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Molecular Genetics & Genomic Medicine Apr 2024Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by loss-of-function mutations of the NTRK1 gene,... (Review)
Review
BACKGROUND
Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by loss-of-function mutations of the NTRK1 gene, affecting the autonomic and sensory nervous system. Clinical manifestation is varied and includes recurrent fever, pain insensitivity, anhidrosis, self-mutilating behavior, and intellectual disability.
METHODS
Clinical and genetic features were assessed in two males and one female with genetically confirmed CIPA using exome or genome sequencing.
RESULTS
CIPA symptoms including recurrent fever, pain insensitivity, and anhidrosis manifested at the age of 1 year (age range: 0.3-8 years). Two patients exhibited self-mutilation tendencies, intellectual disability, and developmental delay. Four NTRK1 (NM_002529.3) mutations, c.851-33T>A (p.?), c.2020G>T (p.Asp674Tyr), c.2303C>T (p.Pro768Leu), and c.574-156_850+1113del (exons 5-7 del) were identified. Two patients exhibited early onset and severe phenotype, being homozygous for c.851-33T>A (p.?) mutations and compound heterozygous for c.851-33T>A (p.?) and c.2020G>T (p.Asp674Tyr) mutation of NTRK1. The third patient with compound heterozygous mutations of c.2303C>T (p.Pro768Leu) and c.574-156_850+1113del (exons 5-7 del) displayed a late onset and milder clinical manifestation.
CONCLUSION
All three patients exhibited variable phenotypes and disease severity. This research enriches our understanding of clinical and genetic aspects of CIPA, highlighting variable phenotypes and disease severity.
Topics: Child; Child, Preschool; Female; Humans; Infant; Male; Channelopathies; Hereditary Sensory and Autonomic Neuropathies; Hypohidrosis; Indoles; Intellectual Disability; Pain; Pain Insensitivity, Congenital; Propionates
PubMed: 38581121
DOI: 10.1002/mgg3.2430 -
BMC Surgery Jan 2021Horner syndrome (HS), mainly characterized by symptoms including ptosis, miosis, and anhidrosis on the affected face, is a condition that is well documented but rarely... (Review)
Review
BACKGROUND
Horner syndrome (HS), mainly characterized by symptoms including ptosis, miosis, and anhidrosis on the affected face, is a condition that is well documented but rarely reported as a postoperative complication of thyroidectomy, particularly in endoscopic thyroid surgery (ETS). We hereby report a case of HS due to ETS with a brief literature review on this topic.
CASE PRESENTATION
A 31-year-old female was admitted to our hospital with an unexpected physical examination finding of two thyroid nodules that were hypoechoic, had an irregular shape, and exhibited calcification. Subsequently, the results of a fine-needle aspiration (FNA) biopsy from the thyroid nodules and BRAF mutation further confirmed the malignancy of these nodules. Thus, total thyroidectomy combined with central lymph node dissection (CLND) by ETS via the bilateral axillo-breast approach was performed on this patient. Histology confirmed the diagnosis of papillary thyroid microcarcinoma (PTMC) concurrent with Hashimoto's thyroiditis (HT). However, this patient developed HS with ptosis in her left eye on postoperative day 3. All symptoms gradually resolved before the 3-month follow-up.
CONCLUSION
HS subsequent to ETS is a rare complication. Thus, standardized and appropriate operative procedures, as well as subtle manipulation, are essential in preventing and reducing the occurrence of HS. In addition, the early diagnosis and management of this rare complication are also important for a favorable outcome.
Topics: Adult; Carcinoma, Papillary; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Female; Hashimoto Disease; Horner Syndrome; Humans; Postoperative Complications; Thyroid Neoplasms; Thyroid Nodule; Thyroidectomy; Treatment Outcome
PubMed: 33441131
DOI: 10.1186/s12893-020-01042-w -
Neurology Mar 2022Sudomotor impairment has been recognized as a key feature in differentiating Parkinson disease (PD) and multiple system atrophy-parkinsonian type (MSA-P), with the...
