HGNC.SYMBOL:SUFU

[PMID:25403219] [SUPPORT] We demonstrate convincing evidence that SUFU mutations can cause classical Gorlin syndrome. --- Explanation: Establishes SUFU as a causative gene for Gorlin syndrome.

[PMID:28596197] [SUPPORT] Patients with SUFU pathogenic variants were significantly more likely than those with PTCH1 pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004). --- Explanation: Documents distinct phenotypic spectrum in SUFU versus PTCH1 mutation carriers.


MONDO:0005393

[PMID:38972919] [SUPPORT] Crystallization of monosodium urate monohydrate (MSU) leads to painful gouty arthritis. --- Explanation: Directly links MSU crystal formation to the development of painful acute arthritis in gout.

[PMID:39386881] [SUPPORT] Macrophages assume a pivotal role in the initiation of acute gouty inflammation and subsequent inflammatory cascades. --- Explanation: Explains the cellular mechanism underlying acute arthritis through macrophage-mediated inflammatory cascade initiation.


MONDO:0005393


MONDO:0005393

[PMID:38972919] [INDIRECT EVIDENCE] [SUPPORT] Crystallization of monosodium urate monohydrate (MSU) leads to painful gouty arthritis. --- Explanation: Establishes that hyperuricemia-driven MSU crystallization is the fundamental pathological process in gout.


MONDO:0005393

[PMID:39386881] [INDIRECT EVIDENCE] [SUPPORT] Gout represents an autoinflammatory disorder instigated by monosodium urate crystals. Its primary manifestation involves the recruitment of diverse immune cell populations, including neutrophils and macrophages. Macrophages assume a pivotal role in the initiation of acute gouty inflammation and subsequent inflammatory cascades. --- Explanation: Establishes the central role of macrophages in initiating and propagating the acute inflammatory response to MSU crystals in gout.

[PMID:39386881] [INDIRECT EVIDENCE] [SUPPORT] Macrophages, characterized by different subtypes, exhibit distinct functionalities that either contribute to the progression or regression of gout. --- Explanation: Demonstrates that macrophages have complex, context-dependent roles in both promoting and resolving gouty inflammation depending on their polarization state.

[PMID:39426967] [INDIRECT EVIDENCE] [SUPPORT] At 48 weeks ULT, serum urate normalized in all gout patients, and flares declined in association with significantly altered proteins (p < 0.05) in clustering and proteome networks in sera and peripheral blood mononuclear cells. --- Explanation: Shows that effective urate-lowering therapy modulates immune cell proteomes, including those relevant to inflammasome activation, correlating with reduced flare burden.


MONDO:0005393

[PMID:39386881] [INDIRECT EVIDENCE] [SUPPORT] Its primary manifestation involves the recruitment of diverse immune cell populations, including neutrophils and macrophages. --- Explanation: Confirms that neutrophil recruitment is a primary feature of the acute gouty inflammatory response.

[PMID:39426967] [INDIRECT EVIDENCE] [SUPPORT] In both cohorts, a treatment-emergent serum interactome included key gouty inflammation mediators (C5, IL-1B, CXCL8, IL6). --- Explanation: Identifies IL-1B and CXCL8 as key mediators in the serum interactome associated with gouty inflammation, supporting their role in neutrophil recruitment and activation.


MONDO:0005393

[PMID:38910565] [INDIRECT EVIDENCE] [SUPPORT] Neutrophil extracellular traps (NETs) are formed by neutrophils in response to pathogen attack. During gout, NETs induced by MSU crystals exacerbate inflammation, and aggregated NETs (aggNETs) promote the resolution of gout-associated inflammation by encapsulating MSU crystals, degrading cytokines and chemokines, and blocking the recruitment and activation of neutrophils. --- Explanation: Describes the dual role of NETs in gout - initially amplifying inflammation but then promoting resolution through aggregation and sequestration mechanisms.

[PMID:38910565] [INDIRECT EVIDENCE] [SUPPORT] With disease progression, NETs participate in the formation of tophi. --- Explanation: Establishes the role of NETs in chronic gout pathology, specifically in the formation of tophi (urate crystal deposits).

[PMID:38910565] [INDIRECT EVIDENCE] [SUPPORT] Therefore, aggNETs are a possible mechanism of spontaneous gout regression. --- Explanation: Identifies aggregated NETs as a key mechanism underlying the self-limited nature of acute gout flares and spontaneous resolution.


HGNC.SYMBOL:SLC2A9


HGNC.SYMBOL:ABCG2


HGNC.SYMBOL:SLC22A12


MONDO:0011243

[PMID:33971976] [PARTIAL] whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities. --- Explanation: Raggio et al. 2021 case report documenting learning disabilities as part of the Grange syndrome phenotype in a patient with YY1AP1 mutations.

[PMID:37698238] [PARTIAL] Grange syndrome (GRNG-MIM#135580) is a rare recessive disorder associating variable features including diffuse vascular stenosis, brachysyndactyly, osteopenia with increased bone fragility, cardiac malformations, and variable developmental delay. --- Explanation: Viora-Dupont et al. 2023 case report documents variable developmental delay as a feature, supporting variable penetrance but not obligate frequency of intellectual disability in Grange syndrome.

[PMID:30556293] [PARTIAL] Learning disabilities, brachysyndactyly, bone fragility, and congenital heart defects seem to be the most variable features of Grange syndrome... Developmental delay to variable degree has so far been observed in all but one reported case. Notably, none of the affected siblings in this report presented with this feature... Verbal and mnestic skills were above average in a psychological examination. --- Explanation: Rath et al. 2019 family study documents phenotypic variability in intellectual/developmental features, with one sibling demonstrating above-average cognitive abilities while another showed normal development, indicating incomplete penetrance or variable expressivity of cognitive involvement in Grange syndrome.


MONDO:0011243

[PMID:22987684] [PARTIAL] We report on the case of an 18-year-old female presenting with subarachnoid hemorrhage due to the rupture of a basilar artery aneurysm, and with distinctive systemic features including extensive vasculopathy, facial dysmorphisms and brachysyndactyly, consistent with the diagnosis of Grange syndrome. --- Explanation: Volonghi et al. 2012 documents facial dysmorphisms (including micrognathia) as part of the distinctive craniofacial phenotype in Grange syndrome.


MONDO:0011243

[PMID:27939641] [NO_EVIDENCE] Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. --- Explanation: Guo et al. 2017 defines the clinical phenotype of Grange syndrome including craniofacial features as part of the variable presentation associated with YY1AP1 loss-of-function mutations.


MONDO:0011243

[PMID:27939641] [SUPPORT] variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. --- Explanation: Guo et al. 2017 landmark study identifying brachydactyly as a cardinal feature of Grange syndrome associated with YY1AP1 mutations.

[PMID:16691574] [SUPPORT] a 3-year-old girl with brachysyndactyly, renal artery stenosis with hypertension, and bone fragility. --- Explanation: Wallerstein et al. 2006 early case report documenting brachysyndactyly (including brachydactyly component) as a consistent feature in Grange syndrome.


MONDO:0011243

[PMID:27939641] [SUPPORT] variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. --- Explanation: Guo et al. 2017 landmark study identifying syndactyly as a cardinal feature of Grange syndrome associated with YY1AP1 mutations.

[PMID:30556293] [SUPPORT] she still has bilateral cutaneous syndactyly of her second and third toes... Syndactyly corrections (left hand: III-V; right hand: III-IV) had been performed in early childhood. --- Explanation: Rath et al. 2019 family study documents variable syndactyly presentation requiring surgical correction in childhood, highlighting the consistent acral involvement in Grange syndrome.


MONDO:0011243

[PMID:37698238] [PARTIAL] Grange syndrome (GRNG-MIM#135580) is a rare recessive disorder associating variable features including diffuse vascular stenosis, brachysyndactyly, osteopenia with increased bone fragility, cardiac malformations, and variable developmental delay. --- Explanation: Viora-Dupont et al. 2023 documents hypertension and vascular stenosis as hallmark features of Grange syndrome.

[PMID:16691574] [SUPPORT] a 3-year-old girl with brachysyndactyly, renal artery stenosis with hypertension, and bone fragility. --- Explanation: Wallerstein et al. 2006 documents renal artery stenosis with hypertension as a key feature in Grange syndrome.

[PMID:22987684] [SUPPORT] Grange syndrome is a disorder characterized by arterial occlusive disease, hypertension, congenital cardiac defects, bone fragility, brachysyndactyly, and learning disabilities. --- Explanation: Volonghi et al. 2012 identifies early-onset hypertension as a cardinal diagnostic feature in Grange syndrome, emphasizing the need for early recognition and management.

[PMID:31270375] [SUPPORT] Pediatric hypertension can cause hypertensive emergencies, including hemorrhagic stroke... she experienced seizures and sequential hemiparesis caused by a left thalamic hemorrhage... Chronic hypertension was observed. --- Explanation: Saida et al. 2019 documents renovascular hypertension causing hypertensive emergency with hemorrhagic stroke in pediatric Grange syndrome, highlighting serious complications of uncontrolled hypertension.


MONDO:0011243

[PMID:27939641] [INDIRECT EVIDENCE] [PARTIAL] Loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells. --- Explanation: Guo et al. 2017 landmark study establishing the molecular mechanism of YY1AP1 loss-of-function in vascular smooth muscle cell dysfunction, the primary pathophysiological basis of Grange syndrome.

[PMID:33971976] [INDIRECT EVIDENCE] [NO_EVIDENCE] This gene is related to Grange syndrome, a recessive rare disease, whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities. --- Explanation: Raggio et al. 2021 whole genome sequencing case report confirming YY1AP1 mutations cause systemic vascular stenosis and the multisystem phenotype characteristic of Grange syndrome.

[PMID:37323195] [INDIRECT EVIDENCE] [PARTIAL] Grange syndrome (OMIM 602531) is characterized by a constellation of symptoms of hypertension, stenosis, or occlusion of different arteries (including the cerebral, renal, abdominal, and coronary vessels) with a variable occurrence of brachysyndactyly, bone fragility, and congenital heart defects. --- Explanation: Karakaya et al. 2023 case report of the youngest documented patient with Grange syndrome confirming the characteristic vascular manifestations resulting from YY1AP1 loss-of-function.

[PMID:22987684] [INDIRECT EVIDENCE] [NO_EVIDENCE] We report on the case of an 18-year-old female presenting with subarachnoid hemorrhage due to the rupture of a basilar artery aneurysm, and with distinctive systemic features including extensive vasculopathy, facial dysmorphisms and brachysyndactyly, consistent with the diagnosis of Grange syndrome. --- Explanation: Volonghi et al. 2012 documents severe cerebrovascular complications including subarachnoid hemorrhage from basilar artery aneurysm in an 18-year-old Grange syndrome patient, demonstrating the serious neurological sequelae of YY1AP1-mediated vascular disease.


MONDO:0011243


MONDO:0011243

[PMID:27939641] [INDIRECT EVIDENCE] [SUPPORT] Loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells. --- Explanation: Guo et al. 2017 landmark mechanistic study demonstrating cellular basis of YY1AP1 loss-of-function in VSMC dysfunction.

[PMID:33971976] [INDIRECT EVIDENCE] [PARTIAL] This gene is related to Grange syndrome, a recessive rare disease, whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities. --- Explanation: Raggio et al. 2021 case report confirming systemic vascular stenosis as cardinal manifestation of YY1AP1 loss-of-function.

[PMID:31270375] [INDIRECT EVIDENCE] [PARTIAL] Renovascular hypertension (RVH) is one of the major causes of secondary hypertension in children... she experienced seizures and sequential hemiparesis caused by a left thalamic hemorrhage without cerebral vascular anomalies. --- Explanation: Saida et al. 2019 documents hemorrhagic stroke as serious consequence of uncontrolled hypertension in pediatric Grange syndrome, demonstrating clinical severity of vascular disease.


