We have previously reported L-serine functions as a competitive inhibitor of L-BMAA toxicity in cell cultures and have since progressed to examine the neuroprotective effects of L-serine independent of L-BMAA-induced neurotoxicity. For example, in a Phase I, FDA-approved human clinical trial of 20 ALS patients, our lab reported 30g L-serine/day was safe, well-tolerated, and slowed the progression of the disease in a group of 5 patients. Despite increasing evidence for L-serine being useful in the clinic, little is known about the mechanism of action of the observed neuroprotection. We have previously reported, in SH-SY5Y cell cultures, that L-serine alone can dysregulate the unfolded protein response (UPR) and increase the translation of the chaperone protein disulfide isomerase (PDI), and these mechanisms may contribute to the clearance of mis- or unfolded proteins. Here, we further explore the pathways involved in protein clearance when L-serine is present in low and high concentrations in cell culture. We incubated SH-SY5Y cells in the presence and absence of L-serine and measured changes in the activity of proteolytic enzymes from the autophagic-lysosomal system, cathepsin B, cathepsin L, and arylsulfatase and specific activities of the proteasome, peptidylglutamyl-peptide hydrolyzing (PGPH) (also called caspase-like), chymotrypsin, and trypsin-like. Under our conditions, we report that L-serine selectively induced the activity of autophagic-lysosomal enzymes, cathepsins B and L, but not any of the proteasome-hydrolyzing activities. To enable comparison with previous work, we also incubated cells with L-BMAA and report no effect on the activity of the autophagic lysosomes or the proteasomes. We also developed an open-source script for the automation of linear regression calculations of kinetic data. Autophagy impairment or failure is characteristic of many neurodegenerative disease; thus, activation of autophagic-lysosomal proteolysis may contribute to the neuroprotective effect of L-serine, which has been reported in cell culture and human clinical trials.

Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1.

ObjectiveTo evaluate the safety and efficacy of l-serine in humans with hereditary sensory autonomic neuropathy type I (HSAN1).MethodsIn this randomized, placebo-controlled, parallel-group trial with open-label extension, patients aged 18–70 years with symptomatic HSAN1 were randomized to l-serine (400 mg/kg/day) or placebo for 1 year. All participants received l-serine during the second year. The primary outcome measure was the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS). Secondary outcomes included plasma sphingolipid levels, epidermal nerve fiber density, electrophysiologic measurements, patient-reported measures, and adverse events.ResultsBetween August 2013 and April 2014, we enrolled and randomized 18 participants, 16 of whom completed the study. After 1 year, the l-serine group experienced improvement in CMTNS relative to the placebo group (−1.5 units, 95% CI −2.8 to −0.1, p = 0.03), with evidence of continued improvement in the second year of treatment (−0.77, 95% CI −1.67 to 0.13, p = 0.09). Concomitantly, deoxysphinganine levels dropped in l-serine-treated but not placebo-treated participants (59% decrease vs 11% increase; p < 0.001). There were no serious adverse effects related to l-serine.ConclusionHigh-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression.Clinicaltrials.gov identifierNCT01733407.Classification of evidenceThis study provides Class I evidence that high-dose oral l-serine supplementation significantly slows disease progression in patients with HSAN1.

Uncoupling neurotrophic function from nociception of nerve growth factor: what can be learned from a rare human disease?

Nerve growth factor (NGF) is a powerful trophic factor that provides essential support for the survival and differentiation of sympathetic and sensory neurons during development. However, NGF also activates nociceptors contributing significantly to inflammatory pain and neuropathic pain after tissue injury. As such anti-NGF based therapies represent a promising strategy for pain management. Because of dose-dependent serious side effects such as back pain, injection site hyperalgesia, clinical trials of using NGF to treat various disorders such as diabetic neuropathies, chemotherapy-induced and human immunodeficiency virus-associated peripheral neuropathies were all discontinued. Thus far, worldwide clinical applications of NGF in treating patients are very limited except in China. Hereditary sensory autonomic neuropathy type V (HSAN V) is an extremely rare disease. Genetic analyses have revealed that HSAN V is associated with autosomal recessive mutations in NGF. One of the mutations occurred at the 100th position of mature NGF resulting in a change of residue from arginine to tryptophan (R100W). Although those HSAN V patients associated with the NGFR100W mutation suffer from severe loss of deep pain, bone fractures and joint destruction, interestingly patients with the NGFR100W mutation do not show apparent cognitive deficits, suggesting important trophic support function is preserved. We believe that NGFR100W provides an ideal tool to uncouple the two important functions of NGF: trophic versus nociceptive. Studies from investigators including ourselves have indeed confirmed in animal testing that the NGFR100W no longer induced pain. More importantly, the trophic function seemed to be largely preserved in NGF harboring the R100W mutation. On the mechanistic level, we found that the NGFR100W mutation was capable of binding to and signaling through the tyrosine receptor kinase A receptor. But its ability to bind to and activate the 75 kDa neurotrophic factor was significantly diminished. The significance of these findings is at least two folds: 1) the NGFR100W mutation can be used as an alternative to the wildtype NGF to treat human conditions without eliciting pain; and 2) the 75 kDa neurotrophic factor may serve as a novel target for pain management. We will discuss all the details in this mini-review.

Comprehensive Computational Analysis of Protein Phenotype Changes Due to Plausible Deleterious Variants of Human SPTLC1 Gene.

