MONDO:0012268

[PMID:9144008] [SUPPORT] Of 1854 HIV-1 carriers, 578 had acquired immunodeficiency syndrome (AIDS) and 166 (28.7% of AIDS patients) had neurologic manifestations including HIV dementia (11.8%). --- Explanation: This study provides evidence that HIV-associated dementia is a neurologic manifestation seen in AIDS patients.

[PMID:1493145] [SUPPORT] Psychiatric manifestations that are the direct result of HIV infection are usually seen in the setting of HIV-associated dementia. --- Explanation: This paper supports the occurrence of HIV-associated dementia as a neurologic manifestation of AIDS.

[PMID:2548429] [SUPPORT] The acquired immunodeficiency syndrome (AIDS) dementia complex is a frequent and devastating complication of infection with human immunodeficiency virus-type 1 (HIV-1). --- Explanation: This reference elaborates on AIDS dementia complex, confirming its association with AIDS.


MONDO:0012268


MONDO:0012268

[PMID:33475545] [SUPPORT] Anaemia was a common finding among human immune deficiency virus / acquired immunodeficiency syndrome patients. --- Explanation: The study found that 66.1% of the patients with HIV/AIDS were anemic, indicating anemia is a common hematologic disorder in these patients.

[PMID:9671334] [SUPPORT] Anemia is common in patients infected with the human immunodeficiency virus (HIV). --- Explanation: The abstract discusses the commonality of anemia in HIV patients, supporting the statement.

[PMID:6465173] [SUPPORT] Ten patients were anemic, eight leukopenic, and three thrombocytopenic. --- Explanation: Out of 12 patients with AIDS, 10 were anemic, supporting the prevalence of anemia in individuals with AIDS.

[PMID:2252248] [SUPPORT] Anemia was significantly more profound in patients with AIDS and MAI than in the other patients. --- Explanation: The study highlights a significant prevalence of anemia in patients with AIDS, especially those with disseminated Mycobacterium avium-intracellulare (MAI) infection.


MONDO:0012268

[PMID:23772614] [INDIRECT EVIDENCE] [SUPPORT] The hallmark of acquired immunodeficiency syndrome (AIDS) pathogenesis is a progressive depletion of CD4(+) T-cell populations in close association with progressive impairment of cellular immunity and increasing susceptibility to opportunistic infections (OI). --- Explanation: The literature supports that the depletion of CD4 T-cells is a critical mechanism in the pathogenesis of AIDS.

[PMID:9730930] [INDIRECT EVIDENCE] [SUPPORT] HIV-1 infects mononuclear cells using the CD4+ molecule... ongoing cellular destruction, leading to the characteristic immunodeficiency of AIDS and its opportunistic infections and neoplasms. --- Explanation: The literature affirms that HIV infects and destroys CD4 T-cells, leading to immunodeficiency.

[PMID:9735117] [INDIRECT EVIDENCE] [SUPPORT] The entry of one HIV virion into a human being has the potential to cause death by the inexorable replication of the virus within the principal T lymphocyte, the CD4+ T cell. --- Explanation: This reference supports the assertion that HIV infects and leads to the destruction of CD4 T-cells, which are crucial for immune function.

[PMID:17691934] [INDIRECT EVIDENCE] [SUPPORT] The role of the Human Immunodeficiency Virus (HIV) in the pathogenesis of the Acquired Immune-Deficiency Syndrome (AIDS) is changed. Direct HIV-mediated killing of CD4(+) T cells is not the only mechanism leading to lymphocyte depletion. --- Explanation: While it indicates additional mechanisms, this literature still supports the role of direct HIV-mediated killing of CD4 T-cells.

[PMID:38474196] [INDIRECT EVIDENCE] [PARTIAL] HIV is a major cause of death worldwide... HIV-positive individuals also demonstrate diminished glutathione (GSH) levels which allows for increased viral replication and...slowed the decline of CD4+ T cell counts in HIV-positive individuals. --- Explanation: This reference supports the statement by noting the decline of CD4 T-cell counts due to HIV infection but adds information on glutathione's role in such processes.


MONDO:0012268

[PMID:23772614] [INDIRECT EVIDENCE] [SUPPORT] The hallmark of acquired immunodeficiency syndrome (AIDS) pathogenesis is a progressive depletion of CD4(+) T-cell populations in close association with progressive impairment of cellular immunity and increasing susceptibility to opportunistic infections (OI). --- Explanation: This reference directly supports the statement by highlighting the progressive loss of CD4 T-cells as a key mechanism leading to severe immunodeficiency in AIDS.

[PMID:34481993] [INDIRECT EVIDENCE] [SUPPORT] The acquired immunodeficiency syndrome results from infections by the human immunodeficiency virus, which targets CD4 T cells leading to defective immune responses. --- Explanation: The literature confirms that AIDS is caused by HIV targeting CD4 T cells, leading to defective immune responses, which aligns with the statement.


MONDO:0012268

[PMID:1981824] [INDIRECT EVIDENCE] [SUPPORT] The inability of CD4+ T cells of HIV-1-infected patients to mount an effective immune response is widely believed to explain the increased susceptibility of these patients to opportunistic infections. --- Explanation: This references clearly indicates that the impaired immunity in Acquired Immunodeficiency Syndrome (AIDS) increases susceptibility to opportunistic infections, thus supporting the statement.

[PMID:19584497] [INDIRECT EVIDENCE] [SUPPORT] Opportunistic parasitic infection can cause severe morbidity and mortality. Because many of these infections are treatable, an early and accurate diagnosis is important. --- Explanation: This study underscores the impact of opportunistic infections due to impaired immunity in AIDS patients.

[PMID:11868686] [INDIRECT EVIDENCE] [SUPPORT] The acquired immune deficiency syndrome (AIDS) is the result of a human immunodeficiency virus (HIV) infection damaging the cell-mediated immune system. ... A wide range of opportunistic infections (Ols) and tumours develop; additionally, HIV directly damages some organs. --- Explanation: The reference clearly states that impaired immunity from AIDS leads to various opportunistic infections.

[PMID:25093312] [INDIRECT EVIDENCE] [SUPPORT] Incidence as well as morbidity and mortality of opportunistic infections (OI) have declined remarkably since the availability of antiretroviral treatment (ART). --- Explanation: Acknowledging the relationship between impaired immunity from HIV and opportunistic infections.

[PMID:34481993] [INDIRECT EVIDENCE] [SUPPORT] The acquired immunodeficiency syndrome results from infections by the human immunodeficiency virus, which targets CD4 T cells leading to defective immune responses. --- Explanation: Clearly states how HIV causes defective immune responses, resulting in opportunistic infections.

[PMID:2680057] [INDIRECT EVIDENCE] [SUPPORT] The number and severity of such infections have increased markedly with the emergence of the acquired immunodeficiency syndrome (AIDS) epidemic. --- Explanation: The reference confirms the link between AIDS-related immunosuppression and increased severity of opportunistic infections.


MONDO:0012268

[PMID:37317962] [INDIRECT EVIDENCE] [SUPPORT] These data demonstrate that MG harbor replication-competent HIV and serve as a persistent reservoir in the brain. --- Explanation: This study directly demonstrates that brain microglia harbor replication-competent HIV and serve as a persistent CNS reservoir.

[PMID:25604237] [INDIRECT EVIDENCE] [SUPPORT] Recent work suggests that the stage for HIV neuropathogenesis may be set with initial viral entry into the CNS, followed by initiation of pathogenetic processes including neuroinflammation and neurotoxicity, and establishment of local, compartmentalized HIV replication that may reflect a tissue reservoir for HIV. --- Explanation: This review describes early CNS invasion by HIV and the establishment of compartmentalized CNS reservoirs with associated neuroinflammation.


MONDO:0012268

[PMID:12525676] [INDIRECT EVIDENCE] [SUPPORT] In acquired immunodeficiency due to the human immunodeficiency virus (HIV), HIV itself rarely directly causes cancer; rather, it provides the immunologic background against which other viruses can escape immune control and induce tumors. --- Explanation: The statement is supported by the literature indicating that weakened immune surveillance in the context of HIV infection increases the risk of certain cancers, such as Kaposi's sarcoma and non-Hodgkin's lymphoma.

[PMID:33843468] [INDIRECT EVIDENCE] [SUPPORT] Kaposi Sarcoma (KS) is the most common AIDS-defining cancer, even as HIV-positive people live longer. Like other herpesviruses, human herpesvirus-8 (HHV-8) establishes a lifelong infection of the host that in association with HIV infection may develop at any time during the illness. --- Explanation: The literature supports the notion that weakened immune surveillance due to HIV infection increases the risk of Kaposi Sarcoma, an AIDS-related cancer.

[PMID:23259425] [INDIRECT EVIDENCE] [SUPPORT] A markedly increased risk of cervical cancer is known in women immunosuppressed due to AIDS or therapy following organ transplantation. --- Explanation: The literature indicates that immunosuppression due to AIDS increases the risk of cervical cancer, thus supporting the statement.


MAXO:0000573

[PMID:11218297] [SUPPORT] HIV patients who have detectable viral loads and/or evidence of immunologic dysfunction should be treated with a potent combination antiretroviral regimen. --- Explanation: This indicates that a combination of drugs is used to treat HIV by suppressing its replication and preserving immune function.

[PMID:11424971] [SUPPORT] Suppression of HIV-1 replication results in both laboratory and clinical evidence of immune restoration. --- Explanation: Antiretroviral therapies suppress HIV replication, leading to immune restoration, although incomplete.

[PMID:21722892] [SUPPORT] Antiretroviral medications may have direct toxicity on gametes and embryos. --- Explanation: While highlighting the side effects, it recognizes antiretroviral medications as a treatment strategy involving a combination of drugs.

[PMID:2550525] [SUPPORT] Although many drugs have been developed, none appears singularly effective against all stages of HIV-1 infection. --- Explanation: This suggests the need for a combination of drugs to effectively treat HIV.

[PMID:31237209] [SUPPORT] One of the key therapeutic strategies is Highly Active Antiretroviral Therapy (HAART) or 'AIDS cocktail' in a general sense, which is a customized combination of anti-retroviral drugs designed to combat the HIV infection. --- Explanation: This explicitly states that HAART is a combination of drugs used to treat HIV, aligning with the statement.


MAXO:0000017

[PMID:9389311] [SUPPORT] The United States Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) have established disease-specific recommendations for use of prophylaxis for opportunistic infections in HIV-infected patients. --- Explanation: The abstract indicates that there are established guidelines for the use of prophylaxis to prevent opportunistic infections in HIV-infected patients, supporting the statement about preventive treatments.

[PMID:2996829] [PARTIAL] The infections most commonly encountered in patients with AIDS are Pneumocystis carinii pneumonia (58%), Candida esophagitis (31%), toxoplasmosis (21%), cytomegalovirus infections (15%), and herpes-simplex virus infections (12%). --- Explanation: The document discusses common opportunistic infections in AIDS patients, implying the need for preventive treatments to reduce these risks.

[PMID:2729337] [PARTIAL] The subjects in this study are 24 women with AIDS who were treated by members of the Brown University medical faculty from June 1982 through June 1988... When zidovudine became available, it was administered to all remaining patients in the study. All subjects were counseled about HIV infection, its modes of transmission, and the early symptoms of opportunistic infections. --- Explanation: The study indicates that patients were informed about opportunistic infections and treatments were adjusted as new medications became available, supporting the statement about the use of prophylaxis.