BACKGROUND AND OBJECTIVES
Sudomotor impairment has been recognized as a key feature in differentiating Parkinson disease (PD) and multiple system atrophy-parkinsonian type (MSA-P), with the latter characterized by diffuse anhidrosis in prospective study, including patients in late stage of disease. We aimed to evaluate morphologic and functional postganglionic sudomotor involvement in patients with newly diagnosed MSA-P and PD to identify possible biomarkers that might be of help in differentiating the 2 conditions in the early stage.
METHODS
One hundred patients with parkinsonism within 2 years from onset of motor symptoms were included in the study. At the time of recruitment, questionnaires to assess nonmotor, autonomic, and small fiber symptoms were administered, and patients underwent postganglionic sudomotor function assessment by the dynamic sweat test and punch skin biopsy from the distal leg. Skin samples were processed for indirect immunofluorescence with a panel of antibodies, including noradrenergic and cholinergic markers. The density of intraepidermal, sudomotor, and pilomotor nerve fibers was measured on confocal images with dedicated software. A follow-up visit 12 months after recruitment was performed to confirm the diagnosis.
RESULTS
We recruited 57 patients with PD (M/F 36/21, age 63.5 ± 9.4 years) and 43 patients with MSA-P (M/F 27/16, age 62.3 ± 9.0 years). Clinical scales and questionnaires showed a more severe clinical picture in patients with MSA-P compared to those with PD. Sweating output and intraepidermal, pilomotor, and sudomotor nerve densities, compared to controls, were lower in both groups but with a greater impairment in patients with MSA-P. Pilomotor and sudomotor nerve density correlated with sweating function and with nonmotor clinical symptoms. A composite sudomotor parameter defined as the arithmetic product of sweat production multiplied by the density of sudomotor fibers efficiently separated the 2 populations; the receiver operating characteristics curve showed an area under the curve of 0.83.
DISCUSSION
Dynamic sweat test and the quantification of cutaneous autonomic nerves proved to be a sensitive morpho-functional approach to assess the postganglionic component of the sudomotor pathway, revealing a more severe involvement in MSA-P than in PD early in the disease course. This approach can be applied to differentiate the 2 conditions early.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that postganglionic sudomotor morpho-functional assessment accurately distinguish patients with PD from patients with MSA-P.
Topics: Aged; Autonomic Nervous System Diseases; Humans; Hypohidrosis; Middle Aged; Multiple System Atrophy; Parkinson Disease; Prospective Studies
PubMed: 35017309
DOI: 10.1212/WNL.0000000000013300 -
Hypertension (Dallas, Tex. : 1979) Jan 2022Injury of the afferent limb of the baroreflex from neck radiation causes radiation-induced afferent baroreflex failure (R-ABF). Identification and management of R-ABF is...
Injury of the afferent limb of the baroreflex from neck radiation causes radiation-induced afferent baroreflex failure (R-ABF). Identification and management of R-ABF is challenging. We aimed to investigate the pattern of autonomic dysfunction on standardized autonomic testing in patients with probable R-ABF. We retrospectively analyzed all autonomic reflex screens performed at Mayo Clinic in Rochester, MN, between 2000 and 2020 in patients with probable R-ABF. Additional tests reviewed included ambulatory blood pressure monitoring, plasma norepinephrine, and thermoregulatory sweat test. We identified 90 patients with probable R-ABF. Median total composite autonomic severity score (range, 0-10) was 7 (interquartile range, 6-7). Cardiovascular adrenergic impairment was seen in 85 patients (94.4%), increased blood pressure recovery time after Valsalva maneuver in 71 patients (78.9%; median 17.4 seconds), and orthostatic hypotension in 68 patients (75.6%). Cardiovagal impairment was demonstrated by abnormal heart rate responses to deep breathing (79.5%), Valsalva ratio (87.2%), and vagal baroreflex sensitivity (57.9%). Plasma norepinephrine was elevated and rose appropriately upon standing (722-1207 pg/mL). Ambulatory blood pressure monitoring revealed hypertension, postural hypotension, hypertensive surges, tachycardia, and absence of nocturnal dipping. Blood pressure lability correlated with impaired vagal baroreflex function. Postganglionic sympathetic sudomotor function was normal in most cases; the most frequent thermoregulatory sweat test finding was focal neck anhidrosis (78.9%). Standardized autonomic testing in R-ABF demonstrates cardiovascular adrenergic impairment with orthostatic hypotension, blood pressure lability, and elevated plasma norepinephrine. Cardiovagal impairment is common, while sudomotor deficits are limited to direct radiation effects.
