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The Pan African Medical Journal 2019Disorders of water balance are a disease commonly encountered in our clinical practice. Analysis of vasopressin receptor type II (V2R) is essential to understand the... (Review)
Review
Disorders of water balance are a disease commonly encountered in our clinical practice. Analysis of vasopressin receptor type II (V2R) is essential to understand the physiology of water balance and it is used as a biological prototype of G protein-coupled receptors (GPCRs). Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a syndrome of inappropriate antidiuretic hormone secretion (SIADH) with low plasmatic vasopressin. The evidence on the role of V2 receptor and of aquaporin (AQP) in the mechanism of action for antidiuretic hormone (ADH) was based on the identification of protein gene mutations in patients with nephrogenic diabetes insipidus and NSIAD syndrome. V2R activating mutations were found in patients with NSIAD, contrasting with the numerous V2R inactivating mutations related to X-linked mutations described in patients with nephrogenic diabetes insipidus.
Topics: Aquaporins; Diabetes Insipidus, Nephrogenic; Genetic Diseases, X-Linked; Humans; Inappropriate ADH Syndrome; Mutation; Neurophysins; Protein Precursors; Receptors, Vasopressin; Vasopressins
PubMed: 31312322
DOI: 10.11604/pamj.2019.32.210.6006 -
Journal of Translational Medicine Jul 2019Wolfram syndrome (WS), a rare genetic disorder, is considered the best prototype of endoplasmic reticulum (ER) diseases. Classical WS features are childhood-onset... (Review)
Review
BACKGROUND
Wolfram syndrome (WS), a rare genetic disorder, is considered the best prototype of endoplasmic reticulum (ER) diseases. Classical WS features are childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus, neurological signs, and other abnormalities. Two causative genes (WFS1 and WFS2) have been identified. The transmission of the disease takes place in an autosomal recessive mode but autosomal dominant mutations responsible for WS-related disorders have been described. Prognosis is poor, death occurs at the median age of 39 years with a major cause represented by respiratory failure as a consequence of brain stem atrophy and neurodegeneration. The aim of this narrative review is to focus on etiology, pathogenesis and natural history of WS for an adequate patient management and for the discussion of future therapeutic interventions.
MAIN BODY
WS requires a multidisciplinary approach in order to be successfully treated. A prompt diagnosis decreases morbidity and mortality through prevention and treatment of complications. Being a monogenic pathology, WS represents a perfect model to study the mechanisms of ER stress and how this condition leads to cell death, in comparison with other prevalent diseases in which multiple factors interact to produce the disease manifestations. WS is also an important disease prototype to identify drugs and molecules associated with ER homeostasis. Evidence indicates that specific metabolic diseases (type 1 and type 2 diabetes), neurodegenerative diseases, atherosclerosis, inflammatory pathologies and also cancer are closely related to ER dysfunction.
CONCLUSIONS
Therapeutic strategies in WS are based on drug repurposing (i.e., investigation of approved drugs for novel therapeutic indications) with the aim to stop the progression of the disease by reducing the endoplasmic reticulum stress. An extensive understanding of WS from pathophysiology to therapy is fundamental and more studies are necessary to better manage this devastating disease and guarantee the patients a better quality of life and longer life expectancy.
Topics: Adolescent; Adult; Child; Child, Preschool; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Disease Progression; Drug Development; Drug Repositioning; Endoplasmic Reticulum; Female; Genes, Recessive; Humans; Infant; Interdisciplinary Communication; Male; Membrane Proteins; Neurodegenerative Diseases; Prognosis; Quality of Life; Wolfram Syndrome; Young Adult
PubMed: 31337416
DOI: 10.1186/s12967-019-1993-1 -
Endokrynologia Polska 2019In the clinical setting, the diagnosis of neurosarcoidosis in patients with central diabetes insipidus (CDI) is typically based both on symptoms (i.e. polydipsia or... (Review)
Review
INTRODUCTION
In the clinical setting, the diagnosis of neurosarcoidosis in patients with central diabetes insipidus (CDI) is typically based both on symptoms (i.e. polydipsia or polyuria) and brain magnetic resonance imaging (MRI) findings (e.g. pituitary abnormality). However, inconsistent changes in the patient's symptoms and brain MRI findings may occur during the clinical course of the disease. This review was performed to summarise the relationship between symptoms and brain MRI findings in previously reported cases of neurosarcoidosis with CDI.
