MONDO:0008815

[PMID:38044746] [SUPPORT] We identified 60 patients and specifically looked for neurodegeneration-related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia/fatigue and abnormal behaviour. --- Explanation: Identifies hypotonia as a neurodegeneration-related symptom tracked in the ASA cohort.


MONDO:0008815

[PMID:38044746] [SUPPORT] We identified 60 patients and specifically looked for neurodegeneration-related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia/fatigue and abnormal behaviour. --- Explanation: Includes abnormal behaviour as a tracked neurodegeneration-related symptom.


MONDO:0008815

[PMID:38198573] [INDIRECT EVIDENCE] [SUPPORT] The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. --- Explanation: Supports ASL molecular deficiency as the initiating event in ASA.


MONDO:0008815


MONDO:0008815

[PMID:38198573] [INDIRECT EVIDENCE] [SUPPORT] Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. --- Explanation: Supports hyperammonemia and systemic disease downstream of urea-cycle impairment.


MONDO:0008815

[PMID:37490345] [INDIRECT EVIDENCE] [SUPPORT] Knockdown of ASL in human brain microvascular endothelial cells (HBMECs) led to decreased transendothelial electrical resistance, indicative of increased cell permeability. --- Explanation: Shows BBB disruption mechanism through ASL loss in brain endothelial cells.


MONDO:0008815

[PMID:38198573] [INDIRECT EVIDENCE] [SUPPORT] Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. --- Explanation: Demonstrates glutathione pathway dysregulation in ASLD patients and mice.


MONDO:0008815

[PMID:31990680] [INDIRECT EVIDENCE] [SUPPORT] We demonstrate a high prevalence of elevated ALT in ASLD (37%). Hyperammonemia and use of nitrogen-scavenging agents, 2 markers of disease severity, were significantly (P < 0.001 and P = 0.001, respectively) associated with elevated ALT in ASLD. --- Explanation: Demonstrates high prevalence of chronic hepatocellular injury in ASLD.

[PMID:31990680] [INDIRECT EVIDENCE] [SUPPORT] This excessive hepatic glycogen is associated with impaired hepatic glycogenolysis and decreased glycogen phosphorylase and is rescued with helper-dependent adenovirus expressing Asl using a liver-specific (ApoE) promoter. --- Explanation: Shows impaired glycogen metabolism in ASLD mouse model and rescue by hepatic ASL gene delivery.


MAXO:0000088

[PMID:30723942] [SUPPORT] the current standard of care and therapeutic strategy, which aims to normalize plasma ammonia and arginine levels --- Explanation: Supports dietary management focused on ammonia and arginine normalization.


MAXO:0000058

[PMID:31990680] [SUPPORT] Hyperammonemia and use of nitrogen-scavenging agents, 2 markers of disease severity, were significantly (P < 0.001 and P = 0.001, respectively) associated with elevated ALT in ASLD. --- Explanation: Confirms nitrogen scavenger use in ASLD management; also notes association with disease severity.


MAXO:0010039

[PMID:38054409] [SUPPORT] LTx enabled metabolic stability by prevention of further hyperammonemic events after transplantation and was associated with a more favorable growth outcome compared with individuals remaining under MM. However, neurocognitive outcome in individuals with LTx did not differ from the medically managed counterparts --- Explanation: Severity-adjusted analysis confirms LT prevents hyperammonemia but does not improve neurocognitive outcomes.


MAXO:0000950

[PMID:30723942] [SUPPORT] The disappointing long-term clinical outcomes of many of the patients have challenged the current standard of care and therapeutic strategy --- Explanation: Supports the need for acute management as part of standard of care in ASA.


MAXO:0000058

[PMID:30075114] [SUPPORT] loss of ASL in endothelial cells leads to endothelial-dependent vascular dysfunction with reduced nitric oxide (NO) production, increased oxidative stress, and impaired angiogenesis --- Explanation: Provides the mechanistic rationale for NO supplementation therapy in ASLD.

[PMID:37490345] [SUPPORT] in vivo assessment of a hypomorphic mouse model of ASLD showed increased BBB leakage, which was partially rescued by NO supplementation --- Explanation: Demonstrates partial rescue of BBB dysfunction by NO supplementation in ASLD.


MAXO:0000079


MAXO:0000124

[PMID:30723942] [PARTIAL] Interrogations have raised about the benefit of newborn screening or liver transplantation on the neurological phenotype. --- Explanation: Supports newborn screening availability while noting uncertainty about neurological benefit.


MAXO:0000058

[PMID:38198573] [SUPPORT] These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria. --- Explanation: Demonstrates preclinical efficacy of mRNA therapy for ASA.


HGNC.SYMBOL:ASL (argininosuccinate lyase) variants

[PMID:30075114] [SUPPORT] the urea cycle disorder, argininosuccinate lyase deficiency (ASLD), can manifest as a Mendelian form of endothelial-dependent hypertension --- Explanation: Establishes ASL as the causal gene with dual urea cycle and NO synthesis roles.

[PMID:37490345] [SUPPORT] Previously, we have shown that argininosuccinate lyase deficiency (ASLD) is a novel model system to investigate cell-autonomous, nitric oxide synthase-dependent NO deficiency. --- Explanation: Confirms ASL role in cell-autonomous NO deficiency beyond ureagenesis.


MONDO:0013301

[PMID:30173221] [NO_EVIDENCE] BACKGROUND: Aromatase deficiency is a rare autosomal recessive disorder. 46,XY-affected patients often remain undiagnosed until late puberty. Only 2 pediatric cases have been reported. Data on pubertal development in affected males are scarce. --- Explanation: The reference discusses aromatase deficiency and mentions pubertal development but does not provide specific evidence supporting delayed puberty as a phenotype.

[PMID:36268624] [NO_EVIDENCE] Isolated hypogonadotropic hypogonadism (IHH) is phenotypically and genetically heterogeneous. --- Explanation: The reference is about IHH, not aromatase deficiency, and does not provide direct evidence for delayed puberty in aromatase deficiency.

[PMID:30550360] [NO_EVIDENCE] Despite the advances in translational medicine, hospitals are yet to adopt genetic testing and counseling facilities in India that shall have potential impact on clinical diagnosis. --- Explanation: The reference provides an overview of genetic testing of disorders of sexual development but does not provide strong evidence supporting delayed puberty due to aromatase deficiency.

[PMID:17581673] [PARTIAL] Alterations of spermatogenesis in terms of number and motility of spermatozoa have been described in men genetically deficient in aromatase. These last observations... suggest that aromatase could be involved in the acquisition of sperm motility. --- Explanation: While the reference discusses reproductive implications of aromatase deficiency, it does not directly address delayed puberty as a high-frequency diagnostic phenotype.

[PMID:24612204] [NO_EVIDENCE] Oestrogen is the final key factor to start the onset of puberty. --- Explanation: The reference discusses the role of estrogen in puberty but does not specifically mention delayed puberty as a phenotype of aromatase deficiency.

[PMID:10418977] [NO_EVIDENCE] The diagnostic term congenital adrenal hyperplasia (CAH) applies to a family of inherited disorders of steroidogenesis. --- Explanation: The reference discusses congenital adrenal hyperplasia but does not provide evidence on delayed puberty linked to aromatase deficiency.


MONDO:0013301

[PMID:18448329] [SUPPORT] The clinical phenotype in the male affected subjects comprises tall stature, persistent linear growth and delayed bone age, osteopenia/osteoporosis, eunuchoid body proportion, different degrees of glucose-insulin and of fertility impairment. --- Explanation: The abstract mentions osteoporosis as one of the phenotypes observed in males with aromatase deficiency due to estrogen deficiency.

[PMID:18448329] [SUPPORT] Estrogens exert a wide range of biological effects in both sexes also on non-reproductive systems and organs. --- Explanation: This reference supports the role of estrogen in bone health, noting its wide biological effects including skeletal outcomes.


MONDO:0013301

[PMID:18448329] [NO_EVIDENCE] The clinical phenotype in the male affected subjects comprises tall stature, persistent linear growth and delayed bone age, osteopenia/osteoporosis, eunuchoid body proportion, different degrees of glucose-insulin and of fertility impairment. --- Explanation: The literature does not mention hypergonadotropic hypogonadism as a phenotype of aromatase deficiency. Various other systemic phenotypes are listed instead.

[PMID:33159679] [NO_EVIDENCE] We report a patient with a late-onset form of TALDO deficiency characterized by hypergonadotropic hypogonadism... --- Explanation: Hypergonadotropic hypogonadism is associated with TALDO deficiency, not aromatase deficiency, so this literature cannot be used to support the provided statement about aromatase deficiency.


MONDO:0013301

[PMID:11305285] [PARTIAL] Aromatase deficiency results from autosomal recessive inheritance of mutations in the CYP19 gene. It gives rise to ambiguous genitalia in 46,XX individuals. At puberty, affected girls have hypergonadotropic hypogonadism, fail to develop secondary sexual characteristics, and exhibit progressive virilization. --- Explanation: The literature mentions that affected girls with aromatase deficiency fail to develop secondary sexual characteristics and exhibit progressive virilization, which can be associated with primary amenorrhea, but it does not explicitly state that primary amenorrhea is a frequent occurrence.

[PMID:35366614] [NO_EVIDENCE] In this study, LHCGR gene mutations were detected in a total of nine patients as a result of the analysis of the index patients presenting with primary amenorrhea from four different families and the examination of the families. --- Explanation: This reference discusses primary amenorrhea in the context of LHCGR gene mutations, not aromatase deficiency.

[PMID:34494333] [NO_EVIDENCE] AIM: The aim of this study was to evaluate the general characteristics, menstruation status, and fertility outcomes of patients with hypogonadotropic hypogonadism (HH). --- Explanation: This reference discusses hypogonadotropic hypogonadism and its association with amenorrhea, not aromatase deficiency.


MONDO:0013301

[PMID:32623730] [SUPPORT] The main characteristics were maternal antenatal virilization (21/29), ambiguous genitalia (mainly Prader IV or III, 19/23), delayed bone age (16/17), low bone mass (5/8), markedly elevated FSH levels and ovarian cysts (13/30). --- Explanation: The statement is supported by the literature which mentions that ovarian cysts, a characteristic of polycystic ovaries, are observed in 46, XX individuals with aromatase deficiency.


MONDO:0013301

[PMID:9300203] [SUPPORT] In females with aromatase deficiency, androgen levels are excessive, causing inappropriate virilization but failing to induce skeletal maturity. Thus, estrogen is the hormone necessary for normal skeletal growth and maturity. --- Explanation: The reference suggests that the absence of estrogen due to aromatase deficiency leads to continued growth and lack of skeletal maturity, which can result in tall stature.

[PMID:27824615] [NO_EVIDENCE] Tall stature is not a widely recognized association. CASE REPORT: A 15-year-old girl presented with primary amenorrhoea... Initially, a 364055-bp deletion on Xp21.2 was reported on array CGH. However, repeat analysis using BlueGnome CytoChip ISCA 4x180k v2.0 array was normal... the patient was remarkably tall with height SDS +2.88. --- Explanation: The reference indicates an association between 46,XX gonadal dysgenesis and tall stature, which is relevant to the statement about aromatase deficiency in 46,XX individuals.