Topics: Aged; Autonomic Nervous System; Autonomic Nervous System Diseases; Baroreflex; Blood Pressure; Female; Heart Rate; Humans; Hypotension, Orthostatic; Male; Middle Aged; Norepinephrine; Radiotherapy; Retrospective Studies; Severity of Illness Index; Valsalva Maneuver
PubMed: 34739766
DOI: 10.1161/HYPERTENSIONAHA.121.17805 -
Cell Death & Disease Mar 2019Several studies have reported inducing adult cells into sweat gland-like cells; however, slow transition and low efficiency limit the potential for cell-based treatment....
Several studies have reported inducing adult cells into sweat gland-like cells; however, slow transition and low efficiency limit the potential for cell-based treatment. Here, we show that overexpression of the transcription factor FoxC1 was sufficient to reprogram epidermal cells to induced functional sweat gland-like cells (iSGCs). The iSGCs expressing secreting-related genes, had a global gene expression profile between fetal SGCs (P5) and adult SGCs (P28). Moreover, iSGCs transplanted into the burn mice model facilitated wound repair and sweat gland regeneration. We further demonstrated that the Foxc1 upregulated BMP5 transcription and BMP5 is responsible for the cell-type transition. Collectively, this study shows that lineage reprogramming of epidermal cells into iSGCs provides an excellent cell source and a promising regenerative strategy for anhidrosis and hypohidrosis.
Topics: Animals; Bone Morphogenetic Protein 5; Burns; Cell Differentiation; Cell Proliferation; Cell Transplantation; Cellular Reprogramming; Epidermal Cells; Forkhead Transcription Factors; Gene Knockdown Techniques; Hypohidrosis; Interferon Regulatory Factors; Mice; Mice, Inbred C57BL; Repressor Proteins; Sweat Glands; Transcriptome; Transfection; Wound Healing
PubMed: 30894517
DOI: 10.1038/s41419-019-1503-7 -
The Journal of Biological Chemistry Dec 2020The inositol 1,4,5-trisphosphate (IP) receptors (IPRs), which form tetrameric channels, play pivotal roles in regulating the spatiotemporal patterns of intracellular...
The inositol 1,4,5-trisphosphate (IP) receptors (IPRs), which form tetrameric channels, play pivotal roles in regulating the spatiotemporal patterns of intracellular calcium signals. Mutations in IPRs have been increasingly associated with many debilitating human diseases such as ataxia, Gillespie syndrome, and generalized anhidrosis. However, how these mutations affect IPR function, and how the perturbation of as-sociated calcium signals contribute to the pathogenesis and severity of these diseases remains largely uncharacterized. Moreover, many of these diseases occur as the result of autosomal dominant inheritance, suggesting that WT and mutant subunits associate in heterotetrameric channels. How the in-corporation of different numbers of mutant subunits within the tetrameric channels affects its activities and results in different disease phenotypes is also unclear. In this report, we investigated representative disease-associated missense mutations to determine their effects on IPR channel activity. Additionally, we designed concatenated IPR constructs to create tetrameric channels with a predefined subunit composition to explore the functionality of heteromeric channels. Using calcium imaging techniques to assess IPR channel function, we observed that all the mutations studied resulted in severely attenuated Ca release when expressed as homotetramers. However, some heterotetramers retained varied degrees of function dependent on the composition of the tetramer. Our findings suggest that the effect of mutations depends on the location of the mutation in the IPR structure, as well as on the stoichiometry of mutant subunits assembled within the tetrameric channel. These studies provide insight into the pathogenesis and penetrance of these devastating human diseases.
Topics: Amino Acid Sequence; Animals; B-Lymphocytes; Calcium; Calcium Signaling; Chickens; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Ion Channel Gating; Mutation; Protein Multimerization; Sequence Homology
PubMed: 33093175
DOI: 10.1074/jbc.RA120.015683 -
Experimental Dermatology May 2022Mutations in the human FAM111B gene are associated with a rare, hereditary multi-systemic fibrosing disease, POIKTMP. To date, there are ten POIKTMP-associated FAM111B... (Review)
Review
Mutations in the human FAM111B gene are associated with a rare, hereditary multi-systemic fibrosing disease, POIKTMP. To date, there are ten POIKTMP-associated FAM111B gene mutations reported in thirty-six patients from five families globally. To investigate the clinical significance of these mutations, we summarized individual cases by clinical features and position of the reported FAM111B gene mutations as those within and outside the putative protease domain (MWPPD and MOPPD respectively). MWPPD cases had more clinical manifestations than MOPPD (25 versus 18). Although the most common clinical features of poikiloderma, alopecia and hypohidrosis overall occurred in 94%, 86% and 75% of all cases with no significant differences between the MOPPD and MWPPD group, less common features included life-threatening (pulmonary fibrosis 47% vs. 13%; liver abnormalities specifically cirrhosis 26% vs. 7%) and physically disabling conditions (myopathy 53% vs. 20%; tendon contracture 55% vs. 7%) were more common in MWPPD cases. Similarly, the only 2 cases of POIKTMP with fatal pancreatic cancers were both only in the MWPPD group. This review thus suggests that mutations within the putative protease domain of the FAM111B protein are associated with a broader range of clinical features and may predict increased POIKTMP severity and a poorer prognosis.
Topics: Cell Cycle Proteins; Humans; Mutation; Peptide Hydrolases; Severity of Illness Index; Skin Diseases, Genetic
PubMed: 35122327
DOI: 10.1111/exd.14537 -
Annals of the New York Academy of... Oct 2022In epithelia, claudin proteins are important components of the tight junctions as they determine the permeability and specificity to ions of the paracellular pathway....
In epithelia, claudin proteins are important components of the tight junctions as they determine the permeability and specificity to ions of the paracellular pathway. Mutations in CLDN10 cause the rare autosomal recessive HELIX syndrome (Hypohidrosis, Electrolyte imbalance, Lacrimal gland dysfunction, Ichthyosis, and Xerostomia), in which patients display severe enamel wear. Here, we assess whether this enamel wear is caused by an innate fragility directly related to claudin-10 deficiency in addition to xerostomia. A third molar collected from a female HELIX patient was analyzed by a combination of microanatomical and physicochemical approaches (i.e., electron microscopy, elemental mapping, Raman microspectroscopy, and synchrotron-based X-ray fluorescence). The enamel morphology, formation time, organization, and microstructure appeared to be within the natural variability. However, we identified accentuated strontium variations within the HELIX enamel, with alternating enrichments and depletions following the direction of the periodical striae of Retzius. These markings were also present in dentin. These data suggest that the enamel wear associated with HELIX may not be related to a disruption of enamel microstructure but rather to xerostomia. However, the occurrence of events of strontium variations within dental tissues might indicate repeated episodes of worsening of the renal dysfunction that may require further investigations.
Topics: Amelogenesis; Claudin-3; Claudin-4; Claudins; Electrolytes; Female; Humans; Strontium; Tight Junctions; Xerostomia
PubMed: 35902997
DOI: 10.1111/nyas.14865 -
ESC Heart Failure Dec 2021Fabry disease (FD) is an X-linked genetic disease caused by mutations in the GLA gene that leads to deficient activity of lysosomal enzymes, accumulation of...
AIMS
Fabry disease (FD) is an X-linked genetic disease caused by mutations in the GLA gene that leads to deficient activity of lysosomal enzymes, accumulation of globotriaosylceramide in multi-organ systems, and variant clinical manifestations. We aimed to detail the clinical and genetic spectrum of FD in Chinese families.
