MONDO:0005015

[PMID:29939616] [INDIRECT EVIDENCE] [SUPPORT] All tissues with insulin receptors can become insulin resistant, but the tissues that primarily drive insulin resistance are the liver, skeletal muscle, and adipose tissue. --- Explanation: This supports tissue-level insulin resistance in key metabolic organs.

[PMID:15832489] [INDIRECT EVIDENCE] [SUPPORT] The pathophysiology, which involves both an insulin secretion defect and resistance to insulin, needs further clarification in pediatric studies. --- Explanation: This supports that insulin resistance is a central event in youth-onset type 2 diabetes pathophysiology.

[PMID:26621825] [INDIRECT EVIDENCE] [SUPPORT] showed a reduced peripheral effect of insulin in subjects with 'non-insulin-dependent' diabetes (insulin resistance). --- Explanation: This supports reduced peripheral insulin effect as a defining mechanistic event in type 2 diabetes.


MONDO:0005015


MONDO:0005015

[PMID:38831203] [INDIRECT EVIDENCE] [PARTIAL] Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge. --- Explanation: This supports clinical relevance of incretin pathway dysfunction in diabetes pathophysiology.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] Type 2 Diabetes Mellitus (T2DM), one of the most common metabolic disorders, is caused by a combination of two primary factors: defective insulin secretion by pancreatic β-cells and the inability of insulin-sensitive tissues to respond appropriately to insulin. --- Explanation: This directly supports beta-cell secretion defects as a primary diabetes mechanism.

[PMID:37035220] [INDIRECT EVIDENCE] [SUPPORT] Insulin resistance and pancreatic β-cell dysfunction are major pathological mechanisms implicated in the development and progression of type 2 diabetes (T2D). --- Explanation: This supports beta-cell dysfunction as a major pathological mechanism in diabetes progression.

[PMID:39742220] [INDIRECT EVIDENCE] [SUPPORT] The pathophysiology of DM is complex, involving insulin resistance, β-cell dysfunction, and associated cardiovascular complications including diabetic cardiomyopathy (DCM) and cardiovascular autonomic neuropathy (CAN). --- Explanation: This provides additional recent support that beta-cell dysfunction is a core component of diabetes pathophysiology.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] On the other hand, IR contributes to increased glucose production in the liver and decreased glucose uptake both in the muscle, liver and adipose tissue. --- Explanation: This supports increased hepatic glucose output as a distinct insulin-resistance-driven event.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] On the other hand, IR contributes to increased glucose production in the liver and decreased glucose uptake both in the muscle, liver and adipose tissue. --- Explanation: This supports reduced peripheral glucose uptake as a distinct insulin-resistance-driven event.


MONDO:0005015

[PMID:41675641] [INDIRECT EVIDENCE] [PARTIAL] KEY FINDINGS: T5DM involves loss of insulin and glucagon alongside exocrine pancreatic insufficiency, malnutrition, and significant glycaemic variability. --- Explanation: This review supports endocrine hormone loss in a pancreatogenic framing that overlaps with current T5DM discussions.


MONDO:0005015

[PMID:41675641] [INDIRECT EVIDENCE] [PARTIAL] KEY FINDINGS: T5DM involves loss of insulin and glucagon alongside exocrine pancreatic insufficiency, malnutrition, and significant glycaemic variability. --- Explanation: This review supports exocrine insufficiency in a pancreatogenic framing that overlaps with current T5DM discussions.


MONDO:0005015

[PMID:33970586] [INDIRECT EVIDENCE] [SUPPORT] Type 1 diabetes is defined as a state of hyperglycemia due to insulin deficiency caused by autoimmune pancreatic beta-cell destruction. --- Explanation: This supports absolute insulin deficiency as a direct driver of hyperglycemia in autoimmune diabetes pathways.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] In the case of β-cell dysfunction, insulin secretion is reduced, limiting the body’s capacity to maintain physiological glucose levels. --- Explanation: This supports relative insulin deficiency as a direct cause of persistent hyperglycemia.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] According to the World Health Organization (WHO) diabetes mellitus is a chronic, metabolic disease characterized by elevated levels of blood glucose, which leads over time to damage to the heart, vasculature, eyes, kidneys and nerves. --- Explanation: This supports chronic hyperglycemia as a central upstream driver of multiorgan diabetic complications.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] The increase in O2− production activates the five major pathways involved in the pathogenesis of diabetes complications: enhancement of the polyol pathway, increased formation of advanced glycation end products (AGEs), increased expression of AGEs receptor and its activating ligands, activation of protein kinase C (PKC) isoforms, and overactivity of the hexosamine pathway [55,56,57]. --- Explanation: This supports oxidative stress as a distinct hyperglycemia-driven complication step.

[PMID:28460155] [INDIRECT EVIDENCE] [SUPPORT] Oxidative stress has been considered as a major hallmark for the pathogenesis and development of type 2 diabetes mellitus (T2DM) --- Explanation: This supports oxidative stress as a major mechanistic hallmark in type 2 diabetes progression.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] The increase in O2− production activates the five major pathways involved in the pathogenesis of diabetes complications: enhancement of the polyol pathway, increased formation of advanced glycation end products (AGEs), increased expression of AGEs receptor and its activating ligands, activation of protein kinase C (PKC) isoforms, and overactivity of the hexosamine pathway [55,56,57]. --- Explanation: This supports AGE-RAGE pathway activation as a distinct glycation-linked injury mechanism.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] Endothelium plays an important role in the regulation of vascular tone and structure through a balanced release of endothelial-derived relaxing and contracting factors. This balance is altered in T2DM leading to alteration of the physicochemical properties of the vascular wall via endothelial dysfunction, oxidative stress, platelet hyperreactivity, and inflammation [240,241]. --- Explanation: This supports endothelial dysfunction as a distinct intermediate event linking hyperglycemia to vascular complications.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] Endothelium plays an important role in the regulation of vascular tone and structure through a balanced release of endothelial-derived relaxing and contracting factors. This balance is altered in T2DM leading to alteration of the physicochemical properties of the vascular wall via endothelial dysfunction, oxidative stress, platelet hyperreactivity, and inflammation [240,241]. --- Explanation: This supports vascular inflammation as a distinct event in diabetic vasculopathy.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] T2DM leads to a two- to four-fold increase in the mortality rate of adults from heart disease and stroke and is associated with both micro- and macro-vascular complications, the latter consisting of accelerated atherosclerosis leading to severe peripheral vascular disease, premature coronary artery disease (CAD) and increased risk of cerebrovascular diseases [178,179,180]. --- Explanation: This supports renal microvascular injury as a distinct organ-specific small-vessel complication pathway.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] T2DM leads to a two- to four-fold increase in the mortality rate of adults from heart disease and stroke and is associated with both micro- and macro-vascular complications, the latter consisting of accelerated atherosclerosis leading to severe peripheral vascular disease, premature coronary artery disease (CAD) and increased risk of cerebrovascular diseases [178,179,180]. --- Explanation: This supports retinal microvascular injury as a distinct organ-specific small-vessel complication pathway.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] T2DM leads to a two- to four-fold increase in the mortality rate of adults from heart disease and stroke and is associated with both micro- and macro-vascular complications, the latter consisting of accelerated atherosclerosis leading to severe peripheral vascular disease, premature coronary artery disease (CAD) and increased risk of cerebrovascular diseases [178,179,180]. --- Explanation: This supports neural microvascular injury as a distinct organ-specific small-vessel complication pathway.


MONDO:0005015


MONDO:0005015

[PMID:41632731] [INDIRECT EVIDENCE] [SUPPORT] Changes in glomerular hemodynamics, glomerular and tubular hypertrophy, hyperfiltration, overactivation of the renin-angiotensin-aldosterone system (RAAS), podocyte injury, inflammation, oxidative stress, renal hypoxia, mitochondrial injury, and epigenetic changes are the main mechanisms leading to albuminuria, glomerulosclerosis and fibrosis. --- Explanation: This supports renal hemodynamic dysregulation as an upstream initiating event in diabetic kidney injury.

[PMID:29556093] [INDIRECT EVIDENCE] [SUPPORT] Specifically, afferent arteriolar remodeling during diabetic nephropathy leads to increased glomerular pressure. --- Explanation: This supports diabetic nephropathy-associated arteriolar remodeling and glomerular pressure elevation as a hemodynamic kidney injury mechanism.


MONDO:0005015

[PMID:41632731] [INDIRECT EVIDENCE] [SUPPORT] Changes in glomerular hemodynamics, glomerular and tubular hypertrophy, hyperfiltration, overactivation of the renin-angiotensin-aldosterone system (RAAS), podocyte injury, inflammation, oxidative stress, renal hypoxia, mitochondrial injury, and epigenetic changes are the main mechanisms leading to albuminuria, glomerulosclerosis and fibrosis. --- Explanation: This supports glomerular and podocyte injury as a distinct event in the DKD cascade.


MONDO:0005015

[PMID:41632731] [INDIRECT EVIDENCE] [SUPPORT] Changes in glomerular hemodynamics, glomerular and tubular hypertrophy, hyperfiltration, overactivation of the renin-angiotensin-aldosterone system (RAAS), podocyte injury, inflammation, oxidative stress, renal hypoxia, mitochondrial injury, and epigenetic changes are the main mechanisms leading to albuminuria, glomerulosclerosis and fibrosis. --- Explanation: This supports tubular injury as a distinct event in diabetic kidney injury progression.


MONDO:0005015

[PMID:41632731] [INDIRECT EVIDENCE] [SUPPORT] Changes in glomerular hemodynamics, glomerular and tubular hypertrophy, hyperfiltration, overactivation of the renin-angiotensin-aldosterone system (RAAS), podocyte injury, inflammation, oxidative stress, renal hypoxia, mitochondrial injury, and epigenetic changes are the main mechanisms leading to albuminuria, glomerulosclerosis and fibrosis. --- Explanation: This supports renal inflammation as a distinct progression event in diabetic kidney injury.


MONDO:0005015

[PMID:41632731] [INDIRECT EVIDENCE] [SUPPORT] Changes in glomerular hemodynamics, glomerular and tubular hypertrophy, hyperfiltration, overactivation of the renin-angiotensin-aldosterone system (RAAS), podocyte injury, inflammation, oxidative stress, renal hypoxia, mitochondrial injury, and epigenetic changes are the main mechanisms leading to albuminuria, glomerulosclerosis and fibrosis. --- Explanation: This supports renal fibrosis as a distinct progression event before overt DKD outcomes.