[PMID:37348676] [PARTIAL] Serum FSH levels were elevated except in preterms, and can be used as a diagnostic marker. --- Explanation: While the reference discusses hormonal parameters in 46,XX aromatase deficiency, it does not directly address tall stature.


MONDO:0013301


MONDO:0013301

[PMID:35837780] [INDIRECT EVIDENCE] [SUPPORT] Aromatase deficiency (AD) is a rare autosomal recessive genetic disease caused by loss-of-function mutations in aromatase gene (CYP19A1), leading to congenital estrogen deficiency syndrome. --- Explanation: The reference clearly states that mutations in the CYP19A1 gene result in deficient aromatase enzyme activity, which causes aromatase deficiency.

[PMID:14968547] [INDIRECT EVIDENCE] [SUPPORT] Aromatase, a key enzyme in estrogen synthesis, is tissue-specifically regulated in various tissues and plays an important role through endocrine and intracrine estrogen production in various physiological functions. Therefore, aromatase deficiency caused crucial impairments of physiological functions in the gonadal tissues as well as extra-gonadal tissues. --- Explanation: This reference details the crucial role of aromatase and how its deficiency, caused by lack of function due to gene mutations, leads to significant physiological impairments.

[PMID:27032764] [INDIRECT EVIDENCE] [PARTIAL] Cytochrome P450 aromatase (CYP19A1), in human placenta metabolizes androgens to estrogens and uses reduced nicotinamide adenine dinucleotide phosphate through cytochrome P450 oxidoreductase (POR) for the energy requirements of its metabolic activities. --- Explanation: The reference indicates that CYP19A1 (cytochrome P450 aromatase) mutations can result in reduced activity of the enzyme, thereby supporting the mechanism of aromatase deficiency due to mutations in CYP19A1.


MONDO:0013301

[PMID:18448329] [INDIRECT EVIDENCE] [SUPPORT] Human congenital estrogen deficiency, due to an inactivating mutation of the aromatase gene, leads to the lack of the estrogen synthesis, with gonadotropins and circulating testosterone ranging from normal to elevated. The aromatese-deficient females show hyperandrogenism and virilization at birth with ambiguous genitalia. During childhood there are a dysfunction in the LHRH-LH/FSH axis and a progressive delay in bone age. --- Explanation: This supports the statement as it describes that aromatase deficiency leads to a lack of estrogen, which affects sexual development and bone maturation.

[PMID:18567553] [INDIRECT EVIDENCE] [PARTIAL] Findings from estrogen-resistant and aromatase-deficient men have provided important insights into the role of estrogen in the male skeleton during growth. --- Explanation: This also supports the statement by indicating that aromatase deficiency affects bone maturation.

[PMID:21874760] [INDIRECT EVIDENCE] [SUPPORT] Several lines of clinical and experimental evidence now clearly indicate that aromatase activity and estrogen production are necessary for longitudinal bone growth, attainment of peak bone mass, the pubertal growth spurt, epiphyseal closure, and normal bone remodeling in young individuals. --- Explanation: The lack of aromatase activity, and hence estrogen deficiency, affects bone maturation, confirming the consequence stated.


MAXO:0000283

[PMID:18448329] [SUPPORT] The estradiol replacement treatment leads to a complete epiphyseal closure and to the skeletal maturation. --- Explanation: The statement claims that estrogen replacement therapy corrects estrogen deficiency and supports bone health. The literature provided supports this by indicating that estradiol replacement leads to skeletal maturation.

[PMID:26680580] [PARTIAL] The overall goal of pubertal sex hormone replacement therapy (HRT) in girls is not only about development of secondary sexual characteristics, but also to establish an adult endocrine and metabolic milieu. --- Explanation: This confirms that estrogen replacement therapy aids in normal sexual development.

[PMID:18567553] [PARTIAL] Findings from estrogen-resistant and aromatase-deficient men have provided important insights into the role of estrogen in the male skeleton during growth. --- Explanation: The study elaborates on the role of estrogen in bone health, using data from aromatase-deficient subjects to underline its significance.


MAXO:0000058


MAXO:0000004

[PMID:19707181] [NO_EVIDENCE] Diagnosis of the condition is supported by the presence of unfused epiphyses and undetectable serum estradiol levels; the condition can be further substantiated by genetic sequencing of CYP19A1. Transdermal estradiol treatment at a daily dose of about 25 microg might be adequate for lifelong replacement therapy. --- Explanation: The literature does not mention surgical management as a treatment for aromatase deficiency. Instead, it suggests hormonal replacement therapy as the primary treatment.

[PMID:32990485] [NO_EVIDENCE] Transgender individuals are those whose gender identity differs from that recorded at birth...clinicians can provide hormone therapy (HT) to bring sex hormone levels to the range associated with the patient''s gender identity. --- Explanation: This literature discusses hormone therapy for transgender individuals but does not specifically address surgical management for ambiguous genitalia or other anatomical abnormalities in the context of aromatase deficiency.


HGNC.SYMBOL:CYP19A1

[PMID:40321354] [SUPPORT] Aromatase deficiency is a rare autosomal recessive condition due to a mutation in the CYP19A1 encoding aromatase enzyme. --- Explanation: This case report confirms that mutations in CYP19A1 encoding aromatase enzyme cause aromatase deficiency.


HGNC.SYMBOL:ESR1


HGNC.SYMBOL:ESR2


HGNC.SYMBOL:POR


ECTO:0000516

[PMID:24482950] [NO_EVIDENCE] Aromatase deficiency should be suspected when a patient presents with primary amenorrhea, absence of female secondary sexual characters, virilization and tall stature with eunuchoid body proportions, and biochemical features of ovarian failure. --- Explanation: This reference discusses aromatase deficiency and alludes to hormonal imbalances related to it, suggesting that hormone replacement therapy, specifically estrogen replacement, is relevant for managing symptoms.


MONDO:0005096

[PMID:16807664] [SUPPORT] Skin hyperpigmentation and hyperkeratosis have long been known to be the hallmark signs of chronic As exposure. --- Explanation: Abstract identifies hyperkeratosis as a hallmark sign of chronic arsenic exposure.


MONDO:0005096

[PMID:16807664] [SUPPORT] Skin hyperpigmentation and hyperkeratosis have long been known to be the hallmark signs of chronic As exposure. --- Explanation: Abstract identifies hyperpigmentation as a hallmark sign of chronic arsenic exposure.


MONDO:0005096

[PMID:16807664] [SUPPORT] Long-term exposure to inorganic arsenic (As) from drinking water has been documented to induce cancers in lung, urinary bladder, kidney, liver and skin in a dose-response relationship. --- Explanation: Abstract documents arsenic-induced skin cancer risk.


MONDO:0005096

[PMID:16807664] [SUPPORT] Long-term exposure to inorganic arsenic (As) from drinking water has been documented to induce cancers in lung, urinary bladder, kidney, liver and skin in a dose-response relationship. --- Explanation: Abstract documents arsenic-induced lung cancer risk.


MONDO:0005096

[PMID:16807664] [SUPPORT] Long-term exposure to inorganic arsenic (As) from drinking water has been documented to induce cancers in lung, urinary bladder, kidney, liver and skin in a dose-response relationship. --- Explanation: Abstract documents arsenic-induced bladder cancer risk.


MONDO:0005096


MAXO:0000004


MAXO:0000647


HGNC.SYMBOL:AS3MT


HGNC.SYMBOL:GSTO1/GSTO2


HGNC.SYMBOL:TP53


ECTO:9000032

[PMID:26411935] [SUPPORT] Naturally occurring inorganic arsenic is known to increase the risk of cancers of the skin and several other organs, including the urinary bladder, lung, and liver. --- Explanation: Supports arsenic exposure as a risk factor for multiple cancers.


MONDO:0005096

[PMID:16807664] [SUPPORT] most common arsenic-induced skin cancers are Bowen's disease (carcinoma in --- Explanation: Abstract lists common arsenic-induced skin cancers including Bowen's disease, BCC, and SCC.


MONDO:0004979

[PMID:20545704] [SUPPORT] It has been suggested that there are several distinct phenotypes of childhood asthma or childhood wheezing. Here, we review the research relating to these phenotypes, with a focus on the methods used to define and validate them. --- Explanation: The reference supports the existence and classification of asthma phenotypes, including wheezing as a common characteristic.

[PMID:8620967] [SUPPORT] Wheezes are usual clinical signs in patients with obstructive airway diseases and particularly during acute episodes of asthma. --- Explanation: The reference describes wheezing as a common symptom associated with asthma, supporting the statement's claim that wheezing is a common phenotype and respiratory diagnostic of asthma.

[PMID:1788358] [SUPPORT] Exercise-induced asthma is a common but frequently undiagnosed problem. The patient may not wheeze, but rather have shortness of breath, chest tightening, and coughing. --- Explanation: This reference mentions exercise-induced asthma and details its symptoms, including wheezing, though noting that wheezing may not always be present.

[PMID:26606077] [SUPPORT] The syndrome of asthma contains a number of different phenotypes that offer the possibility of personalized medicine based on the respective asthma phenotype. --- Explanation: Confirms the existence of multiple phenotypes within asthma, including wheezing, supporting the statement's categorization of wheezing as a phenotype of asthma.

[PMID:21722845] [SUPPORT] Oral corticosteroids are the cornerstone of management of acute moderate or severe asthma whilst preventive inhaled corticosteroids are the mainstay of the preventive management of children with asthma. Yet, variation in the magnitude of response to corticosteroids has been observed. --- Explanation: Supports the statement indirectly by acknowledging variations in asthma phenotypes, which includes wheezing as a common symptom.

[PMID:38716537] [SUPPORT] We want to highlight the presentation of a 75-year-old female who was initially managed as asthma and subsequently diagnosed with concurrent excessive dynamic airway collapse (EDAC). --- Explanation: Although the snippet discusses a different case, it implies that wheezing is commonly associated with asthma management.


MONDO:0004979

[PMID:36096782] [SUPPORT] Asthma is a heterogeneous disease with variable symptoms, which presents with cough either as the sole or predominant symptom with or without wheezing. --- Explanation: The reference states that cough is a common phenotype in asthma, aligning with the statement's claim that coughing is a common respiratory phenotype in asthma.

[PMID:31662445] [SUPPORT] Asthma severity was dependent on variety of symptoms, consisting mostly of wheezing, breathlessness, chest tightness, and cough. --- Explanation: The reference indicates that coughing is one of the primary symptoms associated with asthma, supporting the claim that it is a common respiratory phenotype.

[PMID:36543577] [SUPPORT] Chronic cough is associated with poor quality of life and can negatively affect quality of life. Diseases causing chronic cough are most commonly asthma, eosinophilic bronchitis, gastroesophageal reflux, post-nasal drip syndrome, rhinosinusitis, chronic obstructive pulmonary disease, pulmonary fibrosis, and bronchiectasis. --- Explanation: The reference supports the association of chronic cough with asthma, aligning with the statement that coughing is a common phenotype in asthma.


MONDO:0004979

[PMID:31662445] [SUPPORT] CONCLUSIONS: Asthma severity was dependent on variety of symptoms, consisting mostly of wheezing, breathlessness, chest tightness, and cough. --- Explanation: The literature indicates that chest tightness is among the most common symptoms of asthma, supporting the statement that chest tightness is a frequent phenotype of respiratory symptoms in asthma patients.