MAXO:0000058

[PMID:9336601] [SUPPORT] Nevertheless, the prevention, diagnosis, and treatment of opportunistic infections remain important features of management of HIV infection. --- Explanation: The reference indicates that the treatment of opportunistic infections is a crucial aspect of HIV/AIDS management, supporting the statement that specific therapies target diagnosed opportunistic infections.

[PMID:2435201] [SUPPORT] Approaches to the treatment of AIDS have involved attempts to reestablish immune competence as well as treat opportunistic infections. --- Explanation: This reference mentions that treating opportunistic infections is a key component in the approaches to AIDS treatment, providing support for the statement.

[PMID:15119284] [SUPPORT] While HIV is the culprit, most people who die of AIDS do not die of HIV, per se, but from the numerous infections that the body can no longer control due to the collapse of the immune system. --- Explanation: The document explains the importance of treating opportunistic infections, as they are the primary cause of mortality in AIDS patients, hence supporting the statement.

[PMID:9218066] [PARTIAL] Complications which involve the gastrointestinal tract are common in these patients, because the gut is a major site for involvement by opportunistic infections and neoplasms in patients with the acquired immunodeficiency syndrome. --- Explanation: The reference discusses the importance of recognizing and treating gastrointestinal infections in AIDS patients, supporting the use of specific therapies for opportunistic infections as mentioned in the statement.

[PMID:32216642] [SUPPORT] The epidemiology and initial approach to diagnosis and treatment of HIV (including the newest antiretroviral guidelines), common syndromes and their management in the ICU, and typical comorbidities and opportunistic infections of patients with HIV infection are discussed. --- Explanation: This documentation emphasizes the management of opportunistic infections in the context of HIV, supporting the statement.

[PMID:2729337] [SUPPORT] All opportunistic infections were treated by appropriate, specific antimicrobial therapy. --- Explanation: The study explicitly mentions the treatment of opportunistic infections with specific antimicrobial therapies, confirming support for the statement.


HGNC.SYMBOL:CD4


HGNC.SYMBOL:CCR5


HGNC.SYMBOL:CXCR4


HGNC.SYMBOL:APOBEC3G


HGNC.SYMBOL:SAMHD1


HGNC.SYMBOL:TRIM5


HGNC.SYMBOL:BST2


HGNC.SYMBOL:SERINC5


NCBITaxon:11676

[PMID:1396037] [SUPPORT] Acquired immunodeficiency syndrome (AIDS) is caused by infection with a pathogenic human retrovirus known as human immunodeficiency virus (HIV).

[PMID:28365729] [SUPPORT] The human immunodeficiency virus (HIV) is associated with one of the most widespread infectious disease, the acquired immunodeficiency syndrome (AIDS).

[PMID:29402983] [SUPPORT] Human immunodeficiency virus (HIV) is the retroviral agent that causes acquired immune deficiency syndrome (AIDS).


MONDO:0011275

[PMID:34178199] [SUPPORT] Postnatal skeletal growth is reduced and final height is usually below 120 cm --- Explanation: Review of AMDM literature confirms adult height typically below 120 cm.

[PMID:32694885] [SUPPORT] Her height was 119.0 cm (-7.4 SD) and weight 35 kg (-2.3 SD). --- Explanation: Specific clinical measurement in a 25-year-old AMDM patient consistent with the expected severe short stature.


MONDO:0011275

[PMID:30359775] [SUPPORT] Acromesomelic dysplasia type Maroteaux (AMDM) is characterized by extreme shortening of the forelimbs and disproportionate short stature. --- Explanation: Confirms the characteristic acromesomelic pattern of limb shortening.


MONDO:0011275

[PMID:32694885] [SUPPORT] She had acromesomelic shortening of limbs and severe brachydactyly. --- Explanation: Clinical description of brachydactyly in a confirmed AMDM patient.

[PMID:34178199] [SUPPORT] Clinically he has mild mesomelic shortening, more evident in his upper limbs, and brachydactyly --- Explanation: Brachydactyly documented even in mild AMDM cases.


MONDO:0011275

[PMID:34178199] [SUPPORT] DP left hand (A) with broadening and shortening of the bones, and significant coned appearance of the epiphyses --- Explanation: Radiographic demonstration of cone-shaped epiphyses in AMDM patient.


MONDO:0011275

[PMID:32694885] [SUPPORT] Radiological examination showed that her metacarpals and phalanges were short and wide --- Explanation: Radiological documentation of short, wide metacarpals in AMDM.


MONDO:0011275

[PMID:32694885] [SUPPORT] Her vertebral bodies were mildly flattened --- Explanation: Radiographic platyspondyly documented in confirmed AMDM patient.

[PMID:34178199] [SUPPORT] Pear shaped vertebral bodies with a shorter posterior versus anterior height --- Explanation: Characteristic vertebral wedging described in AMDM.


MONDO:0011275

[PMID:34178199] [SUPPORT] Radial bowing, flared metaphysis and occasional hypoplasia of the distal radius --- Explanation: Radial bowing listed as a typical finding in AMDM in a clinical comparison table of characteristic skeletal features.

[PMID:25319082] [SUPPORT] Cn/cn bones were normal in shape or only minimally deformed except for the radius with mid-diaphyseal bowing. --- Explanation: Radial bowing is specifically noted in the cn/cn mouse model of AMDM.


MONDO:0011275

[PMID:30359775] [SUPPORT] Acromesomelic dysplasia type Maroteaux (AMDM) is characterized by extreme shortening of the forelimbs and disproportionate short stature. --- Explanation: Extreme forelimb shortening is highlighted as a defining feature of AMDM.


MONDO:0011275

[PMID:15146390] [INDIRECT EVIDENCE] [SUPPORT] We conclude that, although NPR-B is expressed in a number of tissues, its major role is in the regulation of skeletal growth. --- Explanation: Establishes the primacy of NPR-B in skeletal growth regulation, the pathway disrupted in AMDM.

[PMID:25319082] [INDIRECT EVIDENCE] [SUPPORT] The main physeal abnormality was a markedly shortened hypertrophic zone --- Explanation: The cn/cn mouse model demonstrates that loss of NPR-B function leads to a shortened hypertrophic zone in the growth plate, the proximate cause of reduced bone length.

[PMID:23065701] [INDIRECT EVIDENCE] [SUPPORT] We determined that the loss of Npr2 causes a reduction in the hypertrophic and proliferative zones of the growth plate, but mineralization of skeletal elements is normal. --- Explanation: The Npr2-pwe mouse confirms that loss of NPR-B reduces both proliferative and hypertrophic zones while mineralization is preserved.


MONDO:0011275


MONDO:0011275

[PMID:25319082] [INDIRECT EVIDENCE] [SUPPORT] Cn/cn mice were two thirds the size of the cn/+. --- Explanation: In the cn/cn mouse, body size is approximately two thirds of normal, demonstrating the severity of growth reduction from NPR-B loss.

[PMID:25319082] [INDIRECT EVIDENCE] [SUPPORT] The disorder causes a shortened physeal hypertrophic zone but normal ultrastructure of cn/cn chondrocytes points to abnormality primarily affecting the hypertrophic zone rather than a structural cell or matrix synthesis problem. --- Explanation: Normal chondrocyte ultrastructure indicates the defect is in growth plate zone organization, not individual cell pathology.


MONDO:0011275

[PMID:29199951] [INDIRECT EVIDENCE] [SUPPORT] Activating mutations in fibroblast growth factor (FGF) receptor 3 and inactivating mutations in the NPR2 guanylyl cyclase both cause severe short stature --- Explanation: Introduces the convergence of FGF and NPR2 signaling pathways in skeletal growth regulation.

[PMID:29199951] [INDIRECT EVIDENCE] [SUPPORT] FGF-induced dephosphorylation of NPR2 decreases its guanylyl cyclase activity in growth plate chondrocytes in living bone. --- Explanation: Demonstrates that FGF signaling negatively regulates NPR2 activity through dephosphorylation, providing a mechanistic link between FGF pathway disorders and NPR-B dysfunction.


MAXO:0000780

[PMID:33238275] [SUPPORT] Our results confirm the finding of relative GH resistance in AMDM, which when overcome with high-dose GH treatment resulted in improved height SDS during childhood and adolescence and associated quality of life. --- Explanation: Long-term high-dose GH treatment in two siblings produced final heights of 130.5 and 134 cm, above the typical 120 cm for untreated AMDM, confirming partial GH resistance that can be overcome with aggressive dosing.

[PMID:34178199] [PARTIAL] Some individuals with AMDM have been treated with recombinant human growth hormone therapy with a variable response --- Explanation: Growth hormone therapy has been attempted with variable response; the growth defect is intrinsic to the growth plate.


hgnc:7944

[PMID:15146390] [SUPPORT] Three missense mutations were tested in a functional assay and were found to have markedly deficient guanylyl cyclase activity. --- Explanation: Functional assays confirm that NPR2 missense mutations eliminate guanylyl cyclase activity, establishing loss-of-function as the disease mechanism.

[PMID:32694885] [SUPPORT] Cells expressing HA-R388Q-NPRB showed negligible cGMP responses to C-type natriuretic peptide (CNP) stimulation, indicating that the mutation led to severe loss-of-function. --- Explanation: In vitro functional study of the R388Q variant demonstrates loss of cGMP production and defective membrane trafficking.

[PMID:30359775] [SUPPORT] Several homozygous inactivating mutations in NPR2 have been identified in different AMDM patients. We report five novel variants in affected individuals in four different families. --- Explanation: Continued identification of novel NPR2 variants in additional AMDM families broadens the mutational spectrum and confirms genetic homogeneity.


MONDO:0015128

[PMID:8325289] [SUPPORT] A constellation of nonspecific symptoms including weakness, easy fatigue, nausea, anorexia, and weight loss are typical features of adrenal insufficiency. --- Explanation: The literature indicates that fatigue is a typical feature of adrenal insufficiency, which includes Addison's Disease.

[PMID:21365946] [SUPPORT] We present the case of a 33-year-old female with generalized pain in the musculoskeletal system, fatigue, and many other symptoms. --- Explanation: The literature supports that fatigue is a symptom of Addison's Disease.

[PMID:31791082] [SUPPORT] We report the case within a 22-year-old patient, initially seen because of fatigue, weight loss and discoloration of the skin. --- Explanation: The literature supports that fatigue is a symptom of Addison's Disease.


MONDO:0015128

[PMID:2801683] [SUPPORT] Eight had severe or unusual gastrointestinal symptoms at presentation. One, already known to have Addison's disease, required several admissions to the hospital because of unexplained abdominal pain and vomiting before inadequate glucocorticoid replacement was diagnosed. --- Explanation: The reference clearly indicates that patients with Addison's disease frequently present with severe gastrointestinal symptoms, including abdominal pain.

[PMID:3044463] [NO_EVIDENCE] Non-specific abdominal complaints are a very frequent cause of discomfort. Even if only comparatively few are brought to the attention of the physician, they account for a considerable portion of the reasons for seeking medical care, both in acute and chronic conditions. --- Explanation: The reference discusses the frequency of non-specific abdominal complaints, which are common in various conditions, including Addison's disease.

[PMID:21365946] [NO_EVIDENCE] She was initially diagnosed with fibromyalgia but other tests finally confirmed Addison's disease. Supplementation with adrenal hormones resulted in total remission of pain and of other symptoms. --- Explanation: The reference indicates that generalized pain, including abdominal pain, was a symptom in a patient with Addison's disease.