MONDO:0005015

[PMID:41632731] [INDIRECT EVIDENCE] [SUPPORT] Diabetes mellitus (DM) is the most prevalent cause of CKD and end-stage kidney disease (ESKD), requiring renal replacement therapy (RRT). --- Explanation: This supports CKD/ESKD as a downstream renal outcome in diabetes.

[PMID:36619566] [INDIRECT EVIDENCE] [PARTIAL] Renal biopsy might aid in the definitive diagnosis of DKD, NDKD, and NDKD combined with DKD. --- Explanation: This case report adds context that diabetic kidney phenotypes can include mixed diabetic and non-diabetic renal pathology.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] Hyperglycemia-associated vascular injury, oxidative stress, inflammation and altered hemodynamic balance may initiate atherosclerosis development and formation of arterial thrombus [247]. --- Explanation: This supports macrovascular atherosclerotic progression as a distinct event upstream of arterial thrombosis.

[PMID:41595732] [INDIRECT EVIDENCE] [SUPPORT] This condition is associated with increased cardiovascular and metabolic risks and leads to an earlier onset of complications compared to adults with type 2 diabetes. --- Explanation: This supports accelerated macrovascular complication risk in youth-onset diabetes trajectories.

[PMID:39742220] [INDIRECT EVIDENCE] [SUPPORT] The predominant form of CVD among diabetic patients is coronary artery disease (CAD), accounting for 29.4% of cases. --- Explanation: This supports coronary-dominant macrovascular cardiovascular burden in diabetes.


MONDO:0005015

[PMID:32872570] [INDIRECT EVIDENCE] [SUPPORT] Hyperglycemia-associated vascular injury, oxidative stress, inflammation and altered hemodynamic balance may initiate atherosclerosis development and formation of arterial thrombus [247]. --- Explanation: This supports arterial thrombus formation as a distinct downstream ischemic event.


MAXO:0000259

[PMID:33970586] [SUPPORT] The mainstay of management is a regimen of multiple daily injections of insulin or continuous subcutaneous insulin delivered via an insulin pump. --- Explanation: This supports insulin replacement as core treatment in insulin-deficient diabetes pathways.


CHEBI:145810

[PMID:33970586] [INDIRECT EVIDENCE] [SUPPORT] The mainstay of management is a regimen of multiple daily injections of insulin or continuous subcutaneous insulin delivered via an insulin pump. --- Explanation: This supports insulin replacement as core treatment in insulin-deficient diabetes pathways.


MAXO:0000058

[PMID:30150719] [SUPPORT] The biguanide drug metformin (N,N-dimethylbiguanide) works principally through inhibition of HGP, although enhanced glucose disposal has also been reported in some studies1. --- Explanation: This supports metformin as a glucose-lowering therapy acting largely via suppression of hepatic glucose production.


CHEBI:6801

[PMID:30150719] [INDIRECT EVIDENCE] [SUPPORT] The biguanide drug metformin (N,N-dimethylbiguanide) works principally through inhibition of HGP, although enhanced glucose disposal has also been reported in some studies1. --- Explanation: This supports metformin as a glucose-lowering therapy acting largely via suppression of hepatic glucose production.


MAXO:0000088

[PMID:38243953] [SUPPORT] The cornerstone of T2DM prevention is the control of modifiable risk factors and lifestyle changes to potentially prevent diabetes. --- Explanation: This supports dietary intervention as a core modifiable lifestyle strategy in diabetes prevention and care.

[PMID:34427594] [PARTIAL] Clinicians should offer or refer patients with prediabetes to effective preventive interventions. --- Explanation: This supports evidence-based preventive lifestyle intervention programs relevant to dietary management.


MAXO:0000065

[PMID:38243953] [SUPPORT] The cornerstone of T2DM prevention is the control of modifiable risk factors and lifestyle changes to potentially prevent diabetes. --- Explanation: This supports physical-activity-focused lifestyle intervention as a core modifiable strategy in diabetes prevention and care.

[PMID:34427594] [PARTIAL] Clinicians should offer or refer patients with prediabetes to effective preventive interventions. --- Explanation: This supports referral to effective preventive intervention programs that include physical activity components.


MAXO:0000058

[PMID:33068776] [SUPPORT] GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. --- Explanation: This supports GLP-1 receptor agonists as a recommended major therapy class in type 2 diabetes management.


CHEBI:167574

[PMID:33068776] [INDIRECT EVIDENCE] [SUPPORT] GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. --- Explanation: This supports GLP-1 receptor agonists as a recommended major therapy class in type 2 diabetes management.


CHEBI:71193


MAXO:0000058

[PMID:33441402] [SUPPORT] In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some differences in benefits and harms. --- Explanation: This supports SGLT2 inhibitors as an evidence-based therapy class with demonstrated outcome benefits in type 2 diabetes.


CHEBI:82720

[PMID:33441402] [INDIRECT EVIDENCE] [SUPPORT] In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some differences in benefits and harms. --- Explanation: This supports SGLT2 inhibitors as an evidence-based therapy class with demonstrated outcome benefits in type 2 diabetes.


CHEBI:85078


CHEBI:73274


MAXO:0000058

[PMID:38831203] [SUPPORT] Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity. --- Explanation: This supports dual incretin agonism as a treatment strategy in type 2 diabetes pathways.


CHEBI:194186

[PMID:38831203] [INDIRECT EVIDENCE] [SUPPORT] Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity. --- Explanation: This supports dual incretin agonism as a treatment strategy in type 2 diabetes pathways.


MAXO:0000058

[PMID:36877454] [SUPPORT] In November 2022, teplizumab was approved in the USA to delay the onset of Stage 3 T1D in adults and pediatric patients 8 years of age and older with Stage 2 T1D --- Explanation: This supports teplizumab as subtype-specific disease-modifying therapy in early type 1 diabetes.


NCIT:C20401

[PMID:36877454] [INDIRECT EVIDENCE] [SUPPORT] In November 2022, teplizumab was approved in the USA to delay the onset of Stage 3 T1D in adults and pediatric patients 8 years of age and older with Stage 2 T1D --- Explanation: This supports teplizumab as subtype-specific disease-modifying therapy in early type 1 diabetes.


hgnc:4942

[PMID:22184118] [SUPPORT] HLA-DQ2 and HLA-DQ8 are strongly predisposing haplotypes for type 1 diabetes (T1D). --- Explanation: This supports HLA-DQA1-containing DQ haplotypes as major susceptibility contributors in type 1 diabetes.


hgnc:4944

[PMID:22184118] [SUPPORT] HLA-DQ2 and HLA-DQ8 are strongly predisposing haplotypes for type 1 diabetes (T1D). --- Explanation: This supports HLA-DQB1-containing DQ haplotypes as major susceptibility contributors in type 1 diabetes.


hgnc:6081

[PMID:26404926] [SUPPORT] The highest non-HLA genetic contribution arises from the INS, PTPN22, CTLA4, and IL2RA genes, with the latter three genes also contributing to susceptibility to other autoimmune diseases (17). --- Explanation: This supports INS as a major non-HLA susceptibility gene in type 1 diabetes.


hgnc:9652

[PMID:26404926] [SUPPORT] The highest non-HLA genetic contribution arises from the INS, PTPN22, CTLA4, and IL2RA genes, with the latter three genes also contributing to susceptibility to other autoimmune diseases (17). --- Explanation: This supports PTPN22 as a major non-HLA susceptibility gene in type 1 diabetes.


hgnc:6008

[PMID:26404926] [SUPPORT] The highest non-HLA genetic contribution arises from the INS, PTPN22, CTLA4, and IL2RA genes, with the latter three genes also contributing to susceptibility to other autoimmune diseases (17). --- Explanation: This supports IL2RA as a major non-HLA susceptibility gene in type 1 diabetes.


hgnc:2505

[PMID:26404926] [SUPPORT] The highest non-HLA genetic contribution arises from the INS, PTPN22, CTLA4, and IL2RA genes, with the latter three genes also contributing to susceptibility to other autoimmune diseases (17). --- Explanation: This supports CTLA4 as a major non-HLA susceptibility gene in type 1 diabetes.


hgnc:11641

[PMID:17463248] [SUPPORT] CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. --- Explanation: This supports TCF7L2 as an established type 2 diabetes risk locus.


hgnc:9236

[PMID:17463248] [SUPPORT] CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. --- Explanation: This supports PPARG as an established type 2 diabetes risk locus.


hgnc:6257

[PMID:17463248] [SUPPORT] CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. --- Explanation: This supports KCNJ11 as an established type 2 diabetes risk locus.

[PMID:33046911] [PARTIAL] We show that, among 74,629 individuals, this burden is probably driven by the pathogenic variants found in GCK, and to a lesser extent in HNF4A, KCNJ11, HNF1B and ABCC8. --- Explanation: This supports additional pathogenic-variant burden involving KCNJ11 in people labeled as common type 2 diabetes.


hgnc:20303

[PMID:17463248] [SUPPORT] CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. --- Explanation: This supports SLC30A8 as an established type 2 diabetes risk locus.


hgnc:11621

[PMID:29931562] [SUPPORT] Although pathogenic mutations in any of the 14 genes may result in MODY, mutations in GCK, HNF1A, and HNF4A are the most common causes of MODY, representing 52, 10, and 32% of MODY cases in the UK, respectively [15, 33]. --- Explanation: This supports HNF1A as a common causative monogenic diabetes gene within MODY.

[PMID:35299962] [SUPPORT] Some single nucleotide polymorphisms (SNPs) cause maturity-onset diabetes of the young type 3 (MODY3) while some others do not cause MODY3 but increase the susceptibility to T2D or GDM. --- Explanation: This supports HNF1A variant-dependent effects across monogenic MODY and broader diabetes susceptibility.

[PMID:36178555] [SUPPORT] When we considered probands of Group 1 with a parental history of hyperglycemia, 58.3% (21/36) had a positive genetic test for GCK or HNF1A genes --- Explanation: This supports frequent involvement of HNF1A in clinically selected pediatric monogenic diabetes evaluations.


hgnc:5024

[PMID:29931562] [SUPPORT] Although pathogenic mutations in any of the 14 genes may result in MODY, mutations in GCK, HNF1A, and HNF4A are the most common causes of MODY, representing 52, 10, and 32% of MODY cases in the UK, respectively [15, 33]. --- Explanation: This supports HNF4A as a common causative gene in monogenic MODY.