[PMID:36292755] [SUPPORT] Asthma is a chronic disease of the airways characterized by inflammation, tightened muscles, and thickened airway walls leading to symptoms such as shortness of breath, chest tightness, and cough in patients. --- Explanation: This article confirms that chest tightness is a common symptom of asthma, supporting the statement.

[PMID:3595047] [SUPPORT] IMPLICATIONS: exercise-induced asthma should be considered in pediatric patients with symptoms of chest pain or dyspnea on exertion. --- Explanation: Exercise-induced asthma includes symptoms like chest pain, which is related to chest tightness, supporting the statement.

[PMID:19463209] [SUPPORT] We present the case of a 42-year-old man with a 2-year history of wheezing, chest tightness, and upper respiratory symptoms. --- Explanation: This case study highlights chest tightness as a symptom, supporting the statement as it shows chest tightness is a common feature in asthma triggered by recreational activities.


MONDO:0004979

[PMID:29601558] [PARTIAL] Dyspnea as a subjective feeling of lack of air is the patients with the pathology of the respiratory system. Objectivization of this phenomenon is difficult, despite the introduction of questionnaires about the degree of dyspnoea. The results of these assessments do not always correlate with the results of spirometric tests. In patients with asthma, dyspnoea is caused by airway obstruction. --- Explanation: While this reference discusses dyspnea in asthma patients, it does not explicitly mention cyanosis. However, dyspnea and airway obstruction could potentially lead to cyanosis in severe cases.


MONDO:0004979

[PMID:33783133] [SUPPORT] Fatigue as a symptom is common in asthmatic patients and correlates with asthma-related quality of life, asthma control, dyspnea, depression and anxiety. --- Explanation: The study indicates that fatigue is a common symptom in asthmatic patients and is associated with various aspects of asthma, supporting the statement that fatigue is frequent in asthma.

[PMID:33783133] [PARTIAL] Future studies are needed to better understand the physical, psychological, behavioural and systemic factors that precipitate or perpetuate fatigue in asthma. --- Explanation: While the study supports the association of fatigue with asthma, it does not explicitly confirm that the increased work of breathing and sleep disturbance are the causes of fatigue, hence the partial support.


MONDO:0004979

[PMID:8088098] [SUPPORT] Given sufficient exercise intensity, exercise can trigger acute exacerbations in virtually all individuals with asthma. --- Explanation: The literature indicates that exercise can trigger asthma symptoms in individuals with asthma, supporting the statement that exercise intolerance is frequent in asthma patients.

[PMID:31662445] [SUPPORT] Asthma severity was dependent on variety of symptoms, consisting mostly of wheezing, breathlessness, chest tightness, and cough. --- Explanation: The study highlights that physical activity can exacerbate asthma symptoms such as wheezing and breathlessness, indicating exercise intolerance.

[PMID:34536613] [SUPPORT] PA can trigger asthma symptoms. --- Explanation: The literature confirms that physical activity can trigger asthma symptoms, supporting the statement about exercise intolerance.

[PMID:20472861] [SUPPORT] Exercise can trigger later bronchoconstriction in many patients. --- Explanation: The literature indicates that exercise can lead to bronchoconstriction, which supports the statement about exercise intolerance in asthma patients.

[PMID:32280032] [SUPPORT] Asthma symptoms can be triggered or magnified during exertion. --- Explanation: The literature confirms that exertion can trigger or magnify asthma symptoms, supporting the statement about exercise intolerance.


MONDO:0004979

[PMID:11990234] [SUPPORT] Nocturnal airway narrowing in asthma is often associated with sleep disorders, such as episodes of nocturnal and early morning awakening, difficulty in maintaining sleep, and day time sleepiness. --- Explanation: This reference supports the statement by indicating that nocturnal asthma is associated with sleep disturbances, including difficulty in maintaining sleep.

[PMID:31541769] [SUPPORT] CoFr during nighttime (asleep) was significantly higher in asthmatic patients than in nonasthmatic patients. --- Explanation: This reference supports the statement by showing that nighttime cough frequency is higher in asthmatic patients, which implies sleep disturbances.

[PMID:19823913] [SUPPORT] Sleep disruption is common in patients with cough and is often the reason why they seek medical attention. --- Explanation: This reference supports the statement by indicating that sleep disruption is common in patients with chronic cough, which includes those with asthma.

[PMID:28526251] [SUPPORT] Results from analyses using structural equation modeling revealed an association between worsening asthma-related lung function and poor sleep quality in the full sample, as well as better asthma-related lung function at night and more optimal sleep efficiency that night. --- Explanation: This reference supports the statement by indicating an association between worsening asthma-related lung function and poor sleep quality.

[PMID:26774954] [SUPPORT] The prevalence of nocturnal symptoms of asthma is high, and most children regularly experience nighttime symptoms. --- Explanation: This reference supports the statement by indicating that nocturnal symptoms of asthma are prevalent and regularly affect sleep in children.


MONDO:0004979

[PMID:10868701] [SUPPORT] Both the attacks themselves and the prospect of attacks generate much anxiety amongst patients. --- Explanation: The reference explains that asthma attacks and the anticipation of such attacks can generate significant anxiety among patients, supporting the statement that asthma can occasionally cause anxiety.

[PMID:32720730] [SUPPORT] Asthma was significantly associated with anxiety in boys, particularly in older boys. --- Explanation: This study found a significant association between asthma and anxiety in boys, further supporting the statement that asthma can occasionally cause anxiety.

[PMID:35278300] [SUPPORT] Another aspect is the relationship of bronchial asthma with the development of mood disorders. --- Explanation: The reference mentions the relationship between bronchial asthma and mood disorders, including anxiety, supporting the statement.


MONDO:0004979


MONDO:0004979

[PMID:18503727] [INDIRECT EVIDENCE] [SUPPORT] The pathogenesis of allergic airway inflammation is complex, involving multiple cell types such as T helper 2 cells, regulatory T cells, eosinophils, dendritic cells, mast cells, and parenchymal cells of the lung. --- Explanation: This reference indicates the involvement of multiple cell types, including mast cells, eosinophils, and T lymphocytes in allergic airway inflammation, which supports the statement.

[PMID:8324396] [INDIRECT EVIDENCE] [SUPPORT] The numbers of eosinophils and neutrophils are increased 4 h after challenge with allergen in the broncho-alveolar lavage fluid (BAL) of asthmatics who show an LPR. --- Explanation: This reference mentions eosinophils and neutrophils as part of the chronic inflammatory response in asthma, supporting the statement.

[PMID:9753516] [INDIRECT EVIDENCE] [SUPPORT] Accumulation of basophils and mast cells in airway tissues during allergic and allergic-type inflammatory responses, including asthma, is one of the hallmarks of these disease processes. --- Explanation: This reference highlights the involvement of basophils and mast cells in airway inflammation in asthma, supporting the statement.

[PMID:38395082] [INDIRECT EVIDENCE] [PARTIAL] Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in response to numerous diverse stimuli, contributing to airflow limitation and symptoms including breathlessness, wheeze, and chest tightness. --- Explanation: This reference supports the clinical manifestations of asthma as described in the statement.

[PMID:23234454] [INDIRECT EVIDENCE] [PARTIAL] Pulmonary edema and pulmonary vascular congestion have been thought to be the primary causes of cardiac asthma but most patients have a poor response to diuretics... Evidence suggests that circulating inflammatory factors and tissue growth factors also lead to airway obstruction suggesting the possibility of developing novel therapies. --- Explanation: While this reference focuses on cardiac asthma, it acknowledges the involvement of inflammatory factors leading to airway obstruction, which partially supports the inflammatory aspect mentioned.

[PMID:1571812] [INDIRECT EVIDENCE] [SUPPORT] Asthmatics can have a blood eosinophilia which in some studies correlates with the severity of the disease... The eosinophils that contribute to asthma will be those in the lung. --- Explanation: Specifically talks about the role of eosinophils in asthma, supporting the statement.

[PMID:28687463] [INDIRECT EVIDENCE] [SUPPORT] NAEB shares similar eosinophilic inflammation of airway and response to corticosteroids with asthma. --- Explanation: This supports the role of eosinophils in airway inflammation in asthma, consistent with the statement.

[PMID:6101920] [INDIRECT EVIDENCE] [NO_EVIDENCE] Exercise-induced asthma can appear as one of many forms of airway hyperreactivity or as a unique clinical entity. --- Explanation: Does not provide specific information about the role of the cell types mentioned in the statement.


MONDO:0004979

[PMID:32037107] [INDIRECT EVIDENCE] [SUPPORT] It is a TH2-driven process. Biomarkers have been identified to distinguish patients with allergic asthma, particularly serum IgE levels, tests to indicate sensitization to aeroallergens such as specific IgE or skin prick test positivity, blood and sputum eosinophil levels --- Explanation: Directly states allergic asthma is TH2-driven and identifies IgE and eosinophils as key biomarkers of this pathway.

[PMID:18503727] [INDIRECT EVIDENCE] [SUPPORT] The pathogenesis of allergic airway inflammation is complex, involving multiple cell types such as T helper 2 cells, regulatory T cells, eosinophils, dendritic cells, mast cells, and parenchymal cells of the lung. The cellular response in allergic airway inflammation is controlled by a broad range of bioactive mediators, including IgE, cytokines and chemokines. --- Explanation: Identifies T helper 2 cells as central to allergic airway inflammation pathogenesis, with IgE and cytokines as key mediators.


MONDO:0004979

[PMID:24914235] [INDIRECT EVIDENCE] [SUPPORT] The other main cause of airway obstruction is contraction of airway smooth muscle. --- Explanation: The reference points out that contraction of airway smooth muscle is a main cause of airway obstruction, thus supporting the statement.

[PMID:22011234] [INDIRECT EVIDENCE] [SUPPORT] Breathing difficulties are caused by excessive narrowing of the pulmonary airways, which is instigated by shortening of the airway smooth muscle (ASM). --- Explanation: This reference explains that the narrowing of the airways, caused by the contraction of airway smooth muscle, leads to breathing difficulties, thus supporting the statement.

[PMID:27603525] [INDIRECT EVIDENCE] [SUPPORT] In acute and chronic allergen driven animal models of asthma, statins reduce airway hyper-responsiveness, inflammation and remodeling. --- Explanation: The use of statins to reduce airway hyper-responsiveness implies the involvement of smooth muscle cells, supporting the statement.

[PMID:16543052] [INDIRECT EVIDENCE] [SUPPORT] ASM plays an important role in regulating bronchomotor tone, in perpetuating airway inflammation, and in remodeling of the airways. --- Explanation: This reference highlights multiple functions of airway smooth muscle in asthma, which supports the statement regarding the role of smooth muscle cells in bronchoconstriction.

[PMID:18669785] [INDIRECT EVIDENCE] [SUPPORT] Airway smooth muscle cells are known to be the main effector cells of airway narrowing. --- Explanation: This reference clearly identifies airway smooth muscle cells as key players in the narrowing of airways (bronchoconstriction), thus supporting the statement.


MONDO:0004979

[PMID:19689269] [INDIRECT EVIDENCE] [PARTIAL] Goblet cells are major mucus-producing cells, and goblet cell hyperplasia (GCH) is one feature of airway remodeling, defined as structural changes occurring in the airway. --- Explanation: The reference confirms Goblet cell involvement in asthma and mucus production but does not mention Mucosal Epithelial Cell specifically.

[PMID:24914235] [INDIRECT EVIDENCE] [PARTIAL] Airway epithelial cells, which are the first line of defense against inhaled pathogens and particles, initiate airway inflammation and produce mucus, an important contributor to airway obstruction. --- Explanation: The reference supports that Bronchial Epithelial Cells play a role in mucus production but does not discuss Mucosal Epithelial Cells specifically.

[PMID:37520564] [INDIRECT EVIDENCE] [PARTIAL] Basal cells... goblet cell hyperplasia and increased epithelial mesenchymal transition, which contribute to impaired mucociliary clearance and airway remodelling. --- Explanation: The reference confirms Goblet cell hyperplasia and the contribution of epithelial cells in asthma but does not detail Mucosal Epithelial Cells.

[PMID:23638644] [INDIRECT EVIDENCE] [PARTIAL] Goblet cell differentiation and mucus production are subject to extensive control. An emerging concept is that not all goblet cells are phenotypically identical suggesting that specific molecular pathways orchestrate mucin overproduction. --- Explanation: The reference supports Goblet cells' role in mucus production but lacks information on Mucosal Epithelial Cells.

[PMID:16101538] [INDIRECT EVIDENCE] [PARTIAL] Bronchial epithelial cells (BEC) are known to play an integral role in the airway defense mechanism via mucociliary system as well as mechanical barriers. --- Explanation: The reference confirms the involvement of Bronchial Epithelial Cells but does not mention Mucosal Epithelial Cells.


MONDO:0004979

[PMID:20500603] [INDIRECT EVIDENCE] [SUPPORT] In asthma, it includes alterations of the epithelial cell layer with goblet cell hyperplasia, thickening of basement membranes, peri-bronchial and peri-bronchoalveolar fibrosis. --- Explanation: The reference acknowledges that airway remodeling in asthma involves changes to the epithelial cell layer, fibroblasts, and smooth muscle cells.

[PMID:10907591] [INDIRECT EVIDENCE] [SUPPORT] In the long-term, asthma may become moderately to fully irreversible. Severe, irreversible airflow obstruction may develop despite apparently appropriate therapy. --- Explanation: The reference supports the idea that long-standing inflammation can result in irreversible structural changes affecting lung function.

[PMID:15896192] [INDIRECT EVIDENCE] [SUPPORT] Structural changes reported in the airways of asthmatics include epithelial fragility, goblet cell hyperplasia, enlarged submucosal mucus glands, angiogenesis, increased matrix deposition in the airway wall, increased airway smooth muscle mass, wall thickening and abnormalities in elastin. --- Explanation: The reference details structural changes involving various cell types, including epithelial cells, smooth muscle cells, and other airway structures resulting from long-term inflammation in asthma.

[PMID:12405265] [INDIRECT EVIDENCE] [SUPPORT] Asthma is a chronic inflammatory disorder of the airways interacting with altered structure and function of the formed elements including smooth muscle. --- Explanation: The reference confirms that chronic inflammation in asthma involves structural alterations involving smooth muscle cells and other components, supporting airway remodeling.

[PMID:24914235] [INDIRECT EVIDENCE] [SUPPORT] Two airway cell types are critical for asthma pathogenesis: epithelial cells and smooth muscle cells. --- Explanation: The reference highlights the importance of epithelial cells and smooth muscle cells in asthma pathogenesis, supporting the role of these cell types in airway remodeling.


MAXO:0000312

[PMID:22559870] [SUPPORT] Current guidelines recommend long-term treatment with inhaled corticosteroids (ICS) because of their superior effectiveness in managing the chronic airway inflammation that characterizes persistent asthma. --- Explanation: This literature supports the statement that inhaled corticosteroids reduce inflammation in asthma.

[PMID:9817746] [SUPPORT] Glucocorticoids are highly effective in the control of asthma and suppression of airway inflammation. --- Explanation: This reference supports the role of glucocorticoids, which includes inhaled corticosteroids, in reducing airway inflammation in asthma.

[PMID:32868307] [SUPPORT] The 2019 Global Initiative for Asthma (GINA) guidelines recommend that all asthma patients be treated with inhaled corticosteroids taken daily or as needed; this improves symptoms and outcomes, even in those with mild disease. --- Explanation: This guideline indicates that inhaled corticosteroids are recommended for improving asthma outcomes, supporting their role in preventing flare-ups.

[PMID:37182593] [SUPPORT] Early treatment with inhaled corticosteroids not only diminishes lung inflammation and airway hyper-responsiveness, but also has a protective effect against the reduction of breathing pattern complexity due to asthma. --- Explanation: The findings indicate that early treatment with inhaled corticosteroids reduces lung inflammation and helps prevent further complications, such as reduced breathing pattern complexity, supporting their role in preventive care.


MAXO:0000312

[PMID:34753370] [SUPPORT] Patients experience significant clinical benefits from therapy with long-acting β2-agonists (LABAs) with efficacy to bronchodilate, and prolonged lung function betterment. --- Explanation: The literature supports that LABAs help in relaxing the muscles around the airways, thereby improving lung function and providing symptomatic relief in asthma management.

[PMID:37489386] [SUPPORT] Long-acting muscarinic antagonists (LAMAs) are a class of inhalers that has recently been included as add-on therapy in the GINA guidelines, either in a single inhaler device with inhaled corticosteroids plus long-acting beta2-agonists (ICS + LABA). --- Explanation: Although primarily about LAMAs, the literature acknowledges that LABAs are part of the recommended treatment regimen for asthma, which implies their role in relaxing airway muscles.

[PMID:32306788] [SUPPORT] Contemporary mainstay therapies (inhaled corticosteroids and bronchodilators), prescribed empirically, control symptoms resulting from airways obstruction tolerably well in many patients... --- Explanation: The literature indicates that LABAs, as bronchodilators, help control symptoms related to airway obstruction by relaxing the airway muscles.


MAXO:0000312

[PMID:14720013] [SUPPORT] Leukotriene modifiers increase the therapeutic options for patients with asthma and, based on recent data, it is expected that future guidelines will describe expanded uses for these agents in clinical circumstances where these drugs are effective.

[PMID:11085767] [SUPPORT] Their unique mechanism of action results in a combination of both bronchodilator and anti-inflammatory effects.

[PMID:19180262] [SUPPORT] Cysteinyl leukotrienes, which are derivatives of the 5-lipoxygenase pathway of arachidonic acid metabolism, are important mediators of airway allergic inflammation and have a role in the pathogenetic mechanism of EIB. Montelukast sodium (Singulair, Merck & Co.) is a selective and orally active leukotriene receptor antagonist with demonstrated activity for treating asthma and allergic rhinitis.


MAXO:0000312

[PMID:29427989] [SUPPORT] Severe allergic asthma and severe eosinophilic asthma are two defined phenotypes for which there are efficacious targeted biologic therapies currently available, namely anti-immunoglobulin E (IgE) and anti-interleukin (IL)-5 antibodies, respectively. --- Explanation: This reference confirms that anti-IgE therapy is used to treat severe allergic asthma.

[PMID:20799475] [SUPPORT] Among these is anti-IgE, which directly targets IgE serum antibodies, thus inhibiting the central mechanism of immediate type hypersensitivity reactions. Application of anti-IgE antibodies effectively reduces IgE serum levels regardless of allergen specificity. --- Explanation: This reference supports that anti-IgE therapy is used in allergic asthma by targeting and reducing IgE.

[PMID:28635659] [SUPPORT] Blocking IgE with monoclonal antibodies such as omalizumab have demonstrated their efficacy, effectiveness, and safety in treating allergic asthma. --- Explanation: This reference confirms that anti-IgE therapy, specifically using omalizumab, is effective in treating allergic asthma.

[PMID:21114196] [SUPPORT] Omalizumab improves quality of life of patients with severe persistent allergic asthma that is inadequately controlled by currently available asthma medications. This therapy is well tolerated and significantly improves symptoms, disease control, reducing asthma exacerbations and the need to use high dosage of inhaled corticosteroids. --- Explanation: This reference further supports the efficacy of anti-IgE therapy (omalizumab) in treating severe allergic asthma by improving symptoms and reducing exacerbations.


MAXO:0000312

[PMID:34369231] [SUPPORT] Albuterol is the most common fast acting medication for asthma, and it exists in multiple forms, including metered-dose inhaler and nebulized therapy. --- Explanation: Albuterol, a commonly used short-acting beta agonist, is indicated as a fast-acting medication for the relief of asthma symptoms.

[PMID:30297688] [SUPPORT] Initial therapy in the stepwise approach for asthma management is short-acting β₂-agonist (SABA) therapy as needed for symptom control. --- Explanation: Short-acting beta agonists are recommended as initial therapy for the control of asthma symptoms, indicating their rapid relief properties.

[PMID:27588581] [SUPPORT] Results demonstrate the efficacy of short-acting beta-agonist (SABA) delivered by metered-dose inhaler as first-line therapy for younger and older children. --- Explanation: The efficacy of SABAs as a first-line therapy in emergency asthma management highlights their role in providing rapid relief from acute asthma symptoms.

[PMID:32482150] [SUPPORT] A majority of patients uses daily quick-relief medication, with the belief that it is the most important treatment because of its rapid onset of action. --- Explanation: The use of quick-relief medication, such as SABAs, by a majority of patients for asthma management is based on their rapid onset of action.

[PMID:11253864] [SUPPORT] Clinical studies comparing the effectiveness of (R)-albuterol (levalbuterol) with racemic albuterol established a strong rationale for using single-isomer beta-agonists in place of the racemic mixture: reduced dosages provide equivalent bronchodilatory effects with fewer beta-mediated side effects. --- Explanation: Levalbuterol, a single-isomer beta-agonist, is shown to provide effective rapid bronchodilation for asthma management.


HGNC.SYMBOL:IL4

[PMID:23070918] [SUPPORT] The results indicated that there were an association between the IL-4 C-33T (P = 0.006) and C-589T (P = 0.04) ... and susceptibility to asthma. --- Explanation: This meta-analysis found a significant association between IL-4 polymorphisms (C-33T and C-589T) and asthma susceptibility.

[PMID:10073323] [SUPPORT] Using both the candidate gene and the positional cloning approaches, there is evidence that predisposing factors, if not the disease itself, are genetically transferred. --- Explanation: This reference generally supports the idea of genetic associations in asthma, including those likely involving IL-4.

[PMID:21325943] [PARTIAL] Genotype combinations of IL-4 receptor-alpha and CD14 single nucleotide polymorphisms (SNPs) were significantly associated with diisocyanate asthma. --- Explanation: This study refers to IL-4 receptor-alpha and not IL-4 directly, and its context is specific to occupational asthma caused by diisocyanate exposure.


HGNC.SYMBOL:IL13

[PMID:23996716] [SUPPORT] Interleukin-13 (IL-13) is known to be a key regulator in immunoglobulin E (IgE) synthesis, mucus hypersecretion and airway hyperresponsiveness... A statistically significant association of the A-1512C polymorphism in IL13 gene was observed with atopy. --- Explanation: The study provides evidence that the IL13 gene polymorphism A-1512C is significantly associated with asthma.