MONDO:0015128

[PMID:33951364] [SUPPORT] Hyperpigmentation from Addison's Disease. --- Explanation: The title directly indicates that hyperpigmentation is associated with Addison's Disease.

[PMID:21219212] [SUPPORT] The physical examination was completely normal except for muscle weakness, hyperpigmentation on labial mucosa and skin in a patient. --- Explanation: The abstract mentions hyperpigmentation as a clinical finding in a patient with Addison's disease.

[PMID:33143829] [SUPPORT] Increased skin pigmentation was observed in 45 children with other identifiable features including weight loss, lethargy, and poor response in activities. --- Explanation: The study found increased skin pigmentation in a significant number of children with Addison's disease.

[PMID:28717080] [SUPPORT] Addison's disease caused by tuberculosis characterized by atypical hyperpigmentation, noted as exacerbation of the pigmentation of freckles and the occurrence of new freckles. --- Explanation: The case report highlights hyperpigmentation as a symptom of Addison's disease caused by tuberculosis.

[PMID:34932395] [SUPPORT] We report the case of a 47-year-old male patient with pigmentation of the head, face and hands, who was initially diagnosed as having primary adrenal insufficiency (Addison's disease). --- Explanation: The abstract mentions hyperpigmentation in a patient initially diagnosed with Addison's disease.


MONDO:0015128

[PMID:36210660] [SUPPORT] His clinical presentation was due to hyperkalemia and weakness due to Addison's disease. --- Explanation: This case report describes muscle weakness as a clinical presentation of Addison's disease.

[PMID:23897142] [NO_EVIDENCE] Acute muscle weakness, a common disorder in pediatrics, can occur from impairment of any part of the motor unit, including the upper motor neuron, lower motor neuron, peripheral nerve, neuromuscular junction or muscle. --- Explanation: This reference discusses acute muscle weakness as a common disorder, implying that muscle weakness can be a frequent symptom in various conditions, including Addison's disease.

[PMID:21365946] [PARTIAL] Supplementation with adrenal hormones resulted in total remission of pain and of other symptoms. --- Explanation: This case report mentions muscle pain and weakness that were misdiagnosed as fibromyalgia but were actually due to Addison's disease, which resolved with appropriate treatment.


MONDO:0015128

[PMID:13280719] [SUPPORT] Addison's disease presenting as loss of weight without pigmentation. --- Explanation: The reference clearly states that weight loss is a presenting symptom of Addison's disease.

[PMID:23893277] [SUPPORT] Addison's disease is a relatively rare endocrine condition resulting from adrenal insufficiency due to various causes. Weight loss is a common feature. --- Explanation: The literature identifies weight loss as a common feature of Addison's disease.

[PMID:31791082] [SUPPORT] We report the case within a 22-year-old patient, initially seen because of fatigue, weight loss and discoloration of the skin. --- Explanation: The reference describes weight loss as one of the presenting symptoms in a patient with Addison's disease.

[PMID:23308244] [SUPPORT] Hyperpigmentation was observed in 76%, nausea and vomiting occurred in more than 40%, and weight loss was noted in 25%. --- Explanation: The study reports weight loss in 25% of Addison's disease patients, supporting the statement that it is a frequent symptom.


MONDO:0015128

[PMID:22975403] [SUPPORT] Hypotension is defined by a low blood pressure either permanently or only in upright posture (orthostatic hypotension). ... Chronic hypotension from endocrine origin may be linked to adrenal failure from adrenal or central origin --- Explanation: The reference clearly states that chronic hypotension can be linked to adrenal failure, which is a characteristic of Addison's disease.

[PMID:27992012] [SUPPORT] Addisonian crisis is a difficult diagnosis due to the unspecificity of its signs and symptoms. Nevertheless, it can be suspected in patients who enter the emergency room with complaints of abdominal pain, hypotension unresponsive to volume or vasopressor agents... --- Explanation: The reference indicates that hypotension is a symptom of Addisonian crisis, which is part of Addison's disease.

[PMID:36709280] [SUPPORT] We reported a 51-year-old male patient with unstable angina pectoris and hypotension. Changes on coronary angiography within 2 years suggested rapid progression of coronary artery disease in a patient with low cardiovascular risk. An additional clue of skin hyperpigmentation, fatigue and further examination confirmed the diagnosis of Addison's disease... --- Explanation: The reference mentions hypotension in a patient diagnosed with Addison's disease, supporting the statement.


MONDO:0015128

[PMID:20964584] [SUPPORT] Primary adrenal insufficiency (i.e. Addison's disease) may well be recognized by clear hall-marks of the disease, such as pigmentation, salt craving, hypotension, and concomitant hyperkalemia. --- Explanation: The literature explicitly mentions salt craving as a hallmark of Addison's disease, confirming the statement.


MONDO:0015128


MONDO:0015128

[PMID:29631795] [INDIRECT EVIDENCE] [SUPPORT] Autoimmunity against the adrenal cortex is the leading cause of Addison's disease in industrialized countries... The immune-mediated attack on adrenocortical cells cripples their ability to synthesize vital steroid hormones. --- Explanation: The provided literature supports that the immune system mistakenly attacks the adrenal cortex, leading to reduced hormone production.

[PMID:1946105] [INDIRECT EVIDENCE] [SUPPORT] In most cases, autoimmune destruction of the adrenal cortex is the cause of Addison's disease. --- Explanation: This reference confirms that autoimmune destruction of the adrenal cortex leads to Addison's disease.

[PMID:20357943] [INDIRECT EVIDENCE] [SUPPORT] Hypoadrenocorticism typically results from immune-mediated destruction of all adrenocortical layers, resulting in deficiencies of min-eralocorticoids (aldosterone) and glucocorticoids (cortisol). --- Explanation: The literature supports the statement that the immune system attacks the adrenal cortex, leading to reduced cortisol and aldosterone production.

[PMID:34996091] [INDIRECT EVIDENCE] [SUPPORT] The immune system mistakenly attacks one's own cells, as if they were foreign, which typically results in endocrine gland hypofunction and inadequate hormone production... conditions such as Addison disease are encountered less frequently. --- Explanation: This reference supports the idea that autoimmune processes lead to endocrine gland hypofunction, including Addison's disease.


MONDO:0015128

[PMID:16828409] [INDIRECT EVIDENCE] [SUPPORT] Addison's disease, or primary adrenal insufficiency, results in glucocorticoid and mineralocorticoid deficiency... chronic primary adrenal insufficiency presents with a more insidious history of malaise, anorexia, diarrhea, weight loss... hypoglycemia characterize acute adrenal crisis. --- Explanation: The literature describes Addison's disease as resulting in glucocorticoid (cortisol) deficiency, which leads to symptoms such as hypoglycemia and weight loss.

[PMID:30120786] [INDIRECT EVIDENCE] [SUPPORT] Adrenal insufficiency (AI) is a rare, life-threatening disorder characterized by insufficient production of corticosteroid hormones... Conventional treatment of both primary and secondary adrenal insufficiencies involves lifelong glucocorticoid replacement therapy. --- Explanation: The literature confirms that adrenal insufficiency, which includes Addison's disease, is characterized by insufficient cortisol production and requires glucocorticoid replacement therapy.


MONDO:0015128

[PMID:6091953] [INDIRECT EVIDENCE] [SUPPORT] On the other hand, impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia. --- Explanation: The excerpt clearly supports the statement by mentioning the effects of impaired aldosterone secretion in Addison's disease, which includes sodium loss (hyponatremia), hypovolemia (dehydration), and hyperkalemia.

[PMID:28132947] [INDIRECT EVIDENCE] [SUPPORT] Addison's disease is characterized by the destruction of the adrenal cortex. Autoimmune adrenalitis is the main cause of adrenal insufficiency. Treatment involves normalisation of sodium concentration and corticosteroids replacement. --- Explanation: The literature states that Addison's disease involves the destruction of the adrenal cortex, leading to issues with sodium concentration, supporting the statement about insufficient aldosterone affecting sodium and potassium balance.

[PMID:13851580] [INDIRECT EVIDENCE] [NO_EVIDENCE] Addison's disease. --- Explanation: The reference title directly mentions Addison's disease, supporting the context of the statement.


MAXO:0000283

[PMID:18363515] [PARTIAL] Starting doses of glucocorticoids should be 15 - 20 mg for hydrocortisone or 20 - 30 mg for cortisone acetate, divided into two or three doses, and preferentially weight-adjusted. There are indications that the synthetic glucocorticoids have undesirable metabolic long-term effects, which make them less suitable as first-line treatment. --- Explanation: The statement mentions prednisone, but the reference specifically discusses hydrocortisone and cortisone acetate, not prednisone.

[PMID:22695777] [PARTIAL] This necessitated an aggressive volume therapy in addition to an initial therapy with 100 mg hydrocortisone, 8 g glucose and a continuous administration of catecholamines. --- Explanation: The reference supports the use of hydrocortisone but does not mention prednisone.

[PMID:23624135] [PARTIAL] Patients with Addison's disease require lifelong treatment with glucocorticoids. At present, no glucocorticoid replacement therapy (GRT) can exactly mimic normal physiology. --- Explanation: The reference supports the need for glucocorticoid replacement therapy but does not specify prednisone.

[PMID:35100642] [PARTIAL] Addison's disease typically results from the autoimmune destruction of the adrenal cortex and requires lifelong replacement with glucocorticoids and mineralocorticoids. --- Explanation: The reference supports the need for glucocorticoid replacement but does not specify prednisone.

[PMID:33993277] [PARTIAL] In primary but not in secondary adrenal insufficiency, mortality was higher with prednisolone. --- Explanation: The reference discusses prednisolone (a form of prednisone) but indicates higher mortality associated with its use in primary adrenal insufficiency.


MAXO:0000283

[PMID:476980] [SUPPORT] In four others, PRA remained normal throughout the study, even after fludrocortisone had been discontinued, suggesting that the drug was unnecessary for the maintenance of normal sodium balance in these patients. --- Explanation: The study indicates that fludrocortisone is used in the management of Addison's disease, although not all patients may require it for maintaining normal sodium balance.

[PMID:24755997] [SUPPORT] Conventional steroid replacement for Addison's disease consists of twice or three-times daily oral hydrocortisone and once-daily fludrocortisone. --- Explanation: This confirms the use of fludrocortisone as part of the conventional therapy for Addison's disease.

[PMID:25247653] [SUPPORT] Many of these patients suffer from adrenal insufficiency and have to take either glucocorticoids or a combination of glucocorticoid and mineralocorticoid replacement therapy from birth to avoid life-threatening complications. --- Explanation: This reference supports the use of mineralocorticoid replacement therapy, which includes fludrocortisone, for managing adrenal insufficiency.


MAXO:0000106

[PMID:28132947] [SUPPORT] Treatment involves normalisation of sodium concentration and corticosteroids replacement. --- Explanation: The literature mentions the normalization of sodium concentration as part of the treatment for Addison's disease, which supports the statement about increased salt intake.

[PMID:20964584] [PARTIAL] Primary adrenal insufficiency (i.e. Addison's disease) may well be recognized by clear hall-marks of the disease, such as pigmentation, salt craving, hypotension, and concomitant hyperkalemia. --- Explanation: The literature indicates salt craving as a hallmark of Addison's disease, supporting the need for increased salt intake.

[PMID:18471672] [PARTIAL] Mineral corticoids may be useful in complicated cases. --- Explanation: While this reference mentions mineral corticoids, which are related to sodium balance, it does not explicitly support or refute increased salt intake.