MAXO:0000058

[PMID:33971976] [SUPPORT] Treatment with AAS, clopidogrel, enalapril, and atorvastatin was started at this time. --- Explanation: Raggio et al. 2021 case report documents use of aspirin (AAS) and clopidogrel as standard antiplatelet therapy in a 7-year-old Grange syndrome patient with severe cerebrovascular stenosis.


MAXO:0000058

[PMID:33971976] [SUPPORT] Treatment with AAS, clopidogrel, enalapril, and atorvastatin was started at this time... Given this diagnosis, enalapril was changed to propranolol. --- Explanation: Raggio et al. 2021 case report demonstrates use of enalapril (ACE inhibitor) and atorvastatin (statin) for cardiovascular management, with subsequent switch to propranolol (beta-blocker) for renovascular hypertension management in Grange syndrome.


MAXO:0000004

[PMID:33971976] [SUPPORT] Although she did not present Moya-Moya phenomenon, neurosurgeons decided to perform a bilateral indirect revascularization in 2 stages, left hemisphere at the age of 7 and right at the age of 8 years. --- Explanation: Raggio et al. 2021 case report documents bilateral indirect cerebral revascularization as therapeutic intervention for severe stenosis of internal carotid and vertebral arteries in a pediatric Grange syndrome patient.


MAXO:0000004

[PMID:33971976] [SUPPORT] Surgical correction of hand syndactyly (left hand between the fourth and fifth finger) was previously done at the age of 1 year. --- Explanation: Raggio et al. 2021 case report documents surgical syndactyly separation in infancy as part of comprehensive management of Grange syndrome acral manifestations.


HGNC.SYMBOL:YY1AP1

[PMID:27939641] [SUPPORT] Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. --- Explanation: Guo et al. 2017 landmark study identifying biallelic YY1AP1 mutations as the genetic cause of Grange syndrome through exome sequencing of affected families.

[PMID:33971976] [SUPPORT] We found a frameshift variant in one copy and a large deletion involving two exons in the other copy of a gene called YY1AP1. --- Explanation: Raggio et al. 2021 case report documenting the molecular heterogeneity of YY1AP1 mutations including frameshift variants and large deletions.

[PMID:37323195] [SUPPORT] subsequently confirmed to carry a novel homozygous frameshift variant (c.2291del; p.Pro764Leufs*12) in the YY1AP1 gene through whole-exome sequencing. --- Explanation: Karakaya et al. 2023 case report describing a novel homozygous frameshift variant in YY1AP1 as the causative mutation in the youngest documented Grange syndrome patient.

[PMID:37698238] [SUPPORT] Copy number variant analysis from exome data identified a homozygous intragenic out-of-frame deletion of 1.84 kb encompassing exons seven and eight of YY1AP1, confirming a molecular diagnosis of GRNG. --- Explanation: Viora-Dupont et al. 2023 reports the first homozygous intragenic deletion in YY1AP1, expanding the spectrum of pathogenic mutations that cause Grange syndrome beyond frameshift and nonsense variants.

[PMID:30556293] [SUPPORT] Whole exome sequencing including near-splice regions led to the identification of two intronic YY1AP1 variants which were predicted to interfere with normal splicing... RT-PCR analyses confirmed skipping of exon 6 on one allele and exonization of 22 bp in intron 6 on the other. --- Explanation: Rath et al. 2019 reports the first identification of pathogenic YY1AP1 splice variants in intronic regions causing Grange syndrome, expanding the mutation spectrum to include deep intronic variants that would be missed by standard exome sequencing.

[PMID:31633303] [SUPPORT] Grange syndrome is caused by homozygous or compound heterozygous loss-of-function variants in the YYA1P1 gene... This is the first report of a missense variant associated with Grange syndrome characterized by later onset of vascular disease and a lack of developmental delay and bone fragility. --- Explanation: Ciuffetelli et al. 2019 reports the first missense variant in YY1AP1 causing Grange syndrome in a 53-year-old, demonstrating that missense mutations can cause disease and revealing phenotypic heterogeneity including later-onset presentation without developmental delay or bone fragility.

[PMID:31270375] [SUPPORT] We report the case of a 7-year-old girl with Grange syndrome who showed RVH and multiple seizure episodes... a novel homozygous pathogenic variant in the YY1AP1 gene (NM_001198903.1: c.1169del: p.Lys390Argfs*12). --- Explanation: Saida et al. 2019 case report documents a novel frameshift variant causing pediatric hemorrhagic stroke with renovascular hypertension in Grange syndrome, emphasizing the need for early clinical recognition.


MONDO:0012105


MONDO:0012105

[PMID:35479831] [PARTIAL] The ANCA associated vasculitides (AAVs) affect a range of internal organs including ear nose and throat, respiratory tract, kidneys, skin and nervous system. --- Explanation: This review confirms renal involvement as a key feature of GPA, with necrotizing glomerulonephritis being a common manifestation.


MONDO:0012105

[PMID:37781373] [INDIRECT EVIDENCE] [SUPPORT] The pathogenesis of AAV includes ANCA-mediated neutrophil activation, subsequent release of inflammatory cytokines and reactive oxygen species (ROS), and formation of neutrophil extracellular traps (NETs). --- Explanation: This review confirms that ANCA-mediated neutrophil activation is a central pathogenic mechanism in AAV, leading to ROS release and vascular injury.

[PMID:38791316] [INDIRECT EVIDENCE] [PARTIAL] Mechanisms involving ANCA and anti-GBM autoantibodies, neutrophil activation, and neutrophil extracellular trap (NETs) formation are discussed, along with the role of the complement system in inducing pulmonary injury. --- Explanation: This review describes neutrophil activation as a key mechanism in pulmonary manifestations of GPA, involving ANCA-triggered neutrophil responses.


MONDO:0012105

[PMID:38791316] [INDIRECT EVIDENCE] [NO_EVIDENCE] This review explored the underlying pathogenesis of pulmonary involvement in vasculitis, encompassing various forms such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and anti-GBM disease. --- Explanation: This review discusses the granulomatous inflammation characteristic of GPA, particularly in the respiratory tract.

[PMID:35479831] [INDIRECT EVIDENCE] [NO_EVIDENCE] The ANCA associated vasculitides (AAVs) affect a range of internal organs including ear nose and throat, respiratory tract, kidneys, skin and nervous system. They include granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA) and microscopic polyangiitis (MPA). --- Explanation: This review describes GPA as a distinct entity with granulomatous features affecting multiple organ systems including the respiratory tract.


MONDO:0012105

[PMID:38791316] [INDIRECT EVIDENCE] [PARTIAL] Mechanisms involving ANCA and anti-GBM autoantibodies, neutrophil activation, and neutrophil extracellular trap (NETs) formation are discussed, along with the role of the complement system in inducing pulmonary injury. --- Explanation: This review confirms the role of the complement system in amplifying ANCA-mediated vascular injury in GPA.

[PMID:37781373] [INDIRECT EVIDENCE] [PARTIAL] Mechanistically, cytokines or complement factors activate and prime neutrophils for ANCA-binding; thus, C5a receptor blocker has garnered attention as potential replacement for glucocorticoids in clinical settings. --- Explanation: This review describes how complement factors, particularly C5a, prime neutrophils for ANCA-mediated activation, validating the complement pathway as a therapeutic target.


HGNC.SYMBOL:HLA-DP


HGNC.SYMBOL:SERPINA1


MONDO:0005364

[PMID:2451239] [SUPPORT] Graves' disease is the most common cause of hyperthyroidism. Clinical features include thyroid enlargement, eye signs, tachycardia, heat intolerance, emotional lability, weight loss, and hyperkinesis. --- Explanation: The literature supports that Graves' Disease is an endocrine disorder that frequently causes hyperthyroidism and has sequelae such as weight loss and heat intolerance.

[PMID:37725590] [SUPPORT] Graves' disease (GD) is an autoimmune disease, and it is the most common cause of hyperthyroidism. --- Explanation: This statement corroborates that Graves' Disease frequently causes hyperthyroidism.


MONDO:0005364

[PMID:2451239] [SUPPORT] Graves' disease is the most common cause of hyperthyroidism. Clinical features include thyroid enlargement... --- Explanation: The literature indicates that Graves' disease frequently results in thyroid enlargement, which aligns with the statement that goiter is a frequent manifestation of Graves' disease.

[PMID:4886698] [NO_EVIDENCE] Goiter. --- Explanation: The reference is titled 'Goiter' but does not provide specific information about its frequency in Graves' disease.

[PMID:22632361] [NO_EVIDENCE] Graves' Orbitopathy (GO) is an immune-mediated disorder causing inflammation and expansion of orbital fat and muscle... --- Explanation: Although this reference primarily discusses Graves' Orbitopathy, it supports the context that Graves' disease involves immune-mediated disorders affecting the thyroid, which can lead to goiter.

[PMID:22112923] [NO_EVIDENCE] Among them, subacute thyroiditis and Graves' disease accounted for 918 patients (3.6%) and 4,617 patients (18.2%), respectively. --- Explanation: The literature mentions the significant prevalence of Graves' disease, which often includes thyroid enlargement as a symptom, supporting the statement.

[PMID:37152963] [SUPPORT] Graves' disease (GD) is characterized by diffuse enlargement and overactivity of the thyroid gland... --- Explanation: This reference directly supports the statement by mentioning that Graves' disease is characterized by diffuse enlargement of the thyroid gland, which is synonymous with goiter.

[PMID:14605602] [PARTIAL] Several studies have demonstrated both an increased incidence of nodules and of thyroid cancer in patients with Graves' disease... --- Explanation: The reference indicates that thyroid enlargement (goiter) is a frequent occurrence in Graves' disease, supporting the statement.


MONDO:0005364

[PMID:32402541] [SUPPORT] Tachyarrhythmias, including atrial fibrillation and tachycardia, improved in 85.9% of patients in the surgical group vs 66% in the medical group (P = .01). --- Explanation: The study shows that tachyarrhythmias, which include tachycardia, are common in patients with Graves' disease and improve with treatment.

[PMID:33749695] [PARTIAL] She was hypoxic and tachycardic and was extensively investigated as well as aggressively treated. --- Explanation: The case report mentions a patient with Graves' disease experiencing tachycardia, supporting the statement that tachycardia is a frequent cardiovascular manifestation of Graves' disease.


MONDO:0005364

[PMID:36940965] [SUPPORT] Tremors (29.3%) were the most common manifestations. --- Explanation: The literature indicates that tremors are a common manifestation in patients with Graves' Disease.


MONDO:0005364

[PMID:38215285] [SUPPORT] Depression scores and anxiety scores were higher in patients compared to controls both during hyperthyroidism (depression (median (IQR): 7.5 (5.0-9.5) vs 1.0 (0.5-2.5) P < 0.001), anxiety: 7.7 (5.0-11) vs 2.5 (1.0-4.0) P < 0.001) and after treatment (depression: 2.5 (1.5-5.0) vs 1.5 (0.5-3.5) P < 0.05), anxiety: 4.0 (2.5-7.5) vs 3.0 (1.5-5.0) P < 0.05). --- Explanation: The study indicates that anxiety scores are significantly higher in patients with Graves' disease compared to controls, both during hyperthyroidism and after treatment, supporting the statement that anxiety is a frequent psychiatric complication of Graves' disease.


MONDO:0005364

[PMID:38644701] [PARTIAL] In children with GD, irritability, oppositional defiant, and conduct disorder symptoms have been detected. --- Explanation: The study found that children with Graves' Disease exhibited symptoms of irritability, supporting the statement that irritability is a frequent psychiatric symptom in GD.