[PMID:30539779] [PARTIAL] An efficient memory Th2 cell response is dependent on IL-13 produced by ILC2s, causing allergic lung inflammation and elevated serum levels of immunoglobulin E. --- Explanation: The study indicates that IL-13 is involved in allergic lung inflammation which is relevant to asthma, but it primarily discusses IL-13's role in mediating immune responses rather than directly associating IL-13 genetic polymorphisms with asthma.

[PMID:23380221] [PARTIAL] Very recently, a novel population of IL-33-responsive innate immune cells, the type 2 innate lymphoid cells, was found to produce hallmark TH2 cytokines, such as IL-5 and IL-13. --- Explanation: The review highlights the role of IL-13 in the pathway involved in asthma pathogenesis but does not directly establish a genetic association between IL-13 and asthma.

[PMID:21681015] [NO_EVIDENCE] Genome-wide association studies of asthma. --- Explanation: The abstract discusses GWAS studies related to asthma but does not specifically mention IL13.


HGNC.SYMBOL:ADAM33

[PMID:26666372] [SUPPORT] A disintegrin and metalloproteinase 33 (ADAM33) gene has been considered as an asthma susceptibility gene due to its possible role in airway remodeling, abnormal cell proliferation, and differentiation. Association of this gene with asthma has been reported in several genetic studies on various populations. --- Explanation: This study and its findings directly support the statement about the association between the ADAM33 gene and asthma.

[PMID:19481925] [SUPPORT] Despite this, the field has identified 43 replicated genes from association studies. The most frequently replicated are: TNF alpha, IL4, FCERB, Adam 33, and GSTP1. --- Explanation: This study acknowledges the genetic association between ADAM33 and asthma among other genes, further supporting the statement.


HGNC.SYMBOL:GSDMB

[PMID:33963941] [SUPPORT] Our results revealed that polymorphic variants rs7216389, rs2290400 and rs2305480 are associated with the development of allergic diseases as well as with asthma and asthma combined with allergic rhinitis. --- Explanation: This reference specifically mentions GSDMB polymorphisms and their association with asthma.


HGNC.SYMBOL:HLA-DQ

[PMID:23181788] [SUPPORT] Overall, our findings further replicate the HLA-DQ region in the pathogenesis of asthma. --- Explanation: The study highlights the association of HLA-DQ genes, specifically HLA-DQA1, with asthma in adults, corroborating previous findings linking HLA-DQ to asthma susceptibility.


HGNC.SYMBOL:ORMDL3

[PMID:25167772] [SUPPORT] The results of this meta-analysis firmly established that genetic variation at the rs7216389 locus, which controls the expression of the ORMDL3, may be a major, independent predisposing factor for asthma in ethnically diverse populations. --- Explanation: The meta-analysis confirms the association between the ORMDL3 gene and asthma susceptibility.

[PMID:18754760] [PARTIAL] It is far from being clear which gene caused the association signal, as it is derived from a large linkage disequilibrium (LD) block. --- Explanation: The study suggests an association signal that includes ORMDL3 but indicates uncertainty about the specific gene responsible due to a large LD block.

[PMID:21276132] [SUPPORT] The first GWAS for asthma discovered a novel associated locus on chromosome 17q21 encompassing the genes ORMDL3, GSDMB and ZPBP2. --- Explanation: This GWAS identifies ORMDL3 as part of a locus associated with asthma.


HGNC.SYMBOL:BACH2


HGNC.SYMBOL:TNFAIP3


HGNC.SYMBOL:STAT3


HGNC.SYMBOL:CD28


HGNC.SYMBOL:EGR2


HGNC.SYMBOL:ETS1


HGNC.SYMBOL:IRF4


HGNC.SYMBOL:SATB1


HGNC.SYMBOL:SMAD3


HGNC.SYMBOL:IL21R


ECTO:0000726

[PMID:26788835] [PARTIAL] Persons with asthma and multiple diagnoses reported odorous/pungent and building-related environmental factors to trigger symptoms to a larger extent than did the reference group, mainly due to perfume and odors from flowers. --- Explanation: This supports the role of environmental factors in triggering symptoms in people with asthma but does not specifically address allergens as a triggering factor.

[PMID:29732974] [SUPPORT] The link between asthma and food allergy has been well researched over the years; although the exact interplay between the two atopic conditions is yet to be fully described. Research suggests that children who have both asthma and food allergy are at greater risk of more severe asthmatic episodes. --- Explanation: This supports the idea that allergens (specifically food allergies) can trigger severe asthma attacks.

[PMID:20406590] [SUPPORT] A complex interplay of genetic predisposition and environmental influences results in the clinical picture of allergic asthma. --- Explanation: This supports the role of environmental influences, which includes allergens, in allergic asthma.

[PMID:29310764] [SUPPORT] The implementation of policies to reduce environmental allergic triggers can be an important adjunct to optimal patient care for allergic rhinitis and allergic asthma. --- Explanation: It supports that allergic asthma can be triggered by environmental allergens.

[PMID:29345235] [SUPPORT] The rising frequency of obstructive respiratory diseases during recent years, in particular allergic asthma, can be partially explained by changes in the environment, with the increasing presence in the atmosphere of chemical triggers (particulate matter and gaseous components such as nitrogen dioxide and ozone) and biologic triggers (aeroallergens). --- Explanation: This directly supports the role of environmental allergens as triggers for allergic asthma.

[PMID:23574397] [SUPPORT] For patients with asthma, exacerbations and poor control can result from exposure to environmental triggers, such as allergens and air particulates. --- Explanation: This supports the idea of allergens being environmental triggers for asthma.

[PMID:31187658] [SUPPORT] Environmental exposures varied across the year and demonstrated seasonal patterns. --- Explanation: This supports the role of environmental allergens like mold in triggering asthma.

[PMID:21277508] [SUPPORT] Extrinsic factors include environmental exposure to temperature, humidity, aeroallergens, irritants, and pollution. --- Explanation: This supports the role of environmental allergens in asthma.

[PMID:37480203] [SUPPORT] Pollen is a key source of aeroallergens responsible for allergic rhinitis, conjunctivitis, and asthma. --- Explanation: This supports the role of environmental allergens like pollen in triggering allergic asthma.


ECTO:8000036

[PMID:10518814] [SUPPORT] Air pollution is convincingly associated with many signs of asthma aggravation. --- Explanation: The article states that air pollution is associated with various signs and symptoms of asthma aggravation, supporting the statement that air pollution exacerbates asthma symptoms.

[PMID:21277508] [SUPPORT] Extrinsic factors include environmental exposure to temperature, humidity, aeroallergens, irritants, and pollution. --- Explanation: The article discusses how environmental factors, including pollution, can result in impaired function of the airways of athletes, which supports the statement.

[PMID:31187658] [SUPPORT] Increases in mold and PM10 were associated with increases in asthma claims. --- Explanation: The study found associations between particulate pollution and increased asthma claims, supporting the statement.

[PMID:31239087] [SUPPORT] Days with historically high associations between pollution and asthma attacks were identified as supplemental warning days. --- Explanation: The framework identifies days with high pollution as high-risk days for asthma attacks, supporting the statement.

[PMID:31765853] [SUPPORT] Exacerbations are largely driven by environmental exposures including pollutants, stress, and viral and bacterial pathogens. --- Explanation: The text supports the notion that pollutants, including air pollution, drive exacerbations of asthma symptoms.

[PMID:35307034] [SUPPORT] The risk ratio for asthma patients to be hospitalised on the same day of NO2 exposure was 1.101 per 10 µg/m3 NO2 increase. --- Explanation: The study observed a significant increase in hospitalization risk for asthma patients due to NO2 exposure, supporting the statement.


ECTO:6000029

[PMID:25584912] [SUPPORT] Exposure to passive smoke as a risk factor for asthma onset in childhood. --- Explanation: The study highlights how environmental tobacco smoke (ETS) is a significant indoor pollutant and a likely cause for asthma onset and severity in childhood.

[PMID:29292313] [SUPPORT] Exposure to environmental tobacco smoke increases pediatric asthma severity. --- Explanation: The study found that higher state tax grades on tobacco were associated with reduced asthma severity, indicating the detrimental impact of tobacco smoke on asthma severity.

[PMID:35236762] [NO_EVIDENCE] We aimed to study the associations between particulate matter with an aerodynamic diameter lower than 2.5 µm (PM2.5), black carbon (BC) and NO2 and the asthma symptom score in adults. --- Explanation: The study focuses on various air pollutants but does not specifically address tobacco smoke as an environmental factor affecting asthma severity.

[PMID:32493146] [NO_EVIDENCE] In this Caribbean population, uncontrolled asthma was independently associated with obesity, late-onset disease, and comorbidities of sleep apnea and depression. --- Explanation: This study does not discuss tobacco smoke specifically as an environmental risk factor for asthma severity.

[PMID:37973258] [NO_EVIDENCE] The objective of this article is to review recent literature on the implications of extreme weather events such as thunderstorms, wildfires, tropical cyclones, freshwater flooding, and temperature extremes in relationship to asthma symptoms. --- Explanation: The study reviews the impact of extreme weather events on asthma but does not mention tobacco smoke.


ECTO:0000231

[PMID:15579371] [SUPPORT] The prevalence of occupational asthma is rising, possibly due to the introduction of different chemicals and substances in the workplace. Etiologic agents include organic and inorganic compounds that are encountered in a variety of industries. --- Explanation: This reference explicitly states that occupational exposures to chemicals and substances in the workplace can trigger asthma.

[PMID:33104273] [SUPPORT] Dentists are exposed to a variety of airborne chemicals that can act as irritants and sensitizers and may give rise to work-related respiratory symptoms. --- Explanation: This supports the statement by indicating that occupational exposure to airborne chemicals can lead to respiratory symptoms including asthma.

[PMID:37971937] [SUPPORT] Multiple respiratory hazards have been identified in the cannabis cultivation and production industry, in which occupational asthma and work-related exacerbation of preexisting asthma have been reported. --- Explanation: This reference highlights occupational asthma caused by exposure to respiratory hazards in the cannabis industry.

[PMID:19463209] [SUPPORT] Common asthma triggers during recreational activities include allergen exposure, concomitant viral infection, and exercise. --- Explanation: Although this reference discusses recreational triggers, the exposure to allergens also supports the idea that similar environmental triggers in occupational settings can lead to asthma.

[PMID:36938642] [SUPPORT] Environmental and occupational exposures contribute to its causation. WTC-related or aggravated asthma is considered a World Trace Center (WTC) Health Program certifiable disease. --- Explanation: This supports the statement by acknowledging that occupational exposures can contribute to asthma.

[PMID:29427981] [SUPPORT] Low-molecular-weight chemical sensitizers, causes of occupational asthma, also cause asthma in a manner analogous to allergen. --- Explanation: This reference supports that occupational exposures to chemical sensitizers can trigger asthma.


MONDO:0008840

[PMID:30888062] [SUPPORT] Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder characterized by progressive cerebellar ataxia, ocular apraxia, immunodeficiency, telangiectasia, elevated serum α-fetoprotein concentration, radiosensitivity and cancer predisposition. --- Explanation: Supports progressive cerebellar ataxia as a core neurologic manifestation.

[PMID:38834764] [SUPPORT] Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0) and 5.0 (3.0-8.0) years, respectively. --- Explanation: Quantifies early onset of symptoms at median age 1 year.