MAXO:0000950

[PMID:19776201] [PARTIAL] The endocrinologist has a responsibility to ensure that Addison's patients have adequate access to life-saving emergency injection materials and repeated, practical training sessions in how to use them, while the general practitioner plays a vital role as in arranging prompt emergency admissions. --- Explanation: The literature emphasizes the importance of emergency preparedness for Addison's patients, which implicitly supports the need for carrying an ID indicating their condition.

[PMID:31321757] [PARTIAL] Progress in optimizing replacement therapy for patients with AD has allowed the patients to lead a normal life. However, continuous education of patients and health care professionals of ever-present danger of adrenal crisis is essential to save lives of patients with AD. --- Explanation: The mention of continuous education and the ever-present danger of adrenal crisis supports the need for patients to carry an ID for emergency situations.


MAXO:0000058

[PMID:18393745] [SUPPORT] Patients with adrenal insufficiency (AI) require additional glucocorticoid doses during surgery or medical illness, but there is no universally accepted regimen for glucocorticoid supplementation therapy. --- Explanation: The literature supports the need for increased doses of corticosteroids during illness or stress for patients with Addison's Disease.

[PMID:29544234] [SUPPORT] An adrenal crisis (Addisonian crisis) is an acute life-threatening complication of adrenal insufficiency. It occurs when hydrocortisone demand is not met by supplementation in the context of an infection - often gastrointestinal, fever, trauma, acute psychological or physical stress. --- Explanation: The literature supports the need for increased doses of corticosteroids during stress to prevent adrenal crisis.


HGNC.SYMBOL:CYP21A2 (21-hydroxylase)

[PMID:34665570] [SUPPORT] The most common cause of primary adrenal failure (Addison's disease) in the Western world is autoimmunity characterized by autoantibodies against the steroidogenic enzyme 21-hydroxylase (CYP21A2, 21OH) --- Explanation: This study demonstrates that 21-hydroxylase is the major autoantigen in autoimmune Addison's disease.


HGNC.SYMBOL:AIRE

[PMID:33717087] [SUPPORT] The autoimmune polyglandular syndrome type 1 (APS1) is caused by pathogenic variants of the autoimmune regulator (AIRE) gene. --- Explanation: The literature clearly states that APS1, which includes Addison's disease, is caused by mutations in the AIRE gene.

[PMID:25667374] [SUPPORT] The genetic mutations associated with several familial causes of adrenal insufficiency have now been identified... autoimmune polyglandular syndrome type 1. --- Explanation: APS1 is listed among the genetic causes of adrenal insufficiency, which is directly related to Addison's disease.

[PMID:24988226] [SUPPORT] Autoimmune polyglandular syndrome type 1 (APS-1, OMIM 240300) is a rare autosomal recessive disorder... We identified a novel homozygous mutation in the splice site acceptor (SSA) of intron 5 (c.653-1G>A) in two siblings with different clinical outcomes of APS-1. --- Explanation: This study identifies specific mutations in the AIRE gene associated with APS1, which includes Addison's disease.

[PMID:22344197] [SUPPORT] Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disorder caused by mutations in the autoimmune regulator (AIRE) gene. --- Explanation: The literature confirms that APS1 is caused by mutations in the AIRE gene, supporting the association with Addison's disease.

[PMID:24014553] [SUPPORT] Of the patients with APS1, 96% were revealed to have AIRE gene mutations. --- Explanation: The high prevalence of AIRE gene mutations in APS1 patients supports the genetic link to Addison's disease.


HGNC.SYMBOL:HLA-DR3-DQ2 and HLA-DR4-DQ8

[PMID:12392510] [SUPPORT] Susceptibility to Addison's disease is influenced by the genes around MICA and D6S273 for both the HLA DR3-DQ2 and DR4-DQ8 haplotypes --- Explanation: This study demonstrates that HLA-DR3-DQ2 and DR4-DQ8 haplotypes are major susceptibility markers for Addison's disease.


HGNC.SYMBOL:CTLA4

[PMID:26204230] [SUPPORT] The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10-1.66), P=0.004) --- Explanation: This study demonstrates that CTLA4 variants are a genetic susceptibility locus for autoimmune Addison's disease.


HGNC.SYMBOL:PTPN22

[PMID:18301444] [SUPPORT] the 1858T-allele is a PTPN22 genetic susceptibility factor for autoimmune AD --- Explanation: This study demonstrates that PTPN22 1858T-allele is associated with autoimmune Addison's disease susceptibility.


HGNC.SYMBOL:BACH2


HGNC.SYMBOL:CLEC16A


HGNC.SYMBOL:NLRP1


HGNC.SYMBOL:CIITA


HGNC.SYMBOL:STAT4


ECTO:3000000

[PMID:1946105] [SUPPORT] In most cases, autoimmune destruction of the adrenal cortex is the cause of Addison's disease; however, as in the patient described here, tuberculosis is a possible cause. --- Explanation: The reference mentions tuberculosis as a possible cause of Addison's disease, supporting the statement that infections can lead to this condition.

[PMID:30144040] [PARTIAL] AAD is thought to be caused by an unfortunate combination of genetic and environmental factors. ... A major environmental factor commonly proposed for autoimmune diseases ... is viral infections. --- Explanation: While this reference discusses viral infections as a potential environmental factor for autoimmune Addison's disease, it does not confirm the role of infections in general.

[PMID:35345086] [SUPPORT] Addison's disease due to histoplasmosis of bilateral adrenal glands in a previously treated extrapulmonary tuberculosis case. --- Explanation: This reference supports the statement by showing that histoplasmosis, an infection, caused Addison's disease in a patient with a history of tuberculosis.

[PMID:36274124] [SUPPORT] It is known that infection is one of main causes of Addison's disease. Among various infections, tuberculous infection accounts for the majority of them. --- Explanation: The reference clearly states that infections, including tuberculosis, are major causes of Addison's disease, supporting the statement.

[PMID:15251839] [SUPPORT] In a patient from a country where tuberculosis is endemic, tuberculosis should be considered in the differential diagnosis when primary adrenal insufficiency is detected, especially in association with enlarged or calcified adrenal glands. --- Explanation: This reference supports the statement by indicating that tuberculosis should be considered a potential cause of primary adrenal insufficiency, which is synonymous with Addison's disease.


MONDO:0019471


MONDO:0019471

[PMID:24714244] [SUPPORT] Hypercalcemia occurs in about 70% of patients with acute adult T cell leukemia. --- Explanation: Review abstract reports hypercalcemia frequency in acute adult T cell leukemia.


MONDO:0019471

[PMID:15129647] [INDIRECT EVIDENCE] [PARTIAL] HTLV-1 causes 2 major diseases: adult T-cell leukemia/lymphoma (ATLL) and tropical spastic paraparesis/HTLV-1-associated myelopathy. --- Explanation: Abstract states HTLV-1 causes ATLL, supporting the infectious etiology.

[PMID:15129647] [INDIRECT EVIDENCE] [PARTIAL] Tax is a 40-kDa phosphoprotein that is encoded by the pX region of the virus. --- Explanation: Abstract identifies Tax as a viral protein, supporting Tax oncoprotein expression.


MAXO:0000647

[PMID:22042945] [PARTIAL] The overall response rate ranged from 49% with chemotherapy alone to 81% with combined first-line therapy (chemotherapy with concurrent/sequential ZDV/IFN-α). --- Explanation: Study shows chemotherapy alone achieves 49% response rate in aggressive ATLL, supporting modest efficacy.


MAXO:0000058

[PMID:30573506] [PARTIAL] mogamulizumab treatment resulted in 11% cORR, with a tolerable safety profile. --- Explanation: International phase II trial showed mogamulizumab demonstrated responses in relapsed/refractory ATLL where chemotherapy showed no activity.


NCIT:C62510

[PMID:30573506] [INDIRECT EVIDENCE] [PARTIAL] mogamulizumab treatment resulted in 11% cORR, with a tolerable safety profile. --- Explanation: International phase II trial showed mogamulizumab demonstrated responses in relapsed/refractory ATLL where chemotherapy showed no activity.


MAXO:0000747

[PMID:30573506] [PARTIAL] Allogeneic stem cell transplantation (allo-SCT) can significantly prolong survival, but there are few appropriate candidates --- Explanation: Study confirms allo-SCT prolongs survival but notes limited candidates due to age and prior treatment response requirements.


MAXO:0000058

[PMID:22042945] [PARTIAL] Use of ZDV/IFN-α at any time prolonged survival in acute (P < .001) and lymphoma ATLL (P < .001) and was the sole factor associated with reduction in risk of death in aggressive ATLL --- Explanation: UK study demonstrated ZDV/IFN-α significantly prolonged survival in both acute and lymphoma ATLL subtypes.


CHEBI:10110

[PMID:22042945] [INDIRECT EVIDENCE] [PARTIAL] Use of ZDV/IFN-α at any time prolonged survival in acute (P < .001) and lymphoma ATLL (P < .001) and was the sole factor associated with reduction in risk of death in aggressive ATLL --- Explanation: UK study demonstrated ZDV/IFN-α significantly prolonged survival in both acute and lymphoma ATLL subtypes.


HGNC.SYMBOL:HTLV-1 Tax


HGNC.SYMBOL:HTLV-1 HBZ


HGNC.SYMBOL:TP53


HGNC.SYMBOL:CCR4


NCBITaxon:11908

[PMID:41553980] [PARTIAL] HTLV-1 is a retrovirus associated with adult T cell leukemia/lymphoma (ATL) and inflammatory diseases, including HTLV-1-associated myelopathy (HAM) and HTLV-1-associated bronchopneumonopathy (HAB). --- Explanation: This abstract explicitly links HTLV-1 to adult T-cell leukemia/lymphoma, supporting the infectious etiology.


MONDO:0019471

[PMID:28796966] [SUPPORT] Adult T-cell lymphoma/leukemia (ATL) is a rare T-cell lymphoproliferative --- Explanation: Abstract characterizes ATL as a rare T-cell lymphoproliferative neoplasm.


MONDO:0007256


MONDO:0007256

[PMID:19376640] [INDIRECT EVIDENCE] [SUPPORT] Hepatocellular Carcinoma (HCC) in high-incidence areas (sub-Saharan Africa, South-Eastern Asia) often contains a somatic mutation at codon 249 in TP53 (R249S). This mutation is rare in low-incidence areas of Europe and the United States. --- Explanation: Review article establishing R249S as a biomarker of aflatoxin exposure and HCC risk in high-incidence geographic regions.


MONDO:0007256

[PMID:14986813] [INDIRECT EVIDENCE] [SUPPORT] With the availability of urinary and serum biomarkers that more accurately reflect dietary exposure to AFB1 than did the initially used food sampling and dietary questionnaires, cohort studies of patients with HCC in China and Taiwan have provided compelling evidence for a multiplicative or sub-multiplicative interaction between HBV and AFB1 in the genesis of human HCC. --- Explanation: Review of cohort studies demonstrating synergistic hepatocarcinogenic interaction between HBV infection and aflatoxin exposure.


MAXO:0000004


MAXO:0010039


MAXO:0000058


MAXO:0000058

[PMID:18650514] [SUPPORT] Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). --- Explanation: SHARP trial demonstrating sorafenib extends median survival by nearly 3 months in advanced hepatocellular carcinoma.


CHEBI:50924

[PMID:18650514] [INDIRECT EVIDENCE] [SUPPORT] Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). --- Explanation: SHARP trial demonstrating sorafenib extends median survival by nearly 3 months in advanced hepatocellular carcinoma.