[PMID:33046911] [PARTIAL] We show that, among 74,629 individuals, this burden is probably driven by the pathogenic variants found in GCK, and to a lesser extent in HNF4A, KCNJ11, HNF1B and ABCC8. --- Explanation: This supports measurable HNF4A pathogenic-variant burden among people with common type 2 diabetes labels.


hgnc:11630

[PMID:29931562] [SUPPORT] HNF1B mutations account for less than 10% of all MODY cases [62, 63]. --- Explanation: This supports HNF1B as an established but less frequent monogenic MODY-related cause.

[PMID:33046911] [PARTIAL] We show that, among 74,629 individuals, this burden is probably driven by the pathogenic variants found in GCK, and to a lesser extent in HNF4A, KCNJ11, HNF1B and ABCC8. --- Explanation: This supports clinically relevant HNF1B pathogenic-variant burden within type 2 diabetes cohorts.


hgnc:59

[PMID:33409956] [SUPPORT] 2 with ABCC8 mutation --- Explanation: This supports ABCC8 as a causal gene in monogenic neonatal diabetes cases.

[PMID:33409956] [SUPPORT] The authors describe 5 novel mutations, in the EIF2AK3, ABCC8, and GCK genes --- Explanation: This supports ABCC8 as a recurrently implicated monogenic diabetes gene.

[PMID:33046911] [PARTIAL] We show that, among 74,629 individuals, this burden is probably driven by the pathogenic variants found in GCK, and to a lesser extent in HNF4A, KCNJ11, HNF1B and ABCC8. --- Explanation: This supports ABCC8 pathogenic-variant burden in subsets of clinically common type 2 diabetes populations.


hgnc:4195

[PMID:33409956] [SUPPORT] 2 siblings with complete glucokinase deficiency --- Explanation: This supports causal involvement of severe GCK defects in permanent neonatal diabetes.

[PMID:33409956] [SUPPORT] The authors describe 5 novel mutations, in the EIF2AK3, ABCC8, and GCK genes --- Explanation: This supports GCK as a monogenic diabetes gene represented in clinically curated cases.

[PMID:33046911] [SUPPORT] We show that, among 74,629 individuals, this burden is probably driven by the pathogenic variants found in GCK, and to a lesser extent in HNF4A, KCNJ11, HNF1B and ABCC8. --- Explanation: This supports GCK as a major contributor to pathogenic monogenic-variant burden detected in type 2 diabetes cohorts.

[PMID:36178555] [SUPPORT] When we considered probands of Group 1 with a parental history of hyperglycemia, 58.3% (21/36) had a positive genetic test for GCK or HNF1A genes --- Explanation: This supports frequent GCK detection in pediatric monogenic diabetes diagnostic pathways.


hgnc:3255

[PMID:33409956] [SUPPORT] The authors describe 5 novel mutations, in the EIF2AK3, ABCC8, and GCK genes --- Explanation: This supports EIF2AK3 as a causative gene in monogenic diabetes-related case series data.


hgnc:12762

[PMID:28432734] [SUPPORT] Pathogenic variants in WFS1 (MIM# 606201) cause Wolfram syndrome (WS) type 1, a rare neurodegenerative disease characterized by DM and optic atrophy (OA). --- Explanation: This supports WFS1 as a causative monogenic diabetes-syndrome gene.


hgnc:428

[PMID:28432734] [SUPPORT] Pathogenic variants in the gene ALMS1 (MIM# 606844) on chromosomes 2p13.1 have been identified in patients with Alström syndrome (AS), an autosomal‐recessive disease characterized by retinal dystrophy, childhood obesity, type 2 DM, and sensorineural hearing loss --- Explanation: This supports ALMS1 as a causative gene in syndromic monogenic diabetes.


hgnc:24212

[PMID:28432734] [SUPPORT] Pathogenic variants in the CISD2 gene (MIM# 611507) have been identified in patients with WS type 2 --- Explanation: This supports CISD2 as a causative gene in a monogenic diabetes syndrome.


hgnc:10938

[PMID:28432734] [SUPPORT] The gene responsible, SLC19A2 (MIM# 603941), is located on chromosome 1q24.2, consists of six exons with 497 amino acids spanning a 22.5‐kb genomic region. --- Explanation: This supports SLC19A2 as a causative gene in a syndromic monogenic diabetes form.


ECTO:3000001

[PMID:10522815] [SUPPORT] Various exogenous triggers, such as certain dietary factors and viruses, are thought to induce the autoimmune process leading in some individuals to extensive beta-cell destruction and ultimately to the clinical manifestation of type 1 diabetes. --- Explanation: This supports viral exposure as an environmental trigger linked to autoimmune diabetes onset.


MONDO:0015253

[PMID:20301769] [SUPPORT] The hematologic complications occur in 90% of affected individuals during the first year of life --- Explanation: Confirms onset of anemia during the first year of life in 90% of cases.


MONDO:0015253

[PMID:9988267] [SUPPORT] constitutional erythroblastopenia characterized by absent or decreased erythroid precursors --- Explanation: Confirms erythroblastopenia (red cell aplasia) as the defining hematologic feature.


MONDO:0015253

[PMID:20301769] [SUPPORT] growth deficiency in 30% of affected individuals --- Explanation: Confirms growth deficiency affects approximately 30% of DBA patients.


MONDO:0015253

[PMID:20301769] [SUPPORT] congenital malformations in up to 50% of affected individuals --- Explanation: Confirms congenital malformations in up to half of DBA patients.


MONDO:0015253

[PMID:19773262] [SUPPORT] A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations --- Explanation: Establishes genotype-phenotype correlation between RPL11 mutations and hand malformations including thumb anomalies.


MONDO:0015253

[PMID:20301769] [SUPPORT] associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma --- Explanation: Confirms increased AML risk in DBA patients.


MONDO:0015253

[PMID:20301769] [SUPPORT] associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma --- Explanation: Confirms increased MDS risk in DBA patients.


MONDO:0015253

[PMID:20301769] [SUPPORT] associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma --- Explanation: Confirms increased osteosarcoma risk in DBA patients.


MONDO:0015253

[PMID:9988267] [INDIRECT EVIDENCE] [SUPPORT] we identified mutations in RPS19 in 10 of 40 unrelated DBA patients, including nonsense, frameshift, splice site and missense mutations --- Explanation: Original discovery of RPS19 mutations as the cause of DBA, establishing the ribosomal protein basis.

[PMID:9988267] [INDIRECT EVIDENCE] [SUPPORT] a function for RPS19 in erythropoiesis and embryogenesis --- Explanation: Confirms RPS19 has specific roles in erythropoiesis and embryonic development.


MONDO:0015253


MONDO:0015253

[PMID:20301769] [INDIRECT EVIDENCE] [SUPPORT] characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets --- Explanation: Confirms the selective erythroid failure (normal leukocytes and platelets) consistent with erythroid-specific apoptosis.


MONDO:0015253

[PMID:20301769] [INDIRECT EVIDENCE] [SUPPORT] the molecular diagnosis can be established in a male proband by identification of a hemizygous pathogenic variant in GATA1 or TSR2 associated with X-linked DBA syndrome --- Explanation: Confirms GATA1 as a distinct X-linked cause of DBA, separate from ribosomal protein genes.


MAXO:0000058

[PMID:20301769] [SUPPORT] Corticosteroid treatment, recommended in children at age 12 months or older, improves the red blood cell count in approximately 60%-80% of affected individuals --- Explanation: Confirms corticosteroid efficacy at 60-80% response rate and recommended age of initiation.


MAXO:0000756

[PMID:20301769] [SUPPORT] Chronic transfusion with packed red blood cells is necessary during the first year of life --- Explanation: Confirms chronic transfusion as necessary during the first year to avoid steroid effects on growth.


MAXO:0000747

[PMID:20301769] [SUPPORT] Hematopoietic stem cell transplantation, the only curative therapy for the hematologic manifestations of DBA syndrome --- Explanation: Confirms HSCT as the only curative therapy for DBA hematologic manifestations.


MAXO:0000058


MAXO:0000079


HGNC.SYMBOL:RPS19

[PMID:9988267] [SUPPORT] we identified mutations in RPS19 in 10 of 40 unrelated DBA patients --- Explanation: Original identification of RPS19 as the first DBA gene, mutated in ~25% of patients.


HGNC.SYMBOL:RPL5

[PMID:19773262] [SUPPORT] Two new genes (RPL5, RPL11), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients --- Explanation: Identifies RPL5 as a DBA gene encoding a large ribosomal subunit protein.

[PMID:19773262] [SUPPORT] About 20% of the patients screened had mutations in RPL5 or RPL11 --- Explanation: Quantifies RPL5/RPL11 mutation frequency at ~20% of RPS19-negative DBA patients.


HGNC.SYMBOL:RPL11

[PMID:19773262] [SUPPORT] About 20% of the patients screened had mutations in RPL5 or RPL11 --- Explanation: Quantifies RPL11 mutation frequency in Italian DBA cohort.

[PMID:19773262] [SUPPORT] A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations --- Explanation: Establishes RPL11-specific genotype-phenotype correlation with hand malformations.


HGNC.SYMBOL:RPL35A

[PMID:19773262] [SUPPORT] Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that Diamond-Blackfan anemia is a disorder of ribosome biogenesis --- Explanation: Identifies RPL35A as a DBA gene, establishing DBA as a ribosomopathy.


HGNC.SYMBOL:RPS26


HGNC.SYMBOL:RPS24


HGNC.SYMBOL:RPS10


HGNC.SYMBOL:RPS17


HGNC.SYMBOL:RPS7


HGNC.SYMBOL:GATA1

[PMID:22706301] [SUPPORT] We performed exome sequencing on two siblings who had no known pathogenic mutations for DBA and identified a mutation in the gene encoding the hematopoietic transcription factor GATA1 --- Explanation: Discovery of GATA1 as a DBA gene through exome sequencing.

[PMID:22706301] [SUPPORT] the reduction in erythropoiesis associated with the disease can arise from causes other than defects in ribosomal protein genes --- Explanation: Establishes that DBA can be caused by non-ribosomal protein gene mutations, specifically GATA1.

[PMID:37973818] [SUPPORT] Recent studies also indicated that non-RP genes like GATA1, TSR2, are associated with DBA --- Explanation: Confirms GATA1 and TSR2 as non-ribosomal protein genes associated with DBA.


MONDO:0015253

[PMID:20301769] [SUPPORT] identification of a heterozygous pathogenic variant in a gene associated with autosomal dominant DBA syndrome --- Explanation: Confirms autosomal dominant as the most common inheritance pattern for DBA.


MONDO:0009107

[PMID:9108864] [SUPPORT] The median adult height was 135.7 cm for the male and 129.0 cm for the female subjects. The growth failure was progressive partly because of absent or weak pubertal growth spurt. --- Explanation: Largest growth study in DTD (121 Finnish patients) with disease-specific growth curves.

[PMID:24598000] [SUPPORT] Clinical features include short stature, joint contractures, spinal deformities, and cleft palate. --- Explanation: Short stature listed as core DTD manifestation in the Swedish cohort.


MONDO:0009107

[PMID:34064542] [SUPPORT] Seven subjects had bilateral club foot deformity, one had unilateral club foot and two had metatarsus adductus deformity. --- Explanation: High prevalence of clubfoot documented in the Finnish pediatric cohort.

[PMID:3065771] [SUPPORT] club feet, ulnar diviation of hands, shortened phalanges, and, in particular, abduction of thumbs ('hitchhiker thumbs') and big toes. --- Explanation: Clubfoot documented as part of the characteristic DTD deformity pattern.


MONDO:0009107

[PMID:3065771] [SUPPORT] and, in particular, abduction of thumbs ('hitchhiker thumbs') and big toes. --- Explanation: Hitchhiker thumbs explicitly reported in a prenatally diagnosed DTD case.

[PMID:34064542] [SUPPORT] the most common findings were symphalangism of the fingers (n = 7), hitchhiker's thumb/abduction of the thumb (n = 7) --- Explanation: Hitchhiker thumb present in half the Finnish pediatric cohort subjects.


MONDO:0009107

[PMID:24598000] [SUPPORT] Clinical features include short stature, joint contractures, spinal deformities, and cleft palate. --- Explanation: Joint contractures listed as core clinical feature in the Swedish SLC26A2 cohort.

[PMID:9546468] [SUPPORT] Flexion contracture of the hip became evident later in 93% and was progressive. --- Explanation: Hip flexion contractures documented in 93% of 50 DTD patients, with progressive course.


MONDO:0009107

[PMID:10528373] [SUPPORT] Typical findings in this rare skeletal dysplasia are sport-limbed short stature, multiple joint contractures, early degeneration of joints, and spinal deformities such as cervical kyphosis, scoliosis, and exaggerated lumbar lordosis. --- Explanation: Longitudinal radiographic series identifying cervical kyphosis as a typical DTD spinal finding.

[PMID:34064542] [SUPPORT] cervical kyphosis was present in 11 subjects (79%). --- Explanation: Cervical kyphosis in 79% of the Finnish pediatric cohort, with variable severity and spontaneous resolution in some.


MONDO:0009107

[PMID:10528373] [SUPPORT] Typical findings in this rare skeletal dysplasia are sport-limbed short stature, multiple joint contractures, early degeneration of joints, and spinal deformities such as cervical kyphosis, scoliosis, and exaggerated lumbar lordosis. --- Explanation: Scoliosis identified as part of the canonical DTD spinal phenotype.


MONDO:0009107

[PMID:10528373] [SUPPORT] spinal deformities such as cervical kyphosis, scoliosis, and exaggerated lumbar lordosis. --- Explanation: Exaggerated lumbar lordosis listed among typical DTD spinal findings.

[PMID:34064542] [SUPPORT] Pronounced lumbar lordosis was present in eight subjects (57%) --- Explanation: Lumbar lordosis prevalence of 57% in the Finnish pediatric DTD cohort.


MONDO:0009107

[PMID:24598000] [SUPPORT] Clinical features include short stature, joint contractures, spinal deformities, and cleft palate. --- Explanation: Cleft palate directly listed among DTD features in the clinical cohort.

[PMID:34064542] [SUPPORT] Cleft palate was present in 64%. --- Explanation: High prevalence (64%) of cleft palate in the Finnish pediatric cohort.


MONDO:0009107

[PMID:3065771] [SUPPORT] micrognathia, cervical kyphosis, persistent extension limitation in elbow and knee joints, club feet --- Explanation: Micrognathia documented among characteristic DTD deformities on prenatal ultrasound.

[PMID:34064542] [SUPPORT] ten had small chin --- Explanation: Small chin (micrognathia) present in 10 of 14 subjects in the Finnish pediatric cohort.


MONDO:0009107

[PMID:34064542] [SUPPORT] five had auricular abnormalities (swelling/deformities). --- Explanation: Auricular swelling and deformities documented in the Finnish cohort.


MONDO:0009107

[PMID:14630837] [SUPPORT] Diastrophic dysplasia results in severe disproportionate short stature, generalized joint deformities, and early osteoarthritis. --- Explanation: Clinical series confirming early osteoarthritis as a defining feature leading to joint replacement surgery.

[PMID:9546468] [SUPPORT] The changes in the hip led to secondary osteoarthritis before early middle age. --- Explanation: Progressive hip deformity leading to secondary osteoarthritis documented radiographically.


MONDO:0009107

[PMID:3065771] [SUPPORT] shortened phalanges --- Explanation: Shortened phalanges noted among characteristic skeletal deformities on prenatal imaging.

[PMID:34064542] [SUPPORT] Hand abnormalities were present in all subjects; the most common findings were symphalangism of the fingers (n = 7), hitchhiker's thumb/abduction of the thumb (n = 7), flexion tendency of the fingers (n = 6) and lack of proximal interphalangeal joints (n = 1). --- Explanation: Hand abnormalities including shortened/absent phalanges present in 100% of the Finnish DTD cohort, supporting VERY_FREQUENT frequency.


MONDO:0009107

[PMID:23369989] [INDIRECT EVIDENCE] [SUPPORT] Diastrophic dysplasia (DTD) is a chondrodysplasia caused by mutations in the SLC26A2 gene, leading to reduced intracellular sulfate pool in chondrocytes, osteoblasts and fibroblasts. --- Explanation: Links SLC26A2 dysfunction to sulfate depletion across skeletal matrix-producing cell types.

[PMID:8702490] [INDIRECT EVIDENCE] [SUPPORT] The results indicate that the defect of sulfate transport is expressed in both chondrocytes and fibroblasts and results in the synthesis of proteoglycans bearing glycosaminoglycan chains which are poorly sulfated but of normal length. --- Explanation: First biochemical proof that proteoglycan sulfation is deficient in chondrocytes from patients with SLC26A2 mutations, while GAG chain length is preserved.

[PMID:22556422] [INDIRECT EVIDENCE] [SUPPORT] undersulfation of dtd was mild in most regions, but strong in narrow articular and growth plate regions crucial for bone development. This undersulfation correlated with the chondroitin synthesis rate measured via radioactive sulfate incorporation --- Explanation: High-definition infrared imaging of dtd mouse cartilage reveals that undersulfation is regionally concentrated in the most developmentally critical zones, explaining why mild overall sulfation deficits produce severe skeletal consequences.


MONDO:0009107


MONDO:0009107

[PMID:15703192] [INDIRECT EVIDENCE] [SUPPORT] The skeletal phenotype included reduced toluidine blue staining of cartilage, chondrocytes of irregular size, delay in the formation of the secondary ossification center and osteoporosis of long bones. --- Explanation: The dtd knock-in mouse shows growth plate disorganization and delayed ossification, modeling the human endochondral bone defect.

[PMID:37454964] [INDIRECT EVIDENCE] [SUPPORT] Lower than normal CXM levels were observed in most patients, even if the marker did not show a clear pattern in our small patient cohort because CXM values are highly dependent on age, gender and growth velocity. --- Explanation: Reduced collagen X marker levels in DTD patients indicate impaired endochondral ossification rate, providing a potential biomarker.

[PMID:22556422] [INDIRECT EVIDENCE] [SUPPORT] Collagen orientation was reduced, and the reduction correlated with chondroitin undersulfation. Such disorientation involved the layer of collagen covering the articular surface and protecting cartilage from degradation. --- Explanation: Collagen disorientation in the dtd mouse growth plate and articular surface directly links proteoglycan undersulfation to structural matrix disruption and progressive cartilage degradation.


MONDO:0009107

[PMID:30685387] [INDIRECT EVIDENCE] [SUPPORT] Unexpectedly, slc26a2-/- chondrocytes are defective for collagen secretion, exhibiting intracellular retention and compromised extracellular deposition of ColII and ColIX. --- Explanation: Demonstrates that collagen retention is a consequence of SLC26A2 loss, distinct from the proteoglycan undersulfation mechanism.


MONDO:0009107

[PMID:30685387] [INDIRECT EVIDENCE] [SUPPORT] As a consequence, the ATF6 arm of the unfolded protein response (UPR) is preferentially triggered to overactivate FGFR3 signaling by inducing excessive FGFR3 in slc26a2-/- chondrocytes. --- Explanation: Identifies preferential ATF6 activation as the UPR branch responsible for downstream FGFR3 dysregulation in SLC26A2-deficient chondrocytes.


MONDO:0009107

[PMID:30685387] [INDIRECT EVIDENCE] [SUPPORT] Consistently, suppressing FGFR3 signaling by blocking either FGFR3 or phosphorylation of the downstream effector favors the recovery of slc26a2-/- cartilage cultures from impaired growth and unbalanced cell proliferation and apoptosis. --- Explanation: Blocking FGFR3 rescues growth and proliferation-apoptosis balance, confirming that FGFR3 overactivation is a key pathogenic driver.

[PMID:38282752] [INDIRECT EVIDENCE] [SUPPORT] Genetic ablation of Fgfr3 in embryonic Slc26a2-deficient chondrocytes slightly attenuated chondrodysplasia. --- Explanation: Genetic evidence from Fgfr3/Slc26a2 double knockout confirming that FGFR3 overactivation contributes to the chondrodysplasia phenotype.


MAXO:0000011

[PMID:34064542] [SUPPORT] There is currently no curative treatment for DTD. The affected individuals are mainly treated with physiotherapy and corrective orthopedic surgery. --- Explanation: Clinical review identifies physiotherapy as standard of care in DTD.


MAXO:0000004

[PMID:34064542] [SUPPORT] There is currently no curative treatment for DTD. The affected individuals are mainly treated with physiotherapy and corrective orthopedic surgery. --- Explanation: Corrective orthopedic surgery identified as standard clinical management.

[PMID:14630837] [SUPPORT] Total knee arthroplasty substantially improved the function of patients with diastrophic dysplasia. --- Explanation: Largest knee replacement series in DTD documenting functional improvement despite frequent complications.


MAXO:0000079

[PMID:34064542] [SUPPORT] Genetic testing together with genetic counselling are important parts of the patient care. --- Explanation: Finnish clinical review emphasizes the role of genetic testing and counseling in DTD management.


MAXO:0000058

[PMID:26206888] [SUPPORT] a marked increase in PG sulfation was observed in newborns from NAC-treated pregnancies when compared with the placebo group. --- Explanation: Prenatal NAC treatment of dtd mice increased proteoglycan sulfation and partially rescued bone morphology.

[PMID:16719839] [SUPPORT] The relative amount of sulfated disaccharides increased in mutant mice treated with NAC compared with the placebo group, indicating an increase in proteoglycan sulfation due to NAC catabolism --- Explanation: Early proof-of-concept showing that exogenous NAC can increase cartilage proteoglycan sulfation in the dtd mouse model.


MAXO:0000058

[PMID:30685387] [SUPPORT] Moreover, administration of an FGFR inhibitor to pregnant females shows therapeutic effects on pathological features in slc26a2-/- newborns. --- Explanation: In utero FGFR inhibitor treatment improved skeletal features in SLC26A2-knockout newborn mice.

[PMID:38282752] [SUPPORT] in vivo experiments showed significant alleviation of impaired chondrocyte differentiation, and micro-CT analysis showed a clear improvement in trabecular bone microarchitectural parameters. --- Explanation: Postnatal NVP-BGJ398 treatment in an inducible Slc26a2-cKO mouse improved trabecular bone architecture, extending the therapeutic evidence from prenatal to postnatal intervention.


hgnc:10994

[PMID:24598000] [SUPPORT] Diastrophic dysplasia (DTD) is an autosomal recessive skeletal dysplasia caused by SLC26A2 mutations. --- Explanation: Clinical cohort explicitly states that SLC26A2 mutations cause DTD.

[PMID:34064542] [SUPPORT] From the subjects with available genetic data, 75% (9/12) were homozygous for the Finnish founder mutation c.-26+2T>C. --- Explanation: Documents the predominance of the Finnish founder mutation and genotype-phenotype correlations within the SLC26A2 spectrum.


MONDO:0024608

[PMID:33137500] [SUPPORT] The most prevalent symptoms were abdominal pain 28.2%, anal itching 27.1%, watery diarrhoea 18.8%, meteorism 16.5% and nausea/lack of appetite 14.1%. --- Explanation: Abdominal pain was the most prevalent symptom among D. fragilis-positive patients in this Italian cohort.

[PMID:10795375] [PARTIAL] The most common clinical symptoms include abdominal pain, persistent diarrhoea, loss of appetite, weight loss and flatulence. --- Explanation: Review identifies abdominal pain as one of the most common symptoms.


MONDO:0024608

[PMID:29404747] [PARTIAL] Data from seven studies of specific populations reported that 22% had D. fragilis in stools of which only 23% had diarrhea. Eleven studies of stool samples submitted to laboratories reported that 4.3% of individuals had D. fragilis of which 54% had diarrhea. --- Explanation: Diarrhea is frequently reported in D. fragilis carriers presenting to laboratories, though prevalence varies by study setting. Evidence that D. fragilis causes diarrhea is inconclusive.

[PMID:10795375] [PARTIAL] The most common clinical symptoms include abdominal pain, persistent diarrhoea, loss of appetite, weight loss and flatulence. --- Explanation: Review identifies persistent diarrhea as one of the most common symptoms associated with D. fragilis infection.


MONDO:0024608

[PMID:10795375] [PARTIAL] The most common clinical symptoms include abdominal pain, persistent diarrhoea, loss of appetite, weight loss and flatulence. --- Explanation: Flatulence is listed among the most common clinical symptoms.

[PMID:33137500] [PARTIAL] The most prevalent symptoms were abdominal pain 28.2%, anal itching 27.1%, watery diarrhoea 18.8%, meteorism 16.5% and nausea/lack of appetite 14.1%. --- Explanation: Meteorism (abdominal bloating/flatulence) was reported at 16.5% in this cohort.


MONDO:0024608

[PMID:33137500] [SUPPORT] The most prevalent symptoms were abdominal pain 28.2%, anal itching 27.1%, watery diarrhoea 18.8%, meteorism 16.5% and nausea/lack of appetite 14.1%. --- Explanation: Nausea and lack of appetite were reported at 14.1% of D. fragilis-positive patients.


MONDO:0024608

[PMID:10795375] [PARTIAL] The most common clinical symptoms include abdominal pain, persistent diarrhoea, loss of appetite, weight loss and flatulence. --- Explanation: Loss of appetite is identified as a common clinical symptom.


MONDO:0024608

[PMID:10795375] [PARTIAL] The most common clinical symptoms include abdominal pain, persistent diarrhoea, loss of appetite, weight loss and flatulence. --- Explanation: Weight loss is listed among the common clinical symptoms of D. fragilis infection.


MONDO:0024608

[PMID:23759351] [PARTIAL] We report a familial cluster of D. fragilis associated with marked peripheral eosinophilia and gastrointestinal symptoms. Dientamoeba fragilis infection should be considered in the setting of unexplained eosinophilia. --- Explanation: Case report of a family cluster showing marked peripheral eosinophilia associated with D. fragilis infection.

[PMID:10795375] [SUPPORT] Occasionally, eosinophilia, urticaria and pruritus have been described. --- Explanation: Review notes occasional eosinophilia in D. fragilis infection.


MONDO:0024608

[PMID:33137500] [PARTIAL] The most prevalent symptoms were abdominal pain 28.2%, anal itching 27.1%, watery diarrhoea 18.8%, meteorism 16.5% and nausea/lack of appetite 14.1%. --- Explanation: Anal itching was the second most prevalent symptom at 27.1%, which was described as unexpectedly common.

[PMID:10795375] [NO_EVIDENCE] Occasionally, eosinophilia, urticaria and pruritus have been described. --- Explanation: Pruritus is noted as an occasional feature of D. fragilis infection.


MONDO:0024608

[PMID:10795375] [PARTIAL] Occasionally, eosinophilia, urticaria and pruritus have been described. --- Explanation: Urticaria is reported as an occasional feature of D. fragilis infection.


MONDO:0024608

[PMID:8794799] [PARTIAL] Primarily characterized by diarrhea and abdominal pain, other symptoms such as flatulence, nausea, vomiting, fatigue, malaise, and weight loss occur. --- Explanation: Case report listing fatigue among the symptoms of D. fragilis infection.

[PMID:31050625] [SUPPORT] Dientamoebiasis is globally distributed and detected in a large number of subjects with diarrhea, abdominal discomfort, flatulence, fatigue and loss of appetite. --- Explanation: Review identifies fatigue as one of the symptoms associated with dientamoebiasis globally.


MONDO:0024608

[PMID:27170141] [INDIRECT EVIDENCE] [SUPPORT] Dientamoeba fragilis is a protozoan parasite of the human bowel, commonly reported throughout the world in association with gastrointestinal symptoms. --- Explanation: Confirms D. fragilis colonizes the human bowel.


MONDO:0024608


MONDO:0024608

[PMID:21637013] [INDIRECT EVIDENCE] [PARTIAL] Usually, carriage of Dientamoeba is associated with symptoms such as abdominal pain and diarrhea. Moreover, antimicrobial therapy followed by resolution of symptoms coincides with the eradication of Dientamoeba. --- Explanation: Supports the pathogenic role of D. fragilis by linking carriage to symptoms and symptom resolution to eradication after treatment.

[PMID:23759351] [INDIRECT EVIDENCE] [PARTIAL] We report a familial cluster of D. fragilis associated with marked peripheral eosinophilia and gastrointestinal symptoms. Dientamoeba fragilis infection should be considered in the setting of unexplained eosinophilia. --- Explanation: Reports marked eosinophilia in D. fragilis infection, suggesting an eosinophilic inflammatory component to the host response.

[PMID:40153748] [INDIRECT EVIDENCE] [SUPPORT] The proportion of individuals with D fragilis and a parasite load less than 1 trophozoite per field was higher in asymptomatic individuals (controls) than in symptomatic cases (47.7% vs 3.1%, respectively) (P < .001). Parasite load is associated with the presence of gastrointestinal symptoms, supporting the pathogenicity of D fragilis. --- Explanation: Case-control study demonstrating a dose-dependent relationship between parasite load and gastrointestinal symptoms, supporting a pathogenic role for D. fragilis mediated through mucosal inflammatory mechanisms.

[PMID:39052010] [INDIRECT EVIDENCE] [REFUTE] no significant difference was observed in the frequency of clinical signs between the 36 patients who tested positive for Dientamoeba fragilis PCR in their stools and the 72 control patients who were PCR negative for this protozoan. --- Explanation: Case-control study found no evidence of pathogenicity, with no significant clinical differences between D. fragilis carriers and controls, suggesting D. fragilis may be a commensal of the digestive tract.

[PMID:39540993] [INDIRECT EVIDENCE] [REFUTE] No difference in decline in IBS-SS was seen comparing the treatment and non-treatment groups at T1 (p = 0.403) or T2 (p = 1.00). --- Explanation: Despite achieving parasitological clearance with treatment, no correlation between parasitological cure and clinical symptom improvement was established, challenging the causal role of D. fragilis in symptom generation.


MONDO:0024608

[PMID:10795375] [INDIRECT EVIDENCE] [PARTIAL] The most common clinical symptoms include abdominal pain, persistent diarrhoea, loss of appetite, weight loss and flatulence. --- Explanation: Lists the gastrointestinal symptoms resulting from intestinal dysfunction in D. fragilis infection.


MONDO:0024608

[PMID:23759351] [INDIRECT EVIDENCE] [PARTIAL] We report a familial cluster of D. fragilis associated with marked peripheral eosinophilia and gastrointestinal symptoms. Dientamoeba fragilis infection should be considered in the setting of unexplained eosinophilia. --- Explanation: Demonstrates systemic immune activation with marked eosinophilia extending beyond the intestinal mucosa.

[PMID:10795375] [INDIRECT EVIDENCE] [PARTIAL] Occasionally, eosinophilia, urticaria and pruritus have been described. --- Explanation: Documents extra-intestinal manifestations including eosinophilia, urticaria, and pruritus consistent with systemic immune activation.


MAXO:0000058

[PMID:33137500] [SUPPORT] Our study showed paromomycin had a high efficacy for treatment of D. fragilis infections 100.0% (45/45), while caution must be used when using metronidazole 53.3% (24/40). We recommend paromomycin for empirical treatment, given its great effectiveness in our population. --- Explanation: Paromomycin achieved 100% eradication rate compared to 53.3% for metronidazole in this Italian cohort.

[PMID:32155096] [SUPPORT] Paromomycin or clioquinol are antibiotics of choice based on their small spectrum of activity, fewer side effects, and better eradication rates than metronidazole. --- Explanation: Systematic review recommends paromomycin over metronidazole for D. fragilis treatment in children based on better eradication and fewer side effects.


CHEBI:7934

[PMID:33137500] [INDIRECT EVIDENCE] [SUPPORT] Our study showed paromomycin had a high efficacy for treatment of D. fragilis infections 100.0% (45/45), while caution must be used when using metronidazole 53.3% (24/40). We recommend paromomycin for empirical treatment, given its great effectiveness in our population. --- Explanation: Paromomycin achieved 100% eradication rate compared to 53.3% for metronidazole in this Italian cohort.

[PMID:32155096] [INDIRECT EVIDENCE] [SUPPORT] Paromomycin or clioquinol are antibiotics of choice based on their small spectrum of activity, fewer side effects, and better eradication rates than metronidazole. --- Explanation: Systematic review recommends paromomycin over metronidazole for D. fragilis treatment in children based on better eradication and fewer side effects.


MAXO:0000058

[PMID:33137500] [PARTIAL] Our study showed paromomycin had a high efficacy for treatment of D. fragilis infections 100.0% (45/45), while caution must be used when using metronidazole 53.3% (24/40). --- Explanation: Metronidazole showed a lower eradication rate of 53.3% compared to paromomycin at 100%, suggesting suboptimal efficacy.

[PMID:39540993] [PARTIAL] Treated patients(n = 64) more often tested PCR negative at T1 (64.1% vs. 16.4%, p < 0.001) and T2 (67.3% vs. 5.3%, p < 0.001) compared to untreated patients. --- Explanation: Prospective study showing metronidazole (and clioquinol) achieve parasitological clearance, but without a corresponding improvement in clinical symptom scores (IBS-SS).


CHEBI:6909

[PMID:33137500] [INDIRECT EVIDENCE] [PARTIAL] Our study showed paromomycin had a high efficacy for treatment of D. fragilis infections 100.0% (45/45), while caution must be used when using metronidazole 53.3% (24/40). --- Explanation: Metronidazole showed a lower eradication rate of 53.3% compared to paromomycin at 100%, suggesting suboptimal efficacy.

[PMID:39540993] [INDIRECT EVIDENCE] [PARTIAL] Treated patients(n = 64) more often tested PCR negative at T1 (64.1% vs. 16.4%, p < 0.001) and T2 (67.3% vs. 5.3%, p < 0.001) compared to untreated patients. --- Explanation: Prospective study showing metronidazole (and clioquinol) achieve parasitological clearance, but without a corresponding improvement in clinical symptom scores (IBS-SS).


MAXO:0000058

[PMID:10795375] [PARTIAL] Treatment is recommended in symptomatic cases, and iodoquinol, tetracycline and metronidazole have been used successfully. --- Explanation: Iodoquinol is listed as one of the agents used successfully for treatment.


CHEBI:5950

[PMID:10795375] [INDIRECT EVIDENCE] [PARTIAL] Treatment is recommended in symptomatic cases, and iodoquinol, tetracycline and metronidazole have been used successfully. --- Explanation: Iodoquinol is listed as one of the agents used successfully for treatment.


MAXO:0000058

[PMID:10795375] [PARTIAL] Treatment is recommended in symptomatic cases, and iodoquinol, tetracycline and metronidazole have been used successfully. --- Explanation: Tetracycline is listed among agents used successfully for D. fragilis treatment, though it has been largely superseded by paromomycin and metronidazole in current practice.


CHEBI:27902

[PMID:10795375] [INDIRECT EVIDENCE] [PARTIAL] Treatment is recommended in symptomatic cases, and iodoquinol, tetracycline and metronidazole have been used successfully. --- Explanation: Tetracycline is listed among agents used successfully for D. fragilis treatment, though it has been largely superseded by paromomycin and metronidazole in current practice.


NCBITaxon:43352

[PMID:27170141] [SUPPORT] Dientamoeba fragilis is a protozoan parasite of the human bowel, commonly reported throughout the world in association with gastrointestinal symptoms. --- Explanation: This comprehensive review identifies D. fragilis as a protozoan parasite of the human bowel with worldwide distribution.

[PMID:10795375] [SUPPORT] Although originally described as an amoeboid organism, it has been reclassified as a flagellate, on the basis of a number of electron microscopic and immunological findings. Except for its lack of a flagellum, D. fragilis closely resembles Histomonas and Trichomonas. --- Explanation: Confirms the taxonomic reclassification of D. fragilis from amoeba to flagellate and its phylogenetic relationship to Histomonas and Trichomonas.

[PMID:38250789] [SUPPORT] These studies of cysts showed a clear cyst wall surrounding an encysted parasite. The cyst wall was double layered with an outer fibrillar layer and an inner layer enclosing the parasite. Hydrogenosomes, endoplasmic reticulum and nuclei were present in the cysts. Pelta-axostyle structures, costa and axonemes were identifiable and internal flagellar axonemes were present. --- Explanation: Transmission electron microscopy of D. fragilis cysts obtained from mice and rats reveals detailed ultrastructure including a double-layered cyst wall and preserved organelles, providing evidence for the cyst life cycle stage.


MONDO:0001427

[PMID:39839160] [SUPPORT] Twenty-five patients (92.6%) presented with hematemesis and melena as chief complaints. --- Explanation: Systematic review shows most patients present with overt gastrointestinal bleeding.

[PMID:35746982] [PARTIAL] a 71-year-old female patient who presented with a bright red bleed per rectum --- Explanation: Colonic Dieulafoy case highlights overt lower GI bleeding presentation.

[PMID:37620810] [PARTIAL] hematochezia of ≥ 2 episodes constituted the independent factor associated with ≥ 2 double-balloon endoscopy diagnoses --- Explanation: Small-bowel Dieulafoy series shows recurrent hematochezia is common and predicts repeat diagnostic endoscopy.


MONDO:0001427

[PMID:37065413] [SUPPORT] These catastrophic bleeding episodes frequently result in hemodynamic instability and the need for transfusion of multiple blood products. --- Explanation: Case report notes hemodynamic instability, consistent with hypotension during bleeding episodes.


MAXO:0000950

[PMID:35243119] [SUPPORT] In regard to treatment, endoscopic therapy was applied in 80% ... The endoscopic treatment was a feasible choice for rectal disease, with a primary hemostasis rate of 88%. --- Explanation: Systematic review shows endoscopic mechanical methods are effective first-line therapy with high primary hemostasis rates.

[PMID:37425531] [PARTIAL] The treatment of duodenal DL includes thermal electrocoagulation, local epinephrine injection, sclerotherapy, banding, and hemoclipping. --- Explanation: Duodenal Dieulafoy case review lists banding and hemoclipping among standard endoscopic hemostasis options.


MAXO:0000950

[PMID:35243119] [SUPPORT] angiographic embolization in 4% --- Explanation: Review notes angiographic embolization employed in a subset of cases as an alternative to endoscopy or surgery.


MAXO:0000004

[PMID:38113567] [SUPPORT] Endoscopic methods ... are preferred for treatment, boasting success rates over 90 %. Surgical measures become a last resort for uncontrolled bleeding. --- Explanation: Case series emphasizes surgery as rescue therapy after failed endoscopic management of Dieulafoy lesions.

[PMID:39298100] [NO_EVIDENCE] Fatal exulceratio simplex (dieulafoy lesion) --- Explanation: Autopsy case underscores that uncontrolled Dieulafoy bleeding can be fatal, highlighting need for definitive rescue measures when endoscopy fails.


MONDO:0018905

[PMID:29167021] [SUPPORT] Patients most often present with a rapidly growing tumour mass in single or multiple, nodal or extranodal sites. --- Explanation: This comprehensive review confirms that rapidly growing nodal masses (lymphadenopathy) are the most common presentation of DLBCL.


MONDO:0018905


MAXO:0000647

[PMID:11807147] [SUPPORT] The rate of complete response was significantly higher in the group that received CHOP plus rituximab than in the group that received CHOP alone (76 percent vs. 63 percent, P=0.005) --- Explanation: The landmark GELA trial established R-CHOP as the standard of care for DLBCL by demonstrating significantly improved complete response rates.


CHEBI:4027

[PMID:11807147] [INDIRECT EVIDENCE] [SUPPORT] The rate of complete response was significantly higher in the group that received CHOP plus rituximab than in the group that received CHOP alone (76 percent vs. 63 percent, P=0.005) --- Explanation: The landmark GELA trial established R-CHOP as the standard of care for DLBCL by demonstrating significantly improved complete response rates.


CHEBI:28748


CHEBI:28445


CHEBI:8382


MAXO:0000058


NCIT:C104153


MAXO:0000647


MAXO:0001002

[PMID:33002134] [SUPPORT] Patients treated with CAR T cell vs alternate therapies demonstrated a CR rate of 52% vs 22% (P < .001) --- Explanation: Real-world comparison demonstrating CAR-T therapy achieves superior complete response rates compared to alternate therapies in relapsed/refractory DLBCL.


MAXO:0000747


MAXO:0000014


HGNC.SYMBOL:BCL2 Translocation


HGNC.SYMBOL:MYC Rearrangement


HGNC.SYMBOL:MYD88 L265P Mutation


HGNC.SYMBOL:BCL6 Rearrangement


MONDO:0018905

[PMID:16613685] [SUPPORT] Diffuse large B-cell lymphoma is the most common pathologic subtype. --- Explanation: Abstract notes DLBCL as the most common pathologic subtype.


MONDO:0005021

[PMID:39298146] [SUPPORT] Accurate risk stratification of nonischemic dilated cardiomyopathy (NIDCM) remains challenging. --- Explanation: Confirms DCM as the defining phenotype.


MONDO:0005021

[PMID:39519012] [SUPPORT] Dilated cardiomyopathy (DCM) is characterized by reduced systolic function and cardiac dilation. --- Explanation: Reduced systolic function leads to heart failure as a primary manifestation.

[PMID:38966492] [SUPPORT] Pediatric dilated cardiomyopathy (DCM) is a rare, yet life-threatening cardiovascular condition characterized by systolic dysfunction with biventricular dilatation and reduced myocardial contractility --- Explanation: Confirms systolic dysfunction and reduced contractility as hallmarks of DCM leading to heart failure.


MONDO:0005021

[PMID:39298146] [SUPPORT] Left ventricular ejection fraction (LVEF) (per 1%) was not associated with all-cause mortality --- Explanation: While LVEF is the standard measure of LV systolic dysfunction in DCM, this study shows it is less prognostic than fibrosis markers.


MONDO:0005021


MONDO:0005021

[PMID:37788487] [SUPPORT] DCM genes can affect a variety of cardiomyocyte functions, and particular genes whose function affects the cell-cell junction and cytoskeleton are associated with increased risk of arrhythmias and sudden cardiac death. --- Explanation: Genetic variants in DCM are associated with increased arrhythmia risk.

[PMID:39298146] [SUPPORT] The presence and extent of LGE were associated with various adverse clinical outcomes --- Explanation: Myocardial fibrosis in DCM is associated with adverse outcomes including arrhythmic events.


MONDO:0005021

[PMID:37962957] [INDIRECT EVIDENCE] [SUPPORT] Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy (DCM). --- Explanation: Confirms TTN truncating variants as the most common genetic cause of DCM.

[PMID:37962957] [INDIRECT EVIDENCE] [SUPPORT] The occurrence of TTNtv was found to be 15% in the DCM cohort. --- Explanation: Provides the 15% frequency of TTNtv in a DCM cohort.

[PMID:37788487] [INDIRECT EVIDENCE] [SUPPORT] Many gene mutations have been identified that contribute to phenotypically significant cardiomyopathy. DCM genes can affect a variety of cardiomyocyte functions, and particular genes whose function affects the cell-cell junction and cytoskeleton are associated with increased risk of arrhythmias and sudden cardiac death. --- Explanation: Confirms that DCM genes affect cardiomyocyte functions including cytoskeletal integrity.


MONDO:0005021

[PMID:37254024] [INDIRECT EVIDENCE] [SUPPORT] renin-angiotensin system inhibitors, evidence-based β-blockers, mineralocorticoid inhibitors and sodium glucose cotransporter 2 inhibitors --- Explanation: Confirms that neurohormonal blockade targeting the renin-angiotensin and sympathetic systems is the cornerstone of HFrEF therapy, validating neurohormonal activation as a key pathophysiological mechanism.

[PMID:33250269] [INDIRECT EVIDENCE] [SUPPORT] Treatment of myocardial diseases with renin-angiotensin system inhibitors and β-blockers has greatly contributed to improving prognosis. --- Explanation: Confirms the therapeutic importance of targeting neurohormonal activation in myocardial diseases including DCM.


MONDO:0005021

[PMID:39298146] [INDIRECT EVIDENCE] [SUPPORT] The presence and extent of LGE were associated with various adverse clinical outcomes, whereas LVEF was not significantly associated with mortality and arrhythmic end points in NIDCM. --- Explanation: Demonstrates the prognostic significance of myocardial fibrosis (detected as LGE) in nonischemic DCM.


MONDO:0005021

[PMID:38288598] [INDIRECT EVIDENCE] [SUPPORT] pathogenic variants in RBM20 are linked to aggressive dilated cardiomyopathy with early onset heart failure and high mortality. --- Explanation: Confirms RBM20 variants cause aggressive DCM with poor outcomes.


MONDO:0005021

[PMID:38321374] [INDIRECT EVIDENCE] [SUPPORT] Our study demonstrated the obvious different ratio of T cell CD4 memory activated, T cell regulatory Tregs, and neutrophils between DCM and control donors. --- Explanation: Demonstrates altered immune cell infiltration patterns in DCM hearts.


MONDO:0005021

[PMID:35418250] [INDIRECT EVIDENCE] [SUPPORT] Doxorubicin reduced SIRT3 expression and markedly affected the cardiac mitochondrial acetylome. Increased M1-SIRT3 expression in vivo prevented doxorubicin-induced cardiac dysfunction --- Explanation: Demonstrates that mitochondrial protein acetylation dysregulation drives dilated cardiomyopathy and that restoring mitochondrial deacetylase function prevents cardiac dysfunction.


MAXO:0000058


MAXO:0000004


MAXO:0010039


MAXO:0000079

[PMID:37788487] [SUPPORT] Through advancements in next-generation sequencing and cardiac imaging, identification of genetic DCM has improved over the past couple decades, and precision medicine is now at the forefront of treatment for these patients and their families. --- Explanation: Confirms the importance of genetic identification and precision medicine in DCM management.

[PMID:39519012] [SUPPORT] Current guidelines recommend genetic counseling and screening, as well as endorsing a handful of genotype-specific therapies --- Explanation: Guidelines explicitly recommend genetic counseling and screening for DCM.


hgnc:12403

[PMID:37962957] [SUPPORT] Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy (DCM). --- Explanation: Confirms TTN truncating variants as the most common genetic cause of DCM.


hgnc:6636

[PMID:39519012] [SUPPORT] Current guidelines recommend genetic counseling and screening, as well as endorsing a handful of genotype-specific therapies (e.g., device placement in LMNA cardiomyopathy). --- Explanation: LMNA cardiomyopathy is recognized as requiring genotype-specific management including device therapy.


hgnc:7577

[PMID:39494569] [SUPPORT] genetic variants in MYH7 are the most frequent cause of pediatric genetic dilated cardiomyopathy (DCM) --- Explanation: Confirms MYH7 as the most frequent cause of pediatric genetic DCM.


hgnc:9907

[PMID:38288598] [SUPPORT] pathogenic variants in RBM20 are linked to aggressive dilated cardiomyopathy with early onset heart failure and high mortality. --- Explanation: Confirms RBM20 variants cause aggressive DCM with poor outcomes.


MONDO:0000001

[PMID:35110524] [SUPPORT] Back pain is a common and debilitating disorder with largely unknown underlying biology. --- Explanation: The study frames back pain as a common debilitating disorder, consistent with dorsalgia.


MONDO:0008608


MONDO:0008608

[PMID:39768129] [SUPPORT] Down syndrome (DS) is characterized by severe neurodevelopmental alterations that ultimately lead to the typical hallmark of DS: intellectual disability. --- Explanation: Directly supports intellectual disability as a core Down syndrome phenotype arising from abnormal brain development.


MONDO:0008608

[PMID:26924435] [SUPPORT] Trisomy 21, or Down syndrome (DS), is the most common genetic cause of developmental delay and intellectual disability. --- Explanation: Supports developmental delay as a major neurodevelopmental phenotype of Down syndrome.


MONDO:0008608

[PMID:26504441] [SUPPORT] The prevalence of congenital heart disease in infants with Down syndrome is 40%, compared with 0.3% in children who have normal chromosomes. --- Explanation: Demonstrates high prevalence of congenital heart defects in Down syndrome.


MONDO:0008608

[PMID:11853334] [SUPPORT] CONCLUSION: The prevalence of congenital hypothyroidism was 1.8% in children with Down's syndrome while 25.3% of them had compensated hypothyroidism. --- Explanation: Supports thyroid dysfunction, including hypothyroidism, as a common Down syndrome comorbidity.


MONDO:0008608

[PMID:33684394] [SUPPORT] Down syndrome remains a strong risk factor for childhood leukemia, and associations with AML are stronger than previously reported. --- Explanation: Confirms increased leukemia risk in children with Down syndrome.


MONDO:0008608

[PMID:14746382] [SUPPORT] CONCLUSIONS: The prevalence of sleep-disordered breathing in children with Down syndrome is very high, particularly in boys. --- Explanation: Supports obstructive sleep apnea and related sleep-disordered breathing as common respiratory manifestations in Down syndrome.


MONDO:0008608

[PMID:31699819] [SUPPORT] Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. --- Explanation: Supports increased autoimmunity as part of the Down syndrome clinical spectrum.


MONDO:0008608

[PMID:2149963] [SUPPORT] Patients with Down syndrome (DS) over 40 years of age, prematurely and consistently develop neurofibrillary tangles (NFT), intracytoplasmic inclusions of highly insoluble straight or paired helical 12-16 nm filaments, and senile plaques (SP) composed of abnormal neurites surrounding a core of beta amyloid. --- Explanation: Supports senile plaques as a characteristic adult neuropathological finding in Down syndrome.

[PMID:3159974] [SUPPORT] The morphometric observations of the brains of these seven patients with AD showed that the numbers of plaques and tangles exceeded 20 per 1.5 X 10(6) microns2 area, in both the prefrontal and hippocampal cortices. --- Explanation: Supports substantial plaque burden in adults with Down syndrome and Alzheimer-type dementia.

[PMID:2149963] [SUPPORT] Clinical evidence of dementia and large numbers of SP and NFT were not always concordant. --- Explanation: Supports using a pathology-level phenotype rather than equating plaques with clinical Alzheimer disease.


MONDO:0008608

[PMID:2149963] [SUPPORT] Patients with Down syndrome (DS) over 40 years of age, prematurely and consistently develop neurofibrillary tangles (NFT), intracytoplasmic inclusions of highly insoluble straight or paired helical 12-16 nm filaments, and senile plaques (SP) composed of abnormal neurites surrounding a core of beta amyloid. --- Explanation: Supports neurofibrillary tangles as a characteristic adult neuropathological finding in Down syndrome.

[PMID:3159974] [SUPPORT] The morphometric observations of the brains of these seven patients with AD showed that the numbers of plaques and tangles exceeded 20 per 1.5 X 10(6) microns2 area, in both the prefrontal and hippocampal cortices. --- Explanation: Supports substantial neurofibrillary tangle burden in adults with Down syndrome and Alzheimer-type dementia.

[PMID:2149963] [SUPPORT] Clinical evidence of dementia and large numbers of SP and NFT were not always concordant. --- Explanation: Supports using a pathology-level phenotype rather than equating tangles with clinical Alzheimer disease.


MONDO:0008608

[PMID:27472900] [INDIRECT EVIDENCE] [SUPPORT] Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. --- Explanation: Demonstrates that interferon signaling is a reproducible upstream pathway activated by trisomy 21.

[PMID:35803230] [INDIRECT EVIDENCE] [SUPPORT] Using induced pluripotent stem cell (iPSC)-based organoid and chimeric mouse models, we report that DS microglia exhibit an enhanced synaptic pruning function, which alters neuronal synaptic functions. --- Explanation: The combined organoid and chimeric mouse experiments include in vitro support that Down syndrome microglia show enhanced synaptic pruning and alter neuronal synaptic function.

[PMID:35803230] [INDIRECT EVIDENCE] [SUPPORT] Using induced pluripotent stem cell (iPSC)-based organoid and chimeric mouse models, we report that DS microglia exhibit an enhanced synaptic pruning function, which alters neuronal synaptic functions. --- Explanation: The combined organoid and chimeric mouse experiments include model-organism support that Down syndrome microglia show enhanced synaptic pruning and alter neuronal synaptic function.

[PMID:35803230] [INDIRECT EVIDENCE] [SUPPORT] In response to human brain tissue-derived pathological tau, DS microglia undergo cellular senescence and exhibit elevated type-I-interferon signaling. --- Explanation: In vivo tau-challenge experiments in the paper support an interferon-linked senescent microglial state in Down syndrome microglia.


MONDO:0008608

[PMID:37360690] [INDIRECT EVIDENCE] [SUPPORT] We differentiated human iPSCs derived from individuals with DS and CHDs, and healthy euploid controls into cardiac cells. We observed that T21 upregulates IFN signaling, downregulates the canonical WNT pathway, and impairs cardiac differentiation. --- Explanation: Human iPSC-based cardiac differentiation experiments support IFN signaling and Wnt suppression as a mechanism for abnormal cardiogenesis in Down syndrome.

[PMID:37360690] [INDIRECT EVIDENCE] [SUPPORT] the Dp(16)1Yey/+ (Dp16) mouse model of DS, we identified downregulation of canonical Wnt signaling downstream of increased dosage of interferon (IFN) receptors (IFNRs) genes on chromosome 21 as a causative factor of cardiogenic dysregulation in DS. --- Explanation: The Dp16 mouse model supports IFN receptor dosage and Wnt suppression as a mechanism for abnormal cardiogenesis in Down syndrome.


MONDO:0008608

[PMID:39768129] [INDIRECT EVIDENCE] [SUPPORT] In the DS brain, since the prenatal life stages, the number of astrocytes is disproportional compared to the healthy brain. --- Explanation: Supports abnormal astrocyte abundance as an early developmental feature of Down syndrome brain pathology.

[PMID:39768129] [INDIRECT EVIDENCE] [SUPPORT] This increase is due to a shift from neuron to astrocyte differentiation during brain development. --- Explanation: Provides direct support for altered lineage allocation from neurons toward astrocytes.


MONDO:0008608

[PMID:30733618] [INDIRECT EVIDENCE] [SUPPORT] Virtually all adults with Down syndrome (DS) show the neuropathological changes of Alzheimer disease (AD) by the age of 40 years. --- Explanation: Supports the age-dependent near-universal emergence of Alzheimer-like neuropathology in adult Down syndrome.

[PMID:30733618] [INDIRECT EVIDENCE] [SUPPORT] This association is partially due to overexpression of amyloid precursor protein, encoded by APP, as a result of the location of this gene on chromosome 21. --- Explanation: Supports APP dosage as a mechanistic driver of Alzheimer-like pathology in Down syndrome.

[PMID:2149963] [INDIRECT EVIDENCE] [SUPPORT] Clinical evidence of dementia and large numbers of SP and NFT were not always concordant. --- Explanation: Supports separating pathology-level findings from clinical Alzheimer disease or dementia in Down syndrome.


MONDO:0008608

[PMID:18812473] [INDIRECT EVIDENCE] [SUPPORT] Our findings indicate that trisomy 21 itself is associated with cell-autonomous expansion of erythro-megakaryocytic progenitors. --- Explanation: Shows that trisomy 21 directly perturbs fetal hematopoiesis even before GATA1 mutation is acquired.

[PMID:35483417] [INDIRECT EVIDENCE] [SUPPORT] In the case of myeloid leukemias, the process of leukemogenesis in Trisomy 21 begins in early fetal life where genetic drivers including GATA1 mutations lead to the development of the preleukemic condition, transient abnormal myelopoiesis (TAM). --- Explanation: Supports the fetal origin of GATA1-associated myeloid leukemogenesis in Down syndrome.


MAXO:0000077

[PMID:32029743] [NO_EVIDENCE] Clinical trials to ameliorate intellectual disability in DS signal a new era in which therapeutic interventions based on knowledge of the molecular pathophysiology of DS can now be explored; these efforts provide reasonable hope for the future. --- Explanation: Supports importance of therapeutic interventions for intellectual disability in Down syndrome.


MAXO:0000004

[PMID:32029743] [NO_EVIDENCE] Since the first description of trisomy 21, we have learned much about intellectual disability and genetic risk factors for congenital heart disease. --- Explanation: Supports the association of congenital heart disease with Down syndrome requiring surgical intervention.


MAXO:0000283

[PMID:11853334] [NO_EVIDENCE] Down's syndrome patients with normal thyroid functions and those with compensated hypothyroidism should be followed annually and every 3 mo, respectively. --- Explanation: Snippet supports monitoring intervals, but does not directly support hormone replacement therapy.


MAXO:0000077

[PMID:32029743] [NO_EVIDENCE] Clinical trials to ameliorate intellectual disability in DS signal a new era in which therapeutic interventions based on knowledge of the molecular pathophysiology of DS can now be explored. --- Explanation: Snippet discusses exploratory clinical interventions broadly, not educational support specifically.


HGNC.SYMBOL:Trisomy 21

[PMID:32029743] [SUPPORT] Trisomy 21, the presence of a supernumerary chromosome 21, results in a collection of clinical features commonly known as Down syndrome (DS). --- Explanation: Directly supports trisomy 21 as the causal genetic lesion underlying Down syndrome.


HGNC.SYMBOL:APP

[PMID:30733618] [SUPPORT] This association is partially due to overexpression of amyloid precursor protein, encoded by APP, as a result of the location of this gene on chromosome 21. --- Explanation: Supports APP dosage as a driver of Alzheimer-like neuropathology in Down syndrome.

[PMID:1671712] [PARTIAL] This suggests that some cases of AD could be caused by mutations in the APP gene. --- Explanation: Indirectly supports APP as a causal driver of Alzheimer pathology, strengthening the mechanistic plausibility that APP triplication contributes to Down syndrome Alzheimer-like neuropathology.


HGNC.SYMBOL:GATA1

[PMID:35483417] [SUPPORT] In the case of myeloid leukemias, the process of leukemogenesis in Trisomy 21 begins in early fetal life where genetic drivers including GATA1 mutations lead to the development of the preleukemic condition, transient abnormal myelopoiesis (TAM). --- Explanation: Supports GATA1 mutation as a key cooperating lesion in Down syndrome-associated myeloid leukemogenesis.


HGNC.SYMBOL:DYRK1A


HGNC.SYMBOL:IFNAR1


HGNC.SYMBOL:IFNAR2


HGNC.SYMBOL:IFNGR2


HGNC.SYMBOL:IL10RB


HGNC.SYMBOL:OLIG2


NCBITaxon:318479

[PMID:27162746] [SUPPORT] Dracunculiasis, otherwise known as guinea worm disease (GWD), is caused by infection with the nematode Dracunculus medinensis. --- Explanation: The abstract identifies D. medinensis as the causative nematode.


MONDO:0100135

[PMID:21463282] [SUPPORT] a devastating infantile-onset epilepsy with ataxia, cognitive dysfunction, and febrile and afebrile seizures resistant to current medications.


MONDO:0100135


MONDO:0100135

[PMID:21463282] [INDIRECT EVIDENCE] [SUPPORT] Loss-of-function in Na(v) 1.1 channels results in severely impaired sodium current and action potential firing in hippocampal γ-aminobutyric acid (GABA)ergic interneurons without detectable changes in excitatory pyramidal neurons.


MONDO:0100135

[PMID:21463282] [INDIRECT EVIDENCE] [SUPPORT] The resulting imbalance between excitation and inhibition likely contributes to hyperexcitability and seizures.


MAXO:0000058


MAXO:0000088


MAXO:0000950


MAXO:0000004


MAXO:0001001


CHEBI:69478


CHEBI:5000


NCIT:C152433


HGNC.SYMBOL:SCN1A

[PMID:21463282] [SUPPORT] Complete loss of function in the Na(v) 1.1 channel encoded by the SCN1A gene is associated with severe myoclonic epilepsy in infancy (SMEI)


HGNC.SYMBOL:SCN1B


HGNC.SYMBOL:SCN9A


HGNC.SYMBOL:GABRA1


HGNC.SYMBOL:GABRG2


HGNC.SYMBOL:STXBP1


HGNC.SYMBOL:HCN1


HGNC.SYMBOL:CHD2


HGNC.SYMBOL:DEPDC5


MONDO:0010679

[PMID:37435300] [SUPPORT] Duchenne muscular dystrophy (DMD) is a severe, progressive, and ultimately fatal disease of skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. --- Explanation: Review confirms progressive skeletal muscle wasting as a defining feature of DMD.


MONDO:0010679

[PMID:15106215] [PARTIAL] Improvements were seen in time taken to rise from the floor (Gowers' time), nine metres walking time, four-stair climbing time, ability to lift weights, leg function grade and forced vital capacity. --- Explanation: Cochrane review uses Gowers time as an outcome measure, confirming its clinical relevance in DMD.


MONDO:0010679


MONDO:0010679

[PMID:34626608] [SUPPORT] the creatine kinase test showed good accuracