A novel homozygous DST variant causes hereditary sensory and autonomic neuropathy in a Pakistani family

The hereditary sensory neuropathies, also known as the hereditary sensory and autonomic neuropathies, are a clinically and genetically heterogeneous group of disorders. As they are not as common as Charcot-Marie-Tooth disease, they do not receive the same level of attention, but there have been major advances in the identification of the causative genes in the past decade. Certain forms of hereditary sensory and autonomic neuropathy, especially hereditary sensory and autonomic neuropathy type I, which has minimal autonomic involvement and is more accurately termed hereditary sensory neuropathy type I, can present in a very similar fashion to certain forms of Charcot-Marie-Tooth disease (Charcot-Marie-Tooth type 2B, see below), and therefore it is important that clinicians who regularly manage patients with neuropathy are familiar with the latest developments in the hereditary sensory and autonomic neuropathies. This review will concentrate on the recent genetic advances in hereditary sensory and autonomic neuropathy, and especially on those forms that overlap clinically with Charcot-Marie-Tooth disease, hence the title of the review 'Hereditary sensory neuropathies' rather than hereditary sensory and autonomic neuropathies.

Hereditary sensory and autonomic neuropathy type 2 is a rare disorder caused by recessive mutations in the WNK1/HSN2 gene located on chromosome 12p13.33. Phenotype of the patients is characterized by severe sensory loss affecting all sensory modalities. We report a novel homozygous Lys179fsX182 (HSN2); Lys965fsX968 (WNK1/HSN2) mutation causing an early childhood onset hereditary sensory and autonomic neuropathy type 2, with acromutilations in upper and lower limbs, and autonomic dysfunction. To the best of our knowledge this is the first genetically proven case of hereditary sensory and autonomic neuropathy type 2 originating from East Europe.

Hereditary sensory and autonomic neuropathies (HSANs) are rare inherited disorders characterized by sensory and autonomic nerve dysfunction classified into eight subtypes. HSAN-VI (OMIM: 614653) is an autosomal recessive subtype which manifests severe pain insensitivity, neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development and autonomic abnormalities. Pathogenic variants in the DST gene, which encodes dystonin have been identified as the underlying cause of HSAN-VI. Thus far, only 15 HSAN-VI patients associated with 11 DST variants, mostly compound heterozygous, have been identified in the literature. We aimed clinical and molecular genetic characterization of a Pakistani family presenting a phenotype consistent with HSAN-VI. The proband's DNA was subjected to whole exome sequencing and homozygosity mapping. Sanger sequencing was used to test variant segregation in the available members of the family. Pathogenicity and deleterious effects of the identified variant on the protein function was tested through bioinformatic in silico prediction tools. Further, we collected clinical and molecular information for all 15 patients reported in the literature. We identified a novel missense DST variant NM_001374736.1:c.21,899A > G; p.(Asp7300Gly), classified as a VUS, in autosomal recessive pattern of inheritance in the family. We summarized and compared clinical manifestations and mutation data of previously reported HSAN-VI patients along with those presented in the current study. Our findings expand the mutation spectrum of DST-associated HSAN-VI potentially adding to its pathophysiology. To our knowledge, this is the second report of a homozygous missense DST variant overall, and first report of HSAN-VI from Pakistan.

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.

BackgroundHereditary sensory and autonomic neuropathy type VIII is a rare autosomal recessive inherited disorder. Chen et al. recently identified the causative gene and characterized biallelic mutations in the PR domain-containing protein 12 gene, which plays a role in the development of pain-sensing nerve cells. Our patient’s family was included in Chen and colleagues’ study. We performed a literature review of the PubMed library (January 1985 to December 2016) on hereditary sensory and autonomic neuropathy type I to VIII genetic disorders and their orofacial manifestations. This case report is the first to describe the oral manifestations, and their treatment, of the recently discovered hereditary sensory and autonomic neuropathy type VIII in the medical and dental literature.Case presentationWe report on the oral manifestations and dental management of an 8-month-old white boy with hereditary sensory and autonomic neuropathy-VIII over a period of 16 years. Our patient was homozygous for a mutation of PR domain-containing protein 12 gene and was characterized by insensitivity to pain and thermal stimuli, self-mutilation behavior, reduced sweat and tear production, absence of corneal reflexes, and multiple skin and bone infections. Oral manifestations included premature loss of teeth, associated with dental traumata and self-mutilation, severe soft tissue injuries, dental caries and submucosal abscesses, hypomineralization of primary teeth, and mandibular osteomyelitis.ConclusionsThe lack of scientific knowledge on hereditary sensory and autonomic neuropathy due to the rarity of the disease often results in a delay in diagnosis, which is of substantial importance for the prevention of many complications and symptoms. Interdisciplinary work of specialized medical and dental teams and development of a standardized treatment protocols are essential for the management of the disease. There are many knowledge gaps concerning the management of patients with hereditary sensory and autonomic neuropathy-VIII, therefore more research on an international basis is needed.

