-
Frontiers in Immunology 2024Cystinosis is a rare autosomal recessive disorder caused by mutations in the gene that encodes cystinosin, a ubiquitous lysosomal cystine/H antiporter. The hallmark of...
Cystinosis is a rare autosomal recessive disorder caused by mutations in the gene that encodes cystinosin, a ubiquitous lysosomal cystine/H antiporter. The hallmark of the disease is progressive accumulation of cystine and cystine crystals in virtually all tissues. At the kidney level, human cystinosis is characterized by the development of renal Fanconi syndrome and progressive glomerular and interstitial damage leading to end-stage kidney disease in the second or third decade of life. The exact molecular mechanisms involved in the pathogenesis of renal disease in cystinosis are incompletely elucidated. We have previously shown upregulation of NLRP2 in human cystinotic proximal tubular epithelial cells and its role in promoting inflammatory and profibrotic responses. Herein, we have investigated the role of NLRP2 using a mouse model of cystinosis in which we have confirmed upregulation of in the renal parenchyma. Our studies show that double knock out animals exhibit delayed development of Fanconi syndrome and kidney tissue damage. Specifically, we observed at 4-6 months of age that animals had less glucosuria and calciuria and markedly preserved renal tissue, as assessed by significantly lower levels of inflammatory cell infiltration, tubular atrophy, and interstitial fibrosis. Also, the mRNA expression of some inflammatory mediators ( and ) and the rate of apoptosis were significantly decreased in 4-6-month old kidneys harvested from mice compared to those obtained from mice. At 12-14 months of age, renal histological was markedly altered in both genetic models, although double KO animals had lower degree of polyuria and low molecular weight proteinuria and decreased mRNA expression levels of and . Altogether, these data indicate that Nlrp2 is a potential pharmacological target for delaying progression of kidney disease in cystinosis.
Topics: Animals; Cystine; Cystinosis; Kidney; Kidney Diseases; RNA, Messenger; Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins; Disease Models, Animal; Mice
PubMed: 38633264
DOI: 10.3389/fimmu.2024.1373224 -
Molecular Genetics & Genomic Medicine Apr 2024Nephrogenic diabetes insipidus (NDI) is a rare genetic disease that causes water imbalance. The kidneys play a crucial role in regulating body fluids by controlling...
INTRODUCTION
Nephrogenic diabetes insipidus (NDI) is a rare genetic disease that causes water imbalance. The kidneys play a crucial role in regulating body fluids by controlling water balance through urine excretion. This highlights their essential function in managing the body's water levels, but individuals with NDI may have excess urine production (polyuria), that leads to excessive thirst (polydipsia). Untreated affected individuals may exhibit poor feeding and failure to thrive. This disease is caused by mutations in the AVPR2 and the AQP2 genes which have the X-linked and autosomal recessive/dominant inheritance, respectively. Both of these genes are expressed in the kidney.
METHODS
Twelve Iranian patients from 10 consanguineous families were studied in this project. DNA was extracted from the whole blood samples of the patients and their parents. All coding exons and exon-intron boundaries of the AVPR2 and AQP2 genes were sequenced in the affected individuals, and the identified variants were investigated in the parents. All variants were analyzed according to the ACMG (American College of Medical Genetics and Genomics) guidelines.
RESULTS
In this study, 6 different mutations were identified in the patients, including 5 in the AQP2 gene (c.439G>A, c.538G>A, c.140C>T, c.450T>A, and the novel c.668T>C) and 1 in the AVPR2 gene (c.337C>T) in the present study.
DISCUSSION
As expected, all the detected mutations in this study were missense. According to the ACMG guideline, the identified mutations were categorized as pathogenic or likely pathogenic. Unlike previous studies which showed more than 90% of mutations were in the AVPR2 gene, and only less than 10% of the mutations were in the AQP2 gene, it was found that more than 90% of our identified mutations located in the AQP2 gene, and only one mutation was observed in the AVPR2 gene, which seems it may be a result of the high rate of consanguineous marriages in the Iranian population. We observed genotype-phenotype correlation in some of our affected individuals, and some of the mutations were observed in unrelated families from same ethnicity which could be suggestive of a founder mutation.
Topics: Humans; Diabetes Insipidus, Nephrogenic; Aquaporin 2; Iran; Mutation; Water; Diabetes Mellitus
PubMed: 38622833
DOI: 10.1002/mgg3.2421 -
Cureus Feb 2024We present the case of a lung transplant candidate under veno-venous membrane oxygenation assistance (VV ECMO) whose diagnosis of emphysema of...
