MONDO:0971031

[PMID:30020718] [NO_EVIDENCE] when fermenting yeast or bacteria becomes pathogenic, extreme blood alcohol levels may result --- Explanation: Extreme blood alcohol levels can cause seizures as a severe complication.


MONDO:0971031

[PMID:33887125] [INDIRECT EVIDENCE] [SUPPORT] The gut fermentation syndrome (GFS), also known as the endogenous alcohol fermentation syndrome or auto brewery syndrome, is a rare and underdiagnosed medical condition where consumed carbohydrates are converted to alcohol by the microbiota in the gastrointestinal or urinary tract. --- Explanation: Systematic review confirms that carbohydrates are fermented to alcohol by microbiota in the GI tract.

[PMID:33887125] [INDIRECT EVIDENCE] [SUPPORT] The species that caused the GFS included Klebsiella pneumoniae, Candida albicans, C. glabrata, Saccharomyces cerevisiae, C. intermedia, C. parapsilosis, and C. kefyr. --- Explanation: Identifies the spectrum of fungal organisms responsible for gut fermentation syndrome.


MONDO:0971031


MONDO:0971031

[PMID:31543403] [INDIRECT EVIDENCE] [SUPPORT] high-alcohol-producing Klebsiella pneumoniae (HiAlc Kpn) is associated with up to 60% of individuals with NAFLD in a Chinese cohort --- Explanation: Demonstrates that high-alcohol-producing Klebsiella strains can generate significant endogenous ethanol.

[PMID:37060744] [INDIRECT EVIDENCE] [SUPPORT] We isolated three species of HiAlc Klebsiella from ABS patients, which were able to induce ABS in mice. --- Explanation: Confirms that Klebsiella species isolated from ABS patients can cause the syndrome in animal models.


MONDO:0971031

[PMID:34682761] [INDIRECT EVIDENCE] [NO_EVIDENCE] The pathophysiology of ABS is reportedly due to a fungal type dysbiosis of the gut that ferments some carbohydrates into ethanol --- Explanation: Describes the metabolic storm where gut dysbiosis leads to ethanol production that can overwhelm hepatic clearance.


MAXO:0000058

[PMID:33887125] [SUPPORT] Current treatments for GFS include antibiotics, antifungal medication, low carbohydrate diet, and probiotics. --- Explanation: Antifungal medication is a standard treatment for GFS.

[PMID:34682761] [SUPPORT] Treatment typically includes antifungal drugs combined with changes in lifestyle and nutrition. --- Explanation: Confirms antifungal drugs are part of standard treatment approach.


MAXO:0000088

[PMID:37060744] [SUPPORT] Treatments with antibiotics, a complex probiotic preparation and a low-carbohydrate diet not only alleviated ABS, but also erased ABS relapse during the follow-up observation of one of the patients. --- Explanation: Low-carbohydrate diet was part of successful treatment regimen.

[PMID:33887125] [SUPPORT] Current treatments for GFS include antibiotics, antifungal medication, low carbohydrate diet, and probiotics. --- Explanation: Low carbohydrate diet is a recognized treatment approach.


MAXO:0000748

[PMID:33887125] [PARTIAL] There might be a potential role of fecal microbiota transplant in the treatment of GFS. --- Explanation: FMT is suggested as a potential treatment for refractory cases.


MONDO:0020640

[PMID:31326280] [SUPPORT] some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease --- Explanation: Seizures identified as a key presenting feature of anti-NMDAR encephalitis.


MONDO:0020640

[PMID:31326280] [SUPPORT] some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease --- Explanation: Rapidly progressive psychiatric symptoms are a hallmark presentation of autoimmune encephalitis.


MONDO:0020640

[PMID:31326280] [SUPPORT] some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease --- Explanation: Cognitive impairment (including memory) is a key presenting feature.


MONDO:0020640

[PMID:31326280] [SUPPORT] some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease --- Explanation: Abnormal movements (dyskinesias) are part of the diagnostic spectrum.


MONDO:0020640


MONDO:0020640

[PMID:31326280] [INDIRECT EVIDENCE] [SUPPORT] autoantibodies serve as a diagnostic marker and alter NMDAR-related synaptic transmission --- Explanation: Confirms antibodies both diagnose and directly cause disease by altering NMDAR synaptic transmission.


MAXO:0001002

[PMID:23290630] [SUPPORT] 472 (94%) underwent first-line immunotherapy or tumour removal, resulting in improvement within 4 weeks in 251 (53%). --- Explanation: Large observational cohort showing majority of patients receive first-line immunotherapy with about half responding within 4 weeks.


MAXO:0000058

[PMID:23290630] [SUPPORT] Of 221 patients who did not improve with first-line treatment, 125 (57%) received second-line immunotherapy that resulted in a better outcome (mRS 0-2) than those who did not --- Explanation: Second-line immunotherapy (rituximab/cyclophosphamide) significantly improves outcomes in treatment-refractory patients.

[PMID:31326280] [SUPPORT] About 80% of patients improve with immunotherapy and, if needed, tumour removal, but the recovery is slow. --- Explanation: Overall 80% response rate to immunotherapy including second-line agents.


MAXO:0000004

[PMID:31326280] [SUPPORT] About 80% of patients improve with immunotherapy and, if needed, tumour removal, but the recovery is slow. --- Explanation: Tumor removal is part of the standard treatment approach for autoimmune encephalitis with associated tumors.


MONDO:0020108


MONDO:0020108

[PMID:38673882] [INDIRECT EVIDENCE] [PARTIAL] Warm-antibody AIHA (wAIHA) exhibits a pan-reactive IgG autoantibody recognizing a portion of band 3 (wherein the DAT may be positive with IgG, C3d or both). Treatment involves glucocorticoids and steroid-sparing agents and may consider IVIG or monoclonal antibodies to CD20, CD38 or C1q. --- Explanation: This comprehensive 2024 review confirms that warm AIHA is mediated by IgG autoantibodies that recognize RBC antigens like band 3, consistent with the FcR-mediated phagocytosis mechanism.

[PMID:29692344] [INDIRECT EVIDENCE] [SUPPORT] Tissue-resident macrophages in the spleen play a major role in the clearance of immunoglobulin G (IgG)-opsonized blood cells, as occurs in immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA). Blood cells are phagocytosed via the Fc-γ receptors (FcγRs) --- Explanation: This study demonstrates that splenic red pulp macrophages express FcγRIIa and FcγRIIIa receptors and are responsible for phagocytosis of IgG-opsonized RBCs in AIHA, directly supporting the mechanism of extravascular hemolysis in warm AIHA.


MONDO:0020108

[PMID:38673882] [INDIRECT EVIDENCE] [PARTIAL] Cold-antibody AIHA due to IgMs range from cold agglutinin syndrome (CAS) to cold agglutin disease (CAD). These are typically specific to the Ii blood group system, with the former (CAS) being polyclonal and the latter (CAD) being a more severe and monoclonal entity. The DAT in either case is positive only with C3d. --- Explanation: This comprehensive review confirms that cold AIHA is mediated by IgM autoantibodies that activate the complement cascade, resulting in C3d deposition on RBCs and complement-mediated hemolysis.

[PMID:30559259] [INDIRECT EVIDENCE] [SUPPORT] Cold agglutinin disease is a difficult-to-treat autoimmune hemolytic anemia in which immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predominantly extravascular hemolysis. --- Explanation: This first-in-human trial of C1s inhibition confirms the central role of classical complement pathway activation in cold agglutinin disease, where IgM binding triggers complement fixation leading to C3b opsonization and extravascular hemolysis.

[PMID:32176765] [INDIRECT EVIDENCE] [SUPPORT] Cold agglutinin disease (CAD) causes predominantly extravascular hemolysis and anemia via complement activation. Sutimlimab is a novel humanized monoclonal antibody directed against classical pathway complement factor C1s. --- Explanation: This clinical study demonstrates that blocking C1s (the serine protease in the C1 complex) effectively stops complement-mediated hemolysis in CAD, confirming that classical pathway activation via C1s is the key mechanism driving RBC destruction in cold agglutinin disease.


MONDO:0020108

[PMID:39371250] [INDIRECT EVIDENCE] [PARTIAL] Therapy is quite different, as steroids and rituximab are effective in the former, but have a lower response rate and duration in the latter. --- Explanation: This 2024 review confirms that B cell-targeting therapy (rituximab, anti-CD20) is effective in warm AIHA, supporting the role of dysregulated B cells in autoantibody production against RBCs.

[PMID:38673882] [INDIRECT EVIDENCE] [PARTIAL] Treatment involves glucocorticoids and steroid-sparing agents and may consider IVIG or monoclonal antibodies to CD20, CD38 or C1q. --- Explanation: The efficacy of anti-CD20 (rituximab) and anti-CD38 (daratumumab) therapies demonstrates that B cells and plasma cells are the cellular sources of pathogenic autoantibodies in AIHA, confirming the role of B cell dysregulation in disease pathogenesis.


MAXO:0000058

[PMID:25271314] [SUPPORT] The first-line therapy for warm AIHA are corticosteroids, which are effective in 70-85% of patients --- Explanation: This review establishes corticosteroids as first-line therapy with 70-85% efficacy.


MAXO:0000058

[PMID:25271314] [SUPPORT] rituximab (effective in approx. 80-90% of cases) --- Explanation: Rituximab demonstrates 80-90% efficacy as second-line therapy.


MAXO:0001077

[PMID:25271314] [SUPPORT] splenectomy (effective approx. in 2 out of 3 cases but with a presumed cure rate of up to 20%) --- Explanation: Splenectomy is effective in approximately 2/3 of cases with up to 20% cure rate.


MAXO:0000015

[PMID:33826820] [SUPPORT] selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue --- Explanation: The CARDINAL trial demonstrated sutimlimab's efficacy in halting complement-mediated hemolysis in cold agglutinin disease.


MONDO:0016264


MONDO:0016264

[PMID:39817450] [INDIRECT EVIDENCE] [PARTIAL] SepSecS-specific CD4+ T cell clones were found in patients with AIH who were anti-SLA-positive and anti-SLA-negative, and, to a lesser extent, in patients with non-AIH liver diseases and in healthy individuals. SepSecS-specific T cell clones from patients with AIH produced IFN-γ, IL-4, and IL-10, targeted multiple SepSecS epitopes, and, in one patient, were clonally expanded in both blood and liver biopsy. --- Explanation: Demonstrates that autoreactive CD4+ T cells targeting the liver autoantigen SepSecS are present and clonally expanded in AIH patients, producing inflammatory cytokines and infiltrating liver tissue.


MONDO:0016264

[PMID:39817450] [INDIRECT EVIDENCE] [SUPPORT] The anti-SepSecS mAbs isolated were primarily IgG1, affinity-matured compared with their germline versions, and recognized at least 3 nonoverlapping epitopes. --- Explanation: Shows that anti-SLA/SepSecS autoantibodies in AIH undergo affinity maturation and class-switching to IgG1, indicating an adaptive B cell response with germinal center involvement.

[PMID:31226726] [INDIRECT EVIDENCE] [PARTIAL] Autoreactive B cells can promote autoimmunity through antigen presentation to autoreactive T cells, production of autoantibodies, generation of cytokines promoting T cell activation and differentiation, and inhibition of regulatory T cells and B cells. --- Explanation: Highlights multiple mechanisms by which B cells and autoantibodies contribute to AIH pathogenesis beyond simple diagnostic markers.


MONDO:0016264

[PMID:31226726] [INDIRECT EVIDENCE] [PARTIAL] Autoreactive B cells can promote autoimmunity through antigen presentation to autoreactive T cells, production of autoantibodies, generation of cytokines promoting T cell activation and differentiation, and inhibition of regulatory T cells and B cells. --- Explanation: Indicates that B cells in AIH can actively inhibit regulatory T cells, contributing to the loss of immune tolerance and allowing autoreactive T cell expansion.


HGNC.SYMBOL:HLA-DR3

[PMID:38089552] [NO_EVIDENCE] Fine-mapping analysis further identified position 67 where phenylalanine of the HLA-B molecule was significantly associated with AIH (p = 3.39×10-139), at the peptide binding groove. --- Explanation: Demonstrates that specific HLA class I alleles, particularly HLA-B residues at the peptide binding groove, are strongly associated with AIH susceptibility, supporting the role of antigen presentation in disease pathogenesis.


HGNC.SYMBOL:HLA-DR4


HGNC.SYMBOL:HLA-B*35:01

[PMID:38089552] [SUPPORT] A total of 588 HLA variants were significantly associated with AIH. Stepwise conditional analysis revealed the strongest allele was in the HLA-B gene (HLA-B*35:01, p = 8.17×10-304; OR = 7.32), with additional independent signals at HLA-B*08:01 (p = 1.35 × 10-33; OR = 4.26) and rs7765379 (p = 5.08 × 10-18; OR = 1.66). --- Explanation: Identifies HLA-B*35:01 as the strongest genetic risk factor for AIH type 1 in Han Chinese populations, with an odds ratio of 7.32, highlighting the critical role of MHC class I in disease susceptibility.


MONDO:0008156

[PMID:11741829] [SUPPORT] the most common form of osteopetrosis, a group of conditions characterized by an increased skeletal mass due to impaired bone and cartilage resorption --- Explanation: Defines ADO2 as the most common osteopetrosis form with increased skeletal mass.


MONDO:0008156

[PMID:17164308] [SUPPORT] subjects with ADO had a significantly increased prevalence of fracture (84 vs. 36%; P < 0.0001) --- Explanation: 84% fracture prevalence in ADO subjects versus 36% in controls.


MONDO:0008156

[PMID:17164308] [SUPPORT] osteomyelitis typically occurred in the maxilla or mandible in older adults --- Explanation: 16% osteomyelitis rate, predominantly mandibular in older adults.


MONDO:0008156

[PMID:17164308] [SUPPORT] Visual loss, which typically had its onset in childhood, and bone marrow failure occurred in 19 and 3% of ADO subjects, respectively --- Explanation: 19% visual loss with childhood onset in the largest ADO2 cohort.


MONDO:0008156

[PMID:11741829] [INDIRECT EVIDENCE] [SUPPORT] seven different mutations in the gene encoding the ClCN7 chloride channel in all 12 ADO II families analysed --- Explanation: Identifies CLCN7 as the causative gene for ADO2.

[PMID:11741829] [INDIRECT EVIDENCE] [SUPPORT] ADO II reflects a dominant negative effect, whereas loss-of-function mutations in ClCN7 do not cause abnormalities in heterozygous individuals --- Explanation: Establishes the dominant negative mechanism for CLCN7 missense mutations in ADO2.

[PMID:12929941] [INDIRECT EVIDENCE] [SUPPORT] Based on the preponderance of missense mutations and the knowledge that chloride channels probably function as dimers, it seems that heterozygous ClCN7 gene mutations may cause ADO2 through a dominant negative mechanism --- Explanation: Proposes that dimeric channel structure enables dominant negative pathogenesis.


MONDO:0008156

[PMID:12929941] [INDIRECT EVIDENCE] [NO_EVIDENCE] disease penetrance was 66% (62 clinically affected individuals/94 subjects with the gene mutation) --- Explanation: Incomplete penetrance reflects variable impact of dominant negative mechanism on osteoclast function.

[PMID:11741829] [INDIRECT EVIDENCE] [SUPPORT] the most common form of osteopetrosis, a group of conditions characterized by an increased skeletal mass due to impaired bone and cartilage resorption --- Explanation: Impaired bone resorption leads to the characteristic increased skeletal mass.


MONDO:0008156

[PMID:11741829] [INDIRECT EVIDENCE] [SUPPORT] the most common form of osteopetrosis, a group of conditions characterized by an increased skeletal mass due to impaired bone and cartilage resorption --- Explanation: Increased skeletal mass results from progressive bone accumulation.


MAXO:0000950


MAXO:0000079


HGNC.SYMBOL:CLCN7 Mutations

[PMID:12929941] [SUPPORT] nine different mutations have been discovered in the ClCN7 gene in 22 of 23 ADO2 families studied --- Explanation: Near-complete genetic homogeneity with CLCN7 mutations in ADO2.

[PMID:11741829] [SUPPORT] ADO II is allelic with a subset of ARO cases --- Explanation: CLCN7 mutations cause both dominant and recessive osteopetrosis depending on zygosity.


MONDO:0009816

[PMID:10888887] [SUPPORT] Osteopetrosis includes a group of inherited diseases in which inadequate bone resorption is caused by osteoclast dysfunction --- Explanation: Defines osteopetrosis as the hallmark feature of osteoclast dysfunction.


MONDO:0009816

[PMID:10888887] [SUPPORT] Infantile malignant autosomal recessive osteopetrosis (MIM 259700) is a severe bone disease with a fatal outcome, generally within the first decade of life --- Explanation: The fatal outcome is largely due to bone marrow failure causing pancytopenia.


MONDO:0009816


MONDO:0009816

[PMID:10888887] [INDIRECT EVIDENCE] [PARTIAL] TCIRG1, encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, is mutated in five of nine patients --- Explanation: Identifies TCIRG1 and the vacuolar proton pump as the pathogenic target.

[PMID:10888887] [INDIRECT EVIDENCE] [PARTIAL] Osteoclasts are present in normal or elevated numbers in individuals affected by autosomal recessive osteopetrosis, suggesting that the defect is not in osteoclast differentiation, but in a gene involved in the functional capacity of mature osteoclasts --- Explanation: Establishes that osteoclasts differentiate normally but are non-functional.


MONDO:0009816

[PMID:10888887] [INDIRECT EVIDENCE] [PARTIAL] mutations in TCIRG1 are a frequent cause of autosomal recessive osteopetrosis in humans --- Explanation: TCIRG1 deficiency causes progressive skeletal sclerosis from failed bone resorption.


MONDO:0009816

[PMID:10888887] [INDIRECT EVIDENCE] [SUPPORT] Infantile malignant autosomal recessive osteopetrosis (MIM 259700) is a severe bone disease with a fatal outcome, generally within the first decade of life --- Explanation: The fatal outcome is primarily due to bone marrow failure from medullary obliteration.


MAXO:0010039


HGNC.SYMBOL:TCIRG1 Mutations

[PMID:10888887] [SUPPORT] TCIRG1, encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, is mutated in five of nine patients with a diagnosis of infantile malignant osteopetrosis --- Explanation: TCIRG1 mutations found in 5/9 (56%) of infantile ARO patients.


MONDO:0019187

[PMID:22199394] [SUPPORT] In the eye, this condition manifests with varying degrees of anterior segment dysgenesis and carries a high risk of glaucoma. --- Explanation: The literature states that Axenfeld-Rieger syndrome carries a high risk of glaucoma, supporting the statement.

[PMID:12015278] [SUPPORT] Individuals with malformations of structures of the anterior segment of the eye frequently develop elevated intraocular pressure and glaucoma. --- Explanation: The literature confirms that malformations of the anterior segment, which are characteristic of Axenfeld-Rieger syndrome, frequently lead to glaucoma.

[PMID:27055677] [SUPPORT] To determine the long-term surgical and visual outcomes in Indian children with early-onset glaucoma associated with Axenfeld-Rieger anomaly (ARA). --- Explanation: The study specifically investigates early-onset glaucoma associated with Axenfeld-Rieger anomaly, supporting the statement.

[PMID:32905845] [SUPPORT] Our study describes the glaucoma phenotype in a family with Axenfeld-Rieger syndrome (ARS) and a FOXC1 variant. --- Explanation: The literature describes glaucoma phenotypes in individuals with Axenfeld-Rieger syndrome, supporting the statement.

[PMID:33367186] [SUPPORT] Glaucoma is the main cause of visual morbidity in patients with ARS, therefore a complete periodic ophthalmological exam is a priority. --- Explanation: The literature states that glaucoma is a major cause of visual morbidity in Axenfeld-Rieger syndrome, supporting the statement.

[PMID:21666320] [PARTIAL] The patient had megalocornea with Haab's striae in the right eye and posterior embryotoxon in both the eyes. In the left eye, there was a white cord-like structure traversing the anterior chamber with adhesions to iris tissue along its course. --- Explanation: The literature describes ocular abnormalities consistent with glaucoma in Axenfeld-Rieger syndrome, supporting the statement.

[PMID:15509533] [SUPPORT] The eye manifests with iris ruptures, irido-corneal adhesions, cloudy corneas, and glaucoma. --- Explanation: The literature explicitly states that glaucoma is a manifestation of Axenfeld-Rieger syndrome, supporting the statement.


MONDO:0019187

[PMID:15492748] [PARTIAL] One of the main ocular features associated with Axenfeld-Rieger is posterior embryotoxon, which is a prominent anteriorly displaced Schwalbe's line. This can be found in up to 15% of normal eyes, without any clinical significance or may represent a forme fruste of an anterior segment dysgenesis. --- Explanation: The literature supports that posterior embryotoxon is a common feature of Axenfeld-Rieger syndrome but does not confirm it as 'VERY_FREQUENT'. Additionally, it may be present without clinical significance.

[PMID:21666320] [SUPPORT] The patient had megalocornea with Haab's striae in the right eye and posterior embryotoxon in both the eyes. --- Explanation: The case report supports the presence of posterior embryotoxon in Axenfeld-Rieger syndrome.

[PMID:34937757] [SUPPORT] Posterior embryotoxon, an anteriorly displaced Schwalbe's line, is the most common feature of Axenfeld Rieger syndrome. --- Explanation: This reference confirms that posterior embryotoxon is a common feature of Axenfeld-Rieger syndrome.

[PMID:38006999] [SUPPORT] Posterior embryotoxon as the initial ophthalmological sign of Axenfeld-Rieger syndrome. --- Explanation: This reference supports the statement that posterior embryotoxon is a diagnostic feature of Axenfeld-Rieger syndrome.


MONDO:0019187

[PMID:16302606] [SUPPORT] Axenfeld-Rieger syndrome is a rare autosomal dominant disorder characterized by various ocular and extraocular malformations. Dental abnormalities are considered as definitive features for the diagnosis and differentiation of Rieger syndrome from other anterior chamber of the eye malformations. --- Explanation: The abstract confirms dental abnormalities are definitive features of Rieger syndrome.

[PMID:35836351] [PARTIAL] Enamel formation is disturbed in some patients with ARS. Pitx2 knockdown can influence the proliferation and ameloblast differentiation of inner enamel epithelial cells, and PITX2 may regulate cell proliferation via Wnt/beta-catenin signaling pathway. --- Explanation: This study provides evidence for enamel hypoplasia in some patients with Axenfeld-Rieger syndrome but does not provide information on the frequency or other dental anomalies such as hypodontia or microdontia.


MONDO:0019187

[PMID:16302606] [SUPPORT] Axenfeld-Rieger syndrome is a rare autosomal dominant disorder characterized by various ocular and extraocular malformations. ... Significant cranio-dento-facial findings that have been observed are, teeth with short and dilacerated roots, hyperplastic frenums and underdeveloped maxilla. --- Explanation: The literature confirms that craniofacial dysmorphism, including an underdeveloped maxilla, is a feature of Axenfeld-Rieger syndrome.

[PMID:33231930] [SUPPORT] Axenfeld-Rieger syndrome is a genetic condition characterized by ocular and systemic features. ... A thin upper lip (55.9%) and a prominent forehead (41.2%) were common facial features shared between both genes. Hypertelorism/telecanthus (81.8% vs 25.0%, p = 0.002) and low-set ears (31.8% vs 0.0%, p = 0.036) were significantly more prevalent in individuals with FOXC1 variants compared with PITX2 variants. --- Explanation: The literature indicates that hypertelorism, a craniofacial feature, is frequently observed in individuals with Axenfeld-Rieger syndrome.


MONDO:0019187

[PMID:27070436] [SUPPORT] Key clinical features comprise facial dysmorphism including mid-face and dental hypoplasia, hearing loss, cardiac anomalies, and involuted periumbilical skin. --- Explanation: The literature mentions hearing loss as a clinical feature of Axenfeld-Rieger syndrome.

[PMID:32741584] [SUPPORT] Axenfeld-Rieger syndrome (ARS) type 3 is a rare autosomal dominant disease, characterized by anterior segment dysgenesis of the eye, hearing loss, and cardiac defects. --- Explanation: This reference confirms hearing loss is associated with ARS type 3 (FOXC1-related).


MONDO:0019187

[PMID:32741584] [SUPPORT] Axenfeld-Rieger syndrome (ARS) type 3 is a rare autosomal dominant disease, characterized by anterior segment dysgenesis of the eye, hearing loss, and cardiac defects. --- Explanation: This reference confirms cardiac defects are associated with ARS type 3 (FOXC1-related).

[PMID:36543336] [SUPPORT] Axenfeld-Rieger syndrome is a rare multi-system disorder associated with cardiac anomalies. --- Explanation: The reference confirms that cardiac anomalies are part of the multi-system presentation of Axenfeld-Rieger syndrome.


MONDO:0019187

[PMID:22199394] [INDIRECT EVIDENCE] [PARTIAL] Recent advances in molecular genetics have identified two major genes, PITX2 and FOXC1, demonstrating a wide spectrum of mutations, which aids in the molecular diagnosis of the disease. --- Explanation: Confirms PITX2 and FOXC1 as the primary genes involved in ARS pathogenesis.


MONDO:0019187


MONDO:0019187

[PMID:19218601] [INDIRECT EVIDENCE] [SUPPORT] Two homeobox mutations, R43W and R90C, resulted in severely reduced DNA-binding and transcriptional activation despite normal nuclear localization. --- Explanation: The reference indicates that some mutations in PITX2 result in reduced DNA-binding and transcriptional activation, which aligns with the statement that mutations disrupt its function.

[PMID:15509533] [INDIRECT EVIDENCE] [SUPPORT] It has been reported that some mutations in PITX2 increase transactivation, whereas most mutations cause defects in DNA binding or transactivation. --- Explanation: This reference supports the statement that mutations in PITX2 can disrupt its function, and mentions that some mutations can increase transactivation activity.

[PMID:12130547] [INDIRECT EVIDENCE] [SUPPORT] The five mutants appeared to be transcriptionally defective despite conserved DNA-binding in CV1 cells. --- Explanation: This reference supports the idea that PITX2 mutations can impair its ability to regulate gene expression.

[PMID:21837767] [INDIRECT EVIDENCE] [SUPPORT] Mutation in either gene caused reduced transcriptional activation to different extents on the FOXO1 and PLOD1 promoters. --- Explanation: This reference supports the idea that PITX2 mutations can disrupt its function as a transcription factor.


MAXO:0000058

[PMID:18929112] [SUPPORT] Treatment for glaucoma consists of reducing intraocular pressure (IOP) to an acceptable target range to prevent further optic-nerve damage. Currently available treatments include topical drug (single then multidrug combinations) followed, for those patients on maximal tolerated medical therapy who still need additional IOP reduction, by laser treatments. --- Explanation: This reference supports the use of medications as first-line treatment for managing glaucoma in patients.


MAXO:0000004

[PMID:32357855] [SUPPORT] The goal of this study is to compare the effectiveness of various glaucoma surgeries on intraocular pressure (IOP) management in ARS. --- Explanation: The study discusses various surgical interventions for managing intraocular pressure in patients with Axenfeld-Rieger syndrome.

[PMID:33881269] [SUPPORT] The article describes a case of 7-year-old child with rare Axenfeld-Rieger syndrome demonstrating the effectiveness and safety of combined laser reconstructive surgeries. --- Explanation: The case report supports the use of laser and surgical therapy as part of the management for Axenfeld-Rieger syndrome.

[PMID:35733478] [SUPPORT] Treatment is predominantly the management of glaucoma and is mostly medical but can be surgical in refractory cases. --- Explanation: Confirms that surgical management is used for refractory glaucoma cases in ARS.


MAXO:0000004

[PMID:22104715] [SUPPORT] The patient showed severe hypodontia, microdontia, and short roots. Different treatment options are discussed. Early diagnosis and an interdisciplinary approach are necessary to provide the best short- and long-term treatment plans, as well as treatment and follow-up for individuals with the syndrome. --- Explanation: The reference discusses the dental anomalies in Axenfeld-Rieger syndrome and the importance of early diagnosis and interdisciplinary treatment, aligning with the statement about orthodontic and dental treatments to address these anomalies.

[PMID:33487449] [SUPPORT] The management of a Moroccan family with Axenfeld-Rieger syndrome. --- Explanation: The reference indicates the management of Axenfeld-Rieger syndrome, which includes addressing dental anomalies, supporting the statement about orthodontic and dental treatments.


HGNC.SYMBOL:PITX2

[PMID:28611552] [SUPPORT] Axenfeld-Rieger syndrome is a rare autosomal dominant condition... A variant of uncertain significance in PITX2 was identified... it is suggested that this variant can be classified as pathogenic. --- Explanation: The study identifies a pathogenic variant in PITX2 associated with Axenfeld-Rieger syndrome, which is an autosomal dominant condition.

[PMID:37539177] [SUPPORT] Mutations in the transcription factors FOXC1 or PITX2 are the most well-studied genetic manifestations of this syndrome. --- Explanation: The review supports the association of PITX2 pathogenic variants with Axenfeld-Rieger syndrome.

[PMID:36442680] [SUPPORT] PITX2 and FOXC1 are the most common pathogenic genes associated with Axenfeld-Rieger syndrome (ARS). --- Explanation: The study confirms that PITX2 is a common pathogenic gene in Axenfeld-Rieger syndrome, which is autosomal dominant.

[PMID:9685346] [SUPPORT] Mutations in the Pitx2 homeobox gene have been linked to Rieger syndrome. --- Explanation: The study identifies PITX2 mutations as linked to Rieger syndrome, which is a part of the Axenfeld-Rieger syndrome spectrum.


HGNC.SYMBOL:FOXC1

[PMID:34809627] [SUPPORT] Mutations in the Forkhead Box C1 (FOXC1) are known to cause autosomal dominant hereditary Axenfeld-Rieger syndrome... --- Explanation: This reference explicitly states that mutations in FOXC1 cause autosomal dominant Axenfeld-Rieger syndrome.

[PMID:37539177] [SUPPORT] Mutations in the transcription factors FOXC1 or PITX2 are the most well-studied genetic manifestations of this syndrome. --- Explanation: This reference confirms the association of FOXC1 with Axenfeld-Rieger syndrome and describes the genetic nature of the condition.

[PMID:22009788] [SUPPORT] Clinical phenotypes of and genetic aberrations in three unrelated Japanese patients with Axenfeld-Rieger anomalies... FOXC1 was apparently deleted in both patients. --- Explanation: This reference supports the association of FOXC1 with Axenfeld-Rieger syndrome through genetic analysis.

[PMID:33530637] [SUPPORT] Mutations of one cascade constituent PITX2 and, separately, the Forkhead transcription factor FOXC1 independently cause a multi-system disorder known as Axenfeld-Rieger syndrome (ARS). --- Explanation: This reference supports the statement by identifying FOXC1 mutations as a cause of Axenfeld-Rieger syndrome.


MONDO:0000390

[PMID:34015078] [SUPPORT] The VMD phenotype consists of a prominent raised central macular lesion that undergoes morphological changes classified into six stages: previtelliform, vitelliform, vitelliruptive, pseudohypopion, atrophic, and cicatricial. --- Explanation: Describes the hallmark vitelliform macular lesion and its staging.


MONDO:0000390

[PMID:34015078] [SUPPORT] The best corrected visual acuity (BCVA) is mildly decreased to 20/50 on average (range 20/20 to 20/200), until later stages, where natural progression and complication create a steep decline. --- Explanation: Documents visual acuity decline particularly in later disease stages.


MONDO:0000390

[PMID:34015078] [SUPPORT] electrophysiology changes show a moderately decreased electro-oculography (EOG) Arden ratio of less than 1.5 with frequently normal full-field electroretinogram (ffERG). --- Explanation: Documents the characteristic EOG abnormality in BVMD with normal ERG.


MONDO:0000390


MONDO:0000390

[PMID:34015078] [SUPPORT] The phenotype additionally encompasses extramacular punctate deposits, intraretinal and subretinal fluid (SRF) accumulation, punctate or diffuse fundus hyperautofluorescence, hyperopia, short axial-length --- Explanation: Hyperopia is listed as part of the ARB phenotype.


MONDO:0000390

[PMID:29507198] [SUPPORT] Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. --- Explanation: Retinal detachment is a direct consequence of BEST1 mutations.


MONDO:0000390

[PMID:30578502] [SUPPORT] decreased AF reflects RPE atrophy. --- Explanation: RPE atrophy is documented as a feature on fundus autofluorescence imaging.


MONDO:0000390

[PMID:30578502] [SUPPORT] Refractive error is hyperopia, predisposing these eyes for acute angle-closure glaucoma. --- Explanation: Hyperopia in ARB predisposes to angle-closure glaucoma.


MONDO:0000390

[PMID:34612806] [INDIRECT EVIDENCE] [SUPPORT] Bestrophins are a family of calcium-activated chloride channels (CaCCs) with relevance to human physiology and a myriad of eye diseases termed "bestrophinopathies". --- Explanation: Confirms bestrophins are CaCCs and their dysfunction causes bestrophinopathies.

[PMID:29507198] [INDIRECT EVIDENCE] [SUPPORT] BEST1 acts as a multifunctional channel protein responsible for mediating transepithelial ion transport, regulation of intracellular calcium signaling and RPE cell volume, and modulation of the homeostatic milieu in the subretinal space --- Explanation: Describes the multifunctional role of BEST1 in RPE physiology.


MONDO:0000390

[PMID:29507198] [INDIRECT EVIDENCE] [SUPPORT] Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. --- Explanation: Directly states that BEST1 mutations cause retinal detachment and PR degeneration from RPE channelopathy.

[PMID:29507198] [INDIRECT EVIDENCE] [SUPPORT] In vivo imaging demonstrated a retina-wide RPE-PR microdetachment, which contracted with dark adaptation and expanded upon exposure to a moderate intensity of light. --- Explanation: Canine model demonstrates retina-wide microdetachments modulated by light.


MONDO:0000390

[PMID:30578502] [INDIRECT EVIDENCE] [SUPPORT] The yellowish lesions are larger and more extensive-extending beyond the arcades-than in the typical autosomal dominant Best disease. --- Explanation: Describes extent of vitelliform lesions in ARB versus BVMD.


MAXO:0000058


MAXO:0000950


MAXO:0000079


MAXO:0001001

[PMID:29507198] [SUPPORT] Subretinal BEST1 gene augmentation therapy using adeno-associated virus 2 reversed not only clinically detectable subretinal lesions but also the diffuse microdetachments. --- Explanation: Canine BEST1 gene therapy reverses both macroscopic and microscopic retinal detachments.

[PMID:29507198] [SUPPORT] Human translation of canine BEST1 gene therapy success in reversal of macro- and microdetachments through restoration of cytoarchitecture at the RPE-PR interface has promise to result in improved visual function and prevent disease progression in patients affected with bestrophinopathies. --- Explanation: Authors state translational promise of canine gene therapy results for human bestrophinopathies.


hgnc:12703

[PMID:34015078] [SUPPORT] mutations in the BEST1 protein lead to a collection of retinopathies: Best vitelliform macular dystrophy (VMD) (OMIM-153700), autosomal dominant vitreoretinochoroidopathy (ADVIRC) and microcornea, rod-cone dystrophy, cataract, and posterior staphyloma syndrome (MRCS) (OMIM-193220), retinitis pigmentosa (RP) (OMIM-613914), and autosomal recessive bestrophinopathy (ARB) (OMIM-611809). --- Explanation: Enumerates the full spectrum of BEST1-related retinopathies.