MATERIAL AND METHODS
Case studies of patients diagnosed with neurosarcoidosis with CDI were collected via a PubMed search of studies published through 30 June 2018.
RESULTS
Thirteen eligible studies were reviewed (20 patients; 12 men, 8 women; mean age 33 years). Polydipsia or polyuria was the first symptom in 13 patients. The mean duration from disease onset to diagnosis was 3.4 months. Brain MRIs showed abnormal findings in the hypothalamus and pituitary for 17 patients. Immunosuppressive drugs were used in 17 patients. For 14 patients, MRI findings improved, while symptoms did not.
CONCLUSION
Patients with both neurosarcoidosis and CDI symptoms often do not improve, despite the fact that brain MRI findings often improve following treatment. More studies involving detailed pathological analyses and longer follow-up periods are necessary.
Topics: Adult; Central Nervous System Diseases; Diabetes Insipidus, Neurogenic; Female; Humans; Male; Pituitary Gland; Sarcoidosis
PubMed: 31681969
DOI: 10.5603/EP.a2019.0035 -
Cell Death & Disease Jun 2023Wolfram syndrome (WS) is a rare neurodegenerative disorder encompassing diabetes mellitus, diabetes insipidus, optic atrophy, hearing loss (HL) as well as neurological...
Wolfram syndrome (WS) is a rare neurodegenerative disorder encompassing diabetes mellitus, diabetes insipidus, optic atrophy, hearing loss (HL) as well as neurological disorders. None of the animal models of the pathology are presenting with an early onset HL, impeding the understanding of the role of Wolframin (WFS1), the protein responsible for WS, in the auditory pathway. We generated a knock-in mouse, the Wfs1 line, presenting a human mutation leading to severe deafness in affected individuals. The homozygous mice showed a profound post-natal HL and vestibular syndrome, a collapse of the endocochlear potential (EP) and a devastating alteration of the stria vascularis and neurosensory epithelium. The mutant protein prevented the localization to the cell surface of the Na/KATPase β1 subunit, a key protein for the maintenance of the EP. Overall, our data support a key role of WFS1 in the maintenance of the EP and the stria vascularis, via its binding partner, the Na/KATPase β1 subunit.
Topics: Animals; Humans; Mice; Adenosine Triphosphatases; Cell Membrane; Deafness; Epithelium; Wolfram Syndrome
PubMed: 37386014
DOI: 10.1038/s41419-023-05912-y -
International Journal of Environmental... Jan 2022Wolfram syndrome (WS) is a rare autosomal recessive disorder that is characterized by the presence of diabetes mellitus, optic atrophy and hearing loss, all of which are... (Review)
Review
BACKGROUND
Wolfram syndrome (WS) is a rare autosomal recessive disorder that is characterized by the presence of diabetes mellitus, optic atrophy and hearing loss, all of which are crucial elements for the diagnosis. WS is variably associated with diabetes insipidus, neurological disorders, urinary tract anomalies, endocrine dysfunctions and many other systemic manifestations. Since Wolfram and Wagener first described WS in 1938, new phenotypic/genotypic variants of the syndrome have been observed and the clinical picture has been significantly enriched. To date, two main subtypes of WS that associated with two different mutations are known: WS type 1 (WS1), caused by the mutation of the wolframine gene (WS1; 606201), and WS type 2 (WS2), caused by the mutation of the CISD2 gene (WS2; 604928).
METHODS
A systematic review of the literature was describe the phenotypic characteristics of WS2 in order to highlight the key elements that differentiate it from the classic form.
CONCLUSION
WS2 is the rarest and most recently identified subtype of WS; its clinical picture is partially overlapping with that of WS1, from which it traditionally differs by the absence of diabetes insipidus and the presence of greater bleeding tendency and peptic ulcers.
