MONDO:0008760

[PMID:35850931] [SUPPORT] At the time of admission, the patient had acidosis, drowsiness, and respiratory failure. --- Explanation: Documents severe acidosis during acute BKD crisis in a pediatric patient.


MONDO:0008760

[PMID:30026775] [SUPPORT] Clinical features characterized by intermittent keto acidotic episodes are associated with clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients --- Explanation: Directly lists lethargy as a clinical sign during ketoacidotic episodes.

[PMID:35850931] [SUPPORT] At the time of admission, the patient had acidosis, drowsiness, and respiratory failure. --- Explanation: Documents drowsiness (altered consciousness) during acute decompensation.


MONDO:0008760

[PMID:30026775] [SUPPORT] clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients --- Explanation: Directly lists vomiting as a clinical sign during ketoacidotic episodes.


MONDO:0008760

[PMID:40598206] [SUPPORT] One patient initially presented with hypotonia and psychomotor delay, later developing a ketoacidotic episode a few months afterward. --- Explanation: Documents hypotonia as an initial presenting feature preceding ketoacidosis.


MONDO:0008760

[PMID:30026775] [SUPPORT] clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients --- Explanation: Directly lists tachypnea as a clinical sign during ketoacidotic episodes.


MONDO:0008760

[PMID:30026775] [SUPPORT] acute episode of fever and toxic encephalopathy with attack of vomiting, hypotonia, lethargy, tonic-clonic seizures and then a day in coma --- Explanation: Documents tonic-clonic seizures during acute metabolic crisis in BKD.


MONDO:0008760

[PMID:30026775] [SUPPORT] clinical signs and symptoms of toxic encephalopathy such as lethargy, hypotonia, vomiting, tachypnea, and coma in some patients --- Explanation: Directly lists coma as a clinical sign in severe presentations.


MONDO:0008760

[PMID:40598206] [SUPPORT] Neurological complications, particularly extrapyramidal signs may occur as sequelae of the ketoacidosis episodes but may also occur without or before any apparent metabolic crisis. --- Explanation: Documents neurological complications including extrapyramidal signs in BKD.

[PMID:23958592] [SUPPORT] Brain CT showed bilateral basal ganglia lesions. --- Explanation: Documents bilateral basal ganglia lesions on imaging in a BKD patient.


MONDO:0008760

[PMID:40598206] [SUPPORT] One patient initially presented with hypotonia and psychomotor delay, later developing a ketoacidotic episode a few months afterward. --- Explanation: Documents psychomotor delay as an early presentation in BKD.


MONDO:0008760

[PMID:38853254] [SUPPORT] Stress hyperglycemia is not uncommon when children with BKD are acutely unwell, with several pediatric case reports describing short-lived hyperglycemia but normal HbA1c measurements during metabolic crises --- Explanation: Documents stress hyperglycemia during acute BKD episodes and the first report of persistent diabetes in an adult with BKD.


MONDO:0008760

[PMID:40598206] [SUPPORT] T2 deficiency is characterized by the accumulation of isoleucine metabolites, 2methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine, detected in urine organic acids and blood acylcarnitines with or without hypoglycemia. --- Explanation: Documents hypoglycemia as a variable associated feature in T2 deficiency; "2methylacetoacetate" is verbatim from the source abstract [sic].


MONDO:0008760

[PMID:35850931] [SUPPORT] At the time of admission, the patient had acidosis, drowsiness, and respiratory failure. --- Explanation: Documents respiratory failure during acute severe BKD crisis in a 9-month-old.


MONDO:0008760

[PMID:31268215] [INDIRECT EVIDENCE] [SUPPORT] Mitochondrial acetoacetyl-CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism. --- Explanation: Supports ACAT1/T2 molecular dysfunction as the proximal defect.


MONDO:0008760


MONDO:0008760

[PMID:38853254] [INDIRECT EVIDENCE] [SUPPORT] Beta-ketothiolase deficiency (BKD) is a rare autosomal recessive condition affecting isoleucine catabolism and ketone body metabolism. --- Explanation: Directly supports impaired isoleucine catabolism as a core feature of BKD.

[PMID:31268215] [INDIRECT EVIDENCE] [SUPPORT] Mitochondrial acetoacetyl-CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism. --- Explanation: Comprehensive review confirming isoleucine metabolism disruption in T2 deficiency.


MONDO:0008760

[PMID:38853254] [INDIRECT EVIDENCE] [SUPPORT] BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age. --- Explanation: Supports recurrent ketoacidosis due to impaired ketone body handling.

[PMID:31268215] [INDIRECT EVIDENCE] [SUPPORT] Mitochondrial acetoacetyl-CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism. --- Explanation: Confirms ketone body metabolism disruption as core pathophysiology.


MONDO:0008760

[PMID:38853254] [INDIRECT EVIDENCE] [SUPPORT] BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age. --- Explanation: Supports episodic nature and age-dependent reduction of decompensation episodes.

[PMID:40598206] [INDIRECT EVIDENCE] [SUPPORT] Ketoacidotic episodes were the predominant manifestations in all patients, and each episode was triggered by either acute gastroenteritis or upper respiratory infections. --- Explanation: Confirms infection-triggered ketoacidotic episodes as the predominant clinical pattern.


MAXO:0000950

[PMID:38853254] [PARTIAL] BKD typically manifests in childhood as recurrent episodes of ketoacidosis, the frequency of which tends to reduce with age. --- Explanation: Episodic nature triggered by catabolic stress supports the importance of trigger avoidance.


MAXO:0000088


MAXO:0000950

[PMID:35850931] [PARTIAL] At the time of admission, the patient had acidosis, drowsiness, and respiratory failure. --- Explanation: Documents the severity of acute crisis presentation requiring intensive care, but the abstract does not detail the treatment protocol itself.


MAXO:0000058


MAXO:0000124

[PMID:38535123] [SUPPORT] The false positive rate for these six conditions after the NGS second-tier test was only 0.017%, and two cases of citrullinemia type II would have been missed as false negatives if only biochemical first-tier testing was performed. --- Explanation: Documents implementation of NGS second-tier NBS including BKD, reducing false positives.


MAXO:0000079

[PMID:40598206] [SUPPORT] By identifying haplotype blocks, founder mutations, and novel pathogenic variants, researchers can significantly improve diagnostic precision, enhance genetic counseling, and lay the groundwork for developing targeted therapies. --- Explanation: Supports the role of genetic counseling in BKD management and family planning.

[PMID:30026775] [SUPPORT] We recommended carrier testing for all informative family members to recognize mutations in asymptomatic family members. --- Explanation: Directly recommends carrier testing as part of genetic counseling for BKD families.


MAXO:0000018

[PMID:38853254] [SUPPORT] This case highlights the importance of checking HbA1c in people with BKD and hyperglycemia in order to uncover potential coexisting diabetes, facilitating timely management and preventing complications. --- Explanation: Directly supports HbA1c monitoring as a new clinical recommendation for BKD.


HGNC.SYMBOL:ACAT1 pathogenic variants

[PMID:31268215] [SUPPORT] To date, 105 ACAT1 variants have been reported in 149 T2-deficient patients. --- Explanation: Comprehensive mutation update cataloging all known ACAT1 variants.


MONDO:0009562

[PMID:32847582] [SUPPORT] clinical manifestation includes deafness and mental retardation --- Explanation: Mental retardation (intellectual disability) is explicitly listed as a clinical manifestation of beta-mannosidosis.


MONDO:0009562

[PMID:32847582] [SUPPORT] 10 beta-mannosidosis patients of Roma origin from eight families in the Czech and Slovak Republics with hearing loss, mental retardation --- Explanation: Hearing loss is a prominent feature in beta-mannosidosis patients, occurring consistently across reported cases.


MONDO:0009562


MONDO:0009562

[PMID:32847582] [INDIRECT EVIDENCE] [PARTIAL] a rare lysosomal storage disorder named beta-mannosidosis whose clinical manifestation includes deafness and mental retardation --- Explanation: Confirms that beta-mannosidosis is a lysosomal storage disorder with neurological and auditory manifestations.


MAXO:0000950


HGNC.SYMBOL:MANBA gene mutations

[PMID:32847582] [SUPPORT] carrier/heterozygote frequency of 3.77%. This is about 925 times higher than the frequency of this variant in the gnomAD public database --- Explanation: Identifies a founder variant with high carrier frequency in Roma populations, demonstrating genetic basis of the disease.


MONDO:0019402

[PMID:20492708] [SUPPORT] Individuals with thalassemia major usually present within the first two years of life with severe anemia, requiring regular red blood cell (RBC) transfusions. --- Explanation: Confirms severe anemia as the defining presentation of thalassemia major.


MONDO:0019402


MONDO:0019402

[PMID:20492708] [INDIRECT EVIDENCE] [SUPPORT] Beta-thalassemias are caused by point mutations or, more rarely, deletions in the beta globin gene on chromosome 11, leading to reduced (beta+) or absent (beta0) synthesis of the beta chains of hemoglobin (Hb). --- Explanation: Confirms that HBB mutations lead to reduced or absent beta-globin chain synthesis.


MONDO:0019402

[PMID:21705976] [INDIRECT EVIDENCE] [SUPPORT] unbalanced alpha globin chain synthesis results in severely rheologically compromised erythrocytes with premature destruction in the peripheral circulation and ineffective erythropoiesis within the bone marrow and in extramedullary sites --- Explanation: Confirms that excess alpha-globin chains cause both peripheral erythrocyte destruction and ineffective erythropoiesis.


MONDO:0019402

[PMID:22631035] [INDIRECT EVIDENCE] [SUPPORT] Ineffective erythropoiesis is the hallmark of beta-thalassemia that triggers a cascade of compensatory mechanisms resulting in clinical sequelae such as erythroid marrow expansion, extramedullary hematopoiesis, splenomegaly, and increased gastrointestinal iron absorption. --- Explanation: Confirms ineffective erythropoiesis as the hallmark mechanism driving marrow expansion, extramedullary hematopoiesis, and iron absorption.


MONDO:0019402

[PMID:21705976] [INDIRECT EVIDENCE] [SUPPORT] unbalanced alpha globin chain synthesis results in severely rheologically compromised erythrocytes with premature destruction in the peripheral circulation --- Explanation: Confirms peripheral destruction of rheologically compromised erythrocytes (hemolysis).


MONDO:0019402

[PMID:21705976] [INDIRECT EVIDENCE] [SUPPORT] erythropoiesis,anemia and hypoxia down-regulate hepcidin, the master regulator of iron homeostasis. Hepcidin deficiency in turn allows excessive duodenal iron absorption and development of systemic iron overload. --- Explanation: Confirms hepcidin suppression from ineffective erythropoiesis as the mechanism of iron overload.

[PMID:20492708] [INDIRECT EVIDENCE] [SUPPORT] Regular transfusion therapy leads to iron overload-related complications including endocrine complication (growth retardation, failure of sexual maturation, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and less commonly, adrenal glands), dilated myocardiopathy, liver fibrosis and cirrhosis) --- Explanation: Confirms iron overload complications affecting heart, liver, and endocrine organs.


MONDO:0019402

[PMID:18691915] [INDIRECT EVIDENCE] [PARTIAL] In this study, we showed that SNPs in BCL11A were associated with F-cell numbers in Chinese with beta-thalassemia trait, and with HbF levels in Thais with either beta-thalassemia or HbE trait and in African Americans with sickle cell anemia. --- Explanation: Provides beta-thalassemia-specific evidence that BCL11A variants modulate HbF-related traits.