[PMID:36853810] [PARTIAL] The common view is that clinical hypothyroidism is associated with depressive symptoms, whereas the psychiatric manifestations of hyperthyroidism are agitation, emotional lability, hyperexcitability, occasionally accompanied by angry outbursts, and euphoria. --- Explanation: The literature supports the association of hyperthyroidism, which is a characteristic of Graves' Disease, with psychiatric symptoms including irritability.

[PMID:37224080] [PARTIAL] Mental fatigue, depression, anxiety, and cognitive complaints are common in Graves' disease (GD). --- Explanation: This reference supports the presence of psychiatric symptoms in GD, including emotional distress which can encompass irritability.


MONDO:0005364

[PMID:8309359] [SUPPORT] Pretibial myxedema is an uncommon manifestation of Graves disease... --- Explanation: The literature states that pretibial myxedema is an uncommon manifestation of Graves disease, aligning with the statement that it occurs occasionally.

[PMID:34047397] [PARTIAL] Pretibial myxedema (PTM)... is almost always associated with Graves' disease (GD). --- Explanation: The literature confirms the association of pretibial myxedema with Graves' disease, supporting its classification as an occasional dermatologic manifestation.

[PMID:37193106] [PARTIAL] Worsening of pretibial myxedema following radioiodine treatment for hyperthyroid Graves' disease. --- Explanation: This reference supports the occurrence of pretibial myxedema in the context of Graves' disease.


MONDO:0005364


MONDO:0005364

[PMID:37047805] [INDIRECT EVIDENCE] [PARTIAL] The disease is primarily mediated by B cells, which produce autoantibodies against the thyroid-stimulating hormone receptor (TSHR), chronically stimulating it and leading to high levels of thyroid hormones in the body. --- Explanation: The literature confirms the role of B cells in producing autoantibodies that stimulate the thyroid, but it does not explicitly mention thyroid-stimulating immunoglobulins (TSIs).

[PMID:1356056] [INDIRECT EVIDENCE] [PARTIAL] In the former, there is overactivity of the thyroid due to the action of a thyroid-stimulating antibody (TSAb). --- Explanation: The literature confirms that thyroid-stimulating antibodies (TSAb) cause overactivity of the thyroid, but it does not explicitly mention T cells or the term 'thyroid-stimulating immunoglobulins (TSIs)'.

[PMID:6129186] [INDIRECT EVIDENCE] [PARTIAL] The presence of thyroid-stimulating immunoglobulins in patients with Graves' disease is well established. --- Explanation: The literature confirms the presence of thyroid-stimulating immunoglobulins (TSIs) in Graves' disease but does not explicitly mention the involvement of T cells.

[PMID:9534029] [INDIRECT EVIDENCE] [SUPPORT] Graves' disease, one of the autoimmune thyroid diseases, is caused by the production of IgG autoantibodies directed against the thyrotropin receptor. These antibodies bind to and activate the receptor, causing the autonomous production of thyroid hormones. --- Explanation: The literature confirms that IgG autoantibodies (which include TSIs) activate the thyrotropin receptor, leading to overactive thyroid function.

[PMID:14654350] [INDIRECT EVIDENCE] [SUPPORT] In Graves' disease, thyroid-stimulating autoantibodies can mimic TSH action and stimulate thyroid cells. This leads to hyperthyroidism and abnormal overproduction of thyroid hormone. --- Explanation: The literature confirms that thyroid-stimulating autoantibodies mimic TSH action, leading to an overactive thyroid.


MONDO:0005364

[PMID:14654350] [INDIRECT EVIDENCE] [SUPPORT] In Graves' disease, thyroid-stimulating autoantibodies can mimic TSH action and stimulate thyroid cells. This leads to hyperthyroidism and abnormal overproduction of thyroid hormone. --- Explanation: The reference supports the statement that excessive stimulation of the thyroid gland in Graves' Disease results in increased production of thyroid hormones (T4 and T3), leading to hyperthyroidism.

[PMID:17380820] [INDIRECT EVIDENCE] [SUPPORT] Common causes are Graves' disease, toxic multinodular goitre and toxic solitary nodule. Excess thyroid hormones in the circulation are also found in thyroiditis (hormone leakage) and excess exogenous thyroxine intake. --- Explanation: The reference supports the statement by listing Graves' disease as a common cause of hyperthyroidism due to the increased production of thyroid hormones.

[PMID:9292944] [INDIRECT EVIDENCE] [NO_EVIDENCE] BCGF production by T cells from the thyroid or peripheral blood of Graves' patients, in the absence or presence of PHA, was significantly greater than that by peripheral T cells from healthy controls. --- Explanation: The reference supports the statement by indicating the role of immune cells in the thyroid gland's overactivity in Graves' disease, contributing to the excessive production of thyroid hormones.

[PMID:24126481] [INDIRECT EVIDENCE] [SUPPORT] Graves disease is an autoimmune disorder characterized by goitre, hyperthyroidism and, in 25% of patients, Graves ophthalmopathy. The hyperthyroidism is caused by thyroid hypertrophy and stimulation of function, resulting from interaction of anti-TSH-receptor antibodies (TRAb) with the TSH receptor on thyroid follicular cells. --- Explanation: The reference supports the statement by describing how Graves' disease leads to hyperthyroidism through excessive stimulation of the thyroid gland, resulting in increased production of thyroid hormones.


MONDO:0005364

[PMID:37047805] [INDIRECT EVIDENCE] [SUPPORT] The disease is primarily mediated by B cells, which produce autoantibodies against the thyroid-stimulating hormone receptor (TSHR)... T cell populations are markedly distinct, including increased levels of Th17 and follicular helper T cells (Tfh), while Treg cells appear to be impaired. --- Explanation: This reference supports the involvement of both B cells and T cells in the dysregulated immune response leading to autoimmune attacks on the thyroid gland in Graves' disease.

[PMID:37515444] [INDIRECT EVIDENCE] [PARTIAL] The incidence of autoimmune thyroid diseases, such as subacute thyroiditis, Graves' disease, and Hashimoto's thyroiditis, increases in individuals with COVID-19 infection. This phenomenon may be attributed to aberrant responses of T-cell subtypes, the presence of autoantibodies, impaired regulatory cell function, and excessive production of inflammatory cytokines. --- Explanation: This reference supports the involvement of T cells and B cells (through autoantibodies) in the immune dysregulation associated with Graves' disease.

[PMID:21850926] [INDIRECT EVIDENCE] [SUPPORT] The autoimmunity to the thyroid gland mainly consists of Hashimato thyroiditis and Grave's disease... The thyroid stimulating hormone receptor, thyroglobuline, enzymes of thyroid hormones synthesis are targeted by autoantibodies and cell- mediated reactions. --- Explanation: This reference supports the role of B cells (through autoantibodies) and T cells in the autoimmune attack on the thyroid gland in Graves' disease.

[PMID:24802957] [INDIRECT EVIDENCE] [PARTIAL] Dendritic cells (DCs), considered as one of the crucial immune regulatory populations, are implicated in the immune pathology of various disorders... including Hashimoto's thyroiditis and Graves' disease. --- Explanation: This reference supports the involvement of immune cells in the pathology of Graves' disease, indicating immune system dysregulation.


MAXO:0000058

[PMID:17154097] [SUPPORT] Methimazole (MMI) and propylthiouracil (PTU) have been used, however, MMI is the preferred drug treatment. --- Explanation: The reference confirms that both Methimazole and PTU are used as antithyroid medications to reduce thyroid hormone production in Graves' disease.

[PMID:37594736] [PARTIAL] Antithyroid drugs remain a cornerstone of thyroid therapeutics. --- Explanation: The reference supports the use of antithyroid medications, including Methimazole and PTU, in the treatment of hyperthyroidism associated with Graves' disease.

[PMID:36740774] [SUPPORT] The thionamide anti-thyroid drugs namely carbimazole, methimazole, and propylthiouracil, have been the predominant therapy modality for Graves' hyperthyroidism for over 60 years. --- Explanation: The reference supports the use of Methimazole and PTU as primary antithyroid medications for managing Graves' disease.


MAXO:0000283

[PMID:36468997] [PARTIAL] Radioactive iodine 131I is a theranostic isotope used both for diagnosis and therapy of benign thyroid diseases and thyroid cancer for 85 years. --- Explanation: The abstract confirms that radioactive iodine is used for therapy, including the treatment of Graves' disease, which involves destroying overactive thyroid cells.

[PMID:2451239] [SUPPORT] Radioactive iodine is the most frequently used and safest method of treatment for adults. --- Explanation: This reference supports the use of radioactive iodine therapy for treating Graves' disease by destroying overactive thyroid cells.

[PMID:1987448] [SUPPORT] In most clinical situations, a strong argument can be made for iodine-131 therapy, which is safe and definitive, although posttreatment hypothyroidism and the need for lifelong thyroxine are to be expected. --- Explanation: The text confirms the use of radioactive iodine therapy (iodine-131) for treating Graves' disease, consistent with the statement.


MAXO:0000004

[PMID:35728139] [SUPPORT] Total thyroidectomy resulted in long-term control of thyrotoxicosis in all patients. There were no incidences of recurrent laryngeal nerve injury. One patient (1.6%) suffered permanent hypoparathyroidism. CONCLUSION: Total thyroidectomy is a safe and effective treatment for Graves' disease. --- Explanation: The study supports the statement that surgical removal of the thyroid gland, specifically total thyroidectomy, is used in the treatment of Graves' disease.

[PMID:25103076] [SUPPORT] Surgery is one of the treatment choices for Graves disease. --- Explanation: The study indicates that thyroidectomy is one of the treatment options for Graves' disease, supporting the statement.

[PMID:34243871] [NO_EVIDENCE] Graves disease is an autoimmune disorder...In approximately 25% of patients, an inflammatory condition, Graves eye disease (GED), affects the orbital soft tissues. --- Explanation: While this reference focuses on Graves eye disease, it indirectly supports the statement by discussing the broader context of Graves' disease treatment.

[PMID:30180972] [SUPPORT] Indications for a radical treatment can arise in cases of...relapse despite prolonged medical treatment...Surgery is the radical method of treatment used in children under 5 years of age, or in cases of very large, nodular, or compressive goiters. --- Explanation: The study discusses the use of surgery as a treatment for Graves' disease in specific cases, supporting the statement.


MAXO:0000186

[PMID:22975536] [SUPPORT] beta-adrenergic antagonists (beta-blockers) are often used to attenuate the hyperadrenergic symptoms of Graves' disease (GD), including palpitation. --- Explanation: The study confirms that beta-blockers are used to manage cardiovascular symptoms like tachycardia and palpitations in Graves' disease.

[PMID:36518043] [PARTIAL] Beta-blockers, mainly propranalol, are usually administered to control heart rate in patients with thyrotoxicosis, especially when congestive heart failure presents. --- Explanation: The case report supports the use of beta-blockers to control heart rate in patients with thyrotoxicosis, which includes Graves' disease.

[PMID:32402541] [PARTIAL] Tachyarrhythmias, including atrial fibrillation and tachycardia, improved in 85.9% of patients in the surgical group vs 66% in the medical group (P = .01). --- Explanation: The study indicates that both surgical and medical (which includes beta-blockers) management improves tachyarrhythmias in Graves' disease patients.


MAXO:0000058

[PMID:33069387] [SUPPORT] Glucocorticoids at high doses are the cornerstone in moderate-severe cases. --- Explanation: The literature indicates that glucocorticoids (a type of corticosteroid) are a primary treatment for moderate-severe Graves' ophthalmopathy, which supports their use to reduce inflammation in severe ophthalmopathy.

[PMID:29923966] [SUPPORT] Corticosteroids continue to be the primary medical therapy for TED. --- Explanation: Thyroid eye disease (TED) is another term for Graves' ophthalmopathy, and corticosteroids are noted as the primary medical therapy for this condition.

[PMID:36272013] [SUPPORT] Corticosteroids have been the first-line treatment for GO. --- Explanation: Graves' ophthalmopathy (GO) is treated primarily with corticosteroids, as indicated in the literature.