Topics: Diabetes Mellitus, Type 2; Humans; Membrane Proteins; Mitochondrial Diseases; Mutation; Optic Atrophy; Wolfram Syndrome
PubMed: 35055657
DOI: 10.3390/ijerph19020835 -
Orphanet Journal of Rare Diseases Nov 2023Wolfram syndrome (WS) is a rare autosomal recessive multisystem neurodegenerative disease characterized by non-autoimmune insulin-dependent diabetes mellitus, optic...
BACKGROUND
Wolfram syndrome (WS) is a rare autosomal recessive multisystem neurodegenerative disease characterized by non-autoimmune insulin-dependent diabetes mellitus, optic atrophy, sensorineural deafness, and diabetes as the main features. Owing to clinical phenotypic heterogeneity, the misdiagnosis rate is high. However, early accurate diagnosis and comprehensive management are key to improving quality of life and prolonging life.
RESULTS
Eleven patients from seven WS pedigrees with 10 mutation sites (c.1314_1317delCTTT, c.C529T, c.C529A, c.G2105A, c.C1885T, c.1859_1860del, c.G2020A, c.C529A, c.G2105A, and c.G1393C) in the WFS1 gene were included. We conducted further expert department analysis to clarify the diagnosis and analyze the correlation between genes and phenotypes.
CONCLUSIONS
The genotypes of these patients were closely associated with their phenotypes. The clinical data of the patients were analyzed to provide a basis for the diagnosis and clinical management of the disease.
Topics: Humans; Wolfram Syndrome; Neurodegenerative Diseases; Quality of Life; Mutation; Optic Atrophy; Diabetes Mellitus, Type 2
PubMed: 37974252
DOI: 10.1186/s13023-023-02938-5 -
International Journal of Molecular... Nov 2021Ensuring the proper amount of water inside the body is essential for survival. One of the key factors in the maintenance of body water balance is water reabsorption in... (Review)
Review
Ensuring the proper amount of water inside the body is essential for survival. One of the key factors in the maintenance of body water balance is water reabsorption in the collecting ducts of the kidney, a process that is regulated by aquaporin-2 (AQP2). AQP2 is a channel that is exclusively selective for water molecules and impermeable to ions or other small molecules. Impairments of AQP2 result in various water balance disorders, including nephrogenic diabetes insipidus (NDI), which is a disease characterized by a massive loss of water through the kidney and consequent severe dehydration. Dysregulation of AQP2 is also a cause of water retention with hyponatremia in heart failure, hepatic cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Antidiuretic hormone vasopressin is an upstream regulator of AQP2. Its binding to the vasopressin V2 receptor promotes AQP2 targeting to the apical membrane and thus enables water reabsorption. Tolvaptan, a vasopressin V2 receptor antagonist, is effective and widely used for water retention with hyponatremia. However, there are no studies showing improvement in hard outcomes or long-term prognosis. A possible reason is that vasopressin receptors have many downstream effects other than AQP2 function. It is expected that the development of drugs that directly target AQP2 may result in increased treatment specificity and effectiveness for water balance disorders. This review summarizes recent progress in studies of AQP2 and drug development challenges for water balance disorders.
Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Aquaporin 2; Body Water; Calcium Signaling; Cytoskeleton; Diabetes Insipidus, Nephrogenic; Endocytosis; Humans; Kidney Tubules, Collecting; Loss of Function Mutation; Molecular Targeted Therapy; Osmolar Concentration; Phosphorylation; Protein Transport; Receptors, Vasopressin; Water-Electrolyte Balance
PubMed: 34884753
DOI: 10.3390/ijms222312950 -
Pediatric Endocrinology, Diabetes, and... 2016Wolfram syndrome is a rare neurodegenerative and genetic disorder, characterized by insulin-dependent diabetes mellitus, caused by non-autoimmune loss of β cells, as...
