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International Journal of Molecular... Dec 2023Fabry disease (FD) is a recessive monogenic disease linked to chromosome X due to more than two hundred mutations in the alfa-galactosidase A (GLA) gene. Modifications... (Review)
Review
Fabry disease (FD) is a recessive monogenic disease linked to chromosome X due to more than two hundred mutations in the alfa-galactosidase A (GLA) gene. Modifications of the GLA gene may cause the progressive accumulation of globotriaosylceramide (Gb3) and its deacylated form, globotriasylsphingosine (lyso-Gb3), in lysosomes of several types of cells of the heart, kidneys, skin, eyes, peripheral and central nervous system (not clearly and fully demonstrated), and gut with different and pleiotropic clinical symptoms. Among the main symptoms are acroparesthesias and pain crisis (involving the peripheral nervous system), hypohidrosis, abdominal pain, gut motility abnormalities (involving the autonomic system), and finally, cerebrovascular ischemic events due to macrovascular involvement (TIA and stroke) and lacunar strokes and white matter abnormalities due to a small vessel disease (SVS). Gb3 lysosomal accumulation causes cytoplasmatic disruption and subsequent cell death. Additional consequences of Gb3 deposits are inflammatory processes, abnormalities of leukocyte function, and impaired trafficking of some types of immune cells, including lymphocytes, monocytes, CD8+ cells, B cells, and dendritic cells. The involvement of inflammation in AFD pathogenesis conflicts with the reported poor correlation between CRP levels as an inflammation marker and clinical scores such as the Mainz Severity Score Index (MSSI). Also, some authors have suggested an autoimmune reaction is involved in the disease's pathogenetic mechanism after the α-galactosidase A deficiency. Some studies have reported a high degree of neuronal apoptosis inhibiting protein as a critical anti-apoptotic mediator in children with Fabry disease compared to healthy controls. Notably, this apoptotic upregulation did not change after treatment with enzymatic replacement therapy (ERT), with a further upregulation of the apoptosis-inducing factor after ERT started. Gb3-accumulation has been reported to increase the degree of oxidative stress indexes and the production of reactive oxygen species (ROS). Lipids and proteins have been reported as oxidized and not functioning. Thus, neurological complications are linked to different pathogenetic molecular mechanisms. Progressive accumulation of Gb3 represents a possible pathogenetic event of peripheral nerve involvement. In contrast, central nervous system participation in the clinical setting of cerebrovascular ischemic events seems to be due to the epitheliopathy of Anderson-Fabry disease with lacunar lesions and white matter hyperintensities (WMHs). In this review manuscript, we revised molecular mechanisms of peripheral and central neurological complications of Anderson-Fabry Disease. The management of Fabry disease may be improved by the identification of biomarkers that reflect the clinical course, severity, and progression of the disease. Intensive research on biomarkers has been conducted over the years to detect novel markers that may potentially be used in clinical practice as a screening tool, in the context of the diagnostic process and as an indicator of response to treatment. Recent proteomic or metabolomic studies are in progress, investigating plasma proteome profiles in Fabry patients: these assessments may be useful to characterize the molecular pathology of the disease, improve the diagnostic process, and monitor the response to treatment.
Topics: Child; Humans; Fabry Disease; Proteomics; Peripheral Nervous System; Biomarkers; Inflammation
PubMed: 38203231
DOI: 10.3390/ijms25010061 -
Critical Care (London, England) Jan 2024
Topics: Humans; Extracorporeal Membrane Oxygenation; Spectroscopy, Near-Infrared; Autonomic Nervous System Diseases; Hypohidrosis
PubMed: 38191427
DOI: 10.1186/s13054-023-04793-z -
Zhonghua Nei Ke Za Zhi Jan 2024We aimed to analyze the clinical data of 10 patients (6 male and 4 female) with Fabry disease (FD). The mean age of the patients was (28.80±9.27) years. Seven patients...