MAXO:0000756


MAXO:0000058


CHEBI:44423


MAXO:0000004


MAXO:0000747


MAXO:0000058

[PMID:32212518] [SUPPORT] The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). --- Explanation: BELIEVE trial demonstrates luspatercept significantly reduces transfusion burden in transfusion-dependent beta-thalassemia.


NCIT:C104012

[PMID:32212518] [INDIRECT EVIDENCE] [SUPPORT] The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). --- Explanation: BELIEVE trial demonstrates luspatercept significantly reduces transfusion burden in transfusion-dependent beta-thalassemia.


MAXO:0001001

[PMID:34891223] [SUPPORT] Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. --- Explanation: Northstar-2 phase 3 trial demonstrates betibeglogene autotemcel achieves transfusion independence in 91% of evaluable patients.


MAXO:0000079


HGNC.SYMBOL:HBB

[PMID:20492708] [SUPPORT] Beta-thalassemias are caused by point mutations or, more rarely, deletions in the beta globin gene on chromosome 11, leading to reduced (beta+) or absent (beta0) synthesis of the beta chains of hemoglobin (Hb). Transmission is autosomal recessive --- Explanation: Confirms HBB mutations cause beta-thalassemia with autosomal recessive inheritance.


HGNC.SYMBOL:BCL11A

[PMID:18691915] [SUPPORT] In this study, we showed that SNPs in BCL11A were associated with F-cell numbers in Chinese with beta-thalassemia trait, and with HbF levels in Thais with either beta-thalassemia or HbE trait and in African Americans with sickle cell anemia. --- Explanation: Supports BCL11A as an HbF modifier in beta-thalassemia populations.


HGNC.SYMBOL:KLF1


HGNC.SYMBOL:HBS1L-MYB


MONDO:0009665

[PMID:37027963] [SUPPORT] BD affected five main organ systems: nervous system (67.2%), skin (53.7%), eye (34.4%), auditory (26.9%) and respiratory system (17.8%) --- Explanation: Nervous system involvement at 67.2% supports seizures as a frequent neurological phenotype.


MONDO:0009665

[PMID:37373384] [SUPPORT] Detailed clinical features included severe psychomotor retardation, hypotonia, as well as failure to thrive --- Explanation: Case report documents severe psychomotor retardation in a child with profound biotinidase deficiency.


MONDO:0009665

[PMID:37373384] [SUPPORT] Detailed clinical features included severe psychomotor retardation, hypotonia, as well as failure to thrive --- Explanation: Case report documents hypotonia as a prominent feature in biotinidase deficiency.

[PMID:37027963] [SUPPORT] BD affected five main organ systems: nervous system (67.2%) --- Explanation: Nervous system involvement at 67.2% in the systematic review supports hypotonia as a frequent neurological manifestation.


MONDO:0009665

[PMID:37027963] [SUPPORT] BD affected five main organ systems: nervous system (67.2%), skin (53.7%), eye (34.4%), auditory (26.9%) and respiratory system (17.8%) --- Explanation: Skin involvement at 53.7% supports alopecia as a frequent phenotype.


MONDO:0009665

[PMID:37027963] [SUPPORT] BD affected five main organ systems: nervous system (67.2%), skin (53.7%) --- Explanation: Skin involvement at 53.7% supports dermatitis as a frequent phenotype.


MONDO:0009665

[PMID:37027963] [SUPPORT] BD affected five main organ systems: nervous system (67.2%), skin (53.7%), eye (34.4%), auditory (26.9%) and respiratory system (17.8%) --- Explanation: Auditory involvement at 26.9% supports hearing impairment as an occasional phenotype.

[PMID:39451125] [SUPPORT] Hearing loss (4 patients) and optic atrophy (1 patient) were mainly observed in patients with the c.38_delinsTCC mutation --- Explanation: Documents hearing loss in a Turkish cohort and links it to specific BTD variants.


MONDO:0009665

[PMID:37027963] [SUPPORT] BD affected five main organ systems: nervous system (67.2%), skin (53.7%), eye (34.4%), auditory (26.9%) --- Explanation: Eye involvement at 34.4% supports optic atrophy as a frequent phenotype.

[PMID:40190376] [SUPPORT] Comprehensive ophthalmic examination revealed bilateral optic neuropathy. Laboratory testing showed a biotinidase level of <0.1 --- Explanation: Case report demonstrates bilateral optic neuropathy with improvement after biotin supplementation.


MONDO:0009665

[PMID:36759144] [PARTIAL] Resultant deficiency of free biotin leads to impaired activity of the enzyme carboxylase and related neurologic, dermatologic, and ocular symptoms --- Explanation: Neuroimaging study documents cerebellar and brainstem involvement consistent with ataxia.


MONDO:0009665

[PMID:37027963] [SUPPORT] metabolic acidosis was present in 42.4% of symptomatic individuals --- Explanation: Directly quantifies metabolic acidosis frequency at 42.4% in the 1113-case systematic review.


MONDO:0009665

[PMID:37027963] [SUPPORT] BD affected five main organ systems: nervous system (67.2%), skin (53.7%), eye (34.4%), auditory (26.9%) and respiratory system (17.8%) --- Explanation: Respiratory system involvement at 17.8% supports respiratory insufficiency as occasional.


MONDO:0009665

[PMID:37373384] [SUPPORT] the therapy failed to show any evident effects on poor feeding and intellectual disability --- Explanation: Case report demonstrates that intellectual disability may be irreversible once established despite biotin treatment.


MONDO:0009665

[PMID:37373384] [SUPPORT] Detailed clinical features included severe psychomotor retardation, hypotonia, as well as failure to thrive --- Explanation: Case report documents failure to thrive as a clinical feature of profound biotinidase deficiency.


MONDO:0009665

[PMID:36759144] [PARTIAL] In this report comprising 14 patients from multiple centers, we demonstrate the MR imaging patterns of this disorder at various age groups --- Explanation: Neuroimaging series supports neurologic involvement but does not directly name spastic paraplegia.


MONDO:0009665

[PMID:38928282] [INDIRECT EVIDENCE] [SUPPORT] Biotin status/homeostasis in human individuals depends on several factors, including efficiency/deficiency of the enzymes involved in biotin recycling within the human organism (biotinidase, holocarboxylase synthetase) --- Explanation: Directly supports the role of biotinidase in biotin recycling and its link to carboxylase function.

[PMID:37373384] [INDIRECT EVIDENCE] [SUPPORT] BTD deficiency may impair the activity of biotin-dependent carboxylases, and thus bring about a buildup of potentially toxic compounds in the body --- Explanation: Confirms that biotinidase deficiency leads to impaired carboxylase activity and toxic metabolite accumulation.


MONDO:0009665


MONDO:0009665

[PMID:37373384] [INDIRECT EVIDENCE] [SUPPORT] BTD deficiency may impair the activity of biotin-dependent carboxylases, and thus bring about a buildup of potentially toxic compounds in the body, primarily 3-hydroxyisovaleryl-carnitine in plasma as well as 3-hydroxyisovaleric acid in urine --- Explanation: Documents the specific metabolite accumulation pattern in biotinidase deficiency.


MONDO:0009665

[PMID:36759144] [INDIRECT EVIDENCE] [SUPPORT] Resultant deficiency of free biotin leads to impaired activity of the enzyme carboxylase and related neurologic, dermatologic, and ocular symptoms --- Explanation: Multicenter neuroimaging study documenting CNS involvement patterns in biotinidase deficiency.

[PMID:37373384] [INDIRECT EVIDENCE] [SUPPORT] The brain MRI at 12 months showed cerebellar hypoplasia and multiple foci of leukodystrophy --- Explanation: Case demonstrating cerebellar and white matter injury in profound biotinidase deficiency.


MONDO:0009665

[PMID:37027963] [INDIRECT EVIDENCE] [SUPPORT] BD affected five main organ systems: nervous system (67.2%), skin (53.7%), eye (34.4%), auditory (26.9%) and respiratory system (17.8%) --- Explanation: Quantifies skin involvement at 53.7% of symptomatic cases in the largest systematic review.


MAXO:0000058

[PMID:37027963] [SUPPORT] Biotin treatment led to clinical stability or improvement in 89.2% of individuals. 1.6% of reported individuals with BD died due to non-availability of treatment or late diagnosis --- Explanation: Systematic review of 1113 cases demonstrating high efficacy of biotin treatment.

[PMID:40190376] [SUPPORT] The patient was treated with oral biotin supplementation with improvement in her visual function --- Explanation: Case demonstrating biotin supplementation improving visual function in an adult patient.


MAXO:0000124

[PMID:37027963] [SUPPORT] Newborn screening has had a major positive impact on the outcome of many individuals with BD --- Explanation: Systematic review confirms the positive impact of newborn screening on outcomes.

[PMID:38141137] [SUPPORT] An analysis of the admission routes of all cases to our clinic revealed 89.5% NBS, 5.7% family screening, and 4.9% suspicious clinical findings suggestive of BD --- Explanation: Large cohort demonstrating that newborn screening identifies the vast majority of cases.


MAXO:0000088

[PMID:38928282] [SUPPORT] administration of biotin at high/"pharmacological" doses has been proposed to treat specific defects/deficiencies and human disorders --- Explanation: Review discusses biotin supplementation as part of the treatment strategy, which includes nutritional management.


MAXO:0000058

[PMID:37373384] [SUPPORT] The result of antiepileptic therapy was not satisfying --- Explanation: Case demonstrates that antiepileptic therapy alone is insufficient and biotin is the essential treatment.


MAXO:0000079

[PMID:37027963] [SUPPORT] Biotinidase deficiency (BD) is an autosomal recessively inherited disorder --- Explanation: Autosomal recessive inheritance pattern supports the role of genetic counseling.

[PMID:38141137] [SUPPORT] Biotinidase deficiency (BD) is an autosomal recessive inherited metabolic disorder --- Explanation: Genetic basis of the disorder supports counseling for recurrence risk assessment.


MAXO:0000950

[PMID:37027963] [SUPPORT] a trial of biotin should be considered in undiagnosed infants and adults exhibiting suspected clinical signs. Enzymatic activity and/or analysis of genetic variants can readily confirm the diagnosis of BD --- Explanation: Supports comprehensive monitoring and supportive care approach for affected individuals.


MAXO:0000950

[PMID:37027963] [SUPPORT] BD affected five main organ systems: nervous system (67.2%), skin (53.7%), eye (34.4%), auditory (26.9%) --- Explanation: Auditory involvement at 26.9% supports the need for audiological monitoring and management.

[PMID:39451125] [SUPPORT] Hearing loss (4 patients) and optic atrophy (1 patient) were mainly observed in patients with the c.38_delinsTCC mutation --- Explanation: Documents hearing loss as a significant complication requiring audiological management.


HGNC.SYMBOL:BTD gene variants causing biotinidase deficiency

[PMID:38141137] [SUPPORT] Two hundred forty-seven cases were included in the study who were admitted to the Department of Pediatric Metabolism --- Explanation: Large cohort study providing comprehensive genotype-phenotype correlations in biotinidase deficiency.

[PMID:39451125] [SUPPORT] This study provides a detailed analysis of genetic diversity and clinical presentation in biotinidase deficiency cases in Eastern Anatolia, demonstrating the efficacy of biotin treatment --- Explanation: Regional cohort study demonstrating genetic diversity and variant-phenotype relationships.