Wolfram syndrome is a rare neurodegenerative and genetic disorder, characterized by insulin-dependent diabetes mellitus, caused by non-autoimmune loss of β cells, as well as optic atrophy; the disease is also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Patients that demonstrate diabetes mellitus are also affected by: optic atrophy in the first decade of their life, diabetes insipidus and sensorineural deafness in the second decade, and urinary tract and neurological abnormalities in the third decade of their life. Patients with Wolfram syndrome usually die due to central respiratory failures caused by brain stem atrophy in their third or at the beginning of their fourth decade of life. The authors present a case of two female siblings with diagnosed Wolfram syndrome that have been diagnosed with diabetes mellitus, optic atrophy, and urological abnormalities. Early diagnosis and adequate hormonal supplementation can improve their quality of life.
Topics: Adolescent; Diabetes Mellitus; Female; Humans; Hypoglycemic Agents; Insulin; Optic Atrophies, Hereditary; Poland; Rare Diseases; Treatment Outcome; Urologic Diseases; Wolfram Syndrome
PubMed: 28132072
DOI: 10.18544/PEDM-22.01.0049 -
American Journal of Physiology. Renal... Dec 2016Fundamental kidney physiology research can provide important insight into how the kidney works and suggest novel therapeutic opportunities to treat human diseases. This... (Review)
Review
Fundamental kidney physiology research can provide important insight into how the kidney works and suggest novel therapeutic opportunities to treat human diseases. This is especially true for nephrogenic diabetes insipidus (NDI). Over the past decade, studies elucidating the molecular physiology and signaling pathways regulating water transport have suggested novel therapeutic possibilities. In patients with congenital NDI due to mutations in the type 2 vasopressin receptor (V2R) or acquired NDI due to lithium (or other medications), there are no functional abnormalities in the aquaporin-2 (AQP2) water channel, or in another key inner medullary transport protein, the UT-A1 urea transporter. If it is possible to phosphorylate and/or increase the apical membrane accumulation of these proteins, independent of vasopressin or cAMP, one may be able to treat NDI. Sildenifil (through cGMP), erlotinib, and simvastatin each stimulate AQP2 insertion into the apical plasma membrane. Some recent human data suggest that sildenafil and simvastatin may improve urine concentrating ability. ONO-AE1-329 (ONO) stimulates the EP4 prostanoid receptor (EP4), which stimulates kinases that in turn phosphorylate AQP2 and UT-A1. Clopidogrel is a P2Y12-R antagonist that potentiates the effect of vasopressin and increases AQP2 abundance. Metformin stimulates AMPK to phosphorylate and activate AQP2 and UT-A1, and it increases urine concentrating ability in two rodent models of NDI. Since metformin, sildenafil, and simvastatin are commercially available and have excellent safety records, the potential for rapidly advancing them into clinical trials is high.
Topics: Adenylate Kinase; Animals; Aquaporin 2; Diabetes Insipidus, Nephrogenic; Erlotinib Hydrochloride; Humans; Metformin; Mutation; Phosphorylation; Receptors, Vasopressin; Sildenafil Citrate; Simvastatin
PubMed: 27534996
DOI: 10.1152/ajprenal.00418.2016 -
F1000Research 2019The alteration of water balance and related disorders has emerged as being strictly linked to the state of activation of the vasopressin-aquaporin-2 (vasopressin-AQP2)... (Review)
Review
The alteration of water balance and related disorders has emerged as being strictly linked to the state of activation of the vasopressin-aquaporin-2 (vasopressin-AQP2) pathway. The lack of responsiveness of the kidney to the vasopressin action impairs its ability to concentrate the urine, resulting in polyuria, polydipsia, and risk of severe dehydration for patients. Conversely, non-osmotic release of vasopressin is associated with an increase in water permeability in the renal collecting duct, producing water retention and increasing the circulatory blood volume. This review highlights some of the new insights and recent advances in therapeutic intervention targeting the dysfunctions in the vasopressin-AQP2 pathway causing diseases characterized by water balance disorders such as congenital nephrogenic diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, nephrogenic syndrome of inappropriate antidiuresis, and autosomal dominant polycystic kidney disease. The recent clinical data suggest that targeting the vasopressin-AQP2 axis can provide therapeutic benefits in patients with water balance disorders.
Topics: Aquaporin 2; Diabetes Insipidus, Nephrogenic; Humans; Kidney; Kidney Diseases; Mutation; Vasopressins
PubMed: 30800291
DOI: 10.12688/f1000research.16654.1