Hereditary sensory and autonomic neuropathy (HSAN) type V is a rare inherited disease caused by a mutation in the neurotrophic tyrosine kinase receptor, type 1 gene located on chromosome 1 (1q21-q22). It is characterized by pain insensitivity, partial anhydrosis without mental retardation and unimpaired touch and pressure sensitivity. Self-mutilation injury involving the teeth, lips, tongue, ears, eyes, nose, and fingers are invariable feature of this disorder. The purpose of this paper was to discuss the diagnosis and oral management of 18-month-old girl with HSAN type V, having typical oral manifestation of bitten tongue and auto-extraction of primary teeth. Modified bite guard was given to the patient to prevent further self-mutilating injuries to the tongue.

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.

Background. The presence of Charcot arthropathies, joint dislocations, infections and fractures in a child without evidence of neurological abnormality should give rise to a suspicion of congenital insensitivity to pain (hereditary sensory and autonomic neuropathy). Hereditary sensory and autonomic neuropathy (HSAN) is a rare syndrome characterized by congenital insensitivity to pain, temperature changes and by autonomic nerve formation disorders. HSAN is classified into five types: sensory radicular neuropathy (HSAN I), congenital sensory neuropathy (HSAN II), familial dysautonomia or Riley Day Syndrome (HSAN III), congenital insensitivity to pain with anhidrosis (HSAN IV) and congenital indifference to pain (HSAN V).
 Case presentation. A 13-year old girl first product of a non-consanguineous marriage, presented with malunion of successive fractures or Charcots ankle joint destruction on top of significant lytic changes/osteonecrosis. The patient had sustained many painless injuries resulting in fractures with subsequent disfiguremnt of her ankle joint. Arthropathy of the knees, ankles, tarsal bones and feet without pain associated with obvious changes in the shape of the ankle joint were present. Despite a normal sense of touch in our patient the indifference to pain made her extremely susceptible to breakdown of the skin over the ankle osseous prominences.
 Conclusion. Generally speaking, the orthopaedic management of such patients is extremely difficult since these patients do not restrict the movements of the involved extremity as they lack the inhibitory pain reflex. Interestingly, our attempts for surgical stabilisation of the ankle joints were succsessfull and eventually the girl became able to walk. It is important to anticipate patient and parent education in joint protection and surveillance for injury as the most important component of the treatment plan for these children. We might postulate that the degree of osteolysis of the ankle joint in our present child might be a form of secondary osteolysis.

Hereditary sensory and autonomic neuropathies (HSAN) are rare diseases. Five different types are described. Hereditary sensory and autonomic neuropathy type V, also known as congenital insensitivity to pain, is a rare autosomal recessive disease seen in early childhood. Self-mutilation is an invariable feature of this disorder involving the teeth, tongue, lips, and fingers. This report described the case of a 2-year-old baby boy who had self-mutilating injuries to her tongue and hands, caused by biting. Protective splints were given to the patient to prevent further self-mutilation.

Hereditary Sensory and Autonomic Neuropathy (HSAN) Type II is an autosomal recessive genetic disease which presents predominantly with sensory neuropathy and neuropathic ulcers. HSAN Type II is a rare disease, and in the few cases that have been reported, the focus has been on identifying genetic markers of the disease. Orthopaedic conditions may be a major presentation of the disease, and the prevention of superficial trauma and foot care is the only definitive management.