MONDO:0008840

[PMID:11280737] [SUPPORT] A-T patients display a pleiotropic phenotype and suffer primarily from progressive ataxia caused by degeneration of cerebellar Purkinje and granule neurons. --- Explanation: Links cerebellar neuron degeneration to progressive atrophy.


MONDO:0008840

[PMID:30888062] [SUPPORT] Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder characterized by progressive cerebellar ataxia, ocular apraxia, immunodeficiency, telangiectasia, elevated serum α-fetoprotein concentration, radiosensitivity and cancer predisposition. --- Explanation: Lists ocular apraxia as a defining characteristic of AT.


MONDO:0008840

[PMID:30685876] [SUPPORT] A-T patients represent a broad range of clinical manifestations including progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, and increased metabolic diseases. --- Explanation: Review evidence supporting telangiectasia as a defining clinical sign.


MONDO:0008840

[PMID:39165363] [SUPPORT] Ataxia telangiectasia (AT) is a rare autosomal-recessive disorder characterized by profound neurodegeneration, combined immunodeficiency, and an increased risk for malignant diseases. --- Explanation: Supports combined immunodeficiency as part of the core AT phenotype.


MONDO:0008840

[PMID:38834764] [SUPPORT] IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases. --- Explanation: Multicenter cohort demonstrates IgA deficiency in 61% of AT patients.

[PMID:34477998] [SUPPORT] IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. --- Explanation: IgA deficiency serves as a prognostic biomarker in classical AT.


MONDO:0008840

[PMID:38834764] [SUPPORT] Most patients presented recurrent airway infections, which was significantly associated with IgA deficiency. --- Explanation: Cohort evidence supports recurrent respiratory infection as a frequent clinical manifestation.


MONDO:0008840

[PMID:30796268] [SUPPORT] Respiratory disease is a major cause of morbidity and mortality in patients with ataxia-telangiectasia (A-T) who are prone to recurrent sinopulmonary infections, bronchiectasis, pulmonary fibrosis, and pulmonary failure. --- Explanation: Supports bronchiectasis as a clinically important respiratory complication in AT.


MONDO:0008840

[PMID:30888062] [SUPPORT] Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder characterized by progressive cerebellar ataxia, ocular apraxia, immunodeficiency, telangiectasia, elevated serum α-fetoprotein concentration, radiosensitivity and cancer predisposition. --- Explanation: Supports elevated alpha-fetoprotein as a characteristic laboratory abnormality in AT.


MONDO:0008840

[PMID:30685876] [SUPPORT] A-T patients represent a broad range of clinical manifestations including progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, and increased metabolic diseases. --- Explanation: Review evidence supporting radiosensitivity as a core AT feature.


MONDO:0008840

[PMID:39521281] [SUPPORT] Non-Hodgkin lymphoma occurred most frequently (n = 39), whereas solid cancers disproportionately affected those 18 years and older (n = 22). --- Explanation: Non-Hodgkin lymphoma is the most common malignancy in AT.


MONDO:0008840

[PMID:30420857] [SUPPORT] most of the A-T patients between 2–9 years and 10–16 years of age are usually below the 10th and 3rd percentile, respectively --- Explanation: Growth data from AT cohort showing most patients fall below normal growth percentiles.


MONDO:0008840

[PMID:30685876] [INDIRECT EVIDENCE] [SUPPORT] The principal role of nuclear ATM is the coordination of cellular signaling pathways in response to DNA double-strand breaks, oxidative stress, and cell cycle checkpoint. --- Explanation: Review evidence linking ATM deficiency to defective DNA-damage and checkpoint signaling.

[PMID:30888062] [INDIRECT EVIDENCE] [SUPPORT] Classical A-T is caused by biallelic variants on ATM (ataxia telangiectasia mutated) gene, leading to a loss of function of the protein kinase ATM, involved in DNA damage repair. --- Explanation: Human genetic evidence that classical AT arises from biallelic ATM loss of function.


MONDO:0008840


MONDO:0008840

[PMID:11280737] [INDIRECT EVIDENCE] [SUPPORT] Our findings support the hypothesis that the absence of functional ATM results in oxidative stress, which may be an important cause of the degeneration of cerebellar neurons in A-T. --- Explanation: Atm-deficient mouse brain data support oxidative stress as a driver of cerebellar neuron loss.

[PMID:11280737] [INDIRECT EVIDENCE] [SUPPORT] We found alterations in the levels of thiol-containing compounds in Atm (-/-) brains, as well as significant changes in the activities of thioredoxin, catalase, and manganese superoxide dismutase in Atm (-/-) cerebella. --- Explanation: Direct biochemical evidence of altered antioxidant enzyme activity in Atm-deficient cerebella.

[PMID:38159274] [INDIRECT EVIDENCE] [SUPPORT] Here, we find evidence of microglial inflammation in the cerebellum of patients with A-T using single-nucleus RNA sequencing. --- Explanation: Patient cerebellar transcriptomics show microglial inflammation in AT.

[PMID:38159274] [INDIRECT EVIDENCE] [SUPPORT] A-T microglia co-culture with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity. --- Explanation: iPSC-derived microglia experiments support a direct pathogenic role for activated microglia.

[PMID:38159274] [INDIRECT EVIDENCE] [SUPPORT] Pseudotime analysis revealed that activation of A-T microglia preceded upregulation of apoptosis-related genes in granule and Purkinje neurons and that microglia exhibited increased neurotoxic cytokine signaling to granule and Purkinje neurons in A-T. --- Explanation: Temporal ordering shows microglial activation precedes neuronal death in AT cerebellum.


MONDO:0008840

[PMID:38834764] [INDIRECT EVIDENCE] [SUPPORT] IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases. --- Explanation: Multicenter cohort data show humoral deficiency and lymphopenia in AT.

[PMID:39165363] [INDIRECT EVIDENCE] [SUPPORT] We observed reduced levels of peripheral blood CD3+CD8+ cytotoxic T cells, CD3+CD4+ T helper cells, and CD19+ B cells, whereas the amount of CD3--CD56+ NK cells and CD3+CD56+ NKT-like cells was similar compared with age-matched controls. --- Explanation: Immune profiling demonstrates major T-cell and B-cell abnormalities in AT.

[PMID:34477998] [INDIRECT EVIDENCE] [SUPPORT] Overall survival of patients with IgA deficiency was significantly diminished. --- Explanation: Shows that more severe humoral immune deficiency is clinically relevant and associated with worse survival.

[PMID:24568663] [INDIRECT EVIDENCE] [SUPPORT] Laboratory evaluations revealed defective CSR while none of the three AT patients without HIgM presentation had a defect in the CSR process. --- Explanation: Direct evidence of impaired class switch recombination in AT patients with hyper-IgM phenotype.


MONDO:0008840

[PMID:30796268] [INDIRECT EVIDENCE] [SUPPORT] These data suggest that the heightened susceptibility of these cells to S. pneumoniae infection is due to both increased oxidative damage and a defect in inflammasome activation, and has implications for lung disease in these patients. --- Explanation: Airway epithelial studies support a cell-intrinsic respiratory mechanism in AT.

[PMID:30796268] [INDIRECT EVIDENCE] [SUPPORT] Further investigation revealed that the ASC-Caspase 1 signalling pathway was defective in A-T airway epithelial cells. --- Explanation: Identifies the specific inflammasome pathway defect in AT airway epithelium.


MONDO:0008840

[PMID:39521281] [INDIRECT EVIDENCE] [SUPPORT] Eighty-four (16.5%) of 508 individuals were diagnosed with a primary cancer, of whom 62 (74%) were hematologic in origin and 22 (26%) were solid-organ cancers. --- Explanation: Large cohort data quantifying cancer incidence and types in AT.

[PMID:39521281] [INDIRECT EVIDENCE] [SUPPORT] Non-Hodgkin lymphoma occurred most frequently (n = 39), whereas solid cancers disproportionately affected those 18 years and older (n = 22). --- Explanation: Identifies NHL as the most common malignancy and age-dependent shift to solid tumors.

[PMID:30420857] [INDIRECT EVIDENCE] [SUPPORT] Apart from a progressive neurodegenerative disorder, A-T leads to significantly increased susceptibility to malignancies. --- Explanation: Confirms increased cancer susceptibility as a core feature of AT.


MAXO:0000011

[PMID:34107524] [SUPPORT] Positive changes were observed in the TCMS, PBBS, GMFM, and motor performance, participation, and quality of life. --- Explanation: Case-report evidence supports physical therapy for functional impairment in AT.


MAXO:0000011

[PMID:34107524] [INDIRECT EVIDENCE] [SUPPORT] Positive changes were observed in the TCMS, PBBS, GMFM, and motor performance, participation, and quality of life. --- Explanation: Case-report evidence supports physical therapy for functional impairment in AT.


MAXO:0000058

[PMID:39152028] [PARTIAL] Although there were no safety concerns, the primary efficacy endpoint was not met, possibly related to delays in treatment reducing the number of participants who received treatment as outlined in the protocol, and potentially different treatment effects according to age. --- Explanation: Supports this as a clinically tested therapy with acceptable safety but insufficient overall efficacy.

[PMID:39152028] [SUPPORT] There were no reports of hyperglycaemia, hypertension, hirsutism, or Cushingoid appearance in any of the treatment groups, nor any treatment-related deaths. --- Explanation: Favorable safety profile without typical systemic steroid side effects.


MAXO:0000058

[PMID:39152028] [INDIRECT EVIDENCE] [PARTIAL] Although there were no safety concerns, the primary efficacy endpoint was not met, possibly related to delays in treatment reducing the number of participants who received treatment as outlined in the protocol, and potentially different treatment effects according to age. --- Explanation: Supports this as a clinically tested therapy with acceptable safety but insufficient overall efficacy.

[PMID:39152028] [INDIRECT EVIDENCE] [SUPPORT] There were no reports of hyperglycaemia, hypertension, hirsutism, or Cushingoid appearance in any of the treatment groups, nor any treatment-related deaths. --- Explanation: Favorable safety profile without typical systemic steroid side effects.


MAXO:0000079

[PMID:30685876] [SUPPORT] Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency (PID) disease that is caused by mutations in ataxia-telangiectasia mutated (ATM) gene encoding a serine/threonine protein kinase. --- Explanation: Autosomal recessive inheritance necessitates genetic counseling for affected families.


MAXO:0000747

[PMID:30420857] [SUPPORT] Pre-emptive alloHSCT can correct immunodeficiency in A-T with an acceptable risk of transplant-related mortality, and might be an early treatment of choice in some A-T patients at high risk of hematological malignancy. --- Explanation: Case series supports preemptive HSCT for immunodeficiency correction in selected AT patients.

[PMID:30420857] [SUPPORT] Furthermore, this treatment provided complete immunological reconstitution and remission of the patient's granulomas without any need for immunosuppression or immunoglobulin replacement. --- Explanation: Demonstrates complete immune reconstitution following transplantation.


MAXO:0000747

[PMID:30420857] [INDIRECT EVIDENCE] [SUPPORT] Pre-emptive alloHSCT can correct immunodeficiency in A-T with an acceptable risk of transplant-related mortality, and might be an early treatment of choice in some A-T patients at high risk of hematological malignancy. --- Explanation: Case series supports preemptive HSCT for immunodeficiency correction in selected AT patients.