[PMID:29507198] [SUPPORT] The most common IRD due to a primary RPE defect is caused by mutations in BEST1 --- Explanation: Confirms BEST1 mutations as the most common cause of primary RPE-mediated inherited retinal dystrophy.


MONDO:0005075


MAXO:0000004


MAXO:0000014


CHEBI:75045


CHEBI:75998


CHEBI:85994


HGNC.SYMBOL:BRAF

[PMID:39502057] [SUPPORT] The common gene mutations in PTC include BRAF V600E,RET/PTC rearrangement,and RAS mutations. --- Explanation: Supports BRAF V600E as a common mutation in papillary thyroid carcinoma.


MONDO:0005075

[PMID:21221869] [SUPPORT] Papillary thyroid carcinomas are the most common thyroid cancers --- Explanation: Abstract notes papillary thyroid carcinoma as the most common thyroid cancer.


MONDO:0005575


MONDO:0005575

[PMID:30739887] [INDIRECT EVIDENCE] [PARTIAL] BRAF mutations confers a poor prognosis in Western CRC patients, particularly in metastatic CRC (mCRC) and its mutations occur in approximately 4-20% CRC, with the vast majority being the V600E hotspot mutation. --- Explanation: This abstract links BRAF mutations in CRC to the V600E hotspot and supports the relevance of V600E in colorectal cancer.


NCIT:C98283


NCIT:C1723


MAXO:0000058


CHEBI:145371


MAXO:0000647


HGNC.SYMBOL:BRAF V600E

[PMID:32674932] [PARTIAL] The BRAFV600E mutation, observed in 8 % of colorectal cancers (CRC), introduces a particular phenotype and a poor prognosis at the localized or metastatic stage. --- Explanation: Abstract reports BRAF V600E frequency and associated poor prognosis in colorectal cancer.


HGNC.SYMBOL:PIK3CA


HGNC.SYMBOL:PTEN


MONDO:0005575

[PMID:35613396] [SUPPORT] Adenocarcinoma is the most common pathologic subtype of colon cancer --- Explanation: Abstract reports adenocarcinoma as the most common pathologic subtype of colon cancer.


MONDO:0005061


MONDO:0005061

[PMID:41158045] [INDIRECT EVIDENCE] [PARTIAL] The incidence of BRAF mutations in non-small cell lung cancer (NSCLC) patients ranges from 1.5% to 5.5%, with BRAF V600 mutations accounting for approximately 30%-50% of all BRAF mutations, among which BRAF V600E represents the most prevalent mutation type. --- Explanation: Supports the presence and predominance of BRAF V600E among BRAF-mutant NSCLC.


CHEBI:75045


CHEBI:75998


HGNC.SYMBOL:BRAF

[PMID:34844291] [PARTIAL] The incidence of BRAF V600E mutation in non-small cell lung carcinoma (NSCLC) is lower than 2%, --- Explanation: Abstract reports low incidence of BRAF V600E mutations in NSCLC.


MONDO:0005061

[PMID:32657049] [SUPPORT] Of 256 patients with NSCLC, 219 were adenocarcinoma --- Explanation: Abstract reports a NSCLC cohort dominated by adenocarcinoma.


MONDO:0005012


MONDO:0005012

[PMID:40023845] [INDIRECT EVIDENCE] [PARTIAL] Hotspot BRAF, hotspot NRAS, and NF1 loss-of-function mutations are found in approximately 50%, 25%, and 15% of cutaneous melanomas, respectively. --- Explanation: This abstract reports frequent hotspot BRAF mutations in cutaneous melanoma, supporting the relevance of BRAF-driven melanoma.


MONDO:0005012

[PMID:33256089] [INDIRECT EVIDENCE] [SUPPORT] Cancer cells including melanoma cells, upregulate PD-L1 expression on the cell surface. T-lymphocytes with surface expression of PD-1, interacts with PD-L1 on the tumor, leading to T-cell exhaustion, thereby, causing dysfunction of the immune system in detecting and eliminating the tumor cells --- Explanation: Review directly describes melanoma cells upregulating PD-L1 to engage PD-1 on T lymphocytes, leading to T cell exhaustion and immune evasion — supporting the adaptive immune resistance mechanism in BRAF-mutant melanoma.


CHEBI:63637


CHEBI:90851


MAXO:0000058


NCIT:C98283


CHEBI:145371


NCIT:C106432


NCIT:C68814


CHEBI:231679


HGNC.SYMBOL:BRAF V600E


HGNC.SYMBOL:BRAF V600K


MONDO:0005012

[PMID:27268913] [SUPPORT] Malignant melanoma represents a neoplasm stemming from melanocytes --- Explanation: Abstract defines melanoma as a neoplasm stemming from melanocytes.


MONDO:0008315


CHEBI:83766


CHEBI:134689


MAXO:0000647


HGNC.SYMBOL:BRCA2

[PMID:36434163] [PARTIAL] Emerging data show that germline mutations in homologous recombination genes (BRCA1/2, ATM, CHECK2), in mismatch repair genes (MLH1, MLH2, MSH6), and other additional genes are associated with the development and aggressiveness of PCa. --- Explanation: Supports BRCA1/2 mutations contributing to prostate cancer development and aggressiveness.


HGNC.SYMBOL:BRCA1


MONDO:0008315

[PMID:36081403] [SUPPORT] The most common prostatic cancers (PCa) are acinary
adenocarcinomas. --- Explanation: Abstract notes that acinary adenocarcinomas are the most common prostatic cancers.


MONDO:0006670

[PMID:34749918] [SUPPORT] secondary headaches related to life threatening infections are most frequently associated with meningitis. --- Explanation: This reference indicates that headaches are frequently associated with meningitis, supporting the statement that headache is a very frequent symptom in bacterial meningitis.

[PMID:36720125] [SUPPORT] The most common symptoms in adults are fever, headache, positive meningeal symptoms and impaired consciousness. --- Explanation: This reference lists headache as one of the most common symptoms in adults with bacterial meningitis, supporting the statement.

[PMID:11301494] [SUPPORT] Headache as a cardinal symptom of acute meningitis reflects activation of trigeminal afferents from the meninges. --- Explanation: This reference describes headache as a cardinal symptom of acute meningitis, supporting the statement.

[PMID:37867184] [SUPPORT] Among the 277 alive patients at M12 87/274 (31.8%), 213/271 (78.6%) and 86/277 (31.0%) reported headaches before, at the onset, and at M12, respectively. --- Explanation: This reference provides statistical evidence of the prevalence of headaches in bacterial meningitis patients, supporting the statement.

[PMID:18528447] [NO_EVIDENCE] Initial symptoms can be non-specific, which can complicate and delay diagnosis, hence the extreme importance of all the information that can be obtained through anamnesis and physical exploration, with frequent complementary explorations. --- Explanation: Although this reference emphasizes the non-specific nature of initial symptoms, it underscores the importance of headache as a diagnostic clue, indirectly supporting the statement.


MONDO:0006670

[PMID:36720125] [SUPPORT] Fever is the most commonly reported symptom in paediatric patients, occurring in up to 93% of cases. Further, it is possible to observe headache, vomiting and positive meningeal phenomena. The most common symptoms in adults are fever, headache, positive meningeal symptoms and impaired consciousness. --- Explanation: The statement is supported as fever is reported as a very frequent symptom in both pediatric and adult patients with bacterial meningitis.

[PMID:6473134] [PARTIAL] The rates of prolonged fever for 10 days or more, persistent fever for 5 to 9 days and secondary fever were 13, 13 and 16%, respectively. --- Explanation: This reference supports the statement by indicating that fever is a common symptom during the treatment of bacterial meningitis, with various durations and patterns observed.

[PMID:35436245] [PARTIAL] A 33-day-old previously healthy term female is admitted to the pediatric intensive care unit with fever, lethargy and bulging fontanel. --- Explanation: The case study of a 33-day-old infant with bacterial meningitis presenting with fever supports the statement that fever is a very frequent symptom.

[PMID:37466696] [PARTIAL] Meningococcal sepsis is a severe clinical feature comprising high fever, chills and disorders of consciousness. --- Explanation: This reference supports the statement by indicating that high fever is a common symptom in severe cases of meningococcal sepsis, a form of bacterial meningitis.


MONDO:0006670

[PMID:20109674] [SUPPORT] Clinical signs suggestive of bacterial meningitis include fever, headache, meningismus, vomiting, photophobia, and an altered level of consciousness. --- Explanation: Lists photophobia among typical presenting signs of bacterial meningitis, supporting its frequency.


MONDO:0006670

[PMID:33330135] [SUPPORT] More recent data from a meta analysis of corticosteroid use for the treatment of bacterial meningitis found no significant reductions in mortality across 25 studies in H. influenzae meningitis cases treated with adjunctive steroid therapy, but similarly did observe a significant reduction in the rate of hearing loss overall in children with H. influenzae meningitis from 12% to 4% after adjunctive corticosteroid therapy. --- Explanation: Notes hearing loss as a measured sequela in H. influenzae meningitis and shows adjunctive steroids reduce its incidence, supporting inclusion of hearing loss.


MONDO:0006670

[PMID:27055168] [SUPPORT] Complications such as acute hydrocephalus, brain abscess, and spine abscess can develop. --- Explanation: Identifies acute hydrocephalus as a complication of bacterial meningitis, supporting its inclusion.


MONDO:0006670

[PMID:29889417] [PARTIAL] Seizures should be avoided, the sedation-pain control optimized and ventilation adapted to assure normal oxygenation and normal CO₂ levels. --- Explanation: Identifies seizures as a complication to monitor and prevent during acute bacterial meningitis management, supporting their clinical relevance.

[PMID:31378869] [PARTIAL] Brain abscess may initially present only with headache, or as a new-onset seizure or with a focal neurological deficit. --- Explanation: Notes that bacterial CNS infections can present with new-onset seizures, reinforcing seizures as a frequent neurological manifestation.


MONDO:0006670

[PMID:36472590] [SUPPORT] Up to 24% of those who survive develop chronic neurological sequelae, such as hearing loss or focal neurological deficits. --- Explanation: Reports focal neurological deficits as a common chronic sequela in bacterial meningitis survivors.

[PMID:36472590] [SUPPORT] Brain imaging should be performed before lumbar puncture if patients present with altered mental status, focal neurological deficits, papilledema, or history of immunocompromising conditions or central nervous system disease. --- Explanation: Highlights focal neurological deficits as a key presenting sign that guides urgent imaging in suspected bacterial meningitis.


MONDO:0006670

[PMID:26804733] [INDIRECT EVIDENCE] [SUPPORT] Streptococcus pneumoniae (the pneumococcus) is the major cause of bacterial meningitis. The mechanisms by which pneumococci from the bloodstream penetrate the blood-brain barrier to reach the brain are not fully understood. --- Explanation: The reference discusses how Streptococcus pneumoniae can penetrate the blood-brain barrier from the bloodstream, which supports the statement about bacterial meningitis involving bacteria entering the bloodstream and crossing the blood-brain barrier.

[PMID:31805229] [INDIRECT EVIDENCE] [SUPPORT] Microbial penetration of the blood-brain barrier, a prerequisite for the development of bacterial meningitis, exploits specific host and bacterial factors as well as host cell signaling molecules. --- Explanation: This reference explicitly states that microbial penetration of the blood-brain barrier is necessary for the development of bacterial meningitis, supporting the statement.

[PMID:27367319] [INDIRECT EVIDENCE] [SUPPORT] If the infection is not controlled at the stage in which the bacterium is in the liver, for instance, due to a severe immunodepression, a secondary bacteraemia can be developed and L. monocytogenes reaches the preferred sites transgressing the blood-brain barrier or the placental barrier. --- Explanation: The reference mentions that Listeria monocytogenes can cross the blood-brain barrier after entering the bloodstream, which supports the statement about the process of bacterial invasion in meningitis.