We aimed to analyze the clinical data of 10 patients (6 male and 4 female) with Fabry disease (FD). The mean age of the patients was (28.80±9.27) years. Seven patients had classical FD and three had delayed onset FD. Among the 10 patients, six had skin involvement and cutaneous angiokeratoma; five had hypohidrosis or anhidrosis; nine had intermittent neuralgia; and three had supraorbital ridge protrusion, forehead bulge, and lip thickening. Five patients had proteinuria, including one with chronic kidney disease stage 3 and one with chronic kidney disease stage 5. Cardiac involvement occurred in three patients, two had myocardial hypertrophy and one had valvular insufficiency. The activity of galactosidase decreased in seven patients (2.80-1.55 μmol·L·h). Plasma deacetyl-GL-3 was elevated in all 10 patients(3.12-120.00 ng/ml). Three patients underwent renal biopsy, wherein two cases of focal segmental glomerulosclerosis and one of mesangial proliferative glomerulonephritis was found. A large number of myeloid and zebra bodies were found in the podocytes in three patients, including a small number of myeloid and zebra bodies in the renal tubular epithelial cells in one patient with occasional zebra bodies in the renal interstitium. Nine patients had GLA gene mutations. One patient was c.102T>A, a de novo mutation. Four patients were treated with agalsidase α injection (0.2 mg/kg, intravenous infusion every 2 weeks), and their prognosis was good. FD has various clinical manifestations and multi-system involvement, which requires multidisciplinary cooperation. Detection of galactosidase activity, plasma globotriaosylsphingosine, and GLA gene mutation can help for accurate diagnosis.
Topics: Humans; Female; Male; Animals; Young Adult; Adult; Fabry Disease; Hypohidrosis; Galactosidases; Renal Insufficiency, Chronic; Equidae
PubMed: 38186123
DOI: 10.3760/cma.j.cn112138-20231011-00204 -
Cureus Dec 2023Ectodermal dysplasia (ED) is a rare disorder that appears differently in clinical cases and can present with a variety of combinations and severities of abnormalities...
Ectodermal dysplasia (ED) is a rare disorder that appears differently in clinical cases and can present with a variety of combinations and severities of abnormalities that can involve a variety of tissues. The disease might appear clinically as hypotrichosis, hypohidrosis, or hypodontia, among other clinical manifestations. The patient, a five-year-old boy, was seen at the Taibah University Dental Clinic and was diagnosed with X-linked hypohidrotic ectodermal dysplasia type 1 based on clinical radiographic and genetic findings. Although there is no base data for reporting this case, the present case presentation could alert dental practitioners and expand scientific database knowledge on the dental and/or oral characteristics of this abnormality.
PubMed: 38164323
DOI: 10.7759/cureus.49840 -
Tomography (Ann Arbor, Mich.) Dec 2023Hereditary sensory and autonomic neuropathy type 4 (HSAN4), also known as congenital insensitivity to pain with anhidrosis (CIPA), is a rare genetic disorder caused by...
Hereditary sensory and autonomic neuropathy type 4 (HSAN4), also known as congenital insensitivity to pain with anhidrosis (CIPA), is a rare genetic disorder caused by NTRK1 gene mutations, affecting nerve growth factor signaling. This study investigates the central nervous system's (CNS) involvement and its relation to pain insensitivity in HSAN4. We present a 15-year-old girl with HSAN4, displaying clinical signs suggestive of CNS impact, including spasticity and a positive Babinski's sign. Using Technetium-99m ethyl cysteinate dimer single-photon emission computed tomography (Tc-99m ECD SPECT) imaging, we discovered perfusion deficits in key brain regions, notably the cerebellum, thalamus, and postcentral gyrus. These regions process pain signals, providing insights into HSAN4's pain insensitivity. This study represents the first visualization of CNS perfusion abnormality in an HSAN4 patient. It highlights the intricate relationship between the peripheral and central nervous systems in HSAN4. The complexity of HSAN4 diagnosis, involving potential unidentified genes, underscores the need for continued research to refine diagnostic approaches and develop comprehensive treatments.
Topics: Female; Humans; Adolescent; Organotechnetium Compounds; Tomography, Emission-Computed, Single-Photon; Hereditary Sensory and Autonomic Neuropathies; Pain
PubMed: 38133079
DOI: 10.3390/tomography9060175 -
Cutis Nov 2023
Topics: Humans; Hypohidrosis; Hypotrichosis; Hair; Hyperpigmentation; Ectodermal Dysplasia
PubMed: 38091441
DOI: 10.12788/cutis.0908 -
Journal of the American Academy of... Apr 2024
Topics: Humans; Retrospective Studies; Sweat; Body Temperature Regulation; Sweating; Flushing; Hypohidrosis
PubMed: 38065321
DOI: 10.1016/j.jaad.2023.11.052 -
Annals of Dermatology Nov 2023Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare disease characterized by insensitivity to pain, anhidrosis, and intellectual disability....
Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare disease characterized by insensitivity to pain, anhidrosis, and intellectual disability. CIPA is caused by a genetic mutation in the neurotrophic tyrosine receptor kinase 1 () gene on chromosome 1. The anhidrosis leads to cutaneous changes such as skin dryness, lichenification, and impetiginization. Moreover, patients with CIPA may experience repeated trauma and recalcitrant eczema due to excessive scratching of wounds on their skin, because they do not feel any pain. Severe whole-body eczema in a patient with CIPA may be overlooked, leading these patients to be frequently diagnosed with atopic dermatitis and common eczema. Indeed, in patients with treatment-resistant or atypically distributed eczema and underlying anhidrosis, CIPA should be considered as a potential causative disease. Increased awareness of CIPA among dermatologists is necessary to ensure that patients receive an appropriate diagnosis. Herein, we report a rare case of generalized xerotic eczema in a patient with CIPA.
PubMed: 38061701
DOI: 10.5021/ad.21.082 -
Proceedings of the National Academy of... Dec 2023The atypical protein kinase ALPK1 is activated by the bacterial nucleotide sugar ADP-heptose and phosphorylates TIFA to switch on a signaling pathway that combats...
The atypical protein kinase ALPK1 is activated by the bacterial nucleotide sugar ADP-heptose and phosphorylates TIFA to switch on a signaling pathway that combats microbial infection. In contrast, ALPK1 mutations cause two human diseases: the ALPK1[T237M] and ALPK1[Y254C] mutations underlie ROSAH syndrome (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis, and migraine headache), while the ALPK1[V1092A] mutation accounts for 45% of spiradenoma and 30% of spiradenocarcinoma cases studied. In this study, we demonstrate that unlike wild-type (WT) ALPK1, the disease-causing ALPK1 mutants trigger the TIFA-dependent activation of an NF-κB/activator protein 1 reporter gene in the absence of ADP-heptose, which can be suppressed by either of two additional mutations in the ADP-heptose binding site that prevent the activation of WT ALPK1 by ADP-heptose. These observations are explained by our key finding that although ALPK1[T237M] and ALPK1[V1092A] are activated by bacterial ADP-heptose, they can also be activated by nucleotide sugars present in human cells (UDP-mannose, ADP-ribose, and cyclic ADP-ribose) which can be prevented by disruption of the ADP-heptose binding site. The ALPK1[V1092A] mutant was also activated by GDP-mannose, which did not activate ALPK1[T237M]. These are new examples of disease-causing mutations permitting the allosteric activation of an enzyme by endogenous molecules that the WT enzyme does not respond to. We propose that the loss of the specificity of ALPK1 for bacterial ADP-heptose underlies ROSAH syndrome and spiradenoma/spiradenocarcinoma caused by ALPK1 mutation.
Topics: Humans; Nucleotides; Sugars; Splenomegaly; Acrospiroma; Mannose; Sweat Gland Neoplasms; Heptoses
PubMed: 38060563
DOI: 10.1073/pnas.2313148120 -
Cureus Nov 2023Hereditary sensory and autonomic neuropathy type 4 (HSAN4), or congenital insensitivity to pain with anhidrosis (CIPA), is a rare autosomal recessive disorder caused by...
Hereditary sensory and autonomic neuropathy type 4 (HSAN4), or congenital insensitivity to pain with anhidrosis (CIPA), is a rare autosomal recessive disorder caused by mutations in the NTRK1 gene, resulting in pain insensitivity, anhidrosis, and temperature dysregulation. This report focuses on oral manifestations in an 11-year-old girl with CIPA, highlighting the need for early intervention and comprehensive care. The patient had a history of recurrent oral injuries and an unexplained fever, with a confirmed HSAN4 diagnosis through genetic analysis. Clinical features included pain insensitivity, anhidrosis, and intellectual disability. Dental history revealed emergency care, suboptimal oral hygiene, early tooth loss, and infections. Extra-oral examination showed nail-biting and injuries, while intra-oral assessment revealed ulcers and scars. Radiographic evaluation indicated mandibular alveolar bone thinning and periapical lesions in the lower incisors. This case emphasizes the complex challenges of CIPA, including pain insensitivity, recurring fever episodes, and self-inflicted injuries. Early diagnosis and specific dental care are vital to prevent orofacial trauma, necessitating a proactive interdisciplinary approach for comprehensive care.
PubMed: 38058353
DOI: 10.7759/cureus.48294