MAXO:0001017


HGNC.SYMBOL:CTNNB1


HGNC.SYMBOL:TERT Promoter


ECTO:0001108

[PMID:40863326] [SUPPORT] Exposure to aflatoxins, potent mycotoxins produced by Aspergillus fungi contaminating staple foods, and chronic hepatitis B virus (HBV) infection are major etiological factors, especially where they co-exist. --- Explanation: This abstract identifies aflatoxin exposure as a major etiological factor for HCC, supporting the environmental risk described.


ECTO:0001108


NCBITaxon:10407

[PMID:14986813] [SUPPORT] Chronic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin B1 (AFB1), two of the major risk factors in the multifactorial aetiology of hepatocellular carcinoma (HCC), co-exist in those countries with the highest incidences of and the youngest patients with this tumour --- Explanation: Review establishing HBV and aflatoxin as co-existing major risk factors in high-incidence HCC regions.


MONDO:0007256

[PMID:27785449] [SUPPORT] Hepatocellular carcinoma (HCC) is the most common primary liver malignancy --- Explanation: Abstract states that HCC is the most common primary liver malignancy.


MONDO:0005150

[PMID:38193957] [SUPPORT] AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision. --- Explanation: Confirms that central vision loss is a direct consequence of AMD pathophysiology through photoreceptor degeneration.


MONDO:0005150


MONDO:0005150

[PMID:38731137] [INDIRECT EVIDENCE] [SUPPORT] Drusen comprise a yellowish white substance that accumulates typically under the retinal pigment epithelium (RPE), and their constituents are lipids, complement, amyloid, crystallin, and others. --- Explanation: This confirms that drusen are lipid and protein deposits under the RPE with characteristic composition including lipids, complement proteins, and other components.


MONDO:0005150

[PMID:38193957] [INDIRECT EVIDENCE] [PARTIAL] AMD occurs when extracellular deposits accumulate in the outer retina, ultimately leading to photoreceptor degeneration and loss of central vision. The late stages of AMD are characterized by outer retinal atrophy, termed geographic atrophy, or neovascularization associated with subretinal and/or intraretinal exudation, termed exudative neovascular AMD. --- Explanation: This describes the progression from deposit accumulation to photoreceptor degeneration and atrophy, supporting the role of RPE dysfunction in geographic atrophy development.


MONDO:0005150

[PMID:38690727] [INDIRECT EVIDENCE] [PARTIAL] Careful regulation of the complement system is critical for enabling complement proteins to titrate immune defense while also preventing collateral tissue damage from poorly controlled inflammation. In the eye, this balance between complement activity and inhibition is crucial, as a low level of basal complement activity is necessary to support ocular immune privilege, a prerequisite for maintaining vision. --- Explanation: This explains the importance of complement regulation in the eye and how dysregulation leads to inflammation and tissue damage, which is central to AMD pathogenesis.

[PMID:38690727] [INDIRECT EVIDENCE] [SUPPORT] Complement dysregulation has been implicated in many ocular diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD). --- Explanation: Direct confirmation that complement dysregulation is implicated in AMD pathogenesis.


MONDO:0005150

[PMID:38193957] [INDIRECT EVIDENCE] [PARTIAL] In exudative neovascular AMD, 94.6% of patients receiving monthly intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections experience less than a 15-letter visual acuity loss after 12 months compared with 62.2% receiving sham treatment. --- Explanation: The effectiveness of anti-VEGF therapy demonstrates that VEGF-driven angiogenesis is the key pathophysiological mechanism in neovascular AMD.


HGNC.SYMBOL:CFH


HGNC.SYMBOL:ARMS2/HTRA1


HGNC.SYMBOL:C3


HGNC.SYMBOL:CFB


MONDO:0007074

[DOI:10.1111/j.1742-481x.2007.00297.x] [SUPPORT] a groove or fissure of constricting tissue forms around the proximal end of the fifth toe. --- Explanation: Constricting tissue groove corresponds to a digital constriction ring.


MONDO:0007074

[DOI:10.1111/j.1742-481x.2007.00297.x] [SUPPORT] Radiograph of the right fifth toe showed absorption of the proximal and intermediate phalanges --- Explanation: Radiograph showed bone absorption, consistent with osteolysis.


MONDO:0007074

[PMID:1539609] [SUPPORT] Ainhum is the spontaneous autoamputation of toes as a result of the formation of a constricting band. --- Explanation: Case report defines ainhum by spontaneous autoamputation due to constricting band formation.

[DOI:10.1111/j.1742-481x.2007.00297.x] [SUPPORT] He reported that his left fifth toe had autoamputated some months before. --- Explanation: Case report documents autoamputation of a digit.

[DOI:10.1111/j.1742-481x.2007.00297.x] [SUPPORT] the underlying structures are absorbed and the toe autoamputates. --- Explanation: Abstract describes autoamputation as the outcome of progressive constriction.


MONDO:0007074

[PMID:17924881] [SUPPORT] It may present as chronic fissuring at the base of the fifth toe or as foot ulceration. --- Explanation: Case report notes foot ulceration as a presentation.


MONDO:0007074

[DOI:10.1111/j.1742-481x.2007.00297.x] [INDIRECT EVIDENCE] [SUPPORT] a groove or fissure of constricting tissue forms around the proximal end of the fifth toe. --- Explanation: The abstract describes the initiating constriction groove around the fifth toe.

[PMID:12500788] [INDIRECT EVIDENCE] [SUPPORT] Dactylolysis spontanea is an idiopathic condition affecting the fifth toe, and sometimes other toes --- Explanation: Radiological survey notes fifth toe predominance with possible involvement of other toes.

[PMID:1539609] [INDIRECT EVIDENCE] [SUPPORT] It usually affects the fifth toe bilaterally --- Explanation: Case report emphasizes typical bilateral fifth toe involvement.


MAXO:0000004

[PMID:31401977] [SUPPORT] She was managed surgically by excision of the band, disarticulated at right fifth metatarsophalangeal joint and skin closure. --- Explanation: Case report documents surgical excision and disarticulation as treatment.


MONDO:0000660

[PMID:39996018] [SUPPORT] Akinetopsia, or visual motion blindness, is a perceptual distortion characteristic of Alice in Wonderland syndrome in which people see moving objects as disjointed 'jumps' or 'freeze frames.' --- Explanation: This description of motion blindness with freeze-frame perception supports the core phenotype.


MONDO:0000660

[PMID:39996018] [SUPPORT] Of the clinical cases, 12% showed hemiakinetopsia, 50% continuous or progressive symptoms, and 52% a chronic course. --- Explanation: This review quantifies hemiakinetopsia among clinical cases.


MONDO:0000660

[PMID:39996018] [INDIRECT EVIDENCE] [SUPPORT] Despite its profound impact, the condition remains poorly understood beyond the established centrality of cortical area V5/MT in visual motion perception. --- Explanation: This systematic review highlights V5/MT as central to motion perception, supporting V5/MT dysfunction as a core mechanism.

[PMID:27193360] [INDIRECT EVIDENCE] [PARTIAL] akinetopsia (cortical syndrome in which patient losses the ability to perceive visual motion) --- Explanation: This review defines akinetopsia as a cortical syndrome with loss of visual motion perception.

[PMID:37938052] [INDIRECT EVIDENCE] [PARTIAL] Our results revealed distinct characteristics for the various etiologies of this phenomenon in addition to a shared pathophysiologic pathway among them. --- Explanation: This systematic review supports a shared pathophysiologic pathway across akinetopsia etiologies.


MONDO:0000660


MONDO:0000660

[PMID:39996018] [INDIRECT EVIDENCE] [SUPPORT] Pathophysiologically, in right-handed individuals, the left area V5/MT was found to be particularly susceptible to acute interference, as evidenced by the experimental studies. --- Explanation: This indicates left V5/MT vulnerability to acute interference in experimental cases.


MONDO:0000660

[PMID:39996018] [INDIRECT EVIDENCE] [SUPPORT] we found a greater prevalence of right-hemispheric afflictions in clinical cases, suggesting that the right area V5/MT plays a more dominant role in motion perception. --- Explanation: This supports right-hemisphere predominance for motion perception in clinical akinetopsia.


MONDO:0000660

[PMID:39996018] [INDIRECT EVIDENCE] [SUPPORT] the severity of the condition also depends on surviving components of the visual motion network as a whole, and-in line with the dynamic parallellism theory-the speed of moving objects. --- Explanation: This supports network redundancy and stimulus speed as modifiers of symptom severity.


MONDO:0000660

[PMID:39996018] [INDIRECT EVIDENCE] [SUPPORT] Aetiologically, most cases were associated with structural neurological conditions such as stroke and neurodegenerative disease, and fewer with intoxications or paroxysmal neurological disorders such as epilepsy. --- Explanation: This supports structural neurological disease as the dominant mechanism leading to motion network damage.


MONDO:0000660

[PMID:39996018] [INDIRECT EVIDENCE] [SUPPORT] Aetiologically, most cases were associated with structural neurological conditions such as stroke and neurodegenerative disease, and fewer with intoxications or paroxysmal neurological disorders such as epilepsy. --- Explanation: This indicates that intoxications and paroxysmal disorders can underlie akinetopsia in some cases.

[PMID:25667833] [INDIRECT EVIDENCE] [SUPPORT] We describe a patient who showed akinetopsia recurrently as epileptic seizures. --- Explanation: This case report documents epileptic seizures presenting as recurrent akinetopsia.


MONDO:0000660

[PMID:25667833] [INDIRECT EVIDENCE] [SUPPORT] We diagnosed his visual symptom as akinetopsia, which was aroused by hyperexcitability of the right temporal and parietal cortices, including area MT/V5. --- Explanation: This case report attributes akinetopsia to hyperexcitability in right temporal/parietal cortices including MT/V5.


MONDO:0000660

[PMID:40605075] [INDIRECT EVIDENCE] [SUPPORT] Recent cases have demonstrated that it is not necessarily attributed only to vascular causes and neurodegenerative diseases but can also be induced through transcranial magnetic stimulation, and certain medications. --- Explanation: This review documents TMS- and medication-induced akinetopsia, supporting reversible circuit disruption mechanisms.


MONDO:0000660

[PMID:39996018] [INDIRECT EVIDENCE] [SUPPORT] Bilateral lesions to V5/MT most often coincided with global akinetopsia and chronicity. --- Explanation: This links bilateral V5/MT lesions to downstream global and chronic akinetopsia.


MONDO:0000660

[PMID:39996018] [INDIRECT EVIDENCE] [SUPPORT] Bilateral lesions to V5/MT most often coincided with global akinetopsia and chronicity. --- Explanation: This supports global and chronic akinetopsia as a frequent outcome of bilateral V5/MT lesions.


MAXO:0000001

[PMID:39996018] [SUPPORT] Treatments were mostly successful when they were aimed at the underlying condition, while cases due to organic lesions tended to be therapy-resistant. --- Explanation: This review indicates treatment success when targeting the underlying condition and resistance in organic lesions.


MAXO:0000058

[PMID:25667833] [SUPPORT] We administered carbamazepine 200 mg/day, which suppressed his akinetopsic symptom completely. --- Explanation: This case report shows carbamazepine suppressed seizure-related akinetopsia.


CHEBI:3387

[PMID:25667833] [INDIRECT EVIDENCE] [SUPPORT] We administered carbamazepine 200 mg/day, which suppressed his akinetopsic symptom completely. --- Explanation: This case report shows carbamazepine suppressed seizure-related akinetopsia.


MONDO:0043693

[PMID:39362713] [SUPPORT] Several intracellular, intrahepatic, and extrahepatic factors influence development of early fatty liver injury leading to inflammation and fibrosis. --- Explanation: The abstract describes early fatty liver injury as part of ALD development.


MONDO:0043693

[PMID:39362713] [SUPPORT] Several intracellular, intrahepatic, and extrahepatic factors influence development of early fatty liver injury leading to inflammation and fibrosis. --- Explanation: The abstract links ALD development to inflammation and fibrosis.


MONDO:0043693

[PMID:39362713] [INDIRECT EVIDENCE] [SUPPORT] Alcohol metabolism, cellular stress, and gut-derived factors contribute to hepatocyte and immune cell injury leading to cytokine and chemokine production. --- Explanation: The review links alcohol metabolism and cellular stress to hepatocyte and immune cell injury with cytokine and chemokine production.


MONDO:0043693


MONDO:0043693

[PMID:37143126] [INDIRECT EVIDENCE] [SUPPORT] ethanol damages the intestinal barrier, resulting in the release of endotoxins and alterations in intestinal flora content and bile acid metabolism. --- Explanation: The review describes ethanol-induced barrier damage and endotoxin release as part of ALD pathogenesis.


MONDO:0008752

[PMID:11138011] [SUPPORT] Infants with Alexander disease develop a leukoencephalopathy with macrocephaly, seizures and psychomotor retardation --- Explanation: Macrocephaly is a cardinal feature of infantile Alexander disease.

[PMID:21917775] [SUPPORT] Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features --- Explanation: Macrocephaly is a defining feature of Type I Alexander disease.


MONDO:0008752

[PMID:11138011] [SUPPORT] Infants with Alexander disease develop a leukoencephalopathy with macrocephaly, seizures and psychomotor retardation --- Explanation: Leukoencephalopathy is a defining feature of infantile Alexander disease.

[PMID:21917775] [SUPPORT] Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features --- Explanation: Typical MRI features including frontal-predominant leukodystrophy define Type I.


MONDO:0008752

[PMID:11138011] [SUPPORT] Infants with Alexander disease develop a leukoencephalopathy with macrocephaly, seizures and psychomotor retardation --- Explanation: Seizures are a primary clinical feature of infantile Alexander disease.

[PMID:17065456] [SUPPORT] The mutant mice have a normal lifespan and show no overt behavioral defects, but are more susceptible to kainate-induced seizures --- Explanation: GFAP mutant knock-in mice recapitulate seizure susceptibility.


MONDO:0008752

[PMID:11138011] [SUPPORT] patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course --- Explanation: Spasticity is a characteristic feature of juvenile/adult Alexander disease.


MONDO:0008752

[PMID:21917775] [SUPPORT] Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features --- Explanation: Dysphagia is part of the bulbar symptom complex defining Type II AxD.


MONDO:0008752

[PMID:11138011] [SUPPORT] patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course --- Explanation: Dysarthria is part of the bulbar signs characterizing juvenile/adult Alexander disease.


MONDO:0008752

[PMID:11138011] [SUPPORT] patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity --- Explanation: Ataxia is characteristic of juvenile/adult Alexander disease.


MONDO:0008752

[PMID:11138011] [SUPPORT] Infants with Alexander disease develop a leukoencephalopathy with macrocephaly, seizures and psychomotor retardation, leading to death usually within the first decade --- Explanation: Psychomotor retardation with progressive decline is a hallmark of infantile Alexander disease.


MONDO:0008752

[PMID:21917775] [SUPPORT] Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features --- Explanation: Autonomic dysfunction is a defining feature of Type II Alexander disease.


MONDO:0008752

[PMID:21917775] [SUPPORT] Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features --- Explanation: Failure to thrive is a defining feature of Type I Alexander disease.


MONDO:0008752

[PMID:21917775] [SUPPORT] Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features --- Explanation: Ocular movement abnormalities including nystagmus are characteristic of Type II Alexander disease.


MONDO:0008752

[PMID:11138011] [INDIRECT EVIDENCE] [SUPPORT] The pathological hallmark of all forms of Alexander disease is the presence of Rosenthal fibers, cytoplasmic inclusions in astrocytes that contain the intermediate filament protein GFAP in association with small heat-shock proteins --- Explanation: Defines Rosenthal fibers as the pathological hallmark, composed of GFAP with small heat-shock proteins.

[PMID:17498694] [INDIRECT EVIDENCE] [SUPPORT] the accumulation of GFAP and the formation of characteristic aggregates, called Rosenthal fibers, (ii) the sequestration of the protein chaperones alpha B-crystallin and HSP27 into Rosenthal fibers, and (iii) the activation of both Jnk and the stress response --- Explanation: Reviews the multi-step pathogenic mechanism: GFAP accumulation, chaperone sequestration, and stress pathway activation.

[PMID:28359321] [INDIRECT EVIDENCE] [SUPPORT] RFs appear to originate as small, osmiophilic masses containing both GFAP and alphaB-crystallin deposited on bundles of intermediate filaments --- Explanation: Mouse model studies reveal the ultrastructural origin of Rosenthal fibers on intermediate filament bundles.


MONDO:0008752


MONDO:0008752

[PMID:17065456] [INDIRECT EVIDENCE] [SUPPORT] further elevation of GFAP via crosses to GFAP transgenic animals leads to a shift in GFAP solubility, an increased stress response, and ultimately death --- Explanation: Mouse model demonstrates dose-dependent GFAP toxicity with solubility shift and lethal stress response.

[PMID:29226998] [INDIRECT EVIDENCE] [SUPPORT] A key feature of pathogenesis is overexpression and accumulation of GFAP, with formation of characteristic cytoplasmic aggregates known as Rosenthal fibers --- Explanation: Confirms GFAP overexpression and accumulation as central to pathogenesis.

[PMID:21414908] [INDIRECT EVIDENCE] [SUPPORT] Both protein aggregation and oxidative stress contribute to activation of a robust autophagic response in glia --- Explanation: Drosophila model shows that GFAP aggregation and oxidative stress activate autophagy in glial cells.


MONDO:0008752

[PMID:17065456] [INDIRECT EVIDENCE] [SUPPORT] when crossed with an antioxidant response element reporter line, the mutant mice show a distinct pattern of reporter-gene induction that is especially prominent in the corpus callosum, and histochemical staining reveals accumulation of iron in the same region --- Explanation: GFAP mutant mice show oxidative stress response and iron accumulation in white matter.


MONDO:0008752

[PMID:21414908] [INDIRECT EVIDENCE] [SUPPORT] Toxicity of mutant GFAP to glial cells induces a non-cell-autonomous stress response and subsequent apoptosis in neurons, which is dependent on glial glutamate transport --- Explanation: Drosophila model demonstrates that mutant GFAP toxicity to glia causes neuronal apoptosis via glutamate-dependent mechanism.


MONDO:0008752

[PMID:38782207] [INDIRECT EVIDENCE] [SUPPORT] We found high molecular weight GFAP species in the RFs of AxD brains, indicating abnormal GFAP crosslinking as a prominent pathological feature of this disease --- Explanation: Analysis of AxD patient brain tissue identifies aberrant GFAP crosslinking as a key pathological modification.

[PMID:38782207] [INDIRECT EVIDENCE] [SUPPORT] we found GFAP was ubiquitinated in RFs of AxD patients and rodent models, supporting this modification as a critical factor linked to GFAP aggregation --- Explanation: GFAP ubiquitination in Rosenthal fibers is a critical factor in aggregation pathology.


MAXO:0000950


MAXO:0000058

[PMID:29226998] [SUPPORT] Nearly complete and long-lasting elimination of GFAP occurred in brain and spinal cord following single bolus intracerebroventricular injections, with a striking reversal of Rosenthal fibers and downstream markers of microglial and other stress-related responses --- Explanation: Antisense oligonucleotides effectively suppress GFAP and reverse pathology in AxD mouse models.

[PMID:29226998] [SUPPORT] GFAP protein was also cleared from cerebrospinal fluid, demonstrating its potential utility as a biomarker in future clinical applications --- Explanation: CSF GFAP clearance provides a potential biomarker for monitoring treatment response.

[PMID:34788075] [SUPPORT] a single treatment with Gfap-targeted ASO provides long-lasting suppression, reverses GFAP pathology, and, depending on age of treatment, prevents or mitigates white matter deficits and motor impairment --- Explanation: Rat model with myelin pathology demonstrates ASO therapy can both prevent and reverse disease features.


hgnc:4235

[PMID:11138011] [SUPPORT] Alexander disease therefore represents the first example of a primary genetic disorder of astrocytes, one of the major cell types in the vertebrate CNS --- Explanation: Landmark paper establishing GFAP mutations as causative for Alexander disease.

[PMID:21917775] [SUPPORT] R79 and R239 GFAP mutations were most common (16.6% and 20.3% of all cases, respectively). These common mutations predicted distinct clinical outcomes, with R239 predicting the most aggressive course --- Explanation: Identifies mutation hotspots and genotype-phenotype correlations in a large cohort.

[PMID:11567214] [SUPPORT] Missense, heterozygous, de novo GFAP mutations were found in exons 1 or 4 for 14 of the 15 patients analyzed --- Explanation: Confirms de novo missense mutations in GFAP rod domain as reliable molecular marker.


MONDO:0005340


MONDO:0005340

[PMID:32682334] [NO_EVIDENCE] Collapse of anagen hair bulb IP is an essential prerequisite for the development of alopecia areata (AA). In AA, lesional HFs are rapidly infiltrated by NKG2D + T cells and natural killer (NK) cells, while perifollicular mast cells acquire a profoundly pro-inflammatory phenotype and interact with autoreactive CD8+ T cells. --- Explanation: While this reference focuses on hair follicle pathology, the immune mechanisms described also affect nail matrix, explaining the nail changes seen in AA patients.


MONDO:0005340

[PMID:32682334] [INDIRECT EVIDENCE] [SUPPORT] Anagen stage hair follicles (HFs) exhibit "immune privilege (IP)" from the level of the bulge downwards to the bulb. Both passive and active IP mechanisms protect HFs from physiologically undesired immune responses and limit immune surveillance. IP is relative, not absolute, and is primarily based on absent, or greatly reduced, intra-follicular antigen presentation via MHC class I and II molecules, along with prominent expression of "no danger" signals like CD200 and the creation of an immunoinhibitory signalling milieu generated by the secretory activities of HFs. --- Explanation: This review describes the mechanisms of hair follicle immune privilege including reduced MHC expression and immunosuppressive signaling, confirming the normal maintenance of immune privilege in anagen hair follicles.

[PMID:38673994] [INDIRECT EVIDENCE] [SUPPORT] Immune privilege collapse has been extensively investigated in AA pathogenesis, including the suppression of immunomodulatory factors (e.g., transforming growth factor-β (TGF-β), programmed death-ligand 1 (PDL1), interleukin-10 (IL-10), α-melanocyte-stimulating hormone (α-MSH), and macrophage migration inhibitory factor (MIF)) and enhanced expression of the major histocompatibility complex (MHC) throughout hair follicles. --- Explanation: This study documents the specific immunomodulatory factors that are suppressed during immune privilege collapse in AA, along with enhanced MHC expression that enables autoreactive T cell recognition.


MONDO:0005340

[PMID:32682334] [INDIRECT EVIDENCE] [SUPPORT] In AA, lesional HFs are rapidly infiltrated by NKG2D + T cells and natural killer (NK) cells, while perifollicular mast cells acquire a profoundly pro-inflammatory phenotype and interact with autoreactive CD8+ T cells. Using animal models, significant functional evidence has accumulated that demonstrates the dominance of the immune system in AA pathogenesis. Purified CD8+T-cell and NK cell populations alone, which secrete fγ, suffice to induce the AA phenotype, while CD4+T-cells aggravate it, and Tregs and iNKT cells may provide relative protection against AA development. --- Explanation: This demonstrates that CD8+ T cells alone are sufficient to induce alopecia areata in animal models, establishing their central role as disease drivers. The NKG2D+ phenotype and IFN-gamma production are key features.

[PMID:37365384] [INDIRECT EVIDENCE] [SUPPORT] Pathogenic activity of CD44s-hiCD49dlo CD8+ T cells was mediated by NKG2D-dependent innate-like cytotoxicity, which was further augmented by IL-15 stimulation and triggered disease onset. --- Explanation: This identifies the specific mechanism of CD8+ T cell cytotoxicity in AA through NKG2D-dependent pathways, and demonstrates that IL-15 stimulation enhances their pathogenic activity.


MONDO:0005340

[PMID:38673994] [INDIRECT EVIDENCE] [SUPPORT] Both AA and vitiligo are autoimmune diseases that share commonalities in pathogenesis, including the involvement of plasmacytoid dendritic cells (and interferon-α (IFN- α) signaling pathways) and cytotoxic CD8+ T lymphocytes (and activated IFN-γ signaling pathways). --- Explanation: This establishes that IFN-gamma signaling pathways are activated in AA pathogenesis, providing the mechanistic basis for JAK-STAT pathway involvement since these cytokines signal through JAK-STAT.

[PMID:37326792] [INDIRECT EVIDENCE] [SUPPORT] In two pivotal placebo-controlled phase 3 clinical trials in adults with severe alopecia areata, oral baricitinib once daily was associated with clinically meaningful scalp, eyebrow, and eyelash hair regrowth over 36 weeks. --- Explanation: The clinical efficacy of baricitinib, a JAK1/2 inhibitor, in promoting hair regrowth provides direct evidence that the JAK-STAT pathway is a critical therapeutic target in AA pathogenesis.

[PMID:38338982] [INDIRECT EVIDENCE] [SUPPORT] Interferon-γ (IFNγ) treatment increased the secretion of CXCL12 from DFs through the signal transducer and activator of transcription 3 (STAT3) pathway, and αCXCL12 treatment protected the hair follicle from IFNγ in hair organ culture. --- Explanation: This demonstrates that IFN-gamma signals through STAT3 to drive pathogenic chemokine production, providing direct mechanistic evidence for JAK-STAT pathway activation in AA.


MONDO:0005340

[PMID:38338982] [INDIRECT EVIDENCE] [SUPPORT] CXCL12 expression is increased in AA mice, while s.c. injection of αCXCL12 significantly inhibited hair loss in AA mice and reduced the number of CD8+, MHC-I+, and MHC-II+ cells in the skin. In addition, injection of αCXCL12 also prevented the onset of AA and reduced the number of CD8+ cells. --- Explanation: This demonstrates that CXCL12 drives CD8+ T cell recruitment to hair follicles, and blocking this chemokine can prevent disease onset and reduce immune cell infiltration in AA.

[PMID:38673994] [INDIRECT EVIDENCE] [PARTIAL] Blood chemokine C-X-C motif ligand 9 (CXCL9) and CXCL10 are elevated in both diseases. --- Explanation: Elevated CXCL9 and CXCL10 chemokines in AA blood support the role of chemokine-mediated immune cell recruitment in disease pathogenesis.


HGNC.SYMBOL:HLA-DRB1


HGNC.SYMBOL:CTLA4


HGNC.SYMBOL:IL2RA


HGNC.SYMBOL:PTPN22


MONDO:0013282

[PMID:20301692] [SUPPORT] Alpha-1 antitrypsin deficiency (AATD) can present with hepatic dysfunction in individuals from infancy to adulthood and with chronic obstructive lung disease (emphysema and/or bronchiectasis), characteristically in individuals older than age 30 years. --- Explanation: Establishes emphysema as a cardinal manifestation of AATD occurring characteristically in adults over 30 years of age

[PMID:35361631] [SUPPORT] Severe alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, is a risk factor for pulmonary emphysema and liver disease. --- Explanation: Confirms that severe AATD (PiZZ phenotype) carries significant risk for emphysema development


MONDO:0013282

[PMID:35715315] [SUPPORT] Pulmonary emphysema and liver disease are the clinical expressions of alpha 1-antitrypsin deficiency, an autosomal recessive genetic disease. --- Explanation: Confirms pulmonary emphysema and COPD as cardinal clinical manifestations of alpha-1 antitrypsin deficiency


MONDO:0013282

[PMID:35868681] [SUPPORT] Liver disease in homozygous ZZ alpha-1 antitrypsin (AAT) deficiency occurs due to the accumulation of large quantities of AAT mutant Z protein polymers in the liver. --- Explanation: Confirms that homozygous ZZ genotype leads to hepatocytic protein accumulation and liver disease


MONDO:0013282

[PMID:35868681] [SUPPORT] The mutant Z protein folds improperly during biogenesis and is retained within the hepatocytes rather than appropriately secreted. --- Explanation: Documents hepatocyte protein accumulation as the mechanism causing hepatomegaly in AAT deficiency


MONDO:0013282

[PMID:36896570] [NO_EVIDENCE] Alpha1 antitrypsin deficiency (AATD), a common hereditary disorder affecting mainly lungs, liver and skin has been the focus of some of the most exciting therapeutic approaches in medicine in the past 5 years. --- Explanation: Confirms that lung disease affecting the respiratory system is a primary manifestation of AATD


MONDO:0013282

[PMID:34356027] [NO_EVIDENCE] Early diagnosis is crucial for treatment outcome. The primary care physician should refer patients younger than 50-years-old with COPD or emphysema, familiar accumulation of A1AD or liver cirrhosis of unknown cause. --- Explanation: Indicates that early-onset COPD with airway obstruction and wheezing is a key diagnostic feature prompting referral for AAT deficiency testing


MONDO:0013282

[PMID:33516773] [SUPPORT] Panniculitis represents a rare and potentially lethal manifestation of alpha-1 antitrypsin deficiency (AATD). --- Explanation: Establishes panniculitis as a rare but significant cutaneous manifestation of AAT deficiency

[PMID:33516773] [SUPPORT] Intravenous AAT augmentation therapy generally resulted in response. --- Explanation: Confirms AAT augmentation as the most effective treatment for AAT-associated panniculitis

[PMID:38958623] [SUPPORT] Panniculitis in α(1)-Antitrypsin Deficiency --- Explanation: Recent clinical case documentation of panniculitis as cutaneous manifestation of AAT deficiency


MONDO:0013282

[PMID:22500781] [INDIRECT EVIDENCE] [PARTIAL] Alpha-1 antitrypsin deficiency (AATD) is a relatively common, but under-recognized condition which manifests commonly with liver cirrhosis and emphysema. --- Explanation: This review confirms that emphysema is a common manifestation of alpha-1 antitrypsin deficiency.


MONDO:0013282


MONDO:0013282

[PMID:22500781] [INDIRECT EVIDENCE] [PARTIAL] Alpha-1 antitrypsin deficiency (AATD) is a relatively common, but under-recognized condition which manifests commonly with liver cirrhosis and emphysema. --- Explanation: Review confirms that AATD manifests with liver cirrhosis due to protein aggregation in hepatocytes.


MONDO:0013282

[PMID:36896570] [INDIRECT EVIDENCE] [NO_EVIDENCE] Alpha1 antitrypsin deficiency (AATD), a common hereditary disorder affecting mainly lungs, liver and skin has been the focus of some of the most exciting therapeutic approaches in medicine in the past 5 years. --- Explanation: Confirms that pulmonary inflammation is a primary manifestation of AATD requiring advanced therapeutic interventions


MAXO:0000058

[PMID:22500781] [SUPPORT] Specific therapy for lung-affected individuals with AATD is augmentation therapy, which consists of intravenous infusion of purified human plasma-derived alpha-1 antitrypsin (AAT). --- Explanation: This review describes augmentation therapy as the specific treatment for alpha-1 antitrypsin deficiency.


MAXO:0000058

[PMID:34356027] [SUPPORT] Most important treatment is smoking cessation, pulmonary rehabilitation and inhaled medication according to current guidelines. --- Explanation: Confirms inhaled bronchodilators as part of standard treatment guidelines for AAT deficiency-related COPD


MAXO:0000068

[PMID:20301692] [SUPPORT] Lung transplantation may be an appropriate option for individuals with end-stage lung disease. --- Explanation: Establishes lung transplantation as appropriate therapeutic option for end-stage AAT deficiency-related emphysema


MAXO:0000068

[PMID:20301692] [SUPPORT] Liver transplantation is the definitive treatment for severe disease (will restore AAT levels). --- Explanation: Establishes liver transplantation as definitive curative treatment that restores normal AAT production from donor liver

[PMID:33824927] [SUPPORT] Rarely, patients require liver transplant and typically the patient outcomes are excellent. --- Explanation: Documents excellent outcomes in AAT deficiency patients undergoing liver transplantation

[PMID:37144533] [SUPPORT] Pi∗ZZ individuals harbor an up to 20 times higher risk of liver fibrosis and cirrhosis than noncarriers and liver transplantation is currently the only available therapeutic option. --- Explanation: Confirms liver transplantation as essential therapeutic option for severe ZZ genotype liver disease

[PMID:36808684] [SUPPORT] Our case provides initial evidence that A1ATD heterozygote donors may be safely used for pediatric patients with A1ATD, thus expanding the donor pool. --- Explanation: Documents that heterozygous donors can be successfully used for AAT deficiency recipients, expanding available donor options


MONDO:0011399

[PMID:38182489] [SUPPORT] ranging from a silent or mild carrier state to severe, transfusion-dependent or lethal disease --- Explanation: Confirms the wide spectrum of anemia severity across alpha-thalassemia genotypes.


MONDO:0011399


MONDO:0011399

[PMID:20301608] [SUPPORT] experience acute episodes of hemolysis in response to infections or exposure to oxidant drugs --- Explanation: Confirms episodic hemolytic anemia triggered by infections or oxidant drugs.


MONDO:0011399

[PMID:20301608] [SUPPORT] Extramedullary erythropoiesis, marked hepatosplenomegaly, and a massive placenta are common --- Explanation: Confirms extramedullary hematopoiesis as a common feature of severe alpha-thalassemia.


MONDO:0011399

[PMID:20301608] [SUPPORT] characterized by prenatal onset of generalized edema and pleural and pericardial effusions as a result of congestive heart failure induced by severe anemia --- Explanation: Confirms hydrops fetalis as the defining feature of Hb Bart syndrome, caused by severe fetal anemia.


MONDO:0011399

[PMID:20301608] [SUPPORT] The majority of individuals have enlargement of the spleen (and less commonly of the liver), mild jaundice, and sometimes thalassemia-like bone changes --- Explanation: Confirms splenomegaly as a majority finding in HbH disease.


MONDO:0011399

[PMID:20301608] [SUPPORT] enlargement of the spleen (and less commonly of the liver) --- Explanation: Confirms hepatomegaly is present but less common than splenomegaly.