[PMID:30420857] [INDIRECT EVIDENCE] [SUPPORT] Furthermore, this treatment provided complete immunological reconstitution and remission of the patient's granulomas without any need for immunosuppression or immunoglobulin replacement. --- Explanation: Demonstrates complete immune reconstitution following transplantation.


hgnc:795

[PMID:30888062] [SUPPORT] Classical A-T is caused by biallelic variants on ATM (ataxia telangiectasia mutated) gene, leading to a loss of function of the protein kinase ATM, involved in DNA damage repair. --- Explanation: Supports ATM as the central disease gene in classical AT.

[PMID:30420857] [SUPPORT] The incidence of cancer does not correlate with the type of ATM mutation, but rather with the extent of immunodeficiency, particularly profound IgA deficiency and a low number of B cells. --- Explanation: Cancer risk in AT correlates with immunodeficiency severity, not mutation type.


MONDO:0007167

[PMID:16752402] [SUPPORT] AOI and AOIII are autosomal dominant lethal skeletal dysplasias characterized by overlapping clinical findings that include vertebral abnormalities, disharmonious skeletal maturation, hypoplastic long bones, and joint dislocations. --- Explanation: This supports severe limb hypoplasia and disproportionate skeletal growth failure.


MONDO:0007167

[PMID:16752402] [SUPPORT] AOI and AOIII are autosomal dominant lethal skeletal dysplasias characterized by overlapping clinical findings that include vertebral abnormalities, disharmonious skeletal maturation, hypoplastic long bones, and joint dislocations. --- Explanation: This directly supports joint dislocations as a core AOI finding.


MONDO:0007167

[PMID:16752402] [SUPPORT] AOI and AOIII are autosomal dominant lethal skeletal dysplasias characterized by overlapping clinical findings that include vertebral abnormalities, disharmonious skeletal maturation, hypoplastic long bones, and joint dislocations. --- Explanation: This directly supports major vertebral abnormalities in AOI.


MONDO:0007167

[PMID:12454961] [SUPPORT] Fetal ultrasonography (US) revealed absent or deficient ossification of the posterior neural arches of the thoracic spine, humeri, radii, ulnae, fibulae, and short tubular bones other than the distal phalanges, in addition to extremely short, thick femora. --- Explanation: This prenatal AOI case directly documents absent/deficient fibular ossification.


MONDO:0007167

[PMID:12454961] [SUPPORT] Fetal magnetic resonance imaging (MRI) using an ultrafast imaging sequence depicted dysmorphic features, pulmonary hypoplasia, and large cisterna magna. --- Explanation: This case provides direct evidence of pulmonary hypoplasia in AOI.


MONDO:0007167

[PMID:16752402] [INDIRECT EVIDENCE] [SUPPORT] Mutations in the gene encoding filamin B (FLNB) cause a spectrum of osteochondrodysplasias, including atelosteogenesis type I (AOI) and atelosteogenesis type III (AOIII). --- Explanation: This supports FLNB as the causal molecular driver of AOI pathophysiology.

[PMID:16752402] [INDIRECT EVIDENCE] [SUPPORT] These results show that clustering of mutations in two regions of FLNB produce AOI/AOIII, and highlight the important role of this cytoskeletal protein in normal skeletogenesis. --- Explanation: This links FLNB mutation clustering to abnormal skeletal development.


MONDO:0007167


MAXO:0000950

[PMID:12454961] [SUPPORT] Autopsy corroborated not only pulmonary hypoplasia but also laryngeal stenosis. --- Explanation: Severe airway and pulmonary abnormalities in AOI support the need for primarily supportive perinatal management.


hgnc:3755

[PMID:16752402] [SUPPORT] In this study, 14 novel missense mutations in FLNB were found in 15 unrelated patients with AOI and AOIII. --- Explanation: This provides direct human genetic evidence for causative FLNB mutations in AOI-spectrum disease.


MONDO:0007167

[PMID:16752402] [SUPPORT] AOI and AOIII are autosomal dominant lethal skeletal dysplasias characterized by overlapping clinical findings that include vertebral abnormalities, disharmonious skeletal maturation, hypoplastic long bones, and joint dislocations. --- Explanation: This directly supports dominant inheritance and lethal disease severity in AOI.


MONDO:0009727

[PMID:20301493] [SUPPORT] Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia). --- Explanation: This directly documents rhizomelic limb shortening.


MONDO:0009727

[PMID:20301493] [SUPPORT] Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia). --- Explanation: This directly reports hitchhiker thumbs in affected individuals.


MONDO:0009727

[PMID:20301493] [SUPPORT] Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia). --- Explanation: This supports a narrow/small thorax phenotype in AOII.


MONDO:0009727

[PMID:20301493] [SUPPORT] Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia). --- Explanation: This directly supports cleft palate as part of the AOII craniofacial phenotype.


MONDO:0009727

[PMID:20301493] [SUPPORT] Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia). --- Explanation: This directly supports depressed nasal bridge.


MONDO:0009727

[PMID:20301493] [SUPPORT] Clinical features of SLC26A2-related atelosteogenesis include rhizomelic limb shortening with normal-sized skull, hitchhiker thumbs, small chest, protuberant abdomen, cleft palate, and distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia). --- Explanation: This directly supports micrognathia in the AOII phenotype spectrum.


MONDO:0009727

[PMID:20301493] [SUPPORT] Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. --- Explanation: This directly supports clubfoot (talipes equinovarus).


MONDO:0009727

[PMID:20301493] [SUPPORT] SLC26A2-related atelosteogenesis is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia. --- Explanation: This directly supports pulmonary hypoplasia as a critical AOII complication.


MONDO:0009727

[PMID:20301493] [SUPPORT] SLC26A2-related atelosteogenesis is usually lethal at birth or shortly thereafter due to pulmonary hypoplasia and tracheobronchomalacia. --- Explanation: This directly supports tracheobronchomalacia in AOII.


MONDO:0009727

[PMID:11448940] [INDIRECT EVIDENCE] [SUPPORT] The diastrophic dysplasia sulfate transporter (DTDST) gene encodes a transmembrane protein that transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans. --- Explanation: This directly links DTDST/SLC26A2 function to sulfate transport and proteoglycan sulfation in chondrocytes.

[PMID:8571951] [INDIRECT EVIDENCE] [SUPPORT] Here, we report that AOII patients also have DTDST mutations, which lead to defective uptake of inorganic sulfate and insufficient sulfation of macromolecules by patient mesenchymal cells in vitro. --- Explanation: This supports sulfate uptake failure and undersulfation as a disease mechanism in AOII.


MONDO:0009727


MONDO:0009727

[PMID:8571951] [INDIRECT EVIDENCE] [SUPPORT] Atelosteogenesis type II (AO II) is a neonatally lethal chondrodysplasia whose clinical and histological characteristics resemble those of another chondrodysplasia, the much less severe diastrophic dysplasia (DTD). --- Explanation: This supports severe chondrodysplasia with pathological cartilage involvement in AOII.

[PMID:8571951] [INDIRECT EVIDENCE] [SUPPORT] The severity of the phenotype appears to be correlated with the predicted effect of the mutations on the residual activity of the DTDST protein. --- Explanation: This supports a mechanism where reduced transporter activity drives severity of skeletal disease.


MAXO:0000950

[PMID:20301493] [SUPPORT] There is no specific treatment currently available, and the aim of therapy (supportive versus palliative) will depend on clinical status and respiratory prognosis of the individual patient. --- Explanation: This supports supportive/palliative management as the current standard approach.


hgnc:10994

[PMID:20301493] [SUPPORT] The diagnosis of SLC26A2-related atelosteogenesis is established in a proband with characteristic clinical, radiologic, and histopathologic features and biallelic pathogenic variants in SLC26A2 identified by molecular genetic testing. --- Explanation: This directly supports biallelic SLC26A2 variants as the molecular basis of disease.

[PMID:8571951] [SUPPORT] Here, we report that AOII patients also have DTDST mutations, which lead to defective uptake of inorganic sulfate and insufficient sulfation of macromolecules by patient mesenchymal cells in vitro. --- Explanation: This supports DTDST (SLC26A2) mutations as causative in AOII.


MONDO:0009727

[PMID:20301493] [SUPPORT] SLC26A2-related atelosteogenesis is inherited in an autosomal recessive manner. --- Explanation: This directly supports autosomal recessive inheritance for Atelosteogenesis Type II.

[PMID:20301493] [SUPPORT] If both parents are known to be heterozygous for an SLC26A2 pathogenic variant, each sib of a proband with SLC26A2-related atelosteogenesis has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. --- Explanation: This supports the expected Mendelian recurrence risk for an autosomal recessive disorder.


MONDO:0007168

[PMID:1442028] [SUPPORT] There was rhizomelic shortness of the limbs and a club-foot. --- Explanation: This directly supports rhizomelic limb shortening.


MONDO:0007168

[PMID:1442028] [SUPPORT] There was rhizomelic shortness of the limbs and a club-foot. --- Explanation: This directly supports talipes equinovarus (club-foot).


MONDO:0007168

[PMID:1442028] [SUPPORT] Radiological examination demonstrated striking hypoplasia of the humerus with proximal rounding and distal tapering giving a 'drumstick' appearance, 'S'-shape configuration of the cervical spine, scoliosis and coronal cleft in the thoracolumbar vertebral bodies. --- Explanation: This directly supports humeral hypoplasia.


MONDO:0007168

[PMID:1442028] [SUPPORT] Radiological examination demonstrated striking hypoplasia of the humerus with proximal rounding and distal tapering giving a 'drumstick' appearance, 'S'-shape configuration of the cervical spine, scoliosis and coronal cleft in the thoracolumbar vertebral bodies. --- Explanation: This directly supports coronal cleft vertebral abnormalities.


MONDO:0007168

[PMID:1442028] [SUPPORT] Radiological examination demonstrated striking hypoplasia of the humerus with proximal rounding and distal tapering giving a 'drumstick' appearance, 'S'-shape configuration of the cervical spine, scoliosis and coronal cleft in the thoracolumbar vertebral bodies. --- Explanation: This directly supports scoliosis.


MONDO:0007168

[PMID:1442028] [SUPPORT] The patient had multiple craniofacial abnormalities at birth, including ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft palate. --- Explanation: This directly supports hypertelorism.


MONDO:0007168

[PMID:1442028] [SUPPORT] The patient had multiple craniofacial abnormalities at birth, including ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft palate. --- Explanation: This supports a depressed/flat nasal bridge phenotype.


MONDO:0007168

[PMID:1442028] [SUPPORT] The patient had multiple craniofacial abnormalities at birth, including ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft palate. --- Explanation: This directly supports micrognathia.


MONDO:0007168

[PMID:1442028] [SUPPORT] The patient had multiple craniofacial abnormalities at birth, including ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft palate. --- Explanation: This directly supports cleft palate.


MONDO:0007168

[PMID:1442028] [SUPPORT] The infant had short broad thumbs in the hands similar to those observed in the feet. --- Explanation: This directly supports broad thumbs.


MONDO:0007168

[PMID:1442028] [SUPPORT] The infant experienced recurrent apnea and persistent severe tracheomalacia, which necessitated tracheostomy at 5 months of age. --- Explanation: This directly supports tracheomalacia as a major AOIII complication.