MONDO:0004985


MONDO:0004985

[PMID:23846857] [PARTIAL] All proband groups showed lower psychosocial functioning than the relatives or comparison group. On average, schizophrenia probands showed more symptoms and lower psychosocial functioning than probands with psychotic bipolar disorder, but there was considerable overlap in clinical manifestations. --- Explanation: The B-SNIP study demonstrates that cognitive and psychosocial impairment is a consistent feature across psychotic disorders including bipolar disorder, though with varying severity.


MONDO:0004985

[PMID:22363263] [INDIRECT EVIDENCE] [PARTIAL] Activation of the dopamine receptor 2 (D2R) has been shown to stimulate the inactivation of Akt by PP2A (Beaulieu et al., 2005; Beaulieu and Gainetdinov, 2011), therefore providing a mechanism through which GPCR activation can inhibit Akt in response to extracellular signals. --- Explanation: Dopamine D2 receptor signaling regulates the Akt/GSK3 pathway, providing a molecular link between monoaminergic neurotransmission and mood regulation in bipolar disorder.

[PMID:22363263] [INDIRECT EVIDENCE] [PARTIAL] This mechanism of D2R signaling appears to play important roles in the regulation of locomotor behavior and sensory motor gating by dopamine (Beaulieu et al., 2004; Emamian et al., 2004). It could also contribute to the therapeutic and/or adverse effects of psychoactive drugs like amphetamines and antpsychotics that act on dopamine neurotransmission --- Explanation: The D2 receptor-mediated regulation of GSK3 activity through beta-arrestin signaling is implicated in behavioral regulation relevant to bipolar disorder and the mechanism of mood stabilizers and antipsychotics.


MONDO:0004985

[PMID:30285728] [INDIRECT EVIDENCE] [NO_EVIDENCE] Psychiatric disorders (such as bipolar disorder, depression, and schizophrenia) affect the lives of millions of individuals worldwide. --- Explanation: This review discusses the molecular mechanisms underlying psychiatric disorders including bipolar disorder, with focus on the DISC1/GSK3 complex which regulates mitochondrial and cellular functions.


MONDO:0004985

[PMID:22363263] [INDIRECT EVIDENCE] [NO_EVIDENCE] For more than 60 years, the mood stabilizer lithium has been used alone or in combination for the treatment of bipolar disorder, schizophrenia, depression, and other mental illnesses. --- Explanation: This comprehensive review discusses lithium as the gold standard treatment for bipolar disorder, noting its mood-stabilizing effects through GSK3 inhibition which affects multiple cellular pathways including circadian regulation.


MONDO:0004985

[PMID:30285728] [INDIRECT EVIDENCE] [PARTIAL] DISC1 binds directly to GSK3 and modulates many cellular functions by negatively inhibiting GSK3 activity. --- Explanation: GSK3 inhibition by DISC1 and mood stabilizers like lithium is a key mechanism in bipolar disorder treatment, affecting synaptic plasticity and neuronal survival pathways.

[PMID:30285728] [INDIRECT EVIDENCE] [PARTIAL] In the present review, we will focus on the emerging roles of TRAX and its interacting proteins (including DISC1 and GSK3β) in psychiatric disorders and the potential implications for developing therapeutic interventions. --- Explanation: The TRAX/DISC1/GSK3β complex is implicated in psychiatric disorders including bipolar disorder and represents a therapeutic target for enhancing neuroplasticity.


MONDO:0004985

[PMID:33958577] [INDIRECT EVIDENCE] [NO_EVIDENCE] considering that schizophrenia is a multifactorial and highly polygenic disorder that shares many risk genes with other psychiatric illnesses including bipolar disorder, depression, intellectual disability and autism spectrum disorders, it is to be expected that these diseases may also share some of these same mechanisms --- Explanation: Microglial activation and inflammatory processes are shared pathophysiological mechanisms across psychiatric disorders including bipolar disorder, contributing to synaptic dysfunction.


HGNC.SYMBOL:CACNA1C

[PMID:18711365] [SUPPORT] We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). --- Explanation: Landmark GWAS study providing genome-wide significant evidence that CACNA1C is a susceptibility locus for bipolar disorder, implicating calcium channel dysfunction in disease pathogenesis.

[PMID:21057379] [SUPPORT] The finding for CACNG5, taken together with the earlier implication of CACNA1C and CACNA1B, strongly suggests a key role for voltage-dependent calcium channel genes in the susceptibility to bipolar disorder and/or schizophrenia. --- Explanation: Case-case GWAS analysis further confirms the critical role of calcium channel genes including CACNA1C in bipolar disorder susceptibility.


HGNC.SYMBOL:ANK3

[PMID:18711365] [SUPPORT] To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). --- Explanation: Genome-wide significant association of ANK3 with bipolar disorder in large-scale GWAS, establishing ankyrin G as a key susceptibility gene that may affect neuronal excitability and synaptic function.


HGNC.SYMBOL:ODZ4


HGNC.SYMBOL:NCAN


MONDO:0005668

[PMID:14503346] [PARTIAL] A 57-year-old woman was admitted to our hospital because of cough and low-grade fever for 2 months and shortness of breath for 2 weeks. --- Explanation: The case report documents shortness of breath in bird fancier's lung.

[PMID:39958101] [PARTIAL] We present the case of a 43-year-old male pigeon keeper with an eight-week history of progressive dyspnea on exertion and intermittent chest pain. --- Explanation: The case report describes progressive dyspnea on exertion in BFL.


MONDO:0005668

[PMID:14503346] [PARTIAL] A 57-year-old woman was admitted to our hospital because of cough and low-grade fever for 2 months and shortness of breath for 2 weeks. --- Explanation: The case report describes cough in bird fancier's lung.


MONDO:0005668

[PMID:37028940] [SUPPORT] Fibrotic hypersensitivity pneumonitis (FHP) is an irreversible lung disease with high morbidity and mortality. --- Explanation: The trial focuses on fibrotic hypersensitivity pneumonitis, supporting pulmonary fibrosis as a clinical phenotype.

[PMID:32145830] [PARTIAL] the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis --- Explanation: The INBUILD subgroup analysis includes hypersensitivity pneumonitis within progressive fibrosing ILD populations, supporting a fibrotic phenotype.

[PMID:24480143] [PARTIAL] In the 3 diseases, most important prognosis-predicting factor is the extent of fibrotic score (the extent of honeycombing and reticulation) calculated on high-resolution computed tomography scans or fibrosis estimated on chest radiographs. --- Explanation: Chronic HP is discussed alongside fibrotic scoring on HRCT, reinforcing pulmonary fibrosis as a key disease feature.

[PMID:38218353] [PARTIAL] Importantly, it was observed that the transfer of MMP14-overexpressing macrophages into mice promoted lung inflammation and fibrosis induced by SR-Ag. --- Explanation: In a hypersensitivity pneumonitis model, fibrosis is a documented outcome, supporting pulmonary fibrosis as a disease phenotype.


MONDO:0005668

[PMID:11131880] [PARTIAL] A 47-year-old woman, without significant past medical history, presented an acute dyspnea with hypoxia, marked pulmonary arterial hypertension (PAH) and signs of right heart failure. --- Explanation: The case demonstrates hypoxia as part of acute bird hypersensitivity pneumonitis.


MONDO:0005668

[PMID:6761066] [SUPPORT] Chronically, these diseases may present with the gradual onset of cough, dyspnea on exertion, fatigue, anorexia, and weight loss which may progress to pulmonary fibrosis or severe pulmonary insufficiency. --- Explanation: The clinical review describes fatigue among chronic hypersensitivity pneumonitis presentations.


MONDO:0005668

[PMID:14503346] [PARTIAL] A 57-year-old woman was admitted to our hospital because of cough and low-grade fever for 2 months and shortness of breath for 2 weeks. --- Explanation: The case report documents low-grade fever in bird fancier's lung.


MONDO:0005668

[DOI:10.3390/ijms24032884] [INDIRECT EVIDENCE] [SUPPORT] Bird-related hypersensitivity pneumonitis (BRHP) is an interstitial lung disease induced by avian proteins. --- Explanation: The review defines BRHP as an avian protein-induced interstitial lung disease.

[PMID:39958101] [INDIRECT EVIDENCE] [SUPPORT] Bird fancier's lung (BFL) is a subtype of hypersensitivity pneumonitis (HP), an immune-mediated interstitial lung disease (ILD) resulting from the repeated inhalation of avian proteins found in bird droppings, feathers, and serum. --- Explanation: The case report links BFL to repeated inhalation of avian proteins as the causative trigger for interstitial lung disease.

[PMID:33318919] [INDIRECT EVIDENCE] [SUPPORT] Bird Fancier's Lung is a type of hypersensitivity pneumonitis, an immunologically mediated lung disease due to repetitive exposure of air-borne avian antigen. --- Explanation: The report characterizes BFL as an immune-mediated interstitial lung disease driven by repetitive avian antigen exposure.


MONDO:0005668

[DOI:10.3390/ijms24032884] [INDIRECT EVIDENCE] [SUPPORT] Both groups presented increases in resident monocytes, interstitial macrophages and type 2 dendritic cells (DCs), but also reductions in inflammatory monocytes, alveolar macrophages and tolerogenic DCs compared with their control groups. --- Explanation: The mouse model reports increased resident monocytes, interstitial macrophages, and type 2 dendritic cells after bird antigen exposure.


MONDO:0005668


MONDO:0005668

[DOI:10.3390/ijms24032884] [INDIRECT EVIDENCE] [SUPPORT] Both groups presented increases in resident monocytes, interstitial macrophages and type 2 dendritic cells (DCs), but also reductions in inflammatory monocytes, alveolar macrophages and tolerogenic DCs compared with their control groups. --- Explanation: The same experiment reports reduced inflammatory monocytes, alveolar macrophages, and tolerogenic dendritic cells.


MONDO:0005668

[DOI:10.3390/ijms24032884] [INDIRECT EVIDENCE] [SUPPORT] In the first stages of BRHP, there is a mixed Th1/Th2 immune response, while during the progression of the disease, although there is a Th1 response, the cytokine levels seem to indicate a switch towards a Th2/Th17 mixed response. --- Explanation: The cytokine profile indicates a stage-dependent shift toward Th2/Th17 responses during disease progression.


MONDO:0005668

[PMID:33041192] [INDIRECT EVIDENCE] [SUPPORT] The levels of sIgG/sIgA against the bird antigens of the three species were significantly higher in subjects with acute bird-related HP and chronic bird-related HP with acute episodes (recurrent type) than in the control subjects. --- Explanation: Elevated bird-specific IgG/IgA in affected patients supports a humoral immune response to avian antigens.


MONDO:0005668

[PMID:38924775] [INDIRECT EVIDENCE] [SUPPORT] Compared with control samples, FHP has elevated classical monocytes (adjusted-P = 2.5 × 10-3) and is enriched in CCL3hi/CCL4hi and S100Ahi classical monocytes (adjusted-P < 2.2 × 10-16). --- Explanation: Single-cell profiling identifies enriched classical monocyte states in fibrotic HP.


MONDO:0005668

[PMID:38924775] [INDIRECT EVIDENCE] [SUPPORT] Trajectory analyses demonstrate that S100Ahi classical monocytes differentiate into SPP1hi lung macrophages associated with fibrosis. --- Explanation: Trajectory analyses link classical monocytes to profibrotic macrophages in fibrotic HP.