We present the case of a lung transplant candidate under veno-venous membrane oxygenation assistance (VV ECMO) whose diagnosis of emphysema of undetermined etiology was redefined as Langerhans cell histiocytosis (LCH) due to a scalp skin biopsy performed years after the beginning of his respiratory symptoms. A 20-year-old patient started three years before his admission with progressive dyspnea leading to a diagnosis of bullous emphysema of undetermined cause, which evolved into respiratory failure and evaluation for bilateral lung transplant. Three years later, he developed bilateral pneumonia requiring mechanical ventilation. When refractory hypoxemia ensued, he had to be placed on VV ECMO. Under these conditions, he was transferred to our center and listed for a bilateral pulmonary transplantation. Forty-eight hours after admission, and due to intense polyuria, central diabetes insipidus was diagnosed. In this clinical context, the presence of cutaneous lesions on the scalp was reconsidered and biopsied under the presumption of possible LCH, with pathology analysis confirming the diagnosis. He continued to be assisted with VV ECMO for 66 more days as a bridge to transplantation, developing multi-organ failure and passing away before a donor organ was available. The diagnosis of LCH should be considered in any adult patient with bullous emphysema of undetermined cause. Given the possibility of early therapeutic interventions, the search for its clinical associations (e.g., diabetes insipidus and/or skin lesions) should be a systematic part of the etiologic workup. The availability of skin specimens to reach a diagnosis makes its thorough search an important part of the diagnostic approach.
PubMed: 38558685
DOI: 10.7759/cureus.55226 -
Journal of Medical Case Reports Mar 2024Diabetes insipidus is a syndrome characterized by polyuria, which is almost always associated with polydipsia. The most frequent cause is central diabetes insipidus,...
BACKGROUND
Diabetes insipidus is a syndrome characterized by polyuria, which is almost always associated with polydipsia. The most frequent cause is central diabetes insipidus, which is the result of an inadequate secretion of the antidiuretic hormone, and diagnosis involves differentiating it from other causes of polyuria and polydipsia.
CASE PRESENTATION
Here, we present a clinical case of a previously healthy 13-year-old Nepali boy, who, in December 2022, was found to have intense polydipsia accompanied by polyuria. He had bilateral lower limb weakness at the time of presentation. Biochemical evaluation demonstrated raised serum sodium (181 mEq/L), serum creatinine (78 μmol/L), and serum uric acid (560 μmol/L) with suppressed serum potassium (2.7 mEq/L), which was the major concern to the clinicians. Further laboratory workup revealed an increased serum osmolarity (393.6 mOsm/kg) with reduced urine osmolarity (222.7 mOsm/kg). On contrast magnetic resonance imaging of the brain, a thick-walled third ventricular cyst with bilateral foramen obstruction, thin membrane-like structure at top of aqueduct of Sylvius with gross obstructive hydrocephalus (inactive), and compressed and thinned pituitary gland with no bright spot was observed. The laboratory findings, radiological findings, and case presentation provided the provisional diagnosis of diabetes insipidus due to hydrocephalus and third ventricular cyst.
CONCLUSIONS
Central diabetes insipidus due to hydrocephalus, though rare, can have serious complications including the predilection to develop a deficit of other pituitary hormones. Thus, even if hydrocephalus is dormant with normal intracranial pressure, it must be addressed during investigations of central diabetes insipidus.
Topics: Male; Humans; Adolescent; Diabetes Insipidus, Neurogenic; Polyuria; Uric Acid; Diabetes Insipidus; Vasopressins; Polydipsia; Hydrocephalus; Cysts
PubMed: 38555457
DOI: 10.1186/s13256-024-04467-6 -
Journal of Cancer Research and... Jan 2024Metastasis to pituitary gland is a rare condition, and patients are usually asymptomatic. Diabetes insipidus (DI) is the most common presenting symptom, and breast...
Metastasis to pituitary gland is a rare condition, and patients are usually asymptomatic. Diabetes insipidus (DI) is the most common presenting symptom, and breast cancer is the most common source of pituitary metastasis (PM). We report a case of PM of breast cancer presenting as DI. A 45-year-old female patient presented to our department with complaints of polyuria and polydipsia. She had a medical history of metastatic breast adenocarcinoma. Laboratory data showed normal fasting plasma glucose level and hypotonic urine. Brain magnetic resonance imaging (MRI) showed infiltration of the pituitary stalk and the absence of the posterior pituitary bright spot consistent with metastasis to the pituitary gland. The water deprivation and vasopressin challenge tests confirmed central DI. Pituitary function tests revealed disconnection hyperprolactinemia with a menopausal profile. The patient was treated with vasopressin with great clinical results. Pituitary metastases are rare but should be suspected in patients with metastatic cancer who present with DI.