[PMID:11008113] [INDIRECT EVIDENCE] [SUPPORT] Transcellular penetration, e.g., transcytosis across the BBB has been demonstrated for Escherichia coli K1, group B streptococcus, Listeria monocytogenes, Citrobacter freundii and Streptococcus pneumonia strains. --- Explanation: Highlights BBB transcytosis by common neonatal and adult meningitis pathogens, reinforcing the invasion step across brain microvascular endothelium.


MONDO:0006670


MONDO:0006670

[PMID:39116800] [INDIRECT EVIDENCE] [SUPPORT] Many in-vitro and in-vivo analyses have shown that after the disruption of the blood-brain barrier (BBB), these pathogens trigger several inflammatory pathways including Toll-Like Receptor (TLR) signaling in response to Pathogen-Associated Molecular Patterns (PAMPs), Nucleotide oligomerization domain (NOD)-like receptor-mediated signaling, pneumolysin related signaling, NF-kappaB signaling and many other pathways that lead to pro-inflammatory cascade and subsequent cytokine release including interleukine (IL)-1beta, tumor necrosis factor(TNF)-alpha, IL-6, IL-8, chemokine (C-X-C motif) ligand 1 (CXCL1) along with other mediators, leading to neuroinflammation. --- Explanation: The reference describes how bacterial meningitis triggers several inflammatory pathways leading to the release of cytokines and chemokines, supporting the statement that bacterial components trigger a strong inflammatory response in the subarachnoid space.

[PMID:37544134] [INDIRECT EVIDENCE] [SUPPORT] The inflammatory response in the subarachnoid space, modulated by different cytokines, plays a major role in the pathogenesis of acute central nervous system infections. --- Explanation: The reference explicitly states that cytokines modulate the inflammatory response in the subarachnoid space during bacterial meningitis, supporting the statement.

[PMID:24412248] [INDIRECT EVIDENCE] [SUPPORT] Complement factors C1q and MBL as well as common complement pathway factors C3a, iC3b, C5a, sC5b-9 and complement regulator CFH were all elevated in patients with bacterial meningitis as compared to the controls. --- Explanation: The reference mentions the elevation of complement factors, which are part of the immune response, supporting the idea that bacterial components trigger a strong inflammatory response in the subarachnoid space.


MONDO:0006670

[PMID:2498090] [INDIRECT EVIDENCE] [SUPPORT] Their presence in the cerebrospinal fluid is associated with the induction of inflammation and with the development of brain edema and increased intracranial pressure. --- Explanation: The literature supports that inflammation in bacterial meningitis is associated with increased intracranial pressure.

[PMID:24413408] [INDIRECT EVIDENCE] [SUPPORT] Fulminant bacterial meningitis is a rare host reaction to infection characterized by sudden onset, rapid deterioration, abrupt cerebral edema and refractory intracranial hypertension. --- Explanation: This supports the statement that bacterial meningitis can lead to increased intracranial pressure due to inflammation.

[PMID:31378869] [INDIRECT EVIDENCE] [NO_EVIDENCE] Acute bacterial meningitis may present with symptoms as nonspecific as headache and fever, but rapid progression to an altered level of consciousness is not unusual. --- Explanation: The literature mentions altered mental status as a downstream effect of bacterial meningitis, supporting the statement.

[PMID:8859061] [INDIRECT EVIDENCE] [NO_EVIDENCE] The clinical course of bacterial meningitis still is characterized by a high mortality and frequent neurological deficits in survivors. --- Explanation: The literature supports that bacterial meningitis can lead to neurological deficits, aligning with the downstream effects mentioned in the statement.


MONDO:0006670

[PMID:39116800] [INDIRECT EVIDENCE] [SUPPORT] Many in-vitro and in-vivo analyses have shown that after the disruption of the blood-brain barrier (BBB), these pathogens trigger several inflammatory pathways including Toll-Like Receptor (TLR) signaling in response to Pathogen-Associated Molecular Patterns (PAMPs). --- Explanation: Describes BBB-breaching bacteria activating TLR signaling during meningitis, matching the TLR-driven innate activation described in this node.

[PMID:16785556] [INDIRECT EVIDENCE] [SUPPORT] We show that both heat-inactivated whole GBS and a secreted proteinaceous factor from GBS (GBS-F) induce neuronal apoptosis via the activation of murine microglia through a TLR2-dependent and MyD88-dependent pathway in vitro. --- Explanation: Shows meningitis-causing GBS activating microglial TLR2/MyD88 signaling and causing neuronal injury, directly supporting TLR-driven innate activation in the CNS.


MONDO:0006670

[PMID:39116800] [INDIRECT EVIDENCE] [SUPPORT] The activation of another protein complex, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, also takes place resulting in the maturation and release of IL-1β and IL-18, hence potentiating neuroinflammation. --- Explanation: States that NLRP3 inflammasome activation in bacterial meningitis drives IL-1β/IL-18 maturation, consistent with inflammasome-driven pyroptotic inflammation.

[PMID:37603152] [INDIRECT EVIDENCE] [SUPPORT] The animals in the meningitis group at 24 h showed increased levels of cytokines, NLRP3, and IBA-1 expression, and the use of the MCC950 significantly reduced those levels. --- Explanation: Experimental pneumococcal meningitis shows NLRP3 upregulation that is blunted by an NLRP3 inhibitor, supporting inflammasome-driven pathology.

[PMID:37001294] [INDIRECT EVIDENCE] [SUPPORT] We found that the formation of the NEK7-NLRP3 complex significantly increased during S. pneumoniae infection and that anaplastic lymphoma kinase (ALK) and Jun N-terminal kinase (JNK) were phosphorylated rapidly. --- Explanation: Shows pneumococcal infection driving NEK7-NLRP3 inflammasome assembly through ALK/JNK signaling, supporting inflammasome activation in meningitis.


MONDO:0006670

[PMID:31805229] [INDIRECT EVIDENCE] [SUPPORT] Microbial penetration of the blood-brain barrier, a prerequisite for the development of bacterial meningitis, exploits specific host and bacterial factors as well as host cell signaling molecules. --- Explanation: Establishes BBB penetration as an early pathogenic step requiring host signaling changes that enable barrier breach, supporting BBB disruption in meningitis pathophysiology.

[PMID:36769171] [INDIRECT EVIDENCE] [SUPPORT] A defining feature of the pathogenesis of bacterial meningitis is the increase in BBB permeability. --- Explanation: States BBB permeability rise as central to meningitis pathogenesis, supporting the barrier-disruption node.


MAXO:0000058

[PMID:3287565] [PARTIAL] The available evidence suggests that if bacterial meningitis is suspected and LP must be delayed, intravenous antibiotics are warranted before CSF is obtained. --- Explanation: This suggests that in cases where lumbar puncture (LP) must be delayed, antibiotics should be administered before LP, but it does not explicitly state that antibiotics should be started immediately after LP.

[PMID:30496558] [PARTIAL] The use of empiric vancomycin plus a third-generation cephalosporin for suspected bacterial meningitis has been recommended since 1997. --- Explanation: This reference supports the use of broad-spectrum antibiotics like vancomycin and ceftriaxone for empiric therapy but does not specify the timing related to lumbar puncture.

[PMID:20109674] [NO_EVIDENCE] Empiric antimicrobial and adjunctive therapy should be initiated as soon as a single set of blood cultures has been obtained. --- Explanation: This reference emphasizes the initiation of empiric therapy after obtaining blood cultures, not specifically after lumbar puncture.

[PMID:25822235] [PARTIAL] Empiric therapy was ampicillin and gentamicin (n = 116, 44%) or third-generation cephalosporin based (n = 149, 56%). --- Explanation: This reference supports the use of empiric antibiotics but does not specify the timing relative to lumbar puncture.


MAXO:0000058

[PMID:24073921] [PARTIAL] Outcome critically depends on the rapid initiation of effective antibiotic therapy. --- Explanation: The reference emphasizes the importance of initiating effective antibiotic therapy, which aligns with the concept of tailoring antibiotics to the specific pathogen once identified.

[PMID:30468130] [SUPPORT] Results of this study provide valuable information about the antibiotic resistance profiles of the etiologic agents of childhood meningitis, which can be used for prescription of more effective empirical therapies. --- Explanation: The study discusses the importance of understanding antibiotic resistance profiles to prescribe more effective therapies, supporting the concept of targeted antibiotic therapy.

[PMID:15301673] [PARTIAL] Ceftriaxone plus penicillin as empirical treatment was appropriate in 97% of ABM cases in the study population. --- Explanation: This reference supports the use of specific antibiotics tailored to the pathogen identified, which is a form of targeted antibiotic therapy.


MAXO:0000058

[PMID:10830026] [PARTIAL] Dexamethasone has been used in a number of clinical trials to moderate the host response and to improve neurologic outcome of meningitis. Results of six randomized, placebo controlled trials are summarized in this review. Dexamethasone treatment did not lower mortality. Only a moderate, but not a significant reduction in the neurologic and audiologic sequelae was seen in dexamethasone recipients when Haemophilus influenzae type b (Hib) was the causative agent of meningitis. ... Presently, there is little or no evidence showing a benefit of dexamethasone therapy in meningitis caused by S. pneumoniae or N. meningitidis. --- Explanation: The statement is partially supported because dexamethasone is used to reduce inflammation in bacterial meningitis, but there is limited evidence of its benefit in reducing complications, particularly for pneumococcal meningitis.

[PMID:31668194] [SUPPORT] Steroids are mandatory in pneumococcal meningitis but not indicated in pneumococcal pneumonia except in the setting of refractory shock. --- Explanation: This reference supports the use of corticosteroids, specifically dexamethasone, in reducing inflammation and complications in pneumococcal meningitis.

[PMID:33330135] [SUPPORT] Steroid therapy is beneficial and supported in pathogens such as pneumococcal meningitis and tuberculosis. --- Explanation: This reference supports the use of corticosteroids in pneumococcal meningitis to reduce inflammation and complications.


MAXO:0000950

[PMID:8196986] [SUPPORT] Fluid administration in children with meningitis should be conservative in an attempt to minimize cerebral edema and electrolyte disturbances that frequently complicate the course of meningitis. --- Explanation: This reference supports the aspect of fluid and electrolyte management as part of supportive care in bacterial meningitis.

[PMID:16034949] [SUPPORT] Careful management of fluid and electrolyte balance is an important supportive therapy. Both over and under hydration are associated with adverse outcomes. --- Explanation: This reference supports the importance of fluid and electrolyte management in the supportive care of bacterial meningitis.

[PMID:29889417] [SUPPORT] Control of intracranial pressure (ICP) as well as a good hemodynamic is based on a continuous monitoring of ICP and arterial pressure in order to assure an adapted cerebral perfusion pressure. --- Explanation: This reference supports the monitoring of intracranial pressure as part of the supportive care in bacterial meningitis.

[PMID:29088943] [PARTIAL] Although intracranial hypertension and subsequent death have long been known to complicate meningitis, no specific guidelines targeting ICP monitoring are available. --- Explanation: This reference acknowledges the role of intracranial pressure monitoring in the context of bacterial meningitis, thus supporting its inclusion in supportive care.

[PMID:29889417] [SUPPORT] Seizures should be avoided, the sedation-pain control optimized and ventilation adapted to assure normal oxygenation and normal CO₂ levels. --- Explanation: This reference supports the aspect of seizure control as part of supportive care in bacterial meningitis.


MAXO:0001017

[PMID:15802609] [SUPPORT] Effective routine immunization against Hib, pneumococcus and serogroupC meningococcus has had a significant impact on both invasive disease and carriage caused by these encapsulated bacteria. --- Explanation: This reference confirms that vaccines are available for the prevention of meningococcal, pneumococcal, and Hib meningitis.

[PMID:26904695] [SUPPORT] The Hib conjugate vaccine is considered protective and safe. --- Explanation: This reference supports the availability and effectiveness of the Hib vaccine.