METHODS AND RESULTS
Five male probands with unexplained left ventricular hypertrophy and their family members were investigated. Genetic screening was available in 11 subjects of the 5 families, 10 of whom proved to be carriers of either GLA gene mutation, including 3 previous reported missense mutations (c.128G > A, c.811G > A, c.950T > C), 1 novel missense mutation (c.37G > C), and 1 novel deletion mutation (c.1241delT). A total of 17 patients were definitely or possibly diagnosed of FD, given their clinical manifestations and hereditary nature of FD. Echocardiography demonstrated normal cardiac structure and function in six female patients. Electrocardiographic pre-excitation occurred in 80% (4/5) of men and 16.7% (1/6) of women. Six patients (6/14, 42.9%) had chronic kidney disease with decreased renal function and all were male (6/7, 85.7%). Six patients presented with acroparesthesia, hypohidrosis, or both. Three female patients and two male patients experienced sudden death, and one male patient with the mutation (c.128G > A) died of progressive heart failure, between 41 and 66 years of age.
CONCLUSIONS
We reported five unrelated families of FD with different GLA mutations. Clinical manifestations were highly heterogeneous between male and female patients even within the same family. Female patients showed relatively low risks of structural heart disease and renal insufficiency. However, the long-term outcomes might be adverse in both sexes. Our study underlines the importance of molecular screening of the GLA gene for early identification and clinical decision making in patients with FD.
Topics: China; Fabry Disease; Female; Genetic Testing; Humans; Male; Mutation; alpha-Galactosidase
PubMed: 34704396
DOI: 10.1002/ehf2.13638 -
Mayo Clinic Proceedings Oct 2018To assess antibody level as a test of autonomic failure (AF) associated with ganglionic nicotinic acetylcholine receptor antibody (AChR-Ab) autoimmunity.
OBJECTIVE
To assess antibody level as a test of autonomic failure (AF) associated with ganglionic nicotinic acetylcholine receptor antibody (AChR-Ab) autoimmunity.
PATIENTS AND METHODS
We searched the Mayo Clinic laboratory database of 926 ganglionic AChR-Ab-seropositive patients seen at our institution between October 1, 1997, and April 1, 2015, for initial level of 0.05 nmol/L or higher and contemporaneous autonomic reflex screen (standardized evaluation of adrenergic, cardiovagal, and sudomotor functions) from which Composite Autonomic Scoring Scale (CASS) scores could be calculated.
RESULTS
Of 289 patients who met inclusion criteria, 163 (56.4%) were women, median age was 54 years (range, 10-87 years), median antibody level was 0.11 nmol/L (range, 0.05-22.10 nmol/L), and median CASS total score was 2.0 (range, 0-10). Using receiver operating characteristic curve analysis, a level above 0.40 nmol/L predicted severe AF (CASS score, ≥7) with 92% specificity and 56% sensitivity. For at least moderate AF (CASS score ≥4 and anhidrosis ≥25%), a level of at least 0.20 nmol/L had 80% specificity and 59% sensitivity. Levels below 0.20 nmol/L were not predictive of the presence or absence of AF. For predicting orthostatic hypotension, ganglionic AChR-Ab level had excellent specificity above 0.4 nmol/L but lacked sensitivity. Autoantibodies to additional targets were present in 61 patients (21.1%).
CONCLUSION
Ganglionic AChR-Ab level of at least 0.40 nmol/L is a moderately sensitive and highly specific marker for severe AF, as is a level of at least 0.20 nmol/L for moderate AF if CASS score is coupled with anhidrosis of 25% or more, among patients with suspected ganglionic AChR-Ab autoimmune autonomic ganglionopathy. Antibody levels of less than 0.20 nmol/L have little clinical importance in the absence of clinical AF.
Topics: Autoantibodies; Autoimmunity; Autonomic Nervous System Diseases; Clinical Laboratory Information Systems; Databases, Factual; Female; Ganglia, Autonomic; Humans; Immunologic Tests; Male; Middle Aged; Predictive Value of Tests; ROC Curve; Receptors, Nicotinic; Sensitivity and Specificity; Severity of Illness Index
PubMed: 30170741
DOI: 10.1016/j.mayocp.2018.05.033