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Esophagus : Official Journal of the... Jun 2024Recently, the incidence of achalasia has been increasing, but its cause remains unknown. This study aimed to examine the initial symptoms and the course of symptoms and...
BACKGROUND
Recently, the incidence of achalasia has been increasing, but its cause remains unknown. This study aimed to examine the initial symptoms and the course of symptoms and to find new insights into the cause and course of the disease.
METHODS
Altogether, 136 patients diagnosed with achalasia by high-resolution manometry (HRM) were enrolled. Questionnaires and chart reviews were conducted to investigate the initial symptoms, time from onset to diagnosis, and comorbidities, as well as the relationship between HRM results, time to diagnosis, and symptom severity.
RESULTS
In total, 67 of 136 patients responded to the questionnaire. The median ages of onset and diagnosis were 42 and 58 years, respectively. The median time from onset to diagnosis was 78.6 months, with 25 cases (37.3%) taking > 10 years to be diagnosed. The symptom onset was gradual and sudden in 52 (77.6%) and 11 (16.4%) patients, respectively. Of the 11 patients with acute onset, three (27.3%) developed anhidrosis at the same time. There was no correlation between the time from onset to diagnosis and esophageal dilatation, resting LES pressure, or mean integrated relaxation pressure (IRP). No correlation was also found between the degree of symptoms and resting LES pressure or IRP.
CONCLUSION
Esophageal achalasia can have acute or insidious onsets. This finding may help to elucidate the cause of achalasia.
PubMed: 38844704
DOI: 10.1007/s10388-024-01069-5 -
Pain May 2024Pathogenic variations in the NTRK1 can cause congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive inherited neuropathy. The precise...
Pathogenic variations in the NTRK1 can cause congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive inherited neuropathy. The precise diagnosis of CIPA relies on the identification of pathogenic genotypes. Therefore, it is essential to expand the NTRK1 variation spectrum and improve molecular diagnosis methods. In this study, 74 probands with typical manifestations of CIPA but unknown genotypes were recruited. A comprehensive molecular genetic analysis was performed to identify variations in the NTRK1, using techniques including Sanger and next-generation sequencing, bioinformatic analysis, quantitative polymerase chain reaction (qPCR), gap-PCR, short tandem repeat (STR) genotyping, and reverse-transcription PCR. In addition, functional assays were conducted to determine the pathogenicity of variants of uncertain significance (VUS) and further characterized changes in glycosylation and phosphorylation of 14 overexpressed mutant vectors with variants at different domains in the TrkA protein, which is encoded by NTRK1. A total of 48 variations in the NTRK1 were identified, including 22 novel ones. When combined with data from another 53 CIPA patients examined in our previous work, this study establishes the largest genotypic and phenotypic spectra of CIPA worldwide, including 127 CIPA families. Moreover, functional studies indicated that the pathogenicity of VUS mainly affected insufficient glycosylation in the extracellular domain and abnormal phosphorylation in the intracellular domain. This study not only provides important evidence for precise diagnosis of CIPA but also further enriches our understanding of the pathogenesis of this disease.
PubMed: 38833577
DOI: 10.1097/j.pain.0000000000003252 -
Neurology India Mar 2024
Topics: Humans; Autonomic Nervous System Diseases; Flushing; Hypohidrosis
PubMed: 38817189
DOI: 10.4103/neurol-india.Neurol-India-D-24-00157 -
Frontiers in Genetics 2024Congenital insensitivity to pain with anhidrosis (CIPA, OMIM #256800), also known as hereditary sensory and autonomic neuropathy type Ⅳ (HSAN-IV), is a rare autosomal...
BACKGROUND
Congenital insensitivity to pain with anhidrosis (CIPA, OMIM #256800), also known as hereditary sensory and autonomic neuropathy type Ⅳ (HSAN-IV), is a rare autosomal recessive disorder characterized by recurrent episodic fevers, anhidrosis, insensitivity to noxious stimuli, self-mutilating behavior and intellectual disability. CIPA can be caused by the variants in gene, which encodes a high-affinity tyrosine kinase receptor for nerve growth factor. To ascertain the hereditary cause of a patient with CIPA accompanied by the additional symptoms of mild growth retardation, prone to fracture, underdeveloped nails of fingers and toes, irregular tooth alignment, enamel hypoplasia, postoperative wound healing difficulty, hand and limb deformity, and dislocation of hip joint, whole exome sequencing was used and revealed a compound heterozygous variant in .
METHODS
DNA was extracted from peripheral blood samples of pediatric patients and their parents, and subjected to comprehensive analysis using whole-exome sequencing (WES), followed by verification of variant sites in the gene through Sanger sequencing. To elucidate the functional impact of the newly discovered variants, an experimental system was established. Splicing analysis was conducted using PCR and Sanger sequencing, while expression levels were assessed through qPCR and Western blot techniques.
RESULTS
One hotspot variant c.851-33T>A(ClinVar ID: 21308) and a novel variant c.850 + 5G>A(ClinVar ID:3069176) was inherited from her father and mother, respectively, identified in the affected individuals. The c.850 + 5G>A variant in resulted in two forms of aberrant mRNA splicing: 13bp deletion (c.838_850del13, p. Val280Ser fs180) and 25bp deletion (826_850del25, p. Val276Ser fs180) in exon 7, both leading to a translational termination at a premature stop codon and forming a C-terminal truncated protein. The expression of two abnormal splicing isoforms was decreased both in the level of mRNA and protein.
CONCLUSION
In conclusion, this study elucidated the genetic cause of a patient with CIPA and identified a novel variant c.850 + 5G>A in , which broadened the and enriched the mutation spectrum.
PubMed: 38798698
DOI: 10.3389/fgene.2024.1345081 -
The Journal of Manual & Manipulative... May 2024Harlequin syndrome is a rare autonomic condition consisting of unilateral facial flushing and sweating induced by heat, emotion or physical activity. The affected side...
BACKGROUND
Harlequin syndrome is a rare autonomic condition consisting of unilateral facial flushing and sweating induced by heat, emotion or physical activity. The affected side presents anhidrosis and midline facial pallor due to denervation of the sympathetic fibers.
CASE DESCRIPTION
This case describes a patient who reported right-side redness of the face associated with hyperhidrosis during physical activity. She had two previous major motor vehicle accidents. The patient demonstrated difficulties in the visual accommodation of the left eye, but cranial nerve assessment was unremarkable; the patient was then referred to an ophthalmologist, who excluded any autonomic dysfunction as the primary cause of convergence and visual acuity.
OUTCOMES
A left-sided sympathetic dysfunction with Harlequin sign diagnosis was made followed by a progressive compensatory adaptation of the right face. The patient was educated and reassured about the benign nature of her problem.
DISCUSSION
Knowledge of the autonomic nervous system is still limited in clinical practice. Although challenging, physiotherapists should develop the knowledge and ability needed to perform appropriate assessment of autonomic dysfunctions.
CONCLUSION
A dispositional reasoning model should be considered in differential diagnosis.
PubMed: 38757409
DOI: 10.1080/10669817.2024.2349338 -
International Journal of Molecular... Apr 2024In cholinergic urticaria (CholU), small, itchy wheals are induced by exercise or passive warming and reduced sweating has been reported. Despite the described reduced...
In cholinergic urticaria (CholU), small, itchy wheals are induced by exercise or passive warming and reduced sweating has been reported. Despite the described reduced muscarinic receptor expression, sweat duct obstruction, or sweat allergy, the underlying pathomechanisms are not well understood. To gain further insights, we collected skin biopsies before and after pulse-controlled ergometry and sweat after sauna provocation from CholU patients as well as healthy controls. CholU patients displayed partially severely reduced local sweating, yet total sweat volume was unaltered. However, sweat electrolyte composition was altered, with increased K concentration in CholU patients. Formalin-fixed, paraffin-embedded biopsies were stained to explore sweat leakage and tight junction protein expression. Dermcidin staining was not found outside the sweat glands. In the secretory coils of sweat glands, the distribution of claudin-3 and -10b as well as occludin was altered, but the zonula occludens-1 location was unchanged. In all, dermcidin and tight junction protein staining suggests an intact barrier with reduced sweat production capability in CholU patients. For future studies, an ex vivo skin model for quantification of sweat secretion was established, in which sweat secretion could be pharmacologically stimulated or blocked. This ex vivo model will be used to further investigate sweat gland function in CholU patients and decipher the underlying pathomechanism(s).
Topics: Humans; Sweat Glands; Female; Tight Junctions; Male; Sweat; Adult; Middle Aged; Urticaria; Sweating; Skin
PubMed: 38731882
DOI: 10.3390/ijms25094658 -
Paediatrics and International Child... Apr 2024A 22-month-old girl of consanguineous parents was admitted with a high-grade fever. She was found to have insensitivity to painful stimuli and an absence of...
A 22-month-old girl of consanguineous parents was admitted with a high-grade fever. She was found to have insensitivity to painful stimuli and an absence of perspiration. She also displayed self-mutilating behaviour and was insensitive to cold/hot water on her body. On examination, there was loss of the tip of the tongue, missing teeth, generalised xerosis, and several ulcers at sites of minor trauma. She also had dysplastic nails and digital ulcers. Sensory examination demonstrated a complete lack of awareness of pain and temperature, vibration and fine touch were intact and lacrimation was normal. Differential diagnoses of hereditary sensory and autonomic neuropathy (HSAN), Lesch-Nyhan syndrome, hypohidrotic ectodermal dysplasia and leprosy were considered. Results of routine blood investigations including serum uric acid were normal. On performing clinical exome sequencing, the diagnosis of congenital insensitivity to pain with anhidrosis (CIPA) of autosomal recessive inheritance was confirmed. A novel, predicted to be pathogenic variant detected at exon 16 of the NTRK1 gene resulting in congenital insensitivity to pain with anhidrosis is reported. CIPA: congenital Insensitivity to pain with anhidrosis; HSAN: hereditary sensory and autonomic neuropathy; NGF: nerve growth factor; NTRK1: neurotrophic tyrosine kinase receptor 1 gene; TrKA: tropomyosin receptor kinase A.
PubMed: 38659257
DOI: 10.1080/20469047.2024.2344879 -
The Journal of Dermatology Apr 2024
PubMed: 38629328
DOI: 10.1111/1346-8138.17222