[PMID:10470562] [SUPPORT] A comprehensive review of all major agents causing bacterial meningitis--meningococcus of the groups A, B, C, W135, and Y, pneumococcus, and Haemophilus influenzae type B (Hib)--is done in terms of preventing them by chemoprophylaxis or vaccination. --- Explanation: This reference supports the availability of vaccines for meningococcal, pneumococcal, and Hib meningitis.

[PMID:20407316] [SUPPORT] The leading causes of bacterial meningitis and pneumonia in children, Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae, are vaccine preventable. --- Explanation: This reference supports the availability of vaccines for Hib and pneumococcal meningitis.

[PMID:22906940] [SUPPORT] The meningococcal conjugate vaccines (MCV) are preferred for reasons of immunogenicity and persistence of immunity. --- Explanation: This reference supports the availability of vaccines for meningococcal meningitis.


NCBITaxon:487

[PMID:17696042] [SUPPORT] Neisseria meningitidis is the most common cause of meningitis in children aged 2-18 with a mortality rate ranging from 4-40% and substantial morbidity in 11-19% of survivors. --- Explanation: The literature states that Neisseria meningitidis is the most common

[PMID:38524112] [SUPPORT] This meningococcal meningitis cluster caused by Neisseria meningitidis serogroup C occurred among non-vaccinated persons mostly aged <18 years in Palorinya Refugee Settlement. --- Explanation: The literature mentions a cluster of meningitis cases caused by Neisseria meningitidis in a population mostly under 18 years old, supporting the statement that it is a common cause of bacterial meningitis in children and young adults.


NCBITaxon:1313

[PMID:9519033] [SUPPORT] S pneumoniae is now the most common cause in children and adults overall. --- Explanation: The reference clearly states that Streptococcus pneumoniae is the most common cause of bacterial meningitis in adults.

[PMID:30873934] [SUPPORT] Streptococcus pneumoniae (the pneumoccus) is the leading cause of otitis media, community-acquired pneumonia, and bacterial meningitis. --- Explanation: The reference confirms that Streptococcus pneumoniae is the leading cause of bacterial meningitis.

[PMID:24568594] [SUPPORT] The most common causative organisms were Neisseria meningitidis (41%) and Streptococcus pneumoniae (30%). --- Explanation: The reference indicates that Streptococcus pneumoniae is one of the most common causes of bacterial meningitis in adults, supporting the statement.


NCBITaxon:727

[PMID:11032188] [SUPPORT] Hib was the most common cause of bacterial meningitis and other invasive bacterial diseases in this age group. --- Explanation: The reference indicates that Haemophilus influenzae type b (Hib) was the most common cause of bacterial meningitis in children before the Hib vaccine was introduced.

[PMID:15907145] [SUPPORT] Recently, Haemophilus influenzae type b (Hib), once a common cause of meningitis, has virtually disappeared in developed nations, reflecting the overwhelming success of Hib vaccination. --- Explanation: This reference supports the statement by noting that Hib was once a common cause of meningitis before the introduction of the Hib vaccine.

[PMID:31981610] [SUPPORT] H. influenzae type b is the leading cause of bacterial meningitis in children before introduction of vaccination. --- Explanation: This reference clearly states that Haemophilus influenzae type b was the leading cause of bacterial meningitis in children before the vaccine was introduced.


NCBITaxon:1639

[PMID:13904618] [SUPPORT] Listeria monocytogenes meningitis in neonates. --- Explanation: This reference specifically mentions Listeria monocytogenes causing meningitis in neonates.

[PMID:33583696] [SUPPORT] Listeria monocytogenes is a foodborne pathogen responsible for listeriosis, an infection that can manifest in humans as bacteremia, meningoencephalitis in immunocompromised patients and the elderly, and fetal-placental infection in pregnant women. --- Explanation: This reference supports the statement by indicating that Listeria monocytogenes can cause meningoencephalitis in immunocompromised patients and fetal-placental infection in pregnant women.

[PMID:28536811] [SUPPORT] Listeria has a predilection to affect immunocompromised patients, elderly people, pregnant women and neonates. --- Explanation: This reference supports the statement by indicating that Listeria monocytogenes affects immunocompromised patients, pregnant women, and neonates.

[PMID:27055168] [SUPPORT] Listeria monocytogenes may cause meningitis, meningoencephalitis, brain abscess, pyogenic arthritis, osteomyelitis, and liver abscess in children. --- Explanation: This reference supports the statement by indicating that Listeria monocytogenes can cause meningitis in children, which includes newborns.

[PMID:6349348] [SUPPORT] Predominant pathogens are Escherichia coli, group B streptococci, Listeria monocytogenes, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae. --- Explanation: This reference supports the statement by listing Listeria monocytogenes as a predominant pathogen in bacterial meningitis.

[PMID:10470563] [NO_EVIDENCE] Bacterial pathogens primarily are associated with the maternal genitourinary tract. --- Explanation: This reference supports the statement by associating bacterial meningitis in neonates with maternal genitourinary tract pathogens, which includes Listeria monocytogenes.


MONDO:0015229

[PMID:15690372] [SUPPORT] Bardet-Biedl syndrome is a genetically heterogeneous multisystem disorder that causes severe visual impairment. Retinitis pigmentosa (RP), hypogonadism, digit and renal anomalies, obesity, and a variable degree of mental retardation characterize the disorder. --- Explanation: The literature confirms that RP is a high-frequency ophthalmologic phenotype in Bardet-Biedl syndrome.

[PMID:36481880] [PARTIAL] Retinitis pigmentosa (RP) is a set of symptoms including tunnel vision, night blindness, and progressive vision loss...as part of a larger syndrome (syndromic)... --- Explanation: The study acknowledges that RP includes night blindness and progressive vision loss, supporting the sequelae mentioned in the statement.

[PMID:35791150] [SUPPORT] Patients with RP in LMBB syndrome present mainly in the first to second decade of life with severe visual acuity impairment to blindness early in life. --- Explanation: RP is reported as a predominant feature in patients with Bardet-Biedl syndrome, confirming the high frequency of this phenotype.

[PMID:31864384] [PARTIAL] Inherited retinal dystrophies are major cause of severe progressive vision loss in children. --- Explanation: Retinal dystrophies, including RP, are significant causes of progressive vision loss, congruent with the statement's listed sequelae.


MONDO:0015229

[PMID:20876674] [PARTIAL] Renal abnormalities, including impairment of renal function and signs of chronic interstitial nephropathy of dysplastic nature, were documented in 82% of the patients. --- Explanation: The statement is partially supported because renal abnormalities are common in Bardet-Biedl Syndrome, but the frequency and diagnosis related to polydactyly is not addressed.

[PMID:6487184] [PARTIAL] The Bardet-Biedl syndrome is characterized by five main features: obesity, polydactyly, pigmentary retinopathy, mental deficiency and hypogonadism; recently a sixth feature, renal disease, has been described. --- Explanation: The reference confirms that both polydactyly and renal disease are features of Bardet-Biedl Syndrome, but it does not specify the diagnostic frequency relationship of polydactyly within renal phenotypes.


MONDO:0015229

[PMID:32700463] [PARTIAL] Despite normal birth weight, most individuals with BBS experience rapid weight gain in early childhood, with high rates of overweight/obesity sustained through adolescence. --- Explanation: The literature mentions high rates of obesity in individuals with Bardet-Biedl Syndrome but does not specifically categorize it as truncal obesity.

[PMID:6487184] [PARTIAL] All had subnormal intelligence, twelve were obese, ten had polydactyly, eight hypogonadism, and two had renal disease. --- Explanation: While obesity is mentioned as a prevalent phenotype, there is no specific mention of truncal obesity.

[PMID:29127258] [PARTIAL] CONCLUSION: CEP19 encodes a centrosomal and ciliary protein, as all BBS genes do. Another truncating mutation p.Arg82* has been reported as responsible for morbid obesity in a family; however, in the family we present, not all homozygotes are obese, although some are severely obese. --- Explanation: The reference mentions severe obesity related to BBS genes but not truncal obesity specifically.

[PMID:12365916] [PARTIAL] RESULTS: All patients had an increased body mass index. The obesity varied between families from moderate to severe. --- Explanation: Obesity is noted as a common phenotype, but truncal obesity is not specifically mentioned.


MONDO:0015229


MONDO:0015229

[PMID:36374067] [PARTIAL] Bardet Biedl syndrome... is a pleiotropic disorder characterised by retinal dystrophy, renal dysfunction, polydactyly, obesity, cognitive deficit and hypogenitalism. --- Explanation: The reference mentions cognitive deficits as a characteristic of Bardet-Biedl Syndrome, which can include intellectual disability. However, it does not explicitly state the frequency of intellectual disability, thus it partially supports the statement.

[PMID:19778711] [PARTIAL] Joubert syndrome (JS) is a primarily autosomal recessive condition characterized by... intellectual disability... Variable features include... polydactyly... disorders called ciliopathies. --- Explanation: This reference is about Joubert syndrome, which is another ciliopathy like Bardet-Biedl Syndrome. It mentions intellectual disability related to ciliopathies in general but does not directly correlate it with Bardet-Biedl Syndrome's frequency.


MONDO:0015229

[PMID:33040131] [PARTIAL] Clinical presentation of this rare condition may affect locomotive, neurological, cardio-vascular, endocrine and metabolic systems. --- Explanation: The abstract mentions that Bardet-Biedl syndrome can affect the neurological system, which can include developmental delay.

[PMID:24194441] [SUPPORT] On the age appropriate Wechsler scale, the mean Verbal Comprehension was 81 (n = 36), Working Memory was 81 (n = 36), Perceptual Reasoning was 78 (n = 24) and Full Scale IQ was 75 (n = 26). --- Explanation: The abstract provides evidence of reduced cognitive functions in patients with Bardet-Biedl syndrome, indicating developmental delays.


MONDO:0015229

[PMID:7726222] [PARTIAL] The major manifestations of the Bardet-Biedl syndrome are digital anomalies, tapetoretinal degeneration, obesity, renal abnormalities, and hypogenitalism (described mainly in males). --- Explanation: The literature mentions hypogenitalism mainly in males but does not provide evidence for its frequency or occurrence in females.

[PMID:19327768] [PARTIAL] To report a patient with Bardet-Biedl syndrome (BBS) with known hypogonadotrophic hypogonadism who developed spontaneous reversal of hypogonadism in adulthood. --- Explanation: This study reports hypogonadism in a male patient but does not discuss its frequency or occurrence in females.

[PMID:31696011] [PARTIAL] The major features of this syndrome are cone-rod dystrophy, polydactyly, obesity, learning disabilities, hypogonadism in males, renal anomalies, nystagmus, speech disorders, developmental delay, polyuria/polydipsia, ataxia, and poor coordination/clumsiness. --- Explanation: The literature mentions hypogonadism in males but does not provide information about its occurrence in females or its frequency.

[PMID:32835378] [PARTIAL] BBS patients frequently presented with genitourinary malformations, such as cryptorchidism (5/11), short scrotum (5/8), and micropenis (5/8), but unexpectedly, with normal testis size (7/8). --- Explanation: The literature discusses genitourinary malformations and hypogonadism in male patients but does not mention its frequency or occurrence in females.


MONDO:0015229

[PMID:26231314] [INDIRECT EVIDENCE] [SUPPORT] From the analysis of the mutational burden in patients to the functional characterization of the BBS proteins, this syndrome has become a model for both understanding oligogenic patterns of inheritance and the biology of a particular cellular organelle: the primary cilium. --- Explanation: This excerpt supports the assertion that BBS mechanisms are related to defects in primary cilia function caused by mutations in BBS genes, leading to a wide range of symptoms.

[PMID:29534263] [INDIRECT EVIDENCE] [PARTIAL] The photoreceptor connecting cilium plays a leading role in these ciliopathy-related retinal dystrophies. Dysfunctional photoreceptor cilia cause the most severe type of retinal dystrophy: Leber's congenital amaurosis (LCA). The most common syndromic ciliopathies with an ocular manifestation are Bardet-Biedl syndrome (BBS) and Usher syndrome. --- Explanation: This reference emphasizes the role of primary cilia dysfunction in BBS and its association with retinal dystrophies, supporting the statement.