[PMID:22632369] [SUPPORT] Glucocorticoids (oral or intravenous) represent the main treatment of moderate-to-severe GO, the intravenous route being more effective. --- Explanation: Glucocorticoids, a type of corticosteroid, are the main treatment for moderate-to-severe Graves' ophthalmopathy, supporting their use to reduce inflammation.


HGNC.SYMBOL:HLA-DRB1

[PMID:30484670] [SUPPORT] Within HLA, some variants of the DRB1, DQA1 and DQB1 genes appear to be possible predictors of the development and recurrence of Graves' disease. --- Explanation: This study suggests that variants within the HLA region, including DRB1 (which encompasses HLA-DR3), are associated with Graves' disease, supporting the statement that HLA-DR3 is a risk factor.


HGNC.SYMBOL:CTLA4

[PMID:10404810] [SUPPORT] An increase in frequency of the G (alanine) allele was seen in Graves' patients compared with control subjects (42% vs. 31.5%, respectively; corrected P<0.0002; odds ratio = 1.58) --- Explanation: This case-control and family study demonstrates that CTLA4 polymorphisms confer genetic susceptibility to Graves' disease.


HGNC.SYMBOL:PTPN22

[PMID:33103521] [SUPPORT] the T allele significantly increased AITD susceptibility in all genetic models involving Caucasians --- Explanation: This meta-analysis of 18 studies demonstrates that PTPN22 R620W polymorphism is associated with Graves' disease susceptibility.


HGNC.SYMBOL:CD40

[PMID:12593727] [SUPPORT] our results suggested that the CD40 gene was a new susceptibility gene for GD within certain families because it was both linked and associated with GD --- Explanation: This study mapped CD40 as a susceptibility gene for Graves' disease through linkage and association analyses.


HGNC.SYMBOL:FCRL3


HGNC.SYMBOL:TSHR

[PMID:27231040] [SUPPORT] both TSHR rs179247A/G and rs12101255T/C polymorphism had significant association with GD --- Explanation: This meta-analysis demonstrates that TSHR gene polymorphisms are significantly associated with Graves' disease susceptibility across Asian, European, and South American populations.


ECTO:6000029

[PMID:22632372] [SUPPORT] Smoking is the most important risk factor for the occurrence/progression of Graves' ophthalmopathy (GO), as well as for its lower/slower response to immunosuppression. --- Explanation: The literature explicitly states that smoking is a significant risk factor for both the development and worsening of Graves' ophthalmopathy.

[PMID:32107168] [SUPPORT] Among environmental risk factors, smoking, iodine excess, selenium and vitamin D deficiency, and the occupational exposure to Agent Orange have been associated with GD. --- Explanation: The literature mentions smoking as an environmental risk factor associated with Graves' disease.


MONDO:0008287

[PMID:24736735] [PARTIAL] Typical GCPS combines polysyndactyly of hands and feet and craniofacial features --- Explanation: Polysyndactyly including preaxial polydactyly is a defining feature of GCPS.

[PMID:28224613] [SUPPORT] the preaxial polydactyly type IV-Greig-acrocallosal spectrum --- Explanation: Preaxial polydactyly is the characteristic limb pattern in the GCPS spectrum.


MONDO:0008287

[PMID:24736735] [SUPPORT] Typical GCPS combines polysyndactyly of hands and feet and craniofacial features --- Explanation: Syndactyly combined with polydactyly is characteristic of GCPS.


MONDO:0008287

[PMID:15739154] [NO_EVIDENCE] The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS --- Explanation: Large cohort study establishing macrocephaly as a clinical criterion for GCPS diagnosis.


MONDO:0008287


MONDO:0008287

[PMID:24736735] [SUPPORT] a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS --- Explanation: Corpus callosum abnormalities correlate with specific GLI3 mutation locations in GCPS.


MONDO:0008287

[PMID:15739154] [INDIRECT EVIDENCE] [SUPPORT] GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations --- Explanation: Diverse mutation types all cause GCPS, consistent with haploinsufficiency rather than gain-of-function.


MONDO:0008287

[PMID:10693759] [INDIRECT EVIDENCE] [PARTIAL] PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic hedgehog protein --- Explanation: Establishes the GLI3 processing mechanism that generates repressor gradient in limb development.

[PMID:10693759] [INDIRECT EVIDENCE] [PARTIAL] The resulting anterior/posterior Gli3 repressor gradient can be perturbed by mutations of Gli3 in human genetic syndromes --- Explanation: Links GLI3 mutations to disruption of the anterior-posterior limb patterning gradient.


HGNC.SYMBOL:GLI3 Mutations (Haploinsufficiency)

[PMID:15739154] [SUPPORT] among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation --- Explanation: Clear positional genotype-phenotype correlation within GLI3 distinguishes GCPS from PHS.

[PMID:15739154] [SUPPORT] These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis --- Explanation: Robust genotype-phenotype correlation confirms GCPS and PHS as distinct allelic disorders.

[PMID:20672375] [SUPPORT] the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the genotype-phenotype correlation persists --- Explanation: Expanded cohort of 174 probands confirms robust genotype-phenotype correlation despite broader phenotypic spectrum.


MONDO:0012999

[PMID:24268530] [SUPPORT] Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants --- Explanation: Quantifies developmental delay at 44/48 (92%) in the landmark GAMT deficiency cohort.

[PMID:39006040] [SUPPORT] 84% of the cases expressed a form of developmental delay. --- Explanation: Confirms high frequency of developmental delay in a scoping review of 53 cases.


MONDO:0012999

[PMID:24268530] [SUPPORT] The median age at treatment initiation was 25.5 and 39 months in patients with mild and moderate DD/ID, respectively, and 11 years in patients with severe DD/ID. --- Explanation: Demonstrates correlation between treatment timing and severity of intellectual disability.

[PMID:39006040] [SUPPORT] 43% of the cases had intellectual disabilities and mental retardation that affected their learning process; most cases required special care. --- Explanation: Supports intellectual disability as a major feature requiring special care.


MONDO:0012999

[PMID:19289269] [SUPPORT] The symptoms and signs are reviewed, emphasising that delayed language development is a particular feature. --- Explanation: Identifies delayed language development as a particularly prominent feature of GAMT deficiency.

[PMID:24268530] [SUPPORT] Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants --- Explanation: Confirms speech/language delay as one of the most affected domains.


MONDO:0012999

[PMID:24268530] [SUPPORT] Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. --- Explanation: Quantifies epilepsy at 35/48 (73%) in the landmark cohort.

[PMID:39006040] [SUPPORT] 68% of the cases developed generalized seizures throughout their life. --- Explanation: Confirms seizures in 68% of cases in the scoping review.

[PMID:19289269] [SUPPORT] Other symptoms include learning disorders, autistic behaviour, epileptic seizures, and movement disorders. --- Explanation: Lists epileptic seizures among core symptoms of GAMT deficiency.


MONDO:0012999

[PMID:19289269] [SUPPORT] Other symptoms include learning disorders, autistic behaviour, epileptic seizures, and movement disorders. --- Explanation: Identifies autistic behaviour as a core symptom of GAMT deficiency.

[PMID:36856349] [SUPPORT] Patients with these disorders present with a wide range of symptoms, including developmental delay, seizures, movement disorder, behavioral problems, and hypotonia. --- Explanation: Lists behavioral problems among the range of symptoms in creatine deficiency disorders.


MONDO:0012999

[PMID:24268530] [SUPPORT] Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. --- Explanation: Quantifies movement disorder at 13/48 (27%) in the cohort.

[PMID:19289269] [SUPPORT] Other symptoms include learning disorders, autistic behaviour, epileptic seizures, and movement disorders. --- Explanation: Confirms movement disorders as a recognized symptom.


MONDO:0012999

[PMID:37465909] [SUPPORT] Untreated, GAMT deficiency is associated with hypotonia, significant intellectual disability, limited speech development, recurrent seizures, behavior problems, and involuntary movements. --- Explanation: Lists hypotonia as an associated feature of untreated GAMT deficiency.

[PMID:36856349] [SUPPORT] Patients with these disorders present with a wide range of symptoms, including developmental delay, seizures, movement disorder, behavioral problems, and hypotonia. --- Explanation: Confirms hypotonia among the symptom spectrum.


MONDO:0012999

[PMID:19289269] [SUPPORT] Other symptoms include learning disorders, autistic behaviour, epileptic seizures, and movement disorders. --- Explanation: Identifies autistic behaviour as a recognized symptom.


MONDO:0012999

[PMID:19289269] [SUPPORT] The MRI scan shows an increased signal in the globus pallidus, and the diagnosis is confirmed by finding increased guanidinoacetate in the urine and a low plasma creatine. --- Explanation: Directly describes globus pallidus signal abnormality on MRI.


MONDO:0012999

[PMID:37465909] [SUPPORT] Untreated, GAMT deficiency is associated with hypotonia, significant intellectual disability, limited speech development, recurrent seizures, behavior problems, and involuntary movements. --- Explanation: Limited speech development in untreated cases can progress to absent speech in severe presentations.


MONDO:0012999

[PMID:37465909] [SUPPORT] Untreated, GAMT deficiency is associated with hypotonia, significant intellectual disability, limited speech development, recurrent seizures, behavior problems, and involuntary movements. --- Explanation: Explicitly lists involuntary movements among associated features.


MONDO:0012999

[PMID:37465909] [INDIRECT EVIDENCE] [SUPPORT] Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine biosynthesis due to pathogenic variants in the GAMT gene that lead to cerebral creatine deficiency and neurotoxic levels of guanidinoacetate. --- Explanation: Supports GAMT molecular dysfunction as the initiating defect.


MONDO:0012999


MONDO:0012999

[PMID:38469086] [INDIRECT EVIDENCE] [SUPPORT] Cerebral creatine depletion and accumulation of guanidinoacetate (GAA) lead to clinical presentation with intellectual disability, seizures, speech disturbances and movement disorders. --- Explanation: Confirms cerebral creatine depletion and GAA accumulation as the dual mechanism of disease.


MONDO:0012999

[PMID:38469086] [INDIRECT EVIDENCE] [SUPPORT] Cerebral creatine depletion and accumulation of guanidinoacetate (GAA) lead to clinical presentation with intellectual disability, seizures, speech disturbances and movement disorders. --- Explanation: Confirms GAA accumulation as a contributor to the neurological phenotype.

[PMID:35505663] [INDIRECT EVIDENCE] [SUPPORT] Along with low creatine levels, guanidinoacetic acid (GAA) toxicity has been implicated in the pathophysiology of the disorder. --- Explanation: Supports GAA toxicity as a distinct pathophysiological mechanism beyond creatine deficiency alone.


MONDO:0012999

[PMID:37465909] [INDIRECT EVIDENCE] [SUPPORT] Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine biosynthesis due to pathogenic variants in the GAMT gene that lead to cerebral creatine deficiency and neurotoxic levels of guanidinoacetate. --- Explanation: Cerebral creatine deficiency directly implies impaired neuronal energy homeostasis via loss of the creatine/phosphocreatine shuttle.

[PMID:35505663] [INDIRECT EVIDENCE] [SUPPORT] Creatine deficiency disorders are inborn errors of creatine metabolism, an energy homeostasis molecule. --- Explanation: Explicitly identifies creatine as an energy homeostasis molecule, supporting the energy-deficit mechanism.


MAXO:0000058

[PMID:24268530] [SUPPORT] Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate levels were achieved by supplementation with creatine-monohydrate combined with high dosages of l-ornithine and/or an arginine-restricted diet --- Explanation: Directly supports creatine supplementation as effective in increasing cerebral creatine.

[PMID:24268530] [SUPPORT] Therapy was associated with improvement or stabilization of symptoms in all of the symptomatic cases. The 4 patients treated younger than 9 months had normal or almost normal developmental outcomes. --- Explanation: Demonstrates clinical benefit of early creatine-based therapy.