MONDO:0005668

[PMID:38924775] [INDIRECT EVIDENCE] [SUPPORT] Compared with both control subjects and IPF, cells from patients with FHP are significantly enriched in GZMhi cytotoxic T cells. These cells exhibit TF activities indicative of TGFβ and TNFα and NFκB pathways. --- Explanation: Cytotoxic T cell enrichment with profibrotic signaling programs supports a T cell-driven inflammatory mechanism.


MONDO:0005668

[PMID:38218353] [INDIRECT EVIDENCE] [SUPPORT] we identified MMP14high macrophage subcluster with a predominant M2 phenotype that exhibited higher activity in promoting fibroblast-to myofibroblast transition (FMT). --- Explanation: The study identifies a macrophage subset driving fibroblast-to-myofibroblast transition, a key fibrotic remodeling process.


MONDO:0005668

[PMID:38218353] [INDIRECT EVIDENCE] [SUPPORT] We demonstrated that suppressing toll-like receptor 2 (TLR2) and nuclear factor kappa-B (NF-κB) could attenuate MMP14 expression and exosome secretion in macrophages stimulation with SR-Ag. --- Explanation: The abstract links TLR2/NF-κB signaling to MMP14 regulation and exosome secretion in HP macrophages.


MAXO:0000640

[clinicaltrials:NCT02496182] [SUPPORT] Actually HP has been treated with Prednisone and occasionally with Azathioprine, but unfortunately the treatment with these drugs have not an effective result to treat the interstitial fibrosis. --- Explanation: The trial summary notes existing use of prednisone and azathioprine in chronic hypersensitivity pneumonitis.

[PMID:39958101] [SUPPORT] The patient was diagnosed with BFL and treated with a tapering regimen of oral corticosteroids, starting at 40 mg/day. --- Explanation: The case report documents corticosteroid treatment for BFL.


CHEBI:8382

[clinicaltrials:NCT02496182] [INDIRECT EVIDENCE] [SUPPORT] Actually HP has been treated with Prednisone and occasionally with Azathioprine, but unfortunately the treatment with these drugs have not an effective result to treat the interstitial fibrosis. --- Explanation: The trial summary notes existing use of prednisone and azathioprine in chronic hypersensitivity pneumonitis.

[PMID:39958101] [INDIRECT EVIDENCE] [SUPPORT] The patient was diagnosed with BFL and treated with a tapering regimen of oral corticosteroids, starting at 40 mg/day. --- Explanation: The case report documents corticosteroid treatment for BFL.


CHEBI:2948


MAXO:0000058

[PMID:27816444] [PARTIAL] We aimed to determine the effect of treatment with mycophenolate mofetil (MMF) or azathioprine (AZA) on lung function in patients with cHP. --- Explanation: The study explicitly evaluates MMF and azathioprine therapy in chronic hypersensitivity pneumonitis.


CHEBI:8764

[PMID:27816444] [INDIRECT EVIDENCE] [PARTIAL] We aimed to determine the effect of treatment with mycophenolate mofetil (MMF) or azathioprine (AZA) on lung function in patients with cHP. --- Explanation: The study explicitly evaluates MMF and azathioprine therapy in chronic hypersensitivity pneumonitis.


MAXO:0000058

[PMID:37028940] [SUPPORT] Pirfenidone was found to be safe and improved PFS in patients with FHP. --- Explanation: The randomized trial reports improved progression-free survival with pirfenidone in fibrotic hypersensitivity pneumonitis.

[clinicaltrials:NCT02958917] [SUPPORT] The use of pirfenidone has not been approved for the treatment of FHP. It is considered experimental treatment in this study. --- Explanation: The trial registry specifies pirfenidone as the studied treatment in fibrotic hypersensitivity pneumonitis.


CHEBI:32016

[PMID:37028940] [INDIRECT EVIDENCE] [SUPPORT] Pirfenidone was found to be safe and improved PFS in patients with FHP. --- Explanation: The randomized trial reports improved progression-free survival with pirfenidone in fibrotic hypersensitivity pneumonitis.

[clinicaltrials:NCT02958917] [INDIRECT EVIDENCE] [SUPPORT] The use of pirfenidone has not been approved for the treatment of FHP. It is considered experimental treatment in this study. --- Explanation: The trial registry specifies pirfenidone as the studied treatment in fibrotic hypersensitivity pneumonitis.


MAXO:0000058

[PMID:32145830] [SUPPORT] The effect of nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis --- Explanation: The INBUILD subgroup analysis supports nintedanib for progressive fibrosing ILD, including the hypersensitivity pneumonitis subgroup.


CHEBI:85164

[PMID:32145830] [INDIRECT EVIDENCE] [SUPPORT] The effect of nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis --- Explanation: The INBUILD subgroup analysis supports nintedanib for progressive fibrosing ILD, including the hypersensitivity pneumonitis subgroup.


hgnc:7516

[PMID:38309995] [SUPPORT] MUC5B rs35705950 and three neighboring TOLLIP variants (rs3750920, rs111521887, and rs5743894) were associated with increased susceptibility to fHP. --- Explanation: The case-control study reports MUC5B association with susceptibility.


hgnc:16476

[PMID:38309995] [SUPPORT] MUC5B rs35705950 and three neighboring TOLLIP variants (rs3750920, rs111521887, and rs5743894) were associated with increased susceptibility to fHP. --- Explanation: The study identifies TOLLIP variants associated with fibrotic HP.


ECTO:7000098

[PMID:33041192] [SUPPORT] Possible sources of bird antigens are bird breeding, feather products and fertilizer with fowl droppings. --- Explanation: The abstract explicitly lists common avian antigen exposure sources.

[PMID:14503346] [SUPPORT] She had raised two budgerigars for the last 15 years and had been using a feather duvet for one year. --- Explanation: The case report documents direct bird exposure and feather product exposure associated with bird fancier's lung.

[PMID:1053441] [SUPPORT] Among fifty-three Salt Lake City, Utah area pigeon fanciers, 21% were found to have the clinical picture of pigeon breeders' disease. --- Explanation: Pigeon fancier exposure is directly tied to bird fancier's lung in this prevalence study.

[PMID:39958101] [SUPPORT] immune-mediated interstitial lung disease (ILD) resulting from the repeated inhalation of avian proteins found in bird droppings, feathers, and serum. --- Explanation: The case report explicitly identifies avian protein sources (droppings, feathers, serum) as exposure triggers.

[PMID:33318919] [SUPPORT] triggered by exposure to highly antigenic avian proteins excreted in bird droppings and waxy proteins covering feathers of a variety of birds --- Explanation: The case report details avian protein sources in droppings and feathers as causative exposures.

[DOI:10.29262/ram.v72i4.1462] [SUPPORT] Objective: Case series of patients with domestic hypersensitivity pneumonitis, focusing on hidden avian exposures or other non-suspected antigens (feather comforters and pillows). --- Explanation: The case series highlights feather bedding as hidden avian exposure sources linked to HP.


MONDO:0005498

[PMID:31157190] [SUPPORT] The clinical manifestations are flaccid, symmetrical, descending paralysis affecting cranial and peripheral nerves. --- Explanation: The abstract describes descending paralysis as the key clinical manifestation.


MAXO:0000058

[PMID:31157190] [SUPPORT] The only specific treatment is botulinum antitoxin. --- Explanation: The abstract identifies botulinum antitoxin as the specific treatment.


MONDO:0007215

[PMID:11455389] [SUPPORT] Brachydactyly type A-1 (BDA-1; MIM 112500) is characterized by shortening or missing of the middle phalanges --- Explanation: Defines the cardinal phenotype of BDA1.

[PMID:21537345] [SUPPORT] Brachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges --- Explanation: Confirms middle phalanx shortening/absence as the defining feature.


MONDO:0007215

[PMID:11455389] [SUPPORT] characterized by shortening or missing of the middle phalanges --- Explanation: Short middle phalanges are the hallmark skeletal finding.


MONDO:0007215

[PMID:11455389] [INDIRECT EVIDENCE] [SUPPORT] mutations in IHH, which encodes Indian hedgehog, cause BDA-1 --- Explanation: Identifies IHH as the causative gene for BDA1.

[PMID:11455389] [INDIRECT EVIDENCE] [SUPPORT] three heterozygous missense mutations in the region encoding the amino-terminal signaling domain --- Explanation: Mutations cluster in the IHH N-terminal signaling domain.

[PMID:21537345] [INDIRECT EVIDENCE] [SUPPORT] all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation --- Explanation: Demonstrates that BDA1 mutations impair IHH-Patched1 receptor binding and reduce signaling capacity.


MONDO:0007215


MONDO:0007215

[PMID:21537345] [INDIRECT EVIDENCE] [SUPPORT] E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN --- Explanation: Shows that specific BDA1 mutations cause protein instability under physiological conditions.

[PMID:21537345] [INDIRECT EVIDENCE] [SUPPORT] these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation --- Explanation: Establishes the multi-level disruption of Hedgehog signaling as the pathogenic mechanism.


MAXO:0000079


HGNC.SYMBOL:IHH Missense Mutations

[PMID:11455389] [SUPPORT] three heterozygous missense mutations in the region encoding the amino-terminal signaling domain in all affected members of three large, unrelated families --- Explanation: Three independent families with distinct IHH missense mutations establish genotype-phenotype relationship.

[PMID:11455389] [SUPPORT] The three mutant amino acids, which are conserved across all vertebrates and invertebrates studied so far, are predicted to be adjacent on the surface of IHH --- Explanation: Deep evolutionary conservation and surface clustering suggest a critical functional domain.

[PMID:21537345] [SUPPORT] Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1 --- Explanation: Confirms IHH missense mutations as the established cause of BDA1.


MONDO:0015262

[PMID:22791835] [SUPPORT] The six patients had short-trunk short stature that became conspicuous during childhood with normal intelligence and facies. --- Explanation: Documents short-trunk short stature with childhood onset in PAPSS2 brachyolmia.

[PMID:24677493] [SUPPORT] Growth was not affected during early childhood but deteriorated with age in some patients due to increasing spinal involvement. --- Explanation: In AD brachyolmia, short stature can develop progressively as spinal involvement worsens.


MONDO:0015262

[PMID:31313512] [SUPPORT] The radiological findings included platyspondyly, irregular end plates of the elongated vertebral bodies, narrow disc spaces and short over-faced pedicles. --- Explanation: Describes the characteristic radiological pattern of platyspondyly in PAPSS2 brachyolmia.

[PMID:23824674] [SUPPORT] Radiographic features include platyspondyly with rectangular vertebral bodies and irregular end plates --- Explanation: Confirms platyspondyly with irregular endplates as a defining radiographic feature.


MONDO:0015262

[PMID:22791835] [SUPPORT] rectangular vertebral bodies with irregular endplates and narrow intervertebral discs --- Explanation: Describes irregular vertebral endplates as a consistent radiographic finding in PAPSS2 brachyolmia.


MONDO:0015262

[PMID:22791835] [SUPPORT] rectangular vertebral bodies with irregular endplates and narrow intervertebral discs --- Explanation: Narrow intervertebral disc spaces are a consistent feature.


MONDO:0015262

[PMID:18587396] [SUPPORT] a short trunk, scoliosis and mild short stature --- Explanation: Lists scoliosis as a defining clinical feature of brachyolmia.


MONDO:0015262

[PMID:22791835] [SUPPORT] precocious calcification of rib cartilages, short femoral neck, and mildly shortened metacarpals --- Explanation: Short femoral neck is a recurrent radiographic finding in PAPSS2 brachyolmia.


MONDO:0015262

[PMID:23824674] [SUPPORT] metaphyseal changes of the proximal femur, including short femoral neck and striation --- Explanation: Documents proximal femoral metaphyseal changes in PAPSS2 brachyolmia.


MONDO:0015262

[PMID:22791835] [SUPPORT] precocious calcification of rib cartilages, short femoral neck, and mildly shortened metacarpals --- Explanation: Precocious rib cartilage calcification is a characteristic radiographic feature of PAPSS2 brachyolmia.


MONDO:0015262

[PMID:24677493] [SUPPORT] clinical symptoms of brachyolmia became evident by school age with chronic pain in the spine and hips --- Explanation: Documents chronic spinal and hip pain from school age in AD brachyolmia.


MONDO:0015262

[PMID:24677493] [SUPPORT] Affected individuals had a wide range of subjective symptoms with chronic pain in the extremities and the spine, and paresthesias. --- Explanation: Paresthesias are part of the long-term morbidity in AD brachyolmia.


MONDO:0015262

[PMID:25669657] [SUPPORT] an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel --- Explanation: Amelogenesis imperfecta is a consistent feature specifically of the LTBP3-related form.


MONDO:0015262

[PMID:18587396] [INDIRECT EVIDENCE] [SUPPORT] both mutations resulted in a dramatic gain of function characterized by increased constitutive activity --- Explanation: Patch clamp studies in transfected HEK cells demonstrate gain-of-function with increased constitutive and agonist-stimulated channel activity.

[PMID:20605796] [INDIRECT EVIDENCE] [SUPPORT] R616Q channels maintain mechanosensitivity but have greater constitutive activity and no change in unitary conductance or rectification --- Explanation: Single-channel analysis confirms the R616Q mutant is directly mechanosensitive with increased constitutive activity.

[PMID:31387748] [INDIRECT EVIDENCE] [SUPPORT] TRPV4-Wt but not the TRPV4-R616Q localizes preferably in cholesterol-enriched lipid rafts in osteogenic cell line Saos2 --- Explanation: Demonstrates that the R616Q mutation disrupts cholesterol binding and lipid raft localization.


MONDO:0015262

[PMID:18587396] [INDIRECT EVIDENCE] [SUPPORT] we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern --- Explanation: TRPV4 was identified as a candidate gene because of its cartilage-selective expression, linking gain-of-function to skeletal dysplasia.

[PMID:31387748] [INDIRECT EVIDENCE] [SUPPORT] TRPV4 is expressed in Mesenchymal stem cells and the localization of TRPV4 in lipid raft is dependent on temperature and cholesterol --- Explanation: Confirms TRPV4 expression in bone cell lineages relevant to skeletal development.


MONDO:0015262


MONDO:0015262

[PMID:22791835] [INDIRECT EVIDENCE] [SUPPORT] identified its disease gene, PAPSS2 (phosphoadenosine-phosphosulfate synthetase 2) --- Explanation: Identifies PAPSS2 as the disease gene, establishing the sulfation pathway defect.

[PMID:23824674] [INDIRECT EVIDENCE] [SUPPORT] In vitro enzyme assays showed that the missense mutations were also loss-of-function mutations. --- Explanation: Functional enzyme assays confirm that PAPSS2 missense mutations cause loss of function.


MONDO:0015262

[PMID:23824674] [INDIRECT EVIDENCE] [SUPPORT] PAPSS2-brachyolmia includes phenotypes of the conventional clinical concept of brachyolmia, the Hobaek and Toledo types, and is associated with abnormal androgen metabolism --- Explanation: Links PAPSS2 mutations to the historical brachyolmia types, supporting cartilage ECM disruption as the pathogenic mechanism.

[PMID:19369399] [INDIRECT EVIDENCE] [SUPPORT] bm limb growth plates showed diminished Indian hedgehog (Ihh) signaling and abnormal Ihh protein distribution in the extracellular matrix --- Explanation: The brachymorphic (Papss2 mutant) mouse demonstrates that chondroitin sulfate undersulfation disrupts Ihh signaling in growth plates.

[PMID:19369399] [INDIRECT EVIDENCE] [SUPPORT] BrdU incorporation exhibited a significant reduction in chondrocyte proliferation --- Explanation: Reduced chondrocyte proliferation in Papss2 mutant growth plates is a direct consequence of diminished Ihh signaling.


MONDO:0015262

[PMID:31313512] [INDIRECT EVIDENCE] [SUPPORT] Low serum DHEAS, but not overt androgen excess was identified. --- Explanation: Low DHEAS reflects impaired steroid sulfation as a parallel consequence of PAPS deficiency.


MONDO:0015262

[PMID:25669657] [INDIRECT EVIDENCE] [SUPPORT] an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel --- Explanation: The brachyolmia component reflects disrupted TGF-beta signaling in skeletal tissue.


MONDO:0015262

[PMID:25669657] [INDIRECT EVIDENCE] [SUPPORT] an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel --- Explanation: The amelogenesis imperfecta component reflects disrupted TGF-beta signaling in dental tissue.


MONDO:0015262

[PMID:22791835] [INDIRECT EVIDENCE] [SUPPORT] Brachyolmia is a heterogeneous group of skeletal dysplasias that primarily affects the spine. --- Explanation: Confirms that brachyolmia primarily affects the spine across genetic subtypes.


hgnc:18083

[PMID:18587396] [SUPPORT] In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. --- Explanation: Identifies the two causative TRPV4 mutations in autosomal dominant brachyolmia.


hgnc:8604

[PMID:23824674] [SUPPORT] we extended our PAPSS2 mutation analysis to 13 patients from 10 families and identified homozygous or compound heterozygous mutations in all --- Explanation: Establishes genetic heterogeneity with multiple loss-of-function mutation types in PAPSS2.

[PMID:31313512] [SUPPORT] In all patients, exome and Sanger sequencing identified homozygous or compound heterozygous PAPSS2 variants, including c.809G>A, common to white European patients. --- Explanation: Confirms PAPSS2 mutations across diverse ethnic backgrounds with a common European variant.


hgnc:6716

[PMID:25669657] [SUPPORT] recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene --- Explanation: Identifies multiple types of LTBP3 loss-of-function mutations across four families.


MONDO:0015262

[PMID:18587396] [SUPPORT] In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. --- Explanation: Documents autosomal dominant inheritance with heterozygous TRPV4 mutations in two families.


MONDO:0015262

[PMID:22791835] [SUPPORT] The patients had a homozygous loss of function mutation, c.337_338insG (p.A113GfsX18). --- Explanation: Demonstrates autosomal recessive inheritance with homozygous PAPSS2 mutations.

[PMID:25669657] [SUPPORT] Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta --- Explanation: Consanguineous families support autosomal recessive inheritance for the LTBP3 form.


MONDO:0015262

[PMID:31313512] [SUPPORT] Low serum DHEAS, but not overt androgen excess was identified. --- Explanation: Confirms low DHEAS as a biochemical marker of PAPSS2 deficiency.


MONDO:0002056

[PMID:11270760] [SUPPORT] Fibroadenoma of the breast is a common cause of a benign breast lump in premenopausal women. --- Explanation: The abstract identifies a benign breast lump as the typical presentation.


MAXO:0000004

[PMID:11270760] [SUPPORT] Traditionally, symptomatic fibroadenomas were treated by surgical excision, and this option should always be offered. --- Explanation: The abstract states surgical excision as a traditional treatment option.


MAXO:0000950

[PMID:11270760] [SUPPORT] There is increasing evidence that a conservative approach is safe and acceptable, provided the result of an adequate triple test is both negative for cancer and consistent with a fibroadenoma. --- Explanation: The abstract supports conservative management in appropriate cases.


HGNC.SYMBOL:MED12

[PMID:25855048] [SUPPORT] Somatic mutations in exon 2 of the mediator complex subunit 12 (MED12) gene have been identified in 60% of breast fibroadenomas (FAs). --- Explanation: The abstract reports frequent MED12 somatic mutations in fibroadenomas.


MONDO:0004822


MAXO:0000011


MAXO:0000058


MAXO:0000312


MAXO:0000004


MAXO:0001017


HGNC.SYMBOL:CFTR


HGNC.SYMBOL:SCNN1A


ECTO:8000036


ECTO:6000029


MONDO:0007243


MONDO:0007243

[PMID:40893393] [INDIRECT EVIDENCE] [SUPPORT] Burkitt lymphoma (BL) is an aggressive B-cell malignancy characterized by rapid progression and MYC gene translocations. --- Explanation: This abstract directly identifies MYC translocations as a defining feature of Burkitt lymphoma.

[PMID:1301171] [INDIRECT EVIDENCE] [SUPPORT] In about 80% of Burkitt's lymphoma cases, the tumour cell harbours a reciprocal chromosomal translocation which invariably transposes the coding exons 2 and 3 of c-myc from chromosome 8 to the immunoglobulin heavy chain locus on chromosome 14. --- Explanation: Abstract reports MYC translocation to immunoglobulin loci in most Burkitt lymphoma cases.


MAXO:0000647


NCIT:C1702


MAXO:0000950


NCIT:C224


NCIT:C2404


HGNC.SYMBOL:MYC


HGNC.SYMBOL:TP53


HGNC.SYMBOL:ID3


HGNC.SYMBOL:TCF3


NCBITaxon:10376

[PMID:7797201] [SUPPORT] There is a strong association (approximately 95%) of endemic Burkitt's lymphoma with Epstein-Barr virus (EBV) --- Explanation: Abstract reports high EBV association in endemic Burkitt lymphoma.


MONDO:0007243

[PMID:36522349] [SUPPORT] Burkitt lymphoma (BL) is an aggressive form of B cell lymphoma that can affect --- Explanation: Abstract describes Burkitt lymphoma as an aggressive B-cell lymphoma.


MONDO:0000327

[PMID:19362692] [SUPPORT] Buruli ulcer is an indolent necrotizing disease of the skin, subcutaneous tissue, and bone --- Explanation: The disease is defined by necrotizing skin disease with ulceration.


MAXO:0000058

[PMID:21240839] [SUPPORT] While antimycobacterial therapy is often effective for the earliest nodular or ulcerative lesions --- Explanation: The abstract describes antimycobacterial therapy effectiveness in early lesions.


MAXO:0000004

[PMID:21240839] [SUPPORT] for advanced ulcerated lesions, surgery is sometimes necessary. --- Explanation: The abstract notes surgery for advanced lesions.


NCBITaxon:1809

[PMID:21240839] [SUPPORT] Buruli ulcer (BU), caused by Mycobacterium ulcerans --- Explanation: The abstract identifies M. ulcerans as the cause of Buruli ulcer.


MONDO:0100254

[PMID:39110218] [SUPPORT] Developmental delay and episodic symptoms were the first disease manifestation in 9/41 (22%) and 32/41 (78%) patients respectively. --- Explanation: In the Austrian natural history cohort, episodic symptoms (including ataxia) were the first manifestation in 78% of patients.


MONDO:0100254

[PMID:39110218] [SUPPORT] Chronic neurological signs encompassed a cerebellar syndrome in 35/41 (85%), which showed almost no progression during the observation period --- Explanation: 85% of patients in the Austrian cohort had a chronic cerebellar syndrome, though progression was minimal during follow-up in non-polyQ cases.


MONDO:0100254

[PMID:39110218] [SUPPORT] Chronic neurological signs encompassed a cerebellar syndrome in 35/41 (85%), which showed almost no progression during the observation period --- Explanation: Nystagmus is a hallmark component of the chronic cerebellar syndrome seen in 85% of non-polyQ CACNA1A patients.