Topics: Female; Humans; Middle Aged; Breast Neoplasms; Diabetes Insipidus; Diabetes Mellitus; Magnetic Resonance Imaging; Pituitary Gland; Pituitary Neoplasms; Vasopressins
PubMed: 38554375
DOI: 10.4103/jcrt.jcrt_224_21 -
AACE Clinical Case Reports 2024Type 1 diabetes (T1D) and myasthenia gravis (MG) are autoimmune conditions that rarely co-occur. Here, we report a child with MG who subsequently developed T1D.
BACKGROUND/OBJECTIVE
Type 1 diabetes (T1D) and myasthenia gravis (MG) are autoimmune conditions that rarely co-occur. Here, we report a child with MG who subsequently developed T1D.
CASE REPORT
An 11-year-old girl with seropositive MG diagnosed at 4 years of age presented with muscle pain, cramps, and weight loss of 3.5 kg over 4 months. Her MG was in remission on daily pyridostigmine. She denied polyuria, polydipsia, recent illnesses, or other medications. She was prepubertal and had stable vitals with normal systemic examination. Initial work up for a probable diagnosis of rhabdomyolysis showed hyperglycemia and glucosuria. She had ketosis without acidosis. Diabetes autoantibodies were positive (anti-glutamic acid decarboxylase antibody 113.5 IU/mL (reference range < 5 IU/mL), anti-zinc transporter 8 antibody > 500 U/mL (reference range < 15 IU/mL)). Screening for autoimmune thyroid disease and celiac disease was negative. Patient was diagnosed with T1D and was started on subcutaneous insulin.
DISCUSSION
The co-existence of MG and T1D is rare. All the 4 prior reported patients from Europe were diagnosed with T1D prior to or concurrently with MG. In contrast, our patient was first diagnosed with MG and subsequently diagnosed with T1D 7 years later.
CONCLUSIONS
Consider screening for T1D in patients with MG and offering treatment to those above 8 years and older with stage 2 T1D to delay its onset. Along with other causes, T1D should also be considered when patients with MG present with nonspecific symptoms such as fatigue and weight loss.
PubMed: 38523857
DOI: 10.1016/j.aace.2023.12.004 -
The Journal of International Medical... Mar 2024Central diabetes insipidus (CDI) typically manifests as a polyuria-polydipsia syndrome, in which normonatremia is generally maintained through the polydipsia. A...
Central diabetes insipidus (CDI) typically manifests as a polyuria-polydipsia syndrome, in which normonatremia is generally maintained through the polydipsia. A 53-year-old woman presented with diabetic ketosis and hyperosmolar hyperglycemic syndrome. Her medical history included herpes meningoencephalitis, which was associated with confusion and amnesia. On physical examination, she was apyretic, confused, and had signs of extracellular dehydration. Her capillary glucose concentration was high and her urine was positive for ketones. Laboratory investigations revealed severe hyperglycemia, hypernatremia (plasma hyperosmolarity of 393.6 mOsm/L), and mild acute renal failure. In addition, she had a paucisymptomatic COVID-19 infection. Intravenous rehydration with isotonic saline solution and insulin therapy were effective at controlling the ketosis and ameliorating the hyperglycemia, but failed to normalize the hypernatremia and hyperosmolarity. She was not thirsty and had a urine output of 1 L/day, with urinary hypotonicity. Desmopressin administration reduced the hypernatremia and hyperosmolarity to within their normal ranges, and the patient's urinary osmolarity increased to 743 mOsm/L. Therefore, adipsic CDI was diagnosed. Endocrine investigations revealed isolated central hypothyroidism. The results of pituitary magnetic resonance imaging were normal. Thus, patients with impaired thirst may have an atypical presentation of CDI. In addition, the diagnosis of adipsic CDI is particularly challenging.
Topics: Humans; Female; Middle Aged; Diabetes Insipidus, Neurogenic; Hypernatremia; COVID-19; Diabetes Insipidus; Hyperglycemia; Polydipsia; Meningoencephalitis; Diabetes Mellitus
PubMed: 38502003
DOI: 10.1177/03000605241235747 -
Molecular Genetics and Metabolism... Mar 2024Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited metabolic disorder caused by biallelic pathogenic variants in genes related to the flavoprotein...