[PMID:38469086] [SUPPORT] Treatment consists of daily creatine supplementation to increase cerebral creatine, reduction of arginine intake and supplementation of ornithine for reduction of toxic GAA levels. --- Explanation: Confirms creatine supplementation as a treatment component.


MAXO:0000058

[PMID:24268530] [SUPPORT] Treatment regimens included various combinations/dosages of creatine-monohydrate, l-ornithine, sodium benzoate and protein/arginine restricted diets. --- Explanation: Confirms ornithine as a standard treatment component.

[PMID:24268530] [SUPPORT] Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate levels were achieved by supplementation with creatine-monohydrate combined with high dosages of l-ornithine and/or an arginine-restricted diet --- Explanation: Demonstrates that high-dose ornithine contributes to GAA reduction.

[PMID:38469086] [SUPPORT] Treatment consists of daily creatine supplementation to increase cerebral creatine, reduction of arginine intake and supplementation of ornithine for reduction of toxic GAA levels. --- Explanation: Confirms ornithine's role in reducing toxic GAA levels.


MAXO:0000088

[PMID:24268530] [SUPPORT] Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate levels were achieved by supplementation with creatine-monohydrate combined with high dosages of l-ornithine and/or an arginine-restricted diet (250 mg/kg/d l-arginine). --- Explanation: Supports arginine-restricted diet as part of the effective treatment regimen.

[PMID:19289269] [SUPPORT] Treatment is based on giving creatine supplementation orally and a low-protein diet with restricted arginine and increased ornithine. --- Explanation: Confirms low-protein, arginine-restricted diet as a standard treatment.


MAXO:0000058

[PMID:24268530] [SUPPORT] Treatment regimens included various combinations/dosages of creatine-monohydrate, l-ornithine, sodium benzoate and protein/arginine restricted diets. --- Explanation: Confirms sodium benzoate as a component of treatment protocols.


MAXO:0000124

[PMID:37465909] [SUPPORT] the feasibility of screening, the low number of positive results, the relative ease of diagnosis, and the expected benefit of presymptomatic dietary therapy led to a recommendation from the Advisory Committee on Heritable Disorders in Newborns and Children to the Secretary of Health and Human Services that GAMT deficiency be added to the Recommended Uniform Screening Panel. This recommendation was accepted in January 2023. --- Explanation: Documents the policy decision to add GAMT deficiency to the RUSP.


MAXO:0000058

[PMID:19289269] [SUPPORT] This results in improvement of many of the symptoms, especially of the epileptic seizures and the abnormal movements. --- Explanation: Notes that treatment improves epileptic seizures, implying anticonvulsant management is part of care.


MAXO:0000079

[PMID:39006040] [SUPPORT] Premarital testing of neurogenetic diseases using whole-exome sequencing is probably a future direction, especially in populations with high consanguinity rates. --- Explanation: Supports genetic counseling and carrier testing, particularly in consanguineous populations.

[PMID:37465909] [SUPPORT] Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine biosynthesis due to pathogenic variants in the GAMT gene --- Explanation: Autosomal recessive inheritance necessitates genetic counseling for family planning.


MAXO:0001001

[PMID:35505663] [SUPPORT] Serial collection of blood demonstrated a marked early and sustained reduction of GAA with normalization of plasma creatine; urinary GAA levels also markedly declined. --- Explanation: Shows sustained biochemical correction in the gene therapy mouse model.

[PMID:35505663] [SUPPORT] The terminal time point demonstrated marked improvement in cerebral and myocardial creatine levels. In conjunction with the biochemical findings, treated mice gained weight to nearly match their wild-type littermates, while behavioral studies demonstrated resolution of abnormalities --- Explanation: Demonstrates improved cerebral/myocardial creatine and resolved behavioral phenotype with gene therapy.


HGNC.SYMBOL:GAMT pathogenic variants

[PMID:37465909] [SUPPORT] Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine biosynthesis due to pathogenic variants in the GAMT gene that lead to cerebral creatine deficiency and neurotoxic levels of guanidinoacetate. --- Explanation: Confirms pathogenic variants in GAMT as the cause.

[PMID:39006040] [SUPPORT] 23% of the affected cases were of consanguineous marriages, and 7% had affected relatives. --- Explanation: Quantifies consanguinity as a risk factor in the scoping review.

[PMID:39006040] [SUPPORT] Guanidinoacetate methyltransferase deficiency (GAMT) is an autosomal recessive inborn error of metabolism. A condition that results from a pathogenic variant in the GAMT gene that maps to 19p13.3. --- Explanation: Confirms the chromosomal location and autosomal recessive nature.


MONDO:0016218


MONDO:0016218

[PMID:24000328] [INDIRECT EVIDENCE] [SUPPORT] Molecular mimicry between sialylated lipooligosaccharide structures on the cell envelope of these bacteria and ganglioside epitopes on the human nerves that generates cross-reactive immune response results in autoimmune-driven nerve damage. --- Explanation: Demonstrates the molecular mimicry mechanism where C. jejuni lipooligosaccharides resemble nerve gangliosides, leading to cross-reactive antibodies that attack peripheral nerves.

[PMID:37108447] [INDIRECT EVIDENCE] [SUPPORT] The presence of specific anti-glycoconjugate antibodies indicates an underlying process of molecular mimicry and sometimes assists in the classification of these disorders. --- Explanation: Confirms that anti-ganglioside antibodies in GBS result from molecular mimicry and help classify disease subtypes.


MONDO:0016218

[PMID:10355667] [INDIRECT EVIDENCE] [PARTIAL] These data indicate that anti-ganglioside antibodies can diffuse into a desheathed nerve, bind to nodes of Ranvier and fix complement in vitro without resulting in any overt physiological deterioration of the nerve over 4-6 h. --- Explanation: Demonstrates that anti-ganglioside antibodies bind nodes of Ranvier and activate complement cascade, establishing the complement-mediated mechanism of nerve damage.

[PMID:8619548] [INDIRECT EVIDENCE] [SUPPORT] Many fibers had a rim of the complement activation marker C3d and the terminal complement complex neoantigen C5b-9 along the outer surface of the Schwann cells. --- Explanation: Immunocytochemistry evidence showing C3d and C5b-9 membrane attack complex deposition on Schwann cell surfaces in AIDP, confirming complement-mediated pathology.


MONDO:0016218

[PMID:37108447] [INDIRECT EVIDENCE] [SUPPORT] The immunological mechanisms, which include macrophage infiltration, inflammation and proliferation of Schwann cells, result in variable degrees of demyelination and axonal degeneration. --- Explanation: Describes macrophage infiltration as a key immunological mechanism leading to demyelination and axonal degeneration in immune-mediated neuropathies including GBS.

[PMID:8619548] [INDIRECT EVIDENCE] [SUPPORT] Vesicular degeneration was seen before the invasion of macrophages into the myelin, and was the predominant change in the subject with symptoms for 3 days. --- Explanation: Shows the temporal sequence of pathology in AIDP, with macrophage invasion into myelin following initial complement-mediated damage.


MONDO:1060171


MONDO:1060171

[PMID:41528563] [INDIRECT EVIDENCE] [PARTIAL] H3 K27-altered diffuse midline glioma (DMG) is a molecularly defined, highly aggressive tumor entity since the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). --- Explanation: This abstract defines H3 K27-altered DMG as a molecularly defined aggressive entity, supporting the disease context for this mutation-driven tumor.


MAXO:0000014


MAXO:0000058


HGNC.SYMBOL:H3F3A

[PMID:22286061] [SUPPORT] Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. --- Explanation: Identifies H3F3A mutations — including K27M and G34R/G34V — in 31% of pediatric GBM.


HGNC.SYMBOL:HIST1H3B/HIST1H3C

[PMID:24705254] [SUPPORT] nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration --- Explanation: Establishes that DIPG harbors K27M mutations in either H3.3 or H3.1 histone variants.


HGNC.SYMBOL:ACVR1

[PMID:24705254] [SUPPORT] uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs --- Explanation: Identifies ACVR1 as a recurrently mutated gene in DIPG, with activating mutations in 20% of cases.


HGNC.SYMBOL:TP53

[PMID:22286061] [SUPPORT] Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. --- Explanation: Reports high frequency of TP53 mutations in pediatric glioblastoma, particularly co-occurring with H3F3A mutations.


HGNC.SYMBOL:PPM1D


HGNC.SYMBOL:PDGFRA

[PMID:24705254] [SUPPORT] K27M-H3.3 with PDGFRA amplifications (OR = 8.0, p = 0.0127) --- Explanation: Reports significant co-occurrence of PDGFRA amplifications with H3.3 K27M mutations in DIPG.


HGNC.SYMBOL:EZHIP


MONDO:1060171

[PMID:35169084] [SUPPORT] Diffuse midline glioma(DMG), H3 K27M-mutant is an infiltrative midline --- Explanation: Abstract describes H3 K27M-mutant diffuse midline glioma as infiltrative and midline.


MONDO:0006244


MONDO:0006244

[PMID:40303293] [INDIRECT EVIDENCE] [PARTIAL] HER2-positive breast cancer, which accounts for approximately 15-20% of all breast cancers, is characterized by its aggressive recurrence, metastasis and reduced survival. --- Explanation: This abstract identifies HER2-positive breast cancer as a distinct, aggressive subtype, supporting the disease definition used here.


CHEBI:231601


NCIT:C38692


NCIT:C128799


NCIT:C77896


CHEBI:61397


HGNC.SYMBOL:ERBB2

[PMID:23628726] [PARTIAL] HER2 gene amplification is observed in about 15% of breast cancers. --- Explanation: Abstract reports HER2 amplification frequency in breast cancer.


HGNC.SYMBOL:PIK3CA


MONDO:0006244

[PMID:39806949] [PARTIAL] Invasive ductal carcinoma (IDC) is the most common type of breast cancer, --- Explanation: Abstract states that invasive ductal carcinoma is the most common breast cancer type.


MONDO:0005575


MONDO:0005575

[PMID:41361014] [INDIRECT EVIDENCE] [PARTIAL] Among 5545 patients, 144 (3.1%) had ERBB2 amp+ mCRC. --- Explanation: This abstract quantifies ERBB2-amplified metastatic colorectal cancer, supporting the existence of this molecular subgroup.


MAXO:0000058


MAXO:0000004


HGNC.SYMBOL:ERBB2 (HER2)


HGNC.SYMBOL:ERBB2 Activating Mutations


HGNC.SYMBOL:RAS/BRAF Wild-Type


MONDO:0005575

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


MONDO:0001056


MONDO:0001056

[PMID:41355925] [INDIRECT EVIDENCE] [PARTIAL] Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) represents a distinct molecular cancer subtype that is often associated with a poor prognosis. --- Explanation: This abstract identifies HER2-positive gastric cancer as a distinct molecular subtype, supporting the disease definition.


CHEBI:231601


NCIT:C128799


NCIT:C70792


CHEBI:45863


HGNC.SYMBOL:TP53


HGNC.SYMBOL:PIK3CA


MONDO:0001056

[PMID:40647518] [PARTIAL] with adenocarcinoma being the most  --- Explanation: Abstract notes adenocarcinoma as the predominant histologic type in a gastric cancer cohort.


MONDO:0032780

[PMID:30940925] [SUPPORT] All the patients have hypotonia (N = 13/13), and either intellectual disability (N = 12/13) or developmental delay --- Explanation: Hypotonia is present in 100% of HIDEA patients.


MONDO:0032780

[PMID:30940925] [SUPPORT] the common presenting features include strabismus (N = 11/13, 85%), epilepsy (N = 10/13, 77%), and central or obstructive sleep apnea --- Explanation: Central or obstructive sleep apnea occurs in most HIDEA patients.