MONDO:0007168

[PMID:14991055] [INDIRECT EVIDENCE] [SUPPORT] We found that filamin B is expressed in human growth plate chondrocytes and in the developing vertebral bodies in the mouse. --- Explanation: This supports a chondrocyte and vertebral developmental context for FLNB-related disease.

[PMID:14991055] [INDIRECT EVIDENCE] [SUPPORT] These data indicate an unexpected role in vertebral segmentation, joint formation and endochondral ossification for this ubiquitously expressed cytoskeletal protein. --- Explanation: This links FLNB dysfunction to core AOIII skeletal developmental mechanisms.


MONDO:0007168


MAXO:0000950

[PMID:1442028] [SUPPORT] The infant experienced recurrent apnea and persistent severe tracheomalacia, which necessitated tracheostomy at 5 months of age. --- Explanation: This supports the need for major supportive airway management in severe AOIII.


hgnc:3755

[PMID:14991055] [SUPPORT] We identified mutations in the gene encoding filamin B in four human skeletal disorders. --- Explanation: This provides direct genetic evidence linking FLNB mutations to severe human skeletal disorders including AOIII.

[PMID:14991055] [SUPPORT] We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721). --- Explanation: This explicitly names missense FLNB mutations in AOIII.


MONDO:0007168

[PMID:14991055] [SUPPORT] We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721). --- Explanation: This directly supports autosomal dominant inheritance for the AOIII FLNB phenotype.


MONDO:0004980

[PMID:28846349] [SUPPORT] This chronic disorder associated with pruritus usually starts in infancy and presents with dry skin, eczematous lesions and lichenification. --- Explanation: Eczematous lesions are a defining feature of atopic dermatitis.


MONDO:0004980

[PMID:39659858] [SUPPORT] Atopic dermatitis, more commonly known as atopic eczema, is a chronic, relapsing inflammatory skin disorder characterized by dry skin, localized erythematous rash, and intense pruritus. --- Explanation: Intense pruritus is a defining clinical characteristic of atopic dermatitis.


MONDO:0004980

[PMID:39659858] [SUPPORT] Atopic dermatitis, more commonly known as atopic eczema, is a chronic, relapsing inflammatory skin disorder characterized by dry skin, localized erythematous rash, and intense pruritus. --- Explanation: Dry skin (xerosis) is a defining clinical characteristic of atopic dermatitis reflecting barrier dysfunction.


MONDO:0004980

[PMID:28846349] [SUPPORT] This chronic disorder associated with pruritus usually starts in infancy and presents with dry skin, eczematous lesions and lichenification. --- Explanation: Lichenification develops from chronic scratching in atopic dermatitis patients.


MONDO:0004980

[PMID:20207111] [SUPPORT] Extrinsic or allergic AD shows high total serum IgE levels and the presence of specific IgE for environmental and food allergens... While extrinsic AD is the classical type with high prevalence, the incidence of intrinsic AD is approximately 20% --- Explanation: Approximately 80% of atopic dermatitis patients have the extrinsic subtype characterized by elevated serum IgE levels.


MONDO:0004980

[PMID:16550169] [INDIRECT EVIDENCE] [SUPPORT] Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X [sic, correct designation is R501X] and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. --- Explanation: Landmark study establishing FLG loss-of-function as the strongest genetic risk factor for atopic dermatitis, with ~9% carrier frequency in Europeans.

[PMID:21388665] [INDIRECT EVIDENCE] [PARTIAL] They are similar in that they are complex inherited diseases involving genes that encode immune components and structural proteins that regulate differentiation of epidermal cells. Each disease is characterized by proliferation of epidermal keratinocytes and abnormal cornification or terminal differentiation in the epidermis --- Explanation: Describes the epidermal barrier dysfunction in atopic dermatitis including abnormal cornification and keratinocyte differentiation.


MONDO:0004980


MONDO:0004980

[PMID:30819278] [INDIRECT EVIDENCE] [SUPPORT] Type 2 cytokines as well as interleukin 17 and interleukin 22 contribute to skin barrier dysfunction and the development of AD. --- Explanation: Confirms the role of type 2 cytokines in AD pathophysiology and their contribution to barrier dysfunction, supporting the Th2/type 2 immune mechanism.

[PMID:21388665] [INDIRECT EVIDENCE] [PARTIAL] skin lesions contain immune infiltrates of T cells, dendritic cells, and other types of leukocytes. We review similarities between the diseases and differences in epidermal barrier defects and immune cells. --- Explanation: Describes the immune cell infiltrates in AD lesions including T cells and dendritic cells, consistent with type 2 immune response.


MONDO:0004980

[PMID:30819278] [INDIRECT EVIDENCE] [PARTIAL] New insights into the pathophysiology of AD have focused on epidermal lipid profiles, neuroimmune interactions, and microbial dysbiosis. --- Explanation: Supports neuroimmune signaling as a component of AD pathophysiology.


MAXO:0000058


NCIT:C162455


HGNC.SYMBOL:FLG

[PMID:16550169] [SUPPORT] two independent loss-of-function genetic variants (R510X [sic, correct designation is R501X] and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. --- Explanation: Landmark Palmer et al. 2006 study establishing FLG loss-of-function as the major genetic predisposing factor for atopic dermatitis.


HGNC.SYMBOL:IL4R


HGNC.SYMBOL:IL13


HGNC.SYMBOL:STAT6


HGNC.SYMBOL:EMSY


HGNC.SYMBOL:BACH2


HGNC.SYMBOL:TNFAIP3


HGNC.SYMBOL:EGR2


HGNC.SYMBOL:ETS1


HGNC.SYMBOL:IRF4


HGNC.SYMBOL:SATB1


HGNC.SYMBOL:SMAD3


HGNC.SYMBOL:REL


MONDO:0004981

[PMID:35873859] [SUPPORT] Palpitations are the cardinal symptom of AF and many AF therapies are targeted towards relieving this symptom. --- Explanation: Confirms that palpitations are the primary symptom of atrial fibrillation.


MONDO:0004981


MONDO:0004981

[PMID:26318825] [SUPPORT] Experiencing fatigue, dyspnea and intermittent symptoms produced symptom representations and emotional and behavioral responses associated with treatment-seeking delay. --- Explanation: Confirms fatigue is a common symptom in atrial fibrillation that affects patient behavior.


MONDO:0004981

[PMID:35873859] [SUPPORT] up to two-third of patients also complain of dyspnea as a predominant self-reported symptom. --- Explanation: Confirms dyspnea is a common and predominant symptom in atrial fibrillation patients.


MONDO:0004981

[PMID:39146015] [INDIRECT EVIDENCE] [SUPPORT] NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden. --- Explanation: This demonstrates that electrical remodeling including altered action potential duration is a key pathophysiological mechanism in AF.

[PMID:38255832] [INDIRECT EVIDENCE] [PARTIAL] Atrial fibrillation (AF) is an arrhythmia that affects the left atrium, cardiac function, and the patients' survival rate. --- Explanation: Confirms AF affects atrial electrical function and is influenced by electrophysiological mechanisms.


MONDO:0004981

[PMID:38255832] [INDIRECT EVIDENCE] [PARTIAL] it is influenced by a complex interplay of autoimmune, inflammatory, and electrophysiological mechanisms. --- Explanation: Inflammatory mechanisms contribute to structural remodeling including fibrosis that maintains AF substrate.


MAXO:0000058

[PMID:37573616] [SUPPORT] DOAC was associated with a significantly lower risk of stroke or systemic embolism (hazard ratio 0.85, 95% confidence interval 0.75 to 0.96, p = 0.008, I2 = 0%), major bleeding, intracranial hemorrhage, and mortality compared with warfarin. --- Explanation: Meta-analysis of 132,980 patients demonstrates DOACs reduce stroke risk in AF patients.


CHEBI:10033

[PMID:37573616] [INDIRECT EVIDENCE] [SUPPORT] DOAC was associated with a significantly lower risk of stroke or systemic embolism (hazard ratio 0.85, 95% confidence interval 0.75 to 0.96, p = 0.008, I2 = 0%), major bleeding, intracranial hemorrhage, and mortality compared with warfarin. --- Explanation: Meta-analysis of 132,980 patients demonstrates DOACs reduce stroke risk in AF patients.


CHEBI:72296


CHEBI:68579


CHEBI:70752


MAXO:0000058


CHEBI:6904


CHEBI:101278


CHEBI:4551


CHEBI:2663


CHEBI:75984


CHEBI:63622


MAXO:0001395


HGNC.SYMBOL:KCNQ1


HGNC.SYMBOL:KCNE2


HGNC.SYMBOL:KCNJ2


HGNC.SYMBOL:SCN5A


HGNC.SYMBOL:PITX2

[PMID:39146015] [PARTIAL] Unbiased transcriptomics analysis revealed that NOX2 mediates atrial remodeling in obesity-mediated AF in DIO mice, PA-treated hiPSC-aCMs, and human atrial tissue from obese individuals by upregulation of paired-like homeodomain transcription factor 2 (PITX2). --- Explanation: Demonstrates PITX2 plays a mechanistic role in AF pathophysiology, supporting its genetic association with AF risk.

[PMID:35980763] [SUPPORT] In patients with cardiovascular conditions, AF PRS is a strong independent predictor of incident AF that provides complementary predictive value when added to a validated clinical risk score and NT-proBNP. --- Explanation: Polygenic risk score including PITX2 and other loci significantly predicts AF risk, validating genetic contributions to AF susceptibility.


MONDO:0971031

[PMID:33887125] [PARTIAL] The symptoms of GFS can have severe impact on patients' wellbeing and can have social and legal consequences. --- Explanation: Documents that GFS symptoms significantly impact patients' functioning, consistent with alcohol intoxication.


MONDO:0971031

[PMID:34682761] [PARTIAL] Patients with this syndrome become inebriated and may suffer the medical and social implications of alcoholism --- Explanation: Inebriation includes symptoms like slurred speech characteristic of alcohol intoxication.


MONDO:0971031

[PMID:31423320] [SUPPORT] The most significant event caused by one of his inebriations was a fall that caused intracranial bleeding --- Explanation: Case report documents falls due to intoxication episodes in ABS patient.


MONDO:0971031

[PMID:31423320] [SUPPORT] personality changes with episodes of depression, 'brain fog', and aggressive behaviour became apparent --- Explanation: Case report documents brain fog and mental changes in ABS patient.


MONDO:0971031

[PMID:31423320] [SUPPORT] He complained of having had memory loss, mental changes, and episodes of depression for over 6 years --- Explanation: Case report documents memory loss as a primary symptom in ABS patient.


MONDO:0971031

[PMID:30020718] [NO_EVIDENCE] Patients with auto-brewery syndrome present with many of the signs and symptoms of alcohol intoxication while denying an intake of alcohol and often report a high-sugar, high-carbohydrate diet. --- Explanation: Gastrointestinal symptoms including bloating are part of the alcohol intoxication symptom profile.


MONDO:0971031

[PMID:30020718] [NO_EVIDENCE] Patients with auto-brewery syndrome present with many of the signs and symptoms of alcohol intoxication --- Explanation: Nausea and vomiting are recognized symptoms of alcohol intoxication in ABS.