MONDO:0100254

[PMID:39110218] [SUPPORT] Non-polyglutamine CACNA1A variants underlie an extremely variable phenotypic spectrum encompassing developmental delay, hemiplegic migraine, epilepsy, psychiatric symptoms, episodic and chronic cerebellar signs. --- Explanation: Hemiplegic migraine is a key component of the non-polyQ CACNA1A phenotypic spectrum.


MONDO:0100254

[PMID:37555011] [SUPPORT] The epileptic manifestations included status epilepticus (n = 64), provoked seizures (n = 49), focal seizures (n = 37), EE (n = 29), absence seizures (n = 26), and myoclonic seizures (n = 10). --- Explanation: Systematic review of 130 epileptic patients showing the broad seizure spectrum, with status epilepticus as the most common manifestation.

[PMID:37555011] [SUPPORT] Status epilepticus correlated with variants located on S4, S5, and S6 (p = 0.000). --- Explanation: Genotype-phenotype correlation showing that variant location within channel transmembrane segments predicts status epilepticus risk.


MONDO:0100254

[PMID:39110218] [SUPPORT] Chronic neurological signs encompassed a cerebellar syndrome in 35/41 (85%), which showed almost no progression during the observation period --- Explanation: Dysarthria is a component of the chronic cerebellar syndrome seen in 85% of patients in the Austrian natural history cohort.


MONDO:0100254

[PMID:39110218] [SUPPORT] Chronic neurological signs encompassed a cerebellar syndrome in 35/41 (85%), which showed almost no progression during the observation period --- Explanation: Cerebellar atrophy on MRI is a hallmark finding in CACNA1A disease; the Austrian cohort showed chronic cerebellar signs in 85% of patients.


MONDO:0100254

[PMID:37555011] [SUPPORT] About 187 individuals with GDD/ID harboring 123 variants were found (case series plus data from literature). --- Explanation: Large systematic aggregation confirming intellectual disability as a prominent feature across CACNA1A variants.

[PMID:37555011] [SUPPORT] GOF variants were linked with severe-profound GDD/ID while LOF variants were associated with mild-moderate GDD/ID (p = 0.001). --- Explanation: Demonstrates genotype-phenotype correlation for intellectual disability severity based on variant functional class.


MONDO:0100254

[PMID:39110218] [SUPPORT] cognitive deficits in 9/20 (45%, MOCA test score < 26) --- Explanation: 45% of tested patients in the Austrian non-polyQ cohort had cognitive deficits on standardized testing.


MONDO:0100254

[PMID:39110218] [SUPPORT] psychiatric and behavioral symptoms in 11/41(27%). --- Explanation: Approximately 27% of patients in the Austrian cohort had psychiatric or behavioral symptoms.


MONDO:0100254

[PMID:38681799] [INDIRECT EVIDENCE] [SUPPORT] This gene encodes the α1 subunit of the P/Q-type calcium channel Cav2.1, which is globally expressed in the brain and crucial for fast synaptic neurotransmission. --- Explanation: Confirms CACNA1A encodes the Cav2.1 P/Q-type calcium channel subunit essential for synaptic transmission.

[PMID:36592223] [INDIRECT EVIDENCE] [SUPPORT] In the last decade, variants in the Ca2+ channel gene CACNA1A emerged as a frequent aetiology of rare neurological phenotypes sharing a common denominator of variable paroxysmal manifestations and chronic cerebellar dysfunction. --- Explanation: Confirms that CACNA1A variants cause cerebellar dysfunction through calcium channel disruption.


MONDO:0100254


MONDO:0100254

[PMID:36592223] [INDIRECT EVIDENCE] [SUPPORT] The spectrum of paroxysmal manifestations encompasses migraine with hemiplegic aura, episodic ataxia, epilepsy and paroxysmal non-epileptic movement disorders. --- Explanation: FHM1 with hemiplegic aura is a hallmark paroxysmal feature driven by gain-of-function CACNA1A variants and cortical spreading depression.


MONDO:0100254

[PMID:38286873] [INDIRECT EVIDENCE] [SUPPORT] Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that manifests in midlife and progressively worsens with age. --- Explanation: Confirms SCA6 as a progressive neurodegenerative process caused by CACNA1A polyglutamine expansion.


MONDO:0100254

[PMID:38286873] [INDIRECT EVIDENCE] [SUPPORT] We explored mitochondrial function and structure and observed that changes in mitochondrial structure preceded changes in function, and that mitochondrial function was not significantly altered at disease onset but was impaired later during disease progression. --- Explanation: Demonstrates that mitochondrial structural changes precede functional decline in SCA6 mouse model.

[PMID:38286873] [INDIRECT EVIDENCE] [SUPPORT] In addition, we observed impairment in mitophagy that exacerbates mitochondrial dysfunction at late disease stages. --- Explanation: Confirms impaired mitophagy as a contributor to disease progression in SCA6.

[PMID:38286873] [INDIRECT EVIDENCE] [SUPPORT] In post-mortem SCA6 patient cerebellar tissue, we observed metabolic changes that are consistent with mitochondrial impairments, supporting our results from animal models being translatable to human disease. --- Explanation: Post-mortem human data supports that mitochondrial dysfunction translates from the animal model to human SCA6.


MONDO:0100254

[PMID:38681799] [INDIRECT EVIDENCE] [SUPPORT] The spectrum of CACNA1A-related seizures is broad across both loss-of-function and gain-of-function variants and includes absence seizures, focal seizures with altered consciousness, generalized tonic-clonic seizures, tonic seizures, status epilepticus, and infantile spasms. --- Explanation: Confirms the broad seizure spectrum across both LOF and GOF variants.

[PMID:38681799] [INDIRECT EVIDENCE] [SUPPORT] Furthermore, over half of CACNA1A-related epilepsies are refractory to current therapies. --- Explanation: Confirms the high rate of treatment-refractory epilepsy in CACNA1A-related DEE.

[PMID:37555011] [INDIRECT EVIDENCE] [SUPPORT] About 49 (42.20%) patients had controlled seizures while 67 (57.80%) individuals remained with refractory seizures. --- Explanation: Systematic aggregation confirming 57.8% of CACNA1A epilepsy patients have refractory seizures.


MAXO:0000058

[PMID:34484942] [SUPPORT] Compared with placebo, fampridine reduced the number of attacks to 63% (95% CI 54%-74%) and acetazolamide to 52% (95% CI 46%-60%). --- Explanation: Phase III RCT demonstrating acetazolamide significantly reduces EA2 attack frequency vs placebo.

[PMID:39110218] [SUPPORT] At the last visit, 27/41 patients (66%) required an interval prophylaxis (including acetazolamide, flunarizine, 4-aminopyridine, topiramate), which was efficacious in reducing the frequency and severity of episodic symptoms in all cases. --- Explanation: Real-world cohort data confirming efficacy of interval prophylaxis including acetazolamide.


MAXO:0000058

[PMID:34484942] [SUPPORT] Compared with placebo, fampridine reduced the number of attacks to 63% (95% CI 54%-74%) and acetazolamide to 52% (95% CI 46%-60%). --- Explanation: Phase III RCT demonstrating fampridine significantly reduces EA2 attack frequency vs placebo.

[PMID:34484942] [SUPPORT] Fampridine 10 mg twice daily had fewer side effects than acetazolamide 250 mg 3 times daily. --- Explanation: Fampridine had a more favorable side effect profile than acetazolamide in the RCT.


MAXO:0000058

[PMID:39110218] [SUPPORT] In one patient in his 70ies with progressively therapy resistant hemiplegic migraine, treatment with the anti-CGRP antibody galcanezumab successfully reduced the frequency of migraine days from 4 to 1/month. --- Explanation: Case report of galcanezumab efficacy in therapy-resistant CACNA1A-related hemiplegic migraine.


hgnc:1388

[PMID:38681799] [SUPPORT] To date, almost 1700 CACNA1A variants have been reported in ClinVar, with over 400 listed as Pathogenic or Likely Pathogenic, but with limited-to-no clinical or functional data. --- Explanation: Confirms the large number of known CACNA1A variants and the challenge of variant interpretation.

[PMID:39110218] [SUPPORT] We recruited 41 subjects with non-polyglutamine CACNA1A disease, of which 38 (93%) familial cases. --- Explanation: High familial rate (93%) supports autosomal dominant inheritance pattern.


MONDO:0007432

[DOI:10.3389/fneur.2025.1573052] [SUPPORT] The clinical manifestations of CADASIL include migraines, recurrent ischemic stroke, progressive cognitive deterioration, and psychiatric symptoms. --- Explanation: This review confirms recurrent ischemic stroke as a core clinical manifestation of CADASIL.

[PMID:30855338] [NO_EVIDENCE] CADASIL is a genotypically and phenotypically diverse condition involving multiple molecular systems affecting small blood vessels. --- Explanation: This review confirms CADASIL as a small vessel disease affecting cerebral vasculature, consistent with lacunar stroke pathology.


MONDO:0007432

[DOI:10.3389/fneur.2025.1573052] [PARTIAL] The clinical manifestations of CADASIL include migraines, recurrent ischemic stroke, progressive cognitive deterioration, and psychiatric symptoms. --- Explanation: This review lists migraines as a core clinical manifestation of CADASIL.


MONDO:0007432

[DOI:10.3389/fneur.2025.1573052] [SUPPORT] The clinical manifestations of CADASIL include migraines, recurrent ischemic stroke, progressive cognitive deterioration, and psychiatric symptoms. --- Explanation: This review confirms progressive cognitive deterioration as a core CADASIL phenotype.

[DOI:10.3389/fneur.2025.1662012] [SUPPORT] CADASIL is an autosomal dominant disorder characterized by midlife-onset cerebrovascular disease and dementia. --- Explanation: This review describes dementia as a defining feature of CADASIL.


MONDO:0007432

[DOI:10.3389/fneur.2025.1573052] [PARTIAL] The clinical manifestations of CADASIL include migraines, recurrent ischemic stroke, progressive cognitive deterioration, and psychiatric symptoms. --- Explanation: Psychiatric symptoms, including mood disturbances, are listed as a core clinical manifestation of CADASIL.


MONDO:0007432

[DOI:10.3389/fneur.2025.1573052] [SUPPORT] The most prevalent and earliest imaging alterations in CADASIL are white matter hyperintensities in the periventricular white matter, temporal pole, external capsule, frontoparietal white matter, and other areas on magnetic resonance imaging. --- Explanation: This review confirms white matter hyperintensities in characteristic locations as the most prevalent and earliest imaging finding in CADASIL.

[PMID:30855338] [SUPPORT] Cerebral white matter changes observed by MRI are a key CADASIL characteristic in young adult patients often before severe symptoms and trigger NOTCH3 genetic testing. --- Explanation: This review confirms cerebral white matter MRI changes as a key early CADASIL characteristic that often prompts genetic testing.


MONDO:0007432

[DOI:10.3389/fneur.2025.1662012] [NO_EVIDENCE] CADASIL is an autosomal dominant disorder characterized by midlife-onset cerebrovascular disease and dementia. It is caused by mutations in the NOTCH3 gene, which affects the amount of cysteine in the extracellular domain (ECD) of the receptor, leading to protein misfolding and receptor aggregation. --- Explanation: Leukoencephalopathy is part of the disease name and a defining feature, supported by the progressive white matter injury from NOTCH3-driven vasculopathy.