[PMID:33560420] [INDIRECT EVIDENCE] [SUPPORT] One ciliopathy, Bardet-Biedl syndrome (BBS; OMIM 209900), presents with diverse clinical features, many of which are attributed to defects in ciliary signaling during both embryonic development and postnatal life --- Explanation: This supports the statement by explaining that BBS symptoms are attributed to ciliary defects.


MAXO:0000011

[PMID:15852167] [NO_EVIDENCE] Based on the history, presentation, ophthalmic clinical examination, obesity, mental retardation and dental alterations, the patient was diagnosed with Bardet-Biedl syndrome. --- Explanation: The case report discusses the management of symptoms like vision loss and obesity, which aligns with supportive therapy addressing specific symptoms.

[PMID:29754569] [PARTIAL] Advances in the understanding of ciliary biology and diagnostic techniques have opened up the prospect of treating BBS in a patient-specific manner. --- Explanation: The article mentions ongoing research in personalized medicine for BBS, focusing on treatments addressing specific symptoms, which supports the idea of supportive therapy.

[PMID:36647077] [PARTIAL] This study highlights the need to address the impaired health-related quality of life in Bardet-Biedl syndrome, and supports utility of setmelanotide for reducing this burden. --- Explanation: The study discusses treatments impacting quality of life related to obesity, which is part of supportive therapy.

[PMID:36700052] [NO_EVIDENCE] We show that subretinal gene therapy slowed photoreceptor cell death and preserved retinal function in treated eyes. Notably, cone photoreceptors regained their electrical function after gene augmentation. --- Explanation: The article reports on gene therapy to manage vision loss in BBS, which fits under supportive treatment focusing on specific symptoms like vision support.

[PMID:27245600] [PARTIAL] Renal transplantation is indicated in cases of end-stage renal disease (ESRD), but transplant centers may be hesitant to perform the necessary transplant in light of the multitude of metabolic comorbidities these patients often face with the potential to complicate outcomes. --- Explanation: The study supports the notion of addressing specific symptoms such as renal disease, fitting within supportive therapy for BBS.


MAXO:0000079

[PMID:20301537] [SUPPORT] Provide an evaluation strategy to identify the genetic cause of Bardet-Biedl syndrome in a proband (when possible); 4. --- Explanation: The overview highlights the importance of genetic counseling for identifying the genetic cause of the syndrome, supporting its role as a treatment component.


MAXO:0000004


MAXO:0000088

[PMID:38302651] [PARTIAL] We review current approaches to the metabolic management of patients with BBS, including the use of weight loss medications and bariatric surgery. --- Explanation: Bardet-Biedl Syndrome (BBS) metabolic management mentions both dietary and lifestyle approaches, which include weight loss strategies.

[PMID:27356116] [PARTIAL] Comprehensive lifestyle interventions, including nutrition, physical activity, and behavioral therapy, are the foundation for clinical obesity management. --- Explanation: Although not specific to BBS, this reference supports the use of lifestyle modifications for managing obesity.

[PMID:36647077] [PARTIAL] Bardet-Biedl syndrome is a rare genetic disease associated with hyperphagia and early-onset, severe obesity...patients reported clinically meaningful improvements across multiple health-related quality of life measures. --- Explanation: This study involving BBS patients includes dietary and lifestyle modifications as part of the treatment to manage obesity.

[PMID:37919024] [SUPPORT] Similar to the general population, lifestyle interventions focused on nutrition and physical activity form the foundation for treating obesity caused by rare genetic disorders. --- Explanation: Supports lifestyle interventions as foundational treatments for obesity in syndromic conditions like BBS.


MAXO:0001001

[PMID:36700052] [SUPPORT] We show that subretinal gene therapy slowed photoreceptor cell death and preserved retinal function in treated eyes. Notably, cone photoreceptors regained their electrical function after gene augmentation. --- Explanation: The article reports on gene therapy to manage vision loss in BBS, showing promising results in preserving retinal function.


MAXO:0000058


NCIT:C152349


HGNC.SYMBOL:BBS1

[PMID:27625843] [PARTIAL] There are 17 BBS genes (BBS1-BBS17) described to date, which explain 70-80% of the patients clinically diagnosed, therefore more BBS genes remain to be identified. --- Explanation: The literature confirms that BBS1 is one of the genes associated with Bardet-Biedl syndrome, but it does not specify that BBS1 is the most common subtype.

[PMID:22940089] [SUPPORT] PURPOSE: To characterize the phenotype of Bardet-Biedl syndrome (BBS) patients homozygous for the BBS1 M390R mutation... Our findings confirm the consistent pathogenicity of the BBS1 M390R mutation. --- Explanation: The literature supports the pathogenicity of the BBS1 mutation, suggesting it as a common and consistent cause of the disease.

[PMID:36833331] [PARTIAL] Whole-exome sequencing revealed 9 pathogenic variants in six genes associated with BBS in 12 families... Three known variants were detected in the BBS1, BBS2, and BBS7 genes. --- Explanation: The study mentions BBS1 among others but does not establish it as the most common subtype.

[PMID:32361989] [PARTIAL] In eight families (12 individuals) we identified the same ARL6/BBS3 variation... Knowledge of this founder effect modifies our diagnostic strategy. --- Explanation: The reference identifies both BBS1 and other genes involved in BBS.

[PMID:12118255] [SUPPORT] Here we report the identification of the gene BBS1 and show that a missense mutation of this gene is a frequent cause of BBS. --- Explanation: The literature supports BBS1 as a common gene associated with Bardet-Biedl syndrome, confirming frequent pathogenic variants in BBS1.


HGNC.SYMBOL:BBS2

[PMID:38407766] [PARTIAL] Our results identified the founder variant c.471G > A in the BBS2 gene in the Baloch ethnicity of the Iranian population. This finding can guide the diagnostic approach of this syndrome in future studies. --- Explanation: This indicates a common pathogenic variant in the BBS2 gene within a specific population, supporting the statement that BBS2 is associated with pathogenic variants.

[PMID:12677556] [PARTIAL] Bardet-Biedl syndrome is a genetically and clinically heterogeneous disorder caused by mutations in at least seven loci (BBS1-7), five of which are cloned (BBS1, BBS2, BBS4, BBS6, and BBS7). --- Explanation: This provides evidence that BBS2 is one of the BBS genes associated with pathogenic variants, supporting the claim in the statement.


HGNC.SYMBOL:Other BBS Genes

[PMID:37239474] [SUPPORT] Bardet-Biedl syndrome (BBS) is a rare clinically and genetically heterogeneous autosomal recessive multi-systemic disorder with 22 known genes. --- Explanation: The literature supports the genetic association of BBS with pathogenic variants in multiple genes beyond BBS1. The abstract mentions 22 known genes related to BBS.

[PMID:27984625] [SUPPORT] So far 21 candidate genes have been discovered, and mutations of such genes can all cause the BBS phenotype. --- Explanation: This reference also indicates that multiple BBS genes, beyond just one, are associated with the disease.

[PMID:37612261] [SUPPORT] This study reports variants in BBS1 and BBS7 in patients with Bardet-Biedl syndrome from the Canadian Maritime provinces. --- Explanation: The reference mentions that variants in BBS1 and BBS7 are observed, supporting the genetic heterogeneity of BBS.

[PMID:29653013] [SUPPORT] To date, more than 21 BBS genes (BBS1 - 21) have been reported to independently cause the disorder. --- Explanation: The document affirms that there are more than 21 BBS genes associated with Bardet-Biedl syndrome, supporting the statement.

[PMID:33777945] [SUPPORT] A total of five known and twelve novel variants in four BBS genes (BBS2, 58.33%; BBS4, 8.33%; BBS7, 16.67%; and BBS9, 16.67%) were identified. --- Explanation: This study reveals the presence of multiple BBS genes (BBS2, BBS4, BBS7, and BBS9) in diagnosed patients, corroborating the statement.


MONDO:0015229

[PMID:36374067] [SUPPORT] Bardet Biedl syndrome is an autosomal recessive ciliopathie. --- Explanation: States autosomal recessive inheritance.

[PMID:19701229] [SUPPORT] Bardet-Biedl syndrome is a clinically variable condition associated with learning disabilities, progressive visual loss, obesity, polydactyly, hypogonadism, and cystic and fibrotic renal changes that can lead to renal failure. --- Explanation: Supports variable expressivity.

[PMID:12524598] [SUPPORT] Finally, we demonstrate that BBS1 is inherited in an autosomal recessive manner and is rarely, if ever, involved in complex inheritance. --- Explanation: Confirms autosomal recessive inheritance for BBS1 and notes complex inheritance is rare.


MONDO:0005341


MONDO:0005341

[PMID:19082818] [INDIRECT EVIDENCE] [PARTIAL] Aberrant activation of sonic hedgehog signaling has been reported for sporadic and hereditary basal cell carcinoma caused by specific genetic mutations. --- Explanation: Supports aberrant Hedgehog signaling as a driver in basal cell carcinoma.


CHEBI:66903


CHEBI:90863


MAXO:0000014


HGNC.SYMBOL:PTCH1


HGNC.SYMBOL:SMO


HGNC.SYMBOL:TP53


MONDO:0005341

[PMID:36921301] [SUPPORT] Basal cell carcinomas are one of the most common cutaneous carcinomas and show --- Explanation: Abstract notes basal cell carcinomas are among the most common cutaneous carcinomas.


MONDO:0007191

[PMID:37435539] [SUPPORT] Major clinical manifestations of BD are oral aphthae, genital aphthous ulcers, skin lesions, arthritis, and uveitis. --- Explanation: Oral aphthae are listed as a major clinical manifestation of Behcet's disease, confirming their central role in diagnosis.


MONDO:0007191


MONDO:0007191

[PMID:38778397] [SUPPORT] Behcet's uveitis (BU) is a common manifestation of BD, occurring in over two-thirds of the patients. BU is characterized by bilateral, chronic, recurrent, non-granulomatous uveitis in association with complications such as retinal ischemia and atrophy, optic atrophy, macular ischemia, macular edema, and further neovascular complications (vitreous hemorrhage, neovascular glaucoma). --- Explanation: This review confirms that uveitis occurs in over two-thirds of Behcet's disease patients and describes its bilateral, recurrent nature and sight-threatening complications including potential blindness.


MONDO:0007191

[PMID:38778397] [INDIRECT EVIDENCE] [PARTIAL] genetic factors (such as HLA-B51), dysregulated immune responses of both the innate and adaptive immune systems, infections (such as streptococcus), and environmental factors (such as GDP) are all involved in its development. --- Explanation: This review confirms that HLA-B51 is a key genetic factor in Behcet's disease pathogenesis, supporting the role of aberrant antigen presentation in disease development.


MONDO:0007191

[PMID:38778397] [INDIRECT EVIDENCE] [PARTIAL] Innate immunity, including hyperactivity of neutrophils and γδT cells and elevated NK1/NK2 ratios, has been shown to play an essential role in this disease. --- Explanation: This review highlights neutrophil hyperactivity as a key feature of innate immune dysregulation in Behcet's uveitis, supporting the role of neutrophil activation in pathogenesis.

[PMID:37435539] [INDIRECT EVIDENCE] [SUPPORT] Skin histopathology demonstrates the overactivation of innate immunity, such as neutrophilic dermatitis/panniculitis, in patients with BD. --- Explanation: Histopathological evidence confirms neutrophil overactivation in Behcet's disease skin lesions, demonstrating the pathologic role of neutrophils in tissue inflammation.


MONDO:0007191

[PMID:38778397] [INDIRECT EVIDENCE] [SUPPORT] Adaptive immune system disturbance, including homeostatic perturbations, Th1, Th17 overaction, and Treg cell dysfunction, is thought to be involved in BU pathogenesis. --- Explanation: This review describes the imbalance between pro-inflammatory Th1/Th17 responses and regulatory T cell dysfunction as central to Behcet's uveitis pathogenesis, supporting the role of cytokine imbalance in disease progression.


HGNC.SYMBOL:HLA-B51


HGNC.SYMBOL:ERAP1


HGNC.SYMBOL:IL10


MONDO:0001714

[PMID:2771355] [SUPPORT] Results of clinical examination showed uveitis in nine patients, optic atrophy in six, and chorioretinitis scars in six. --- Explanation: The abstract reports uveitis among bejel patients.


MONDO:0001714

[PMID:2771355] [SUPPORT] Results of clinical examination showed uveitis in nine patients, optic atrophy in six, and chorioretinitis scars in six. --- Explanation: The abstract reports optic atrophy among bejel patients.


MAXO:0000058

[PMID:16615610] [SUPPORT] Although penicillin therapy is effective, these infectious diseases have yet to be eliminated. --- Explanation: The abstract notes penicillin therapy is effective for endemic treponematoses.


NCBITaxon:53436

[PMID:35687593] [SUPPORT] Bejel (endemic syphilis) is a neglected non-venereal disease caused by Treponema pallidum subsp. endemicum (TEN). --- Explanation: The abstract identifies the causative treponeme for bejel.


MONDO:0005665

[PMID:36397921] [SUPPORT] Bell's palsy, also known as "acute facial palsy of unknown cause", is a common cranial neuropathy leading to facial muscle paresis or complete paralysis characteristically on one side, occurring suddenly and may progress over 48 hours. --- Explanation: This directly supports acute unilateral peripheral facial weakness as the core phenotype of Bell's palsy.


MONDO:0005665

[PMID:33088514] [SUPPORT] Bell's palsy is an idiopathic facial nerve paralysis which often presents with unilateral facial weakness commonly characterized by an inability to close the eye, disappearance of the nasolabial fold, and eyebrow drooping at the affected corner of the mouth. --- Explanation: This supports incomplete eye closure as a common acute manifestation of Bell's palsy.


MONDO:0005665

[PMID:33088514] [SUPPORT] There may also be decreased tearing, hyperacusis, and/or loss of taste sensation on the anterior two thirds of the tongue. --- Explanation: This supports abnormal taste sensation as a recognized Bell's palsy phenotype.


MONDO:0005665

[PMID:33088514] [SUPPORT] There may also be decreased tearing, hyperacusis, and/or loss of taste sensation on the anterior two thirds of the tongue. --- Explanation: This supports hyperacusis as a recognized though non-universal clinical manifestation.


MONDO:0005665

[PMID:39939082] [SUPPORT] Oral corticosteroids improve recovery rates and antiviral medications reduce synkinesis. --- Explanation: This supports facial synkinesis as a recognized sequela important enough to be targeted therapeutically.


MONDO:0005665

[PMID:33602968] [INDIRECT EVIDENCE] [PARTIAL] While the pathogenesis remains unknown, previous studies have implicated post-viral inflammation and resulting compression of the facial nerve. --- Explanation: This supports post-viral inflammation as a leading but not definitively proven Bell's palsy mechanism.

[PMID:33088514] [INDIRECT EVIDENCE] [PARTIAL] Even though the underlying pathophysiology remains elusive, Bell's palsy is thought to result due to virus-mediated inflammation resulting in swelling of the CN VII and its compression at the geniculate ganglion. --- Explanation: This supports the commonly proposed geniculate-ganglion-centered viral inflammatory mechanism while making clear that it remains inferential.


MONDO:0005665


MONDO:0005665

[PMID:40299566] [INDIRECT EVIDENCE] [PARTIAL] Our study identifies causal relationships between inflammatory proteins, metabolites, immune cells, and Bell's palsy, highlighting that the JAK/STAT signaling pathway may be a potentially critical target for intervention in Bell's palsy, and that its modulation may provide new directions and opportunities for therapeutic strategies and drug discovery for the disease. --- Explanation: This computational Mendelian-randomization and network-analysis study supports JAK/STAT-centered inflammatory signaling as a plausible mechanistic contributor, but not yet a definitive established pathway in human Bell's palsy.


MONDO:0005665

[PMID:33088514] [INDIRECT EVIDENCE] [SUPPORT] Bell's palsy is thought to result due to virus-mediated inflammation resulting in swelling of the CN VII and its compression at the geniculate ganglion. --- Explanation: This directly supports facial nerve swelling as a central mechanistic event in Bell's palsy.


MONDO:0005665

[PMID:39939082] [INDIRECT EVIDENCE] [SUPPORT] Bell's palsy is acute weakness of the facial muscles associated with compression of cranial nerve VII. --- Explanation: This supports nerve compression as the mechanism linking facial nerve pathology to weakness of facial musculature.


MONDO:0005665

[PMID:36397921] [INDIRECT EVIDENCE] [SUPPORT] But there is always a risk of residual paresis after treatment or recovery, which may require medical help. --- Explanation: This supports persistent motor dysfunction in a subset of patients after the acute episode.

[PMID:39939082] [INDIRECT EVIDENCE] [SUPPORT] Oral corticosteroids improve recovery rates and antiviral medications reduce synkinesis. --- Explanation: This supports synkinesis as a recognized downstream sequela relevant to treatment decisions.


MAXO:0000058

[PMID:39939082] [SUPPORT] Oral corticosteroids improve recovery rates and antiviral medications reduce synkinesis. --- Explanation: This supports oral corticosteroids as the central evidence-backed acute therapy for Bell's palsy.


MAXO:0000058

[PMID:27689547] [SUPPORT] The combination of steroid and antiviral treatment increases the possibility of recovery in moderately severe to complete acute Bell's palsy. --- Explanation: This randomized trial supports benefit from adding antiviral therapy in moderate-to-severe acute Bell's palsy.

[PMID:39939082] [SUPPORT] Oral corticosteroids improve recovery rates and antiviral medications reduce synkinesis. --- Explanation: This supports a role for antivirals in reducing sequelae such as synkinesis.


MAXO:0000011

[PMID:39939082] [SUPPORT] Physical therapy and Botox injections can help patients with persistent symptoms. --- Explanation: This supports physical therapy as a symptomatic treatment for persistent Bell's palsy deficits.


MAXO:0009016

[PMID:39939082] [SUPPORT] Physical therapy and Botox injections can help patients with persistent symptoms. --- Explanation: This supports botulinum toxin treatment for persistent Bell's palsy sequelae such as synkinesis and asymmetry.


MAXO:0009016

[PMID:39939082] [INDIRECT EVIDENCE] [SUPPORT] Physical therapy and Botox injections can help patients with persistent symptoms. --- Explanation: This supports botulinum toxin treatment for persistent Bell's palsy sequelae such as synkinesis and asymmetry.


HGNC.SYMBOL:Common susceptibility locus at 6p21.1

[PMID:33602968] [SUPPORT] Here, we report findings from a meta-analysis of genome-wide association studies uncovering the first unequivocal association with Bell's palsy (rs9357446-A; P = 6.79 × 10-23, OR = 1.23; Ncases = 4714, Ncontrols = 1,011,520). --- Explanation: This supports a reproducible common-genetic susceptibility signal for Bell's palsy.


MONDO:0010811


MONDO:0010811

[PMID:37827216] [PARTIAL] One-month treatment of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency. --- Explanation: This evidence shows that voiding frequency (including nocturia) is a key symptom of BPH that can be reduced through therapeutic intervention targeting oxidative stress.


MONDO:0010811

[PMID:38654277] [INDIRECT EVIDENCE] [SUPPORT] Proliferative nodular formation represents a characteristic pathological feature of benign prostatic hyperplasia (BPH) and serves as the primary cause for prostate volume enlargement and consequent lower urinary tract symptoms (LUTS). --- Explanation: This evidence confirms that proliferative nodular formation in the transition zone is the primary pathological feature driving BPH symptoms.


MONDO:0010811

[PMID:37827216] [INDIRECT EVIDENCE] [PARTIAL] Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms. --- Explanation: This evidence supports that BPH-related enlargement causes lower urinary tract symptoms through bladder outlet obstruction and detrusor dysfunction.


MONDO:0010811

[PMID:38654277] [INDIRECT EVIDENCE] [SUPPORT] A distinct subgroup of basal epithelial (BE) cells, referred to as BE5, was identified to play a crucial role in driving this progression through the hypoxia-induced epithelial-mesenchymal transition (EMT) signaling pathway. --- Explanation: This evidence identifies BE5 cells as key drivers of BPH through hypoxia-induced EMT, establishing a molecular mechanism for nodular formation.


MONDO:0010811

[PMID:38711089] [INDIRECT EVIDENCE] [SUPPORT] The aberrant activation of transforming growth factor β (TGF-β)/Rho kinase 1 (ROCK1) increased the stemness of BPH tissue by recruiting mesenchymal stem cells (MSCs), indicating the important role of embryonic reawakening in BPH. --- Explanation: This evidence demonstrates that TGF-beta/ROCK1 activation drives prostatic stromal hyperplasia through MSC recruitment and differentiation.

[PMID:39455522] [INDIRECT EVIDENCE] [SUPPORT] ROCK1 and ROCK2 were significantly up-regulated in BPH tissues, correlating with clinical parameters. --- Explanation: This evidence confirms upregulation of ROCK1/2 in human BPH tissues and their correlation with disease severity.


MONDO:0010811

[PMID:39455522] [INDIRECT EVIDENCE] [SUPPORT] ROCK downregulation inhibited the β-catenin signaling pathway (such as C-MYC, Snail and Survivin) and decreased β-catenin protein stability, while inhibiting TGF-β/Smad2/3 signaling. --- Explanation: This evidence shows ROCK signaling converges on beta-catenin pathway to drive BPH pathophysiology, providing a therapeutic target.


MONDO:0010811

[PMID:37827216] [INDIRECT EVIDENCE] [PARTIAL] Pb-PRL mouse prostates exhibited increased vulnerability to oxidative stress due to reduction of antioxidant enzyme expression. One-month treatment of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency. --- Explanation: This evidence demonstrates that oxidative stress contributes to BPH progression and that antioxidant therapy can reduce prostate enlargement and symptoms.


MONDO:0010811

[PMID:38764065] [INDIRECT EVIDENCE] [PARTIAL] P. gingivalis infection promoted prostate cell proliferation, inhibited apoptosis, and upregulated the expression of inflammatory cytokines interleukin-6 (IL-6; 4.47-fold), interleukin-6 receptor-α (IL-6Rα; 5.74-fold) and glycoprotein 130 (gp130; 4.47-fold) in prostatic tissue. --- Explanation: This evidence links oral-prostate inflammation to BPH progression through IL-6/IL-6R/gp130-mediated Akt signaling, representing a novel pathophysiological axis.


HGNC.SYMBOL:SRD5A2


HGNC.SYMBOL:AR


HGNC.SYMBOL:ROCK1

[PMID:39455522] [PARTIAL] ROCK1 and ROCK2 were significantly up-regulated in BPH tissues, correlating with clinical parameters. --- Explanation: This evidence establishes ROCK1 as causally implicated in BPH pathogenesis through upregulation and correlation with disease severity.


HGNC.SYMBOL:ROCK2

[PMID:39455522] [PARTIAL] Y-27632 targeted the inhibition of ROCK1 & ROCK2 expression and inhibited cell proliferation, fibrosis, epithelial-mesenchymal transition (EMT), while induced cell apoptosis in a dose-dependent manner. --- Explanation: This evidence demonstrates ROCK2 as a causal factor in BPH through its role in proliferation, fibrosis, and EMT.


HGNC.SYMBOL:FOS

[PMID:38654277] [PARTIAL] A distinguishing characteristic of the BE5 cell subgroup in patients with BPH was its heightened hypoxia and upregulated expression of FOS. --- Explanation: This evidence identifies FOS upregulation as a key molecular driver of hypoxia-induced EMT in BPH nodular formation.


MONDO:0008760

[PMID:38853254] [SUPPORT] BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age. --- Explanation: Directly supports recurrent ketoacidosis as the hallmark phenotype.