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited metabolic disorder caused by biallelic pathogenic variants in genes related to the flavoprotein complex. Dysfunction of the complex leads to impaired fatty acid oxidation and ketone body production which can cause hypoketotic hypoglycemia with prolonged fasting. Patients with fatty acid oxidation disorders (FAODs) such as MADD are treated primarily with a dietary regimen consisting of high-carbohydrate foods and avoidance of prolonged fasting. However, information on the long-term sequelae associated with this diet have not been accumulated. In general, high-carbohydrate diets can induce diseases such as type 2 diabetes mellitus (T2DM), although few patients with both MADD and T2DM have been reported.
CASE
We present the case of a 32-year-old man with MADD who was on a high-carbohydrate diet for >30 years and exhibited symptoms resembling diabetic ketoacidosis. He presented with polydipsia, polyuria, and weight loss with a decrease in body mass index from 31 to 25 kg/m over 2 months. Laboratory tests revealed a HbA1c level of 13.9%; however, the patient did not show metabolic acidosis but only mild ketosis.
DISCUSSION/CONCLUSION
This report emphasizes the potential association between long-term adherence to high-carbohydrate dietary therapy and T2DM development. Moreover, this case underscores the difficulty of detecting diabetic ketosis in patients with FAODs such as MADD due to their inability to produce ketone bodies. These findings warrant further research of the long-term complications associated with this diet as well as warning of the potential progression of diabetes in patients with FAODs such as MADD.
PubMed: 38469101
DOI: 10.1016/j.ymgmr.2024.101061 -
Journal of Diabetes Investigation Mar 2024Diabetes mellitus (DM) and arginine vasopressin deficiency (AVP-D) are characterized by polyuria. Marfan syndrome is an autosomal dominant disorder caused by...
Diabetes mellitus (DM) and arginine vasopressin deficiency (AVP-D) are characterized by polyuria. Marfan syndrome is an autosomal dominant disorder caused by pathogenetic variants in FBN1. Here, we report a patient with type 2 diabetes mellitus, AVP-D, and Marfan syndrome. Although the coexistence of type 2 diabetes mellitus and AVP-D is rare, for those patients with type 2 diabetes mellitus, the existence of AVP-D should be considered when polyuria is not in accordance with the blood glucose levels, especially for those with a low urine specific gravity. Specific symptoms or signs help to identify Marfan syndrome early, and genetic testing of the FBN1 pathogenetic variant helps to make a definitive diagnosis.
PubMed: 38429969
DOI: 10.1111/jdi.14169 -
Cureus Jan 2024Dupilumab is a fully humanized monoclonal antibody that binds to IL-4 receptors and blocks IL-4 and IL-13 mediated T-helper 2 (Th2) responses. Dupilumab is estimated to...
Dupilumab is a fully humanized monoclonal antibody that binds to IL-4 receptors and blocks IL-4 and IL-13 mediated T-helper 2 (Th2) responses. Dupilumab is estimated to be used by over 600,000 patients worldwide for the treatment of atopic dermatitis and other immunologic conditions. Recently, a 66-year-old male patient being treated for atopic dermatitis with dupilumab presented to the clinic with complaints of polyuria and polydipsia. Upon initial testing, the patient was found to have considerable hyperglycemia. Upon genetic testing, he showed no predisposition for autoimmune diabetes and was negative for type I diabetes mellitus-associated human leukocyte antigen (HLA) genes. After immediate cessation of dupilumab, and with subsequent insulin therapy, the patient was able to obtain glycemic control. Following taper and eventual cessation of insulin therapy and over the course of seven months, the patient was able to achieve a full resolution of symptoms and his glycosylated hemoglobin (HgBA1c) levels returned to normal ranges. This case represents only the second documented case of dupilumab-induced diabetes mellitus and is the first known documented case of dupilumab-induced diabetes mellitus in a non-genetically predisposed individual. This case also describes a previously unobserved spontaneous resolution of symptoms upon cessation of the drug. This case further illustrates the potential existence of immunogenic or immunomodulatory side effects of the monoclonal antibody dupilumab that can affect patients who are both genetically and non-genetically predisposed to autoimmune diabetes mellitus.
PubMed: 38414708
DOI: 10.7759/cureus.53080