Genetic variations found in the coding and non-coding regions of a geneare known to influence the structure as well as the function of proteins. Serine palmitoyltransferase long chain subunit 1 a member of α-oxoamine synthase family is encoded by SPTLC1 gene which is a subunit of enzyme serine palmitoyltransferase (SPT). Mutations in SPTLC1 have been associated with hereditary sensory and autonomic neuropathy type I (HSAN-I). The exact mechanism through which these mutations elicit protein phenotype changes in terms of structure, stability and interaction with other molecules is unknown. Thus, we aimed to perform a comprehensive computational analysis of single nucleotide polymorphisms (SNPs) of SPTLC1 to prioritize a list of potential deleterious SNPs and to investigate the protein phenotype change due to functional polymorphisms. In this study, a diverse set of SPTLC1 SNPs were collected and scrutinized to categorize the potential deleterious variants. Our study concordantly identified 21 non- synonymous SNPs as pathogenic and deleterious that might induce alterations in protein structure, flexibility and stability. Moreover, evaluation of frameshift, 3’ and 5’ UTR variants shows c.*1302T> Gas effective. This comprehensive in silico analysis of systematically characterized list of potential deleterious variants could open avenues as primary filter to substantiate plausible pathogenic structural and functional impact of variants.

Hereditary sensory autonomic neuropathy type V: a rare case report

Hereditary sensory autonomic neuropathy (HSAN) type V is a rare autosomal recessive condition caused by mutation in neurotrophic tyrosine kinase receptor type 1 gene located on chromosome 1 (1q21-1q22). It is characterized by pain insensitivity, partial anhydrosis without mental retardation and unimpaired touch and pressure sensitivity. Self-mutilation injury involving teeth, lips, tongue, ears, eyes, nose and fingers are invariable feature of this disorder. This rare disorder can be extremely challenging for the physicians as the symptoms like pain, tenderness is absent and hence most of the symptoms and injuries are frequently missed. Here we report a case of 1-year old female child with HSAN type V, having the typical clinical manifestations of pain insensitivity causing self-mutilation. Apart from the classical manifestations of HSAN type V, our case also had bilateral corneal opacity.

Exome sequencing identifies novel NTRK1 mutations in patients with HSAN-IV phenotype.

Hereditary sensory autonomic neuropathy type IV (HSAN-IV) is a rare autosomal recessive disorder that usually begins in infancy and is characterized by anhidrosis, insensitivity to noxious stimuli leading to self-mutilating behavior, and intellectual disability. HSAN-IV is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene, NTRK1, encoding the high-affinity receptor of nerve growth factor (NGF) which maps to chromosome 1q21-q22. Patients with HSAN-IV lack all NGF-dependent neurons, the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we report nine patients from nine unrelated families with HSAN-IV due to various mutations in NTRK1, five of which are novel. These are three missense and two nonsense mutations distributed in various domains of NTRK1 involved in binding of NGF. The affected patients had variable intellectual deficits, and some had delayed diagnosis of HSAN-IV. In addition to being the first report of HSAN-IV from the Arabian Peninsula, this report expands the mutational spectrum of patients with NTRK1 mutations and provides further insights for molecular and clinical diagnosis.

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic β-cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D.

Hereditary Sensory Autonomic Neuropathy Type IV in a Newborn

Hereditary sensory autonomic neuropathy Type IV is an autosomal recessive disorder due to lack of maturation of small myelinated and unmyelinated fibers of peripheral nerves, which convey sensation of pain and temperature. There is anhidrosis due to lack of innervation of normal sweat glands resulting in recurrent episodes of hyperpyrexia. These patients usually present in late infancy. Here we present a case of HSAN Type IV who presented with fever from day 2 of life and so the possibility of HSAN should be kept in mind while dealing a case of fever without focus in a neonate.

The child who felt no pain: A case of hereditary sensory autonomic neuropathy (HSAN) type IV

Hereditary sensory autonomic neuropathy (HSAN) is the term used to describe a group of inherited disorders that are associated with sensory dysfunction (reduced reflexes, altered pain and temperature perception) and varying degrees of autonomic dysfunction (gastro-esophageal reflux, postural hypotension, excessive sweating). Five different entities have been described under HSAN (types I-V) we report a case of HSAN IV in a one and a half year old female child, with the classical features of this disorder - insensitivity to pain, self mutilating behaviour, recurrent episodic fevers and anhidrosis.

128. Functional and morphological demonstration of autonomic nervous system involvement in HSAN type II

The assessment of autonomic nervous system (ANS) in hereditary sensory autonomic neuropathy (HSAN) type II is still lacking. To this aim we investigated the ANS involvement in a new family with HSAN II phenotype. Three siblings from non consanguineous healthy parents were clinically and electrophysiologically evaluated. Two of them underwent quantitative sensory testing (QST), cardiovascular and dynamic sweat tests and skin biopsy. Genetic testing for WNK1 and FAM134B mutations is ongoing. Onset occurred in the first decade, with impaired pain sensitivity and progressive distal mutilating ulceration with amputation and joint deformity. Autonomic disturbances included hypohidrosis with heat intolerance, pupillary abnormalities and chronic diarrhoea. Nerve conduction studies showed a severe axonal sensory neuropathy. Sympathetic skin response was absent. QST was altered for both painful and nonpainful sensory modalities. Autonomic functional studies detected the impairment of both sudomotor and cardiovascular systems. Skin biopsy revealed a lack of epidermal and dermal sensory and autonomic nerve fibers with complete denervation of sweat glands and arteriovenous anastomoses. Our findings expand the HSAN II phenotype providing pathological and functional evidence of a widespread ANS impairment. The complete sensory and arteriovenous denervation accounts for the severe sensory loss and distal ulcerations in HSAN type II.