The DST gene is located on chromosome 6p and encodes for a large protein. Alternative splicing of this protein produces the neuronal (a1-a3), muscular (b1-b3), and epithelial (e) isoforms. Hereditary sensory and autonomic neuropathy (HSAN) type VI is a rare autosomal recessive disorder due to mutations affecting the a2 isoform. We present a case of HSAN-VI in a male neonate born to consanguineous parents. Genome sequencing revealed a novel homozygous variant (DST_c.1118C > T; p.Pro373Leu) inherited from both parents. This case further expands the phenotype and genotype of this rare syndrome.

We report a case of hereditary sensory and autonomic neuropathy presenting with childhood-onset symmetric distally predominant limb hypoesthesia to tactile, thermal, and painful stimuli. Exome sequencing identified a homozygous pathogenic variant in the with-no-lysine (K) kinase 1 (WNK1), lysine deficient protein kinase 1 gene. The clinical, electrophysiological, and genetic findings confirmed a diagnosis of hereditary sensory and autonomic neuropathy type 2A (HSAN 2A). This case highlights the importance of genetic confirmation in the evaluation of early-onset neuropathies, especially when the most common causes have been ruled out. Significantly, our observations underscore the potential role of skin biopsy in identifying autonomic abnormalities in HSAN 2, possibly contributing to a better understanding of these rare neuropathies. We also reviewed the reported cases of this disease in the literature to highlight its phenotypic variability.

Objective: To quantify the impact of the SPTLC1 mutation upon neurological outcome measures in HSAN1 patients. Background Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is the most common inherited neuropathy to predominantly affect sensory neurons. The disorder is caused by mutations in SPTCL1, which encodes the enzyme serine palmitoyltransferase. Design/Methods: We studied two HSAN1 families with different mutations (n = 8). Five patients carried the C133Y mutation, three the C133W mutation. The median age was 34 years (range 26-59); the median age of onset was 19 (range 15-54). All eight patients underwent neurological examination and were scored using the CMT symptom score (CMTSS). Nerve conduction studies (NCS) of the upper and lower extremities were conducted in all (including 3 motor NCS and 4 sensory NCS). Six patients had skin biopsies at the distal leg and proximal thigh to assess the intraepidermal nerve fiber density (IENFD). Results: The average CMTSS was 12.38 (SD +/-6.74). All patients complained of neuropathic pain apart from two patients who had the highest CMTSS. Sensory symptoms (average score 2.9) were prominent but motor symptoms (average score 1.2) were present as well. No sensory responses were obtainable in 5/8; lower extremity motor responses were absent in 6/8 patients. None of these 6 patients had epidermal nerve fibers detected at the distal leg, while they were present in the thigh in all patients. The correlation coefficient between CMTSS and IENFD was -0.8 and between CMTSS and median motor amplitudes was -0.75. Conclusions: Beyond sensory there is also motor impairment present in HSAN1 patients. In our limited sample size we found an inverse correlation between both CMTSS and IENFD and CMTSS and nerve conduction studies. This study provides important clinical characterization of both neurophysiology and the IENFD in HSAN1. Disclosure: Dr. David has nothing to disclose. Dr. Oaklander has nothing to disclose. Dr. Pan has nothing to disclose. Dr. Novak has nothing to disclose. Dr. Brown has received personal compensation for activities as an advisory board member. Dr. Eichler has nothing to disclose.

We describe a case of hereditary sensory and autonomic neuropathy (HSAN) type II in a child with a penetrating foot ulcer, acral sensory impairment, and anhidrosis. This is the first documentation of HSAN in Sri Lanka.

Hereditary sensory and autonomic neuropathy (HSAN) type IV, also known as congenital insensitivity to pain with anhidrosis (OMIM 256800), is part of a family of neurodegenerative disorders that manifest with variable sensory and autonomic neuropathies. In this report, we present a unique dermatological finding in a patient with HSAN type IV: bilateral harlequin syndrome that occurred in association with unilateral Horner syndrome, traumatic alopecia and Riga-Fede disease.