MONDO:0032780

[PMID:30940925] [SUPPORT] All the patients have hypotonia (N = 13/13), and either intellectual disability (N = 12/13) or developmental delay --- Explanation: Global developmental delay is a core feature of the syndrome.


MONDO:0032780

[PMID:30940925] [SUPPORT] All the patients have hypotonia (N = 13/13), and either intellectual disability (N = 12/13) or developmental delay --- Explanation: Intellectual disability is present in 12 of 13 patients.


MONDO:0032780

[PMID:30940925] [SUPPORT] the common presenting features include strabismus (N = 11/13, 85%), epilepsy (N = 10/13, 77%), and central or obstructive sleep apnea --- Explanation: Epilepsy is present in 77% of HIDEA patients.


MONDO:0032780

[PMID:30940925] [SUPPORT] Some patients also show dysautonomia, including constipation (N = 6/13, 46%), recurrent hypothermia or hyperthermia (N = 4/13, 31%), and reduced sweating (N = 2/13, 15%) --- Explanation: Dysautonomia features including temperature dysregulation and constipation are present in subsets of HIDEA patients.


MONDO:0032780

[PMID:30940925] [SUPPORT] the common presenting features include strabismus (N = 11/13, 85%), epilepsy (N = 10/13, 77%) --- Explanation: Strabismus is a common feature of HIDEA syndrome.


MONDO:0032780

[PMID:30940925] [SUPPORT] All the patients with P4HTM gene variants have developmental delay or intellectual disability and visual abnormalities—such as strabismus, rotating eye movements, nystagmus, or cortical blindness --- Explanation: Visual abnormalities are part of the eye phenotype in HIDEA.


MONDO:0032780


MONDO:0032780

[PMID:30940925] [SUPPORT] Six patients (N = 6/13, 46%) have a body mass index (BMI) over 25 kg/m2 --- Explanation: Some HIDEA patients have elevated BMI/obesity.


MONDO:0032780

[PMID:30940925] [INDIRECT EVIDENCE] [SUPPORT] Hypoventilation, obstructive and central sleep apnea, and dysautonomia were identified as novel features associated with the phenotype. --- Explanation: The foundational HIDEA paper identified hypoventilation and central sleep apnea as core features.


MONDO:0032780

[PMID:30940925] [INDIRECT EVIDENCE] [SUPPORT] The muscle biopsy of patient 1 showed low activity of mitochondrial respiratory chain complex III. In addition, the muscle biopsy of patient 2 was suggestive of a mitochondrial, neurometabolic disease. --- Explanation: Evidence from muscle biopsies showing mitochondrial respiratory chain deficiency in some HIDEA patients.


MAXO:0000950


MAXO:0000058


MAXO:0000011


HGNC.SYMBOL:P4HTM

[PMID:30940925] [SUPPORT] Variant characterization demonstrates that the variants affect protein folding by yielding an insoluble protein product. --- Explanation: The study demonstrated that P4HTM variants cause loss of function through protein misfolding.

[PMID:25078763] [SUPPORT] Whole-genome sequencing of one affected individual pinpointed three genes with potentially protein damaging homozygous sequence changes within the predisposition locus transketolase (TKT), prolyl 4-hydroxylase transmembrane (P4HTM), and ubiquitin specific peptidase 4 (USP4). --- Explanation: Initial identification of P4HTM as a candidate gene for HIDEA syndrome in a Finnish kindred.


MONDO:0010150


MONDO:0010150

[PMID:25631445] [INDIRECT EVIDENCE] [SUPPORT] Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation --- Explanation: TCGA HNSCC abstract reports near-universal TP53 loss and CDKN2A inactivation in smoking-related tumors.


MAXO:0000004


MAXO:0000014


CHEBI:27899


NCIT:C1723


HGNC.SYMBOL:TP53


HGNC.SYMBOL:CDKN2A


HGNC.SYMBOL:PIK3CA


HGNC.SYMBOL:NOTCH1


HGNC.SYMBOL:EGFR


ECTO:6000029

[PMID:36414699] [PARTIAL] Besides tobacco and alcohol abuse, human papilloma virus (HPV) infection is an independent risk factor, particularly in oropharyngeal squamous cell carcinomas (OPSCC). --- Explanation: Identifies tobacco (and alcohol) as major risk factors for HNSCC.


ECTO:9000027

[PMID:39244563] [SUPPORT] Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. --- Explanation: Abstract reports alcohol increases risk for HPV-negative HNSCC.


MONDO:0010150

[PMID:36414699] [PARTIAL] Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer --- Explanation: Abstract explicitly names head and neck squamous cell carcinoma.


MONDO:0044926


MAXO:0000058


MAXO:0001017


NCBITaxon:333760

[PMID:37861207] [SUPPORT] HPV16 accounts for the majority of HPV positive oropharyngeal SCC cases. --- Explanation: Supports HPV16 predominance in HPV-positive oropharyngeal cancers.


MONDO:0044926

[PMID:36414699] [SUPPORT] Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer --- Explanation: Abstract explicitly names head and neck squamous cell carcinoma.


MONDO:0007698

[PMID:9020844] [SUPPORT] Limb anomalies include short first metacarpals of normal thickness, small distal phalanges of the thumbs, short middle phalanges of the fifth fingers --- Explanation: Short first metacarpals are a cardinal hand feature of HFGS.


MONDO:0007698

[PMID:9020844] [SUPPORT] small distal phalanges of the thumbs --- Explanation: Small distal phalanges of the thumbs are a typical hand feature.


MONDO:0007698

[PMID:9020844] [SUPPORT] the great toe is shorter due to a short first metatarsal and a small, pointed distal phalanx --- Explanation: Short great toe from short first metatarsal is the hallmark foot feature.


MONDO:0007698

[PMID:9020844] [SUPPORT] Uterine anomalies are common in females with HFG, and typically involve a partially divided (bicornuate) or completely divided (didelphic) uterus, representing defects of Müllerian duct fusion --- Explanation: Mullerian duct fusion defects causing bicornuate or didelphic uterus are common in affected females.


MONDO:0007698

[PMID:9020844] [SUPPORT] affected males may have hypospadias (ventrally misplaced urethral opening) of variable severity --- Explanation: Hypospadias of variable severity is a feature in affected males.


MONDO:0007698

[PMID:9020844] [INDIRECT EVIDENCE] [SUPPORT] the identification of a HOXA13 nonsense mutation in a family with hand-foot-genital syndrome --- Explanation: Identifies HOXA13 as the causative gene for HFGS.

[PMID:10839976] [INDIRECT EVIDENCE] [SUPPORT] Mutations in HOXA13 can therefore cause more-severe limb abnormalities than previously suspected and may act by more than one mechanism --- Explanation: Demonstrates wider severity spectrum than initially recognized, through multiple pathogenic mechanisms.

[PMID:10839976] [INDIRECT EVIDENCE] [SUPPORT] nonsense mutations truncating the encoded protein N-terminal to or within the homeodomain produce typical limb and genitourinary abnormalities --- Explanation: Establishes that truncating mutations in the homeodomain cause the typical HFGS phenotype.


MONDO:0007698


MONDO:0007698

[PMID:9020844] [INDIRECT EVIDENCE] [SUPPORT] the identification of a HOXA13 nonsense mutation in a family with hand-foot-genital syndrome --- Explanation: HOXA13 mutations underlie both limb and genitourinary features of HFGS.


MAXO:0000004


MAXO:0000079


HGNC.SYMBOL:HOXA13 Mutations

[PMID:9020844] [SUPPORT] a HOXA13 nonsense mutation in a family with hand-foot-genital syndrome. The mutation converts a highly conserved tryptophan residue in the homeodomain to a stop codon --- Explanation: Identifies the first HOXA13 nonsense mutation causing HFGS.

[PMID:10839976] [SUPPORT] an expansion of an N-terminal polyalanine tract produces a similar phenotype --- Explanation: Polyalanine tract expansion is an alternative mutation mechanism in HFGS.

[PMID:19591980] [SUPPORT] Affected members of a family with HFGS showed a novel expansion of the third polyalanine tract of HOXA13, inserting 10 alanines in-frame --- Explanation: Specific polyalanine expansion of 10 residues in the third tract causes HFGS.

[PMID:19591980] [SUPPORT] The cause of uterovaginal septa without hand and foot symptoms differs from true HFGS --- Explanation: Isolated uterine septa without limb involvement are not caused by HOXA13 mutations, clarifying the diagnostic boundary.


MONDO:0005779

[DOI:10.1186/s12929-023-00908-4] [SUPPORT] characterized by typical manifestations such as oral herpes and rashes on the hands and feet --- Explanation: Confirms vesicular rash on hands and feet as a hallmark feature.


MONDO:0005779

[PMID:36284392] [SUPPORT] Hand, foot, and mouth disease is characterized by a painful oral enanthem and asymptomatic exanthem on the palms and soles. --- Explanation: Confirms exanthem on palms and soles as a characteristic feature.


MONDO:0005779

[PMID:36226004] [SUPPORT] serotyping identified Coxsackievirus A16 (CV A16) in 83%, Coxsackievirus A6 (CV A6) in 17% --- Explanation: CV-A6, known to cause onychomadesis, was identified in 17% of cases in this Indian cohort.


MONDO:0005779

[DOI:10.1186/s12929-023-00908-4] [SUPPORT] characterized by typical manifestations such as oral herpes and rashes on the hands and feet --- Explanation: Confirms oral lesions as a hallmark feature of HFMD.


MONDO:0005779

[PMID:36284392] [SUPPORT] Hand, foot, and mouth disease is characterized by a painful oral enanthem and asymptomatic exanthem on the palms and soles. --- Explanation: Painful oral enanthem causes dysphagia and drooling in young children.


MONDO:0005779

[PMID:36284392] [SUPPORT] Hand, foot, and mouth disease is characterized by a painful oral enanthem and asymptomatic exanthem on the palms and soles. --- Explanation: Painful oral enanthem leads to reduced oral intake and poor appetite.


MONDO:0005779

[PMID:36284392] [SUPPORT] Hand, foot, and mouth disease is characterized by a painful oral enanthem and asymptomatic exanthem on the palms and soles. --- Explanation: Painful oral enanthem includes pharyngeal involvement causing sore throat.


MONDO:0005779

[PMID:36284392] [SUPPORT] the disease is usually benign and resolves in 7 to10 days without sequelae. Given the self-limited nature of most cases, treatment is mainly symptomatic and supportive. --- Explanation: Fever is part of the self-limited illness requiring symptomatic treatment.


MONDO:0005779

[PMID:36284392] [SUPPORT] the disease is usually benign and resolves in 7 to10 days without sequelae. --- Explanation: Malaise is part of the prodromal and acute symptomatology.


MONDO:0005779

[PMID:36284392] [SUPPORT] Children younger than 5 years are most commonly affected. --- Explanation: Irritability is a common presentation in young children with painful oral lesions.


MONDO:0005779

[PMID:10029254] [SUPPORT] Seven children with encephalitis and five with aseptic meningitis caused by Enterovirus 71 were seen at Otsu Municipal Hospital during the summer of 1997. --- Explanation: Directly documents aseptic meningitis occurring in children with EV-A71-associated HFMD-spectrum illness.


MONDO:0005779

[DOI:10.3389/fimmu.2024.1374447] [SUPPORT] IP-10 and TNF-α treatments exacerbated clinical symptoms, mortality and pathological changes in the brain of CV-A16-infected mice, but Anti-IP-10 and Anti-TNF-α treatments alleviated these changes. --- Explanation: Demonstrates neuroinflammatory mechanisms underlying brainstem encephalitis in an animal model.


MONDO:0005779

[DOI:10.1186/s12929-023-00908-4] [SUPPORT] the disease may be associated with potentially fatal neurological complications --- Explanation: Acute flaccid paralysis is among the severe neurological complications of EV-A71 HFMD.