MONDO:0011399

[PMID:20301608] [SUPPORT] may develop gallstones and experience acute episodes of hemolysis --- Explanation: Confirms gallstone formation in individuals with HbH disease.


MONDO:0011399

[PMID:20301608] [SUPPORT] mild jaundice, and sometimes thalassemia-like bone changes --- Explanation: Confirms mild jaundice as a feature of HbH disease.


MONDO:0011399

[PMID:20301608] [SUPPORT] iron chelation therapy should be instituted --- Explanation: Confirms that iron overload requiring chelation occurs in chronically transfused HbH disease patients.


MONDO:0011399

[PMID:20301608] [SUPPORT] congestive heart failure induced by severe anemia --- Explanation: Confirms congestive heart failure as a consequence of severe anemia in Hb Bart syndrome.


MONDO:0011399

[PMID:20301608] [SUPPORT] sometimes thalassemia-like bone changes --- Explanation: Confirms thalassemia-like bone changes can occur in HbH disease.


MONDO:0011399

[PMID:38182489] [INDIRECT EVIDENCE] [SUPPORT] characterized by decreased synthesis of α-globin chains that results in an imbalance of α and β globin --- Explanation: Confirms the core defect of reduced alpha-globin chain synthesis causing globin chain imbalance.

[PMID:20301608] [INDIRECT EVIDENCE] [SUPPORT] biallelic pathogenic variants in both HBA1 and HBA2 that result in deletion or inactivation of all four --- Explanation: Confirms that pathogenic variants in HBA1 and HBA2 cause alpha-thalassemia through gene deletion or inactivation.


MONDO:0011399

[PMID:38182489] [INDIRECT EVIDENCE] [SUPPORT] varying degrees of ineffective erythropoiesis, decreased red blood cell (RBC) survival, chronic hemolytic anemia, and subsequent comorbidities --- Explanation: Confirms that alpha-thalassemia leads to ineffective erythropoiesis, decreased RBC survival, and chronic hemolytic anemia.


MONDO:0011399

[PMID:20301608] [INDIRECT EVIDENCE] [SUPPORT] may develop gallstones and experience acute episodes of hemolysis in response to infections or exposure to oxidant drugs --- Explanation: Confirms episodic hemolysis triggered by infections or oxidant drugs in HbH disease.


MONDO:0011399

[PMID:38182489] [INDIRECT EVIDENCE] [SUPPORT] disease modifying agents that target ineffective erythropoiesis and chronic hemolytic anemia --- Explanation: Confirms ineffective erythropoiesis as a key therapeutic target in alpha-thalassemia.


MONDO:0011399

[PMID:38182489] [INDIRECT EVIDENCE] [SUPPORT] chelation therapy for iron overload --- Explanation: Confirms iron overload as a recognized complication requiring chelation therapy.


MAXO:0000058

[PMID:20301608] [SUPPORT] iron chelation with deferasirox can be considered to reduce liver iron concentration --- Explanation: Confirms deferasirox-based iron chelation for non-transfusion-dependent patients.

[PMID:38182489] [SUPPORT] chelation therapy for iron overload --- Explanation: Confirms chelation therapy as part of alpha-thalassemia management.


MAXO:0000004


MAXO:0000747

[PMID:20301608] [SUPPORT] rarely curative hematopoietic stem cell transplant may allow survival of children --- Explanation: Confirms HSCT as a rare but curative option for severe alpha-thalassemia.


MAXO:0000079

[PMID:20301608] [SUPPORT] Couples who are members of populations at risk --- Explanation: Confirms the importance of carrier testing in at-risk populations.


HGNC.SYMBOL:HBA1

[PMID:20301608] [SUPPORT] biallelic pathogenic variants in both HBA1 and HBA2 that result in deletion or inactivation of all four --- Explanation: Confirms HBA1 and HBA2 pathogenic variants cause alpha-thalassemia.


HGNC.SYMBOL:HBA2

[PMID:20301608] [SUPPORT] biallelic pathogenic variants in HBA1 and HBA2 that result in deletion or inactivation of three --- Explanation: Confirms HBA2 involvement in alpha-thalassemia pathogenesis.


MONDO:0009994


MONDO:0009994

[PMID:39686893] [INDIRECT EVIDENCE] [PARTIAL] According to literature data, the frequency of the PAX3::FOXO1 translocation is 70-90% and the PAX7::FOXO1 translocation 10-30%. --- Explanation: Supports the prevalence of PAX3/7-FOXO1 fusions in alveolar rhabdomyosarcoma.


MAXO:0000647


CHEBI:28445


CHEBI:27666


CHEBI:4026


MAXO:0000014


HGNC.SYMBOL:PAX3-FOXO1 Fusion


HGNC.SYMBOL:PAX7-FOXO1 Fusion


HGNC.SYMBOL:MYCN Amplification


MONDO:0009994

[PMID:10337369] [SUPPORT] Rhabdomyosarcoma (RMS) is a malignant tumor of mesenchymal origin thought to --- Explanation: Abstract describes rhabdomyosarcoma as a malignant tumor of mesenchymal origin.


MONDO:0004975

[PMID:31724515] [SUPPORT] Memory impairment has been considered as one of the earliest clinical hallmarks of Alzheimer's disease. --- Explanation: This reference supports the statement that memory loss is a very frequent and early diagnostic symptom of Alzheimer's disease.


MONDO:0004975

[PMID:24011643] [SUPPORT] Impairment of executive functions is common in neurodegenerative disorders such as Alzheimer's disease. --- Explanation: The literature states that executive dysfunction, which includes difficulties in planning, decision-making, and judgment, is common in Alzheimer's disease.

[PMID:31930617] [SUPPORT] Alzheimer's disease (AD) is a neurodegenerative disease characterised by neurocognitive impairments, especially memory impairment, as core symptoms linked to reductions in activities of daily life. --- Explanation: The literature mentions neurocognitive impairments in Alzheimer's disease, which includes executive dysfunction.

[PMID:36279224] [SUPPORT] The cognitive decline in cerebrovascular disease, including small vessel disease, is also usually gradual and gradual, progresses slowly, and the underlying defect extends to processing speed, complex attention, and fronto-executive functions. --- Explanation: This reference indicates that executive dysfunction is a common feature in cognitive decline related to Alzheimer's disease.


MONDO:0004975

[PMID:38157881] [SUPPORT] Neuropsychiatric or behavioral symptoms of dementia encompass a series of disorders, such as anxiety, depression, apathy, psychosis, and agitation, all commonly present in individuals living with dementia. --- Explanation: The abstract confirms that behavioral changes, including irritability, depression, and apathy, are common in Alzheimer's disease.

[PMID:28413709] [SUPPORT] Using the median split approach, greater apathy and lower depression were associated with poorer awareness on the Self-Consciousness Scale (respectively: odds ratio ... = 4.8, p = .03; OR = 4.84, p = .04), and the PCRS (only apathy: OR = 9.3, p = .003). --- Explanation: This study indicates that apathy and depression are significant behavioral symptoms in Alzheimer's disease.

[PMID:34580191] [SUPPORT] Alzheimer Disease and Mood. --- Explanation: The title suggests a focus on mood disturbances, which includes behavioral changes such as depression.

[PMID:34755541] [SUPPORT] The most frequent NPS in CAA were depression/dysphoria (48.8%), irritability/lability (37.2%), agitation/aggression (37.2%), apathy/indifference (34.9%), and anxiety (32.6%). --- Explanation: Although the primary focus is on cerebral amyloid angiopathy, the study draws parallels with Alzheimer's disease regarding the prevalence of behavioral changes like depression, irritability, and apathy.


MONDO:0004975

[PMID:24035593] [SUPPORT] Language disorders of degenerative origin are frequently tied to Alzheimer disease (AD) the different variants of which can result in primary and secondary aphasia syndromes. --- Explanation: The literature clearly supports that aphasia, which involves difficulty with speech and understanding language, is a frequent neurologic symptom in Alzheimer's Disease.


MONDO:0004975

[PMID:36375032] [SUPPORT] Limb apraxia is a common early sign of Alzheimer''s disease (AD) and is thought to occur specifically in early-onset (before the age of 65) AD. --- Explanation: The literature indicates that limb apraxia is a common early sign of Alzheimer's disease, supporting the statement that apraxia can occur in Alzheimer's disease.


MONDO:0004975

[PMID:28320296] [INDIRECT EVIDENCE] [SUPPORT] These intra- or extracellular insoluble aggregates (fibers or plaques) are hallmarks of many neurodegenerative pathologies including Alzheimer's disease (AD)... --- Explanation: This reference supports the statement by confirming that amyloid plaques are a hallmark of Alzheimer's disease and discusses the formation and role of amyloid aggregates in AD.

[PMID:26322584] [INDIRECT EVIDENCE] [SUPPORT] Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-beta peptide. --- Explanation: This reference supports the statement by indicating that the accumulation of amyloid plaques, composed of amyloid-beta peptide, is a characteristic of Alzheimer's disease.

[PMID:22351073] [INDIRECT EVIDENCE] [SUPPORT] Generation of amyloid peptide (Abeta) is at the beginning of a cascade that leads to Alzheimer's disease (AD)... soluble assembly states of Abeta peptides can cause cognitive problems by disrupting synaptic function... --- Explanation: This reference supports the statement by mentioning that amyloid-beta peptides lead to Alzheimer's disease and cause synaptic dysfunction.

[PMID:10911965] [INDIRECT EVIDENCE] [SUPPORT] Alzheimer's disease (AD) pathology is characterized by A beta peptide-containing plaques, neurofibrillary tangles consisting of hyperphosphorylated tau, extensive neuritic degeneration, and distinct neuron loss. --- Explanation: This reference supports the statement by describing Alzheimer's disease pathology, including amyloid-beta peptide-containing plaques.

[PMID:10702374] [INDIRECT EVIDENCE] [SUPPORT] beta-amyloid (Abeta) is the main constituent of the amyloidogenic plaques which are a primary pathological hallmark of Alzheimer's disease... --- Explanation: This reference supports the statement by confirming that beta-amyloid is the main constituent of amyloid plaques, a hallmark of Alzheimer's disease.

[PMID:36555791] [INDIRECT EVIDENCE] [SUPPORT] Neuritic plaques are one of the major pathological hallmarks of Alzheimer's disease. They are formed by the aggregation of extracellular amyloid-beta protein (Abeta)... --- Explanation: This reference supports the statement by indicating that neuritic plaques, formed by the aggregation of amyloid-beta protein, are a hallmark of Alzheimer's disease.

[PMID:25941885] [INDIRECT EVIDENCE] [SUPPORT] The 'amyloid cascade hypothesis' posits that an extracellular build-up of amyloid-beta oligomers (Abeta-os) and polymers (fibrils) subsequently inducing toxic hyperphosphorylated (p)-Tau oligomers (p-Tau-os) and neurofibrillary tangles starts the sporadic late-onset Alzheimer's disease (LOAD)... --- Explanation: This reference supports the statement by discussing the amyloid cascade hypothesis, which involves the build-up of amyloid-beta leading to Alzheimer's disease.

[PMID:16611586] [INDIRECT EVIDENCE] [SUPPORT] The amyloidogenesis occurring in Alzheimer's disease represents a fundamental membrane-related pathology... the amyloid-beta peptide (Abeta), which accumulates extracellularly as plaques in the brains of Alzheimer's disease patients... --- Explanation: This reference supports the statement by describing the accumulation of amyloid-beta peptide as plaques in Alzheimer's disease.


MONDO:0004975