MONDO:0007432

[DOI:10.3389/fneur.2025.1662012] [SUPPORT] CADASIL is an autosomal dominant disorder characterized by midlife-onset cerebrovascular disease and dementia. --- Explanation: Dementia is identified as a defining characteristic of CADASIL.


MONDO:0007432

[DOI:10.3389/fneur.2025.1573052] [PARTIAL] The clinical manifestations of CADASIL include migraines, recurrent ischemic stroke, progressive cognitive deterioration, and psychiatric symptoms. --- Explanation: Apathy is a common psychiatric symptom in CADASIL, grouped under the broader psychiatric manifestations.


MONDO:0007432

[DOI:10.3389/fneur.2025.1573052] [NO_EVIDENCE] The clinical manifestations of CADASIL include migraines, recurrent ischemic stroke, progressive cognitive deterioration, and psychiatric symptoms. --- Explanation: Gait disturbance results from cumulative subcortical ischemic injury in CADASIL, consistent with the progressive motor disability described in this review.


MONDO:0007432

[PMID:38386425] [INDIRECT EVIDENCE] [SUPPORT] wild-type Notch3ECD coaggregated with mutant Notch3ECD and that elimination of 1 copy of wild-type Notch3 in TgNotch3R169C was sufficient to attenuate Notch3ECD accumulation and arterial pathology. These findings suggest that Notch3ECD accumulation, involving mutant and wild-type NOTCH3, is a major driver of arterial SMC loss in CADASIL, paving the way for NOTCH3-lowering therapeutic strategies. --- Explanation: This study demonstrates that wild-type and mutant NOTCH3 ECD co-aggregate, and that reducing wild-type NOTCH3 attenuates both ECD accumulation and arterial pathology in a mouse model, supporting aggregation-driven toxicity as a major disease mechanism.

[DOI:10.3390/biom14010127] [INDIRECT EVIDENCE] [SUPPORT] CADASIL caused by NOTCH3 is adult-onset and considered to be caused by accumulation of the mutant NOTCH3 extracellular domain (N3ECD) and, possibly, by an impairment in Notch signaling. --- Explanation: This review confirms the dual-mechanism framework for CADASIL: N3ECD accumulation combined with possible Notch signaling impairment.


MONDO:0007432


MONDO:0007432

[PMID:30855338] [INDIRECT EVIDENCE] [SUPPORT] Granular osmiophilic material deposits around blood vessels are also a unique CADASIL feature and appear to have a role in sequestering proteins that are essential for blood vessel homeostasis. --- Explanation: This review confirms GOM deposits as a unique pathological feature of CADASIL that sequesters proteins important for vascular homeostasis.

[DOI:10.3389/fnmol.2024.1391040] [INDIRECT EVIDENCE] [SUPPORT] The NOTCH3 R75Q mouse model showed pathological characteristics of CADASIL, with age-dependent NOTCH3ECD, granular osmiophilic material, and degenerated smooth muscle cells detected in the brain. --- Explanation: The NOTCH3 R75Q knock-in mouse model recapitulates GOM deposition and smooth muscle cell degeneration in an age-dependent manner, confirming the link between GOM accumulation and VSMC loss.


MONDO:0007432

[PMID:38386425] [INDIRECT EVIDENCE] [SUPPORT] Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation of the extracellular domain of the NOTCH3 receptor (Notch3ECD) are the 2 core features of CADASIL, a common cerebral small vessel disease caused by highly stereotyped dominant mutations in NOTCH3. --- Explanation: This paper identifies arterial smooth muscle cell loss and NOTCH3 ECD accumulation as the two core pathological features of CADASIL.


MONDO:0007432

[DOI:10.3390/jcm13113138] [INDIRECT EVIDENCE] [SUPPORT] Significant differences in protein expression were observed between CADASIL patients and controls. RSPO1 and FGF-19 exhibited elevated levels (p < 0.05), while PPY showed downregulation (p < 0.05) in CADASIL patients, suggesting their involvement in disease pathogenesis. --- Explanation: Proteomic analysis identifies differentially expressed proteins in CADASIL plasma with enrichment of complement/inflammatory and ECM organization pathways.


MAXO:0000058


MAXO:0000950


MAXO:0000079


hgnc:7883

[DOI:10.3389/fneur.2025.1662012] [SUPPORT] It is caused by mutations in the NOTCH3 gene, which affects the amount of cysteine in the extracellular domain (ECD) of the receptor, leading to protein misfolding and receptor aggregation. Emerging evidence indicates that beyond classical missense mutations, other variants including cysteine-sparing missense mutations, homozygous mutations, small deletions, duplications, splice site mutations, a deletion/insertion and loss-of-function mutations may lead to distinct phenotypes with variable severity and disease penetrance. --- Explanation: This review confirms NOTCH3 mutations as causative and describes the expanding spectrum of pathogenic variants beyond classical cysteine-altering mutations.

[PMID:30855338] [SUPPORT] NOTCH3 mutation locations are highly variable, correlate to disease severity and consistently affect the cysteine balance within extracellular Notch3. --- Explanation: This review confirms that NOTCH3 mutations consistently affect cysteine balance and that mutation location correlates with disease severity.

[DOI:10.3389/fnmol.2024.1391040] [SUPPORT] We demonstrate that NOTCH3ECD induced by NOTCH3 R75Q mutation has toxic effects on cells and reveal the deposition characteristics of NOTCH3ECD in the brain. This provides a feasible model and lays the foundation for further studies on the pathogenesis and therapeutic strategies of NOTCH3 cysteine-sparing mutations. --- Explanation: This study provides in vitro and in vivo evidence that the cysteine-sparing NOTCH3 R75Q mutation is pathogenic, expanding the spectrum of causative NOTCH3 variants.


MONDO:0010221

[PMID:22444671] [SUPPORT] CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies --- Explanation: Landmark PIGL mutation study identifying coloboma as a cardinal diagnostic feature of CHIME syndrome.


MONDO:0010221

[PMID:22444671] [SUPPORT] CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies --- Explanation: PIGL mutations cause cardiac defects as a cardinal feature of CHIME syndrome, requiring cardiac surveillance in affected individuals.


MONDO:0010221

[PMID:22444671] [SUPPORT] CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies --- Explanation: Landmark study identifying migratory ichthyosiform dermatosis as a defining feature of PIGL-related CHIME syndrome.


MONDO:0010221

[PMID:22444671] [SUPPORT] CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies --- Explanation: Landmark study establishing intellectual disability as a defining feature of CHIME syndrome caused by PIGL mutations.


MONDO:0010221

[PMID:22444671] [SUPPORT] CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies, including conductive hearing loss --- Explanation: Landmark PIGL mutation study documenting conductive hearing loss and ear anomalies as defining features of CHIME syndrome.


MONDO:0010221

[PMID:7666399] [SUPPORT] The main features include ocular colobomas, congenital heart disease, early onset migratory ichthyosiform dermatosis, mental retardation, conductive hearing loss, seizures, and typical facial features. --- Explanation: Early case series documenting seizures as a defining feature of CHIME syndrome alongside cardinal features.

[PMID:7666399] [SUPPORT] Long term follow up information on this patient, as well as the previously described cases, provides information regarding the outcome for these patients, which includes general good health, severe mental retardation, seizures that worsen after puberty, conductive hearing loss, and chronic migratory ichthyosiform skin rash without scarring. --- Explanation: Long-term follow-up data documenting that seizures are a persistent feature that may worsen after puberty in CHIME syndrome.


MONDO:0010221

[PMID:7666399] [SUPPORT] The main features include ocular colobomas, congenital heart disease, early onset migratory ichthyosiform dermatosis, mental retardation, conductive hearing loss, seizures, and typical facial features. --- Explanation: Early case series identifying typical facial features as a consistent manifestation of CHIME syndrome.


MONDO:0010221


MONDO:0010221

[PMID:9295069] [SUPPORT] Her major problems included a migratory ichthyosiform dermatosis, multiple skin infections and infestations, bilateral retinal coloboma, developmental delay, seizures, infantile macrosomia, facial anomalies, a duplicated renal collecting system, and conductive hearing loss. --- Explanation: Schnur et al. 1997 documents infantile macrosomia as a clinical feature in a CHIME syndrome patient, expanding the growth-related phenotype spectrum.


MONDO:0010221

[PMID:22444671] [INDIRECT EVIDENCE] [SUPPORT] CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies, including conductive hearing loss. Whole-exome sequencing on five previously reported cases identified PIGL, the de-N-acetylase required for glycosylphosphatidylinositol (GPI) anchor formation, as a strong candidate. --- Explanation: Establishes PIGL mutations as the cause of CHIME syndrome and describes the gene's role in GPI anchor biosynthesis.


MONDO:0010221

[PMID:22444671] [INDIRECT EVIDENCE] [SUPPORT] Furthermore, cell lines derived from these cases had significantly reduced levels of the two GPI anchor markers, CD59 and a GPI-binding toxin, aerolysin (FLAER), confirming the pathogenicity of the mutations. --- Explanation: Demonstrates functional consequences of PIGL mutations showing reduced GPI anchor markers in patient cells.


MAXO:0000004


MAXO:0000058

[PMID:38773877] [SUPPORT] Here, we report a case of severe ichthyosiform dermatosis in a child with CHIME syndrome who was recalcitrant to multiple topical medications and dupilumab. This is the first reported case of successful treatment of congenital ichthyosiform dermatosis in a CHIME syndrome patient with ixekizumab, an IL-17A antagonist. --- Explanation: Flowers et al. 2024 documents the first successful treatment of severe ichthyosiform dermatosis in CHIME syndrome using ixekizumab (IL-17A antagonist), providing a therapeutic option for treatment-resistant cases.


MAXO:0000077


HGNC.SYMBOL:PIGL

[PMID:22444671] [SUPPORT] Whole-exome sequencing on five previously reported cases identified PIGL, the de-N-acetylase required for glycosylphosphatidylinositol (GPI) anchor formation, as a strong candidate. --- Explanation: Identifies PIGL as the causal gene for CHIME syndrome through whole-exome sequencing.

[PMID:28371479] [SUPPORT] CHIME syndrome is a rare autosomal recessive neuroectodermal disorder associated with biallelic mutations in PIGL. To date, six molecularly confirmed cases of CHIME syndrome have been reported. Here, we report the seventh patient with biallelic PIGL mutations associated with CHIME syndrome and describe the first characterization of an intragenic deletion in PIGL. --- Explanation: Knight Johnson et al. 2017 documents the first Alu-mediated intragenic deletion in PIGL as a disease-causing mechanism in CHIME syndrome, expanding the mutation spectrum beyond point mutations.

[PMID:29473937] [SUPPORT] In CHIME syndrome, a recurrent missense mutation c.500T > C (p.Leu167Pro) is found in the majority of patients, associated with a null mutation in the other allele, including an overrepresentation of large deletions. The latter are not detected by the standard analysis in sequencing techniques, including next-generation sequencing. Thus, in individuals with a clinical diagnosis of CHIME syndrome in which only one mutation is found, an active search for a large deletion should be sought. --- Explanation: Ceroni et al. 2018 establishes that large deletions are a common mutational mechanism in CHIME syndrome, often missed by standard sequencing, and recommends active screening for deletions in diagnostic workup.

[PMID:35258128] [SUPPORT] A novel 'likely pathogenic' PIGL missense variant (c.154G>A, p.(Asp52Asn)) was detected on the maternal allele. This case provides new insights into the clinical spectrum of CHIME syndrome and highlights the potential for phenotypic/genotypic variations. --- Explanation: Rolland et al. 2022 documents a novel p.(Asp52Asn) PIGL variant and demonstrates phenotypic heterogeneity in CHIME syndrome, including mild phenotypes with atypical features, emphasizing genotype-phenotype variation.


MONDO:0011776

[PMID:16899778] [SUPPORT] All 18 patients had a rapid response to anakinra, with disappearance of rash. --- Explanation: All 18 NOMID patients in the landmark NEJM trial had urticarial rash at baseline which resolved rapidly with anakinra, confirming universality and IL-1 dependence of this phenotype.

[PMID:38481988] [SUPPORT] The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%). --- Explanation: Chinese NLRP3-AID cohort of 9 patients confirming rash in 100% of cases, consistent with OBLIGATE frequency across different populations.


MONDO:0011776

[PMID:16899778] [SUPPORT] Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. --- Explanation: NEJM trial establishing fever as a cardinal feature of NOMID/CINCA.

[PMID:38481988] [SUPPORT] The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%). --- Explanation: Chinese NLRP3-AID cohort showing fever in 77.8% of patients, consistent with VERY_FREQUENT classification.


MONDO:0011776

[PMID:16899778] [SUPPORT] Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. --- Explanation: NEJM trial identifying deforming arthropathy as a cardinal feature of NOMID/CINCA.

[PMID:38481988] [SUPPORT] The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%). --- Explanation: Chinese NLRP3-AID cohort showing arthritis/arthralgia in 88.9% (8/9) of patients, with two CINCA cases also having clubbed fingers.


MONDO:0011776

[PMID:16899778] [SUPPORT] Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. --- Explanation: NEJM trial establishing chronic aseptic meningitis as a hallmark neurological manifestation of NOMID/CINCA.

[PMID:37548074] [SUPPORT] These, along with significant cerebral atrophy, ventriculomegaly, and an absence of other injuries, raised concerns for a genetic disorder, prompting genetic consultation. --- Explanation: Case report of an infant with CINCA/NOMID presenting with subdural hemorrhage, macrocephaly, cerebral atrophy, and ventriculomegaly secondary to chronic CNS inflammation, initially raising suspicion of abusive head trauma.

[PMID:34059097] [SUPPORT] the examination of the cerebrospinal fluid (CSF) showed a WBC cell count of 667 /µL (polymorphonuclear: mononuclear 4:1), glucose at 21 mg/dL, and protein at 191 mg/dL --- Explanation: Neonatal case documenting severe CSF pleocytosis (667 cells) with neutrophilic predominance, hypoglycorrhachia, and markedly elevated protein at birth, confirming intrauterine-onset aseptic meningitis.


MONDO:0011776

[PMID:16899778] [SUPPORT] Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. --- Explanation: NEJM trial documenting cochlear inflammatory lesions on MRI in NOMID patients that improved with anakinra, linking hearing loss to reversible cochlear inflammation.


MONDO:0011776

[PMID:37809096] [SUPPORT] Among these novel mutations, percentages of severe musculoskeletal, ophthalmologic, and neurological symptoms were higher compared with other case serials. --- Explanation: Large pediatric CAPS cohort confirming high prevalence of ophthalmologic involvement including papilledema in severe CAPS phenotypes.


MONDO:0011776

[PMID:16899778] [SUPPORT] Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. --- Explanation: NEJM description of NOMID encompassing growth retardation and developmental delay as part of the multisystem disease burden.

[PMID:38481988] [SUPPORT] The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%). --- Explanation: Chinese NLRP3-AID cohort documenting growth retardation in 44.4% of patients, consistent with FREQUENT frequency classification.

[PMID:37548074] [SUPPORT] multidisciplinary evaluation identified multiple abnormalities, including rash, macrocephaly, growth failure, and elevated inflammatory markers, which were all atypical for trauma. --- Explanation: Case report documenting growth failure as part of the clinical presentation of CINCA/NOMID in an infant.


MONDO:0011776

[PMID:31077002] [SUPPORT] Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder characterized by systemic, cutaneous, musculoskeletal, and central nervous system inflammation. --- Explanation: Review characterizing CAPS as a systemic inflammatory disorder with widespread organ involvement including hepatosplenomegaly from reticuloendothelial activation.

[PMID:34059097] [SUPPORT] She also exhibited atypical symptoms such as severe hepatosplenomegaly with cholestasis. --- Explanation: Case report documenting severe hepatosplenomegaly with cholestasis as a neonatal manifestation of CINCA/NOMID, which gradually improved in parallel with decreasing inflammatory markers after canakinumab treatment.


MONDO:0011776

[PMID:37809096] [SUPPORT] Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10-20 months follow-up. --- Explanation: Pediatric cohort confirming visual manifestations (including uveitis) as a major disease domain in severe CAPS responsive to IL-1 blockade.


MONDO:0011776

[PMID:31077002] [INDIRECT EVIDENCE] [SUPPORT] Gain-of-function mutations in NLRP3 in CAPS patients lead to activation of the cryopyrin inflammasome, resulting in the inappropriate release of inflammatory cytokines including IL-1beta and CAPS-related inflammatory symptoms. --- Explanation: Review describing constitutive inflammasome activation as the central pathogenic mechanism in CAPS, with gain-of-function mutations driving inappropriate caspase-1 activation and cytokine release.

[DOI:10.1111/imr.13292] [INDIRECT EVIDENCE] [SUPPORT] Activated by a panoply of pathogen-associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18. --- Explanation: Review detailing normal and pathological NLRP3 inflammasome assembly mechanisms, including ASC speck formation and regulatory nodes disrupted by CAPS mutations.

[PMID:39816134] [INDIRECT EVIDENCE] [SUPPORT] Dysregulated NLRP3 activation has been implicated in a variety of autoimmune and inflammatory diseases, including cryopyrin-associated periodic fever syndromes, diabetes, atherosclerosis, Alzheimer's disease, inflammatory bowel disease, and cancer. --- Explanation: Review of NLRP3 spatiotemporal dynamics implicating mitochondria, lysosomes, ER, Golgi, endosomes, and the centrosome in NLRP3 localization and inflammasome assembly, providing mechanistic context for how CAPS mutations disrupt normal subcellular regulation.


MONDO:0011776

[PMID:31077002] [INDIRECT EVIDENCE] [SUPPORT] Gain-of-function mutations in NLRP3 in CAPS patients lead to activation of the cryopyrin inflammasome, resulting in the inappropriate release of inflammatory cytokines including IL-1beta and CAPS-related inflammatory symptoms. --- Explanation: Review confirming that excessive IL-1beta release from constitutively active inflammasome is the proximate cause of CAPS symptoms.

[PMID:34059097] [INDIRECT EVIDENCE] [SUPPORT] These evidences suggest that foetal inflammation, probably due to overproduction of IL-1β, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID. --- Explanation: Case report with histopathological evidence that IL-1beta overproduction begins in utero, causing necrotizing funisitis and villitis as the earliest manifestations of CINCA/NOMID even before birth.

[PMID:38808101] [INDIRECT EVIDENCE] [SUPPORT] Histopathologic examination of the placenta and umbilical cord can provide crucial insights into the intrauterine onset of inflammation, which is the first manifestation of CINCA syndrome/NOMID in newborns. --- Explanation: Case report confirming intrauterine onset of IL-1beta-driven inflammation in CINCA/NOMID, with severe funisitis leading to umbilical cord rupture and neonatal asphyxia.


MONDO:0011776


MONDO:0011776

[DOI:10.1111/imr.13292] [INDIRECT EVIDENCE] [SUPPORT] Activated by a panoply of pathogen-associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18. --- Explanation: Review identifying IL-18 alongside IL-1 as a key downstream inflammatory mediator of the NLRP3 inflammasome, confirming its role in CAPS pathogenesis.


MONDO:0011776

[PMID:16899778] [INDIRECT EVIDENCE] [SUPPORT] Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. --- Explanation: Landmark NEJM trial characterizing the multisystem neutrophilic inflammation in NOMID/CINCA affecting skin, CNS, joints, and sensory organs.

[PMID:34059097] [INDIRECT EVIDENCE] [SUPPORT] the inflammation of the umbilical vessels typically begins in the vein (phlebitis) and is followed by involvement of the arteries (arteritis) and the Wharton's jelly --- Explanation: Histopathological evidence of neutrophilic infiltration in umbilical cord vessels and Wharton's jelly, demonstrating that neutrophilic inflammation begins in utero in CINCA/NOMID and can involve the placenta and umbilical cord.


MONDO:0011776

[PMID:16899778] [INDIRECT EVIDENCE] [SUPPORT] Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. --- Explanation: MRI documentation of cochlear and leptomeningeal inflammatory lesions in NOMID patients, which improved with anakinra treatment, confirming active CNS inflammation.

[PMID:37809096] [INDIRECT EVIDENCE] [SUPPORT] Among these novel mutations, percentages of severe musculoskeletal, ophthalmologic, and neurological symptoms were higher compared with other case serials. --- Explanation: Large pediatric CAPS cohort showing high prevalence of severe neurological symptoms in patients with novel NLRP3 mutations, consistent with the CNS inflammatory burden in CINCA/NOMID.


MONDO:0011776

[PMID:37809096] [INDIRECT EVIDENCE] [SUPPORT] Ten patients received Canakinumab treatment, which proved effective at alleviating musculoskeletal, neurological, auditory, visual manifestations, fever, and rash for 10-20 months follow-up. --- Explanation: Pediatric CAPS cohort documenting musculoskeletal involvement as a major disease domain responsive to IL-1 blockade, confirming IL-1-driven skeletal overgrowth.


MONDO:0011776

[PMID:16899778] [INDIRECT EVIDENCE] [SUPPORT] Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. --- Explanation: Landmark NEJM trial identifying deforming arthropathy as a cardinal feature of NOMID/CINCA, distinct from bony overgrowth and reflecting cartilage destruction.


MONDO:0011776

[PMID:16899778] [INDIRECT EVIDENCE] [SUPPORT] serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 --- Explanation: NEJM trial documenting markedly elevated baseline serum amyloid A levels (median 174 mg/L) in NOMID patients, reflecting the chronic inflammatory state that drives AA amyloidosis risk. SAA normalized rapidly with anakinra.


MAXO:0000058

[PMID:16899778] [SUPPORT] All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. --- Explanation: Landmark NEJM trial of 18 NOMID patients demonstrating rapid and sustained response to anakinra with normalization of inflammatory markers and improvement of MRI-documented cochlear and leptomeningeal lesions.

[PMID:38720945] [SUPPORT] After a 12-year follow-up, the patient has not experienced chronic complications. --- Explanation: Case report demonstrating that early initiation of IL-1 inhibition (anakinra followed by canakinumab) in a CINCA patient with somatic mosaicism prevented development of chronic sequelae over 12 years of follow-up.


MAXO:0000058

[PMID:16899778] [INDIRECT EVIDENCE] [SUPPORT] All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. --- Explanation: Landmark NEJM trial of 18 NOMID patients demonstrating rapid and sustained response to anakinra with normalization of inflammatory markers and improvement of MRI-documented cochlear and leptomeningeal lesions.

[PMID:38720945] [INDIRECT EVIDENCE] [SUPPORT] After a 12-year follow-up, the patient has not experienced chronic complications. --- Explanation: Case report demonstrating that early initiation of IL-1 inhibition (anakinra followed by canakinumab) in a CINCA patient with somatic mosaicism prevented development of chronic sequelae over 12 years of follow-up.


MAXO:0000058