MONDO:0005779

[DOI:10.1186/s12929-023-00908-4] [SUPPORT] the disease may be associated with potentially fatal neurological complications --- Explanation: Seizures are part of the spectrum of neurological complications in severe HFMD.


MONDO:0005779

[PMID:36284392] [SUPPORT] Circulatory failure secondary to myocardial impairment and neurogenic pulmonary edema secondary to brainstem damage are the main causes of death. --- Explanation: Confirms neurogenic pulmonary edema as a major cause of death in severe HFMD.


MONDO:0005779

[PMID:36284392] [SUPPORT] Circulatory failure secondary to myocardial impairment and neurogenic pulmonary edema secondary to brainstem damage are the main causes of death. --- Explanation: Confirms myocardial impairment as a contributor to mortality in severe HFMD.


MONDO:0005779

[PMID:36284392] [SUPPORT] Hand, foot, and mouth disease is characterized by a painful oral enanthem and asymptomatic exanthem on the palms and soles. --- Explanation: Painful oral enanthem causes reduced fluid intake, leading to dehydration in young children.


MONDO:0005779

[DOI:10.1371/journal.ppat.1012022] [INDIRECT EVIDENCE] [SUPPORT] SCARB2 is highly concentrated in lysosomes and late endosomes, where it is likely to trigger acid-dependent uncoating of virions, the critical final step of the entry process. --- Explanation: Demonstrates that SCARB2 acts intracellularly for uncoating rather than as a cell-surface receptor.

[DOI:10.1371/journal.ppat.1012022] [INDIRECT EVIDENCE] [SUPPORT] virus attachment to these cells requires only PSGL-1 --- Explanation: Shows PSGL-1 is the primary attachment receptor on lymphocytes.


MONDO:0005779


MONDO:0005779

[DOI:10.1186/s12929-023-00908-4] [INDIRECT EVIDENCE] [SUPPORT] Enteroviruses are highly contagious and have a predilection for the nervous system, particularly in child populations, which contributes to the ongoing outbreak. --- Explanation: Supports systemic dissemination and neurotropism of enteroviruses following initial infection.

[DOI:10.3390/ijms25115688] [INDIRECT EVIDENCE] [SUPPORT] Enterovirus A71 (EV-A71) is a major pathogen causing hand, foot, and mouth disease (HFMD) in children worldwide. It can lead to severe gastrointestinal, pulmonary, and neurological complications. --- Explanation: Multi-system complications (gastrointestinal, pulmonary, neurological) confirm systemic viral dissemination beyond the initial mucosal site.


MONDO:0005779

[DOI:10.1186/s12929-023-00908-4] [INDIRECT EVIDENCE] [SUPPORT] characterized by typical manifestations such as oral herpes and rashes on the hands and feet. These symptoms typically resolve spontaneously within a few days without complications. --- Explanation: Supports mucocutaneous tropism as the hallmark clinical manifestation.


MONDO:0005779

[DOI:10.3390/ijms25115688] [INDIRECT EVIDENCE] [SUPPORT] The innate immune system, which rapidly detects pathogens via pathogen-associated molecular patterns or pathogen-encoded effectors, serves as the first defensive line against EV-A71 infection. Concurrently, the virus has developed various sophisticated strategies to evade host antiviral responses and establish productive infection. --- Explanation: Reviews the interplay between innate immune sensing and EV-A71 immune evasion strategies.


MONDO:0005779

[DOI:10.3389/fimmu.2024.1374447] [INDIRECT EVIDENCE] [SUPPORT] the expression levels of Claudin5, Occludin, ZO-1 and VE-Cadherin were notably decreased in CV-A16-infected HUVECs, but these indicators were restored in CV-A16-infected HUVECs with Eldelumab treatment --- Explanation: Demonstrates IP-10-mediated BBB tight junction protein loss during CV-A16 infection.

[DOI:10.3389/fimmu.2024.1374447] [INDIRECT EVIDENCE] [SUPPORT] IP-10 and TNF-α were observed to reduce junctional complexes and enhance virus entry into the CNS --- Explanation: Confirms the IP-10/TNF-alpha axis as a mechanism of BBB disruption facilitating neuroinvasion.


MONDO:0005779

[DOI:10.3389/fimmu.2024.1374447] [INDIRECT EVIDENCE] [SUPPORT] Taken together, this study provides the first evidence that CV-A16 activates the IP-10/TNF-α regulatory axis to cause BBB damage and accelerate the formation of neuroinflammation in infected hosts --- Explanation: Supports inflammatory brain injury as a core CNS event following enteroviral neuroinvasion.


MONDO:0005779

[PMID:11826236] [INDIRECT EVIDENCE] [SUPPORT] Magnetic resonance imaging revealed that all 5 infants had brainstem lesions. --- Explanation: Provides direct human clinical evidence of brainstem structural injury in fulminant EV71 infection.


MONDO:0005779

[PMID:28647185] [INDIRECT EVIDENCE] [SUPPORT] The plasma norepinephrine level of severe group was significantly higher than the mild group in children with EV71 infection in HFMD (P < 0.05) --- Explanation: Demonstrates elevated catecholamine levels in severe EV71 HFMD.


MONDO:0005779

[DOI:10.1002/pmic.202200362] [INDIRECT EVIDENCE] [SUPPORT] The upregulated proteins are mainly involved in metabolic process, especially in the glycolysis pathway. Alpha-enolase (ENO1) protein was found to increase with temporal dependence following EV71 infection. --- Explanation: Demonstrates EV-A71-induced glycolytic reprogramming via ENO1 upregulation.

[DOI:10.1002/pmic.202200362] [INDIRECT EVIDENCE] [SUPPORT] EV71 infection was inhibited by depleting ENO1 or using DCA --- Explanation: Shows glycolysis inhibition as a potential host-directed therapeutic strategy.


MAXO:0000950

[DOI:10.1186/s12929-023-00908-4] [SUPPORT] These symptoms typically resolve spontaneously within a few days without complications. --- Explanation: Supports supportive care as the mainstay of treatment given self-limiting nature.


MAXO:0000058

[PMID:31573162] [SUPPORT] Treatment is supportive and directed toward hydration and pain relief as needed with acetaminophen or ibuprofen. --- Explanation: Directly supports acetaminophen or ibuprofen for symptomatic treatment of HFMD.


MAXO:0001017

[DOI:10.1186/s12929-023-00908-4] [SUPPORT] An inactivated Enterovirus A71 (EV-A71) vaccine that has been approved by the China Food and Drug Administration (CFDA) has been shown to provide a high level of protection against EV-A71-related HFMD. --- Explanation: Confirms the efficacy and regulatory approval of the EV-A71 vaccine.

[DOI:10.1186/s12985-023-02169-x] [SUPPORT] There was a significant reduction in the number and proportion of EV-A71 cases after 2016, from 1713 cases (13.60%) in 2013–2015 to 150 cases (1.83%) in 2017–2019. --- Explanation: Demonstrates real-world impact of EV-A71 vaccine on reducing EV-A71-associated HFMD.


HGNC.SYMBOL:SCARB2 polymorphisms and disease severity

[DOI:10.17305/bb.2023.8948] [SUPPORT] SCARB2 polymorphisms (rs74719289, rs3733255 and rs17001551) are related to the severity of EV71 infection (A vs G: OR 0.330; 95% CI 0.115 - 0.947; T vs C: OR 0.336; 95% CI 0.118 - 0.958; and A vs G: OR 0.378; 95% CI 0.145 - 0.984) --- Explanation: Demonstrates protective SCARB2 SNPs reducing risk of severe EV-A71 HFMD.


NCBITaxon:31704

[DOI:10.1186/s12985-023-02169-x] [SUPPORT] The proportion of CV-A16 cases decreased from 13.96% in 2013–2015 to 10.84% in 2017–2019 and then to 4.54% in 2020–2022. --- Explanation: Confirms CV-A16 as a significant HFMD pathogen, though its proportion has been declining.


NCBITaxon:39054

[DOI:10.1186/s12929-023-00908-4] [SUPPORT] HFMD has been linked to severe cardiopulmonary complications, as well as severe neurological sequelae that can be observed during follow-up. --- Explanation: Supports EV-A71 as the primary agent associated with severe neurological and cardiopulmonary complications of HFMD.


NCBITaxon:86107

[DOI:10.1186/s12985-023-02169-x] [SUPPORT] Other (non-EV-A71 and non-CV-A16) serotypes accounted for 95.45% during 2020–2022, with CV-A6 accounting for 50.39% and CV-A10 accounting for 10.81%. --- Explanation: Demonstrates CV-A6 as the dominant HFMD pathogen in recent years.

[DOI:10.2196/59604] [SUPPORT] CV-A6 emerged as the major pathogen for HFMD in 2022 (203/732, 27.73%) and 2023 (262/708, 37.01%). --- Explanation: Confirms CV-A6 as the leading HFMD pathogen in recent Chinese surveillance.


MONDO:0014196

[PMID:26937548] [SUPPORT] HPE spectrum disorder, resulting from failed or incomplete forebrain division early in gestation, includes alobar, semilobar, or lobar HPE. --- Explanation: Describes holoprosencephaly as a core feature with variable severity.


MONDO:0014196

[PMID:26937548] [SUPPORT] Ectrodactyly spectrum disorders are unilateral or bilateral malformations of the hands and/or feet characterized by a median cleft of hand or foot due to absence of the longitudinal central rays --- Explanation: Describes ectrodactyly as the second core feature.


MONDO:0014196

[PMID:26937548] [SUPPORT] HPE spectrum disorder, resulting from failed or incomplete forebrain division early in gestation, includes alobar, semilobar, or lobar HPE. --- Explanation: Corpus callosum agenesis is part of the midline brain malformation spectrum in Hartsfield syndrome.


MONDO:0014196

[PMID:26937548] [SUPPORT] neurologic issues (developmental delay, spasticity, seizures, hypothalamic dysfunction) --- Explanation: Seizures are listed among the neurologic manifestations.


MONDO:0014196

[PMID:26937548] [SUPPORT] neurologic issues (developmental delay, spasticity, seizures, hypothalamic dysfunction) --- Explanation: Developmental delay is listed among neurologic manifestations.


MONDO:0014196

[PMID:26937548] [SUPPORT] endocrine issues (hypogonadotropic hypogonadism and central insipidus diabetes) are common. --- Explanation: Hypogonadotropic hypogonadism is documented as a common endocrine feature.


MONDO:0014196

[PMID:26937548] [SUPPORT] Cleft lip/palate surgical repair is performed under the direction of a craniofacial team. --- Explanation: Cleft lip/palate is noted as requiring surgical management.


MONDO:0014196

[PMID:26937548] [INDIRECT EVIDENCE] [SUPPORT] FGFR1-related Hartsfield syndrome comprises two core features: holoprosencephaly (HPE) spectrum disorder and ectrodactyly spectrum disorder. --- Explanation: Establishes holoprosencephaly as one of the two core features resulting from FGFR1 disruption.


MONDO:0014196


MONDO:0014196

[PMID:26937548] [INDIRECT EVIDENCE] [SUPPORT] FGFR1-related Hartsfield syndrome comprises two core features: holoprosencephaly (HPE) spectrum disorder and ectrodactyly spectrum disorder. --- Explanation: Establishes ectrodactyly as the second core feature resulting from FGFR1 disruption of limb bud patterning.


MAXO:0000058

[PMID:26937548] [SUPPORT] Medically refractory epilepsy typically requires multiple anti-seizure medications. --- Explanation: Confirms need for pharmacological seizure management.


MAXO:0000004

[PMID:26937548] [SUPPORT] Cleft lip/palate surgical repair is performed under the direction of a craniofacial team. --- Explanation: Surgical repair of cleft lip/palate is a standard management approach.


MAXO:0000950

[PMID:26937548] [SUPPORT] Developmental delay is managed with an emphasis on early intervention and an individualized education plan and therapies as needed. --- Explanation: Early intervention is recommended for developmental delay management.


hgnc:3688

[PMID:26937548] [SUPPORT] The diagnosis of FGFR1-related Hartsfield syndrome is established in a proband with suggestive findings and either an FGFR1 heterozygous pathogenic variant (in those with autosomal dominant inheritance) or FGFR1 biallelic pathogenic variants (in those with autosomal recessive inheritance) identified by molecular genetic testing. --- Explanation: Establishes FGFR1 as the causative gene with both AD and AR patterns.


MONDO:0014196

[PMID:26937548] [SUPPORT] FGFR1-related Hartsfield syndrome is typically an autosomal dominant (AD) disorder. --- Explanation: GeneReviews confirms autosomal dominant as the typical inheritance pattern.


MONDO:0007699

[PMID:35235282] [SUPPORT] Signs and symptoms include fatigue, weight gain, dry skin, constipation, and cold intolerance. --- Explanation: Hashimoto-associated hypothyroidism commonly presents with fatigue.


MONDO:0007699

[PMID:35235282] [SUPPORT] Signs and symptoms include fatigue, weight gain, dry skin, constipation, and cold intolerance. --- Explanation: Weight gain is a common hypothyroid symptom in Hashimoto's thyroiditis.


MONDO:0007699

[PMID:35235282] [SUPPORT] Signs and symptoms include fatigue, weight gain, dry skin, constipation, and cold intolerance. --- Explanation: Constipation is a recognized symptom in hypothyroid states.


MONDO:0007699

[PMID:35235282] [SUPPORT] Signs and symptoms include fatigue, weight gain, dry skin, constipation, and cold intolerance. --- Explanation: Dry skin is a common dermatologic manifestation of hypothyroidism.


MONDO:0007699

[PMID:35235282] [SUPPORT] Signs and symptoms include fatigue, weight gain, dry skin, constipation, and cold intolerance. --- Explanation: Cold intolerance is a common symptom of hypothyroidism in Hashimoto's thyroiditis.


MONDO:0007699

[PMID:38731922] [PARTIAL] Hashimoto's thyroiditis (HT) is generally characterized by the presence of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration of lymphocytes in the thyroid. --- Explanation: Goiter develops due to lymphocytic infiltration and inflammatory enlargement of the thyroid gland.


MONDO:0007699

[PMID:23744563] [PARTIAL] The most common presenting symptoms may include anxiety, negative mood, depression, dry skin, cold intolerance, puffy eyes, muscle cramps and fatigue, deep voice, constipation, slow thinking and poor memory. --- Explanation: Depression is reported among common presenting symptoms in Hashimoto's thyroiditis.


MONDO:0007699

[PMID:39003267] [INDIRECT EVIDENCE] [PARTIAL] We identify damaged antigen-presenting TFCs with upregulated CD74 and MIF expression in thyroid samples from AITD patients. --- Explanation: Spatial transcriptomics demonstrates that thyroid follicular cells actively participate in autoimmune destruction by presenting antigens via CD74/MIF upregulation.

[PMID:38731922] [INDIRECT EVIDENCE] [PARTIAL] Hashimoto's thyroiditis (HT) is generally characterized by the presence of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration of lymphocytes in the thyroid. --- Explanation: Confirms the characteristic antibody profile and lymphocytic infiltration pattern in Hashimoto's thyroiditis.

[PMID:40535343] [INDIRECT EVIDENCE] [PARTIAL] Through this review, we aim to establish mechanistic connections between ICI pharmacodynamics and thyroid tissue immunopathology. --- Explanation: ICI-induced thyroiditis provides a mechanistic model that mirrors the autoimmune destruction seen in spontaneous Hashimoto's thyroiditis.


MONDO:0007699


MONDO:0007699

[PMID:38731922] [INDIRECT EVIDENCE] [PARTIAL] Hashimoto's thyroiditis (HT) is generally characterized by the presence of thyroid peroxidase and thyroglobulin antibodies, with a concomitant infiltration of lymphocytes in the thyroid. --- Explanation: Lymphocytic infiltration is a defining histological feature of Hashimoto's thyroiditis.

[PMID:39003267] [INDIRECT EVIDENCE] [PARTIAL] Here, we use spatial transcriptomics to explore the molecular architecture, heterogeneity and location of different cells present in the thyroid tissue, including thyroid follicular cells (TFCs), stromal cells such as fibroblasts, endothelial cells, and thyroid infiltrating lymphocytes. --- Explanation: Spatial analysis confirms the presence and organization of infiltrating lymphocytes in the thyroid microenvironment.


MONDO:0007699

[PMID:38731922] [INDIRECT EVIDENCE] [PARTIAL] Due to the progressive destruction of cells, AITD can lead to subclinical or overt hypothyroidism. --- Explanation: Progressive thyroid destruction in Hashimoto's thyroiditis results in hypothyroidism through loss of hormone-producing cells.


HGNC.SYMBOL:HLA-DR3

[PMID:26235382] [SUPPORT] AITD susceptibility genes can be categorized as either thyroid specific (Tg, TSHR) or immune-modulating (FOXP3, CD25, CD40, CTLA-4, HLA), with HLA-DR3 carrying the highest risk. --- Explanation: HLA-DR3 is identified as a major immune-genetic risk factor in autoimmune thyroid disease, including HT.


HGNC.SYMBOL:HLA-DR4

[PMID:29174716] [PARTIAL] 'DRB1*04+GG' (PL: p=0.003; HT: p=0.008) --- Explanation: HLA-DRB1*04 contributes to susceptibility in combination with CTLA4 risk genotype in HT cohorts.


HGNC.SYMBOL:CTLA4

[PMID:41498152] [SUPPORT] CTLA4 polymorphisms were associated with an elevated risk of a thyroid disease and poorer glycemic control; --- Explanation: CTLA4 polymorphisms are associated with increased autoimmune thyroid disease risk.


HGNC.SYMBOL:PTPN22

[PMID:33103521] [SUPPORT] This meta-analysis showed that the PTPN22 R620W polymorphism is associated with the risk of GD and HT in the overall study population. --- Explanation: Meta-analysis supports PTPN22 as a susceptibility locus for Hashimoto's thyroiditis.


MONDO:0005252

[PMID:40892534] [PARTIAL] Myocardial fibrosis and its surrogate changes in LV structure and geometry lead to functional impairments such as increased diastolic stiffness and elevated filling pressures and are associated with reduced exercise tolerance and poor prognosis in patients with HFpEF. --- Explanation: Dyspnea results from elevated filling pressures and reduced exercise tolerance caused by diastolic dysfunction and myocardial fibrosis in heart failure.


MONDO:0005252

[PMID:36769308] [PARTIAL] The pathophysiology between the heart and the kidneys is bidirectional. Common mechanisms leading to the dysfunction of these organs result in a vicious cycle of cardiorenal deterioration. --- Explanation: Peripheral edema results from the cardiorenal interaction where reduced cardiac output leads to renal dysfunction, sodium retention, and fluid accumulation in peripheral tissues.


MONDO:0005252


MONDO:0005252

[PMID:40892534] [SUPPORT] Myocardial fibrosis and its surrogate changes in LV structure and geometry lead to functional impairments such as increased diastolic stiffness and elevated filling pressures and are associated with reduced exercise tolerance and poor prognosis in patients with HFpEF. --- Explanation: Exercise intolerance in heart failure is directly caused by increased diastolic stiffness and elevated filling pressures from myocardial fibrosis and structural remodeling.


MONDO:0005252

[PMID:38636927] [PARTIAL] In the isoproterenol (ISO)-induced animal model, it is often accompanied by myocardial hypertrophy, fibrosis, and inflammation. --- Explanation: Cardiomegaly in heart failure results from myocardial hypertrophy, which is a structural adaptation to increased workload and sympathetic activation.


MONDO:0005252

[PMID:33432192] [INDIRECT EVIDENCE] [PARTIAL] Heart failure with preserved ejection fraction (HFpEF) affects half of all patients with heart failure worldwide, is increasing in prevalence, confers substantial morbidity and mortality, and has very few effective treatments. --- Explanation: This review discusses the prevalence and severity of HFpEF, a form characterized by diastolic dysfunction rather than systolic dysfunction, demonstrating the importance of both contractile mechanisms in heart failure.

[PMID:40892534] [INDIRECT EVIDENCE] [SUPPORT] Myocardial fibrosis and its surrogate changes in LV structure and geometry lead to functional impairments such as increased diastolic stiffness and elevated filling pressures and are associated with reduced exercise tolerance and poor prognosis in patients with HFpEF. --- Explanation: This demonstrates how structural changes lead to diastolic dysfunction and impaired cardiac output, supporting the mechanism of contractile dysfunction in heart failure.


MONDO:0005252

[PMID:37895150] [INDIRECT EVIDENCE] [SUPPORT] In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the arginine vasopressin (AVP) system, are activated to various degrees producing often-observed tachycardia and concomitant increased systemic vascular resistance. --- Explanation: This directly confirms the activation of neurohormonal systems (RAAS and SNS) in heart failure patients, supporting the compensatory mechanism described.

[PMID:37895150] [INDIRECT EVIDENCE] [SUPPORT] Furthermore, sustained neurohormonal activation plays a key role in the progression of HF and may be responsible for the pathogenetic mechanisms leading to the perpetuation of the pathophysiology and worsening of the HF signs and symptoms. --- Explanation: This supports the concept that while initially compensatory, sustained neurohormonal activation leads to maladaptive effects and disease progression.

[PMID:33432192] [INDIRECT EVIDENCE] [NO_EVIDENCE] This multiorgan involvement makes HFpEF difficult to model in experimental animals because the condition is not simply cardiac hypertrophy and hypertension with abnormal myocardial relaxation. --- Explanation: This highlights the complexity of neurohormonal effects extending beyond the heart to multiple organ systems in heart failure pathophysiology.


MONDO:0005252

[PMID:40892534] [INDIRECT EVIDENCE] [SUPPORT] Comorbidities such as hypertension, obesity, or diabetes are present in many HFpEF patients and are hypothesized to contribute to adverse cardiac remodelling and myocardial fibrosis through a variety of haemodynamic and metabolic impairments, with nearly half of all HFpEF patients exhibiting left ventricular (LV) hypertrophy or concentric remodelling. --- Explanation: This demonstrates the prevalence and mechanisms of ventricular remodeling including hypertrophy and fibrosis in heart failure patients, particularly in HFpEF.

[PMID:38636927] [INDIRECT EVIDENCE] [PARTIAL] Heart failure is usually accompanied by activation of the sympathetic nerve, and excessive activation of the sympathetic nerve promotes cardiac remodeling and cardiac dysfunction. In the isoproterenol (ISO)-induced animal model, it is often accompanied by myocardial hypertrophy, fibrosis, and inflammation. --- Explanation: This confirms that cardiac remodeling, including hypertrophy and fibrosis, is a key pathophysiological mechanism promoted by sympathetic activation in heart failure.

[PMID:38636927] [INDIRECT EVIDENCE] [PARTIAL] Lilrb4a alleviates cardiac dysfunction and ISO-induced arrhythmogenic remodeling associated with cardiac fibrosis and inflammation through the regulation of NF-κB signaling and MAPK signaling activation. --- Explanation: This identifies specific signaling pathways (NF-κB and MAPK) involved in cardiac remodeling and fibrosis, demonstrating the molecular mechanisms underlying structural changes.


HGNC.SYMBOL:TTN


HGNC.SYMBOL:MYH7


HGNC.SYMBOL:LMNA


MONDO:0006507

[PMID:37168645] [PARTIAL] One of the most serious clinical characteristics associated with early-onset iron overload is liver disease with eventual cirrhosis --- Explanation: Liver involvement early in disease course leads to enlargement and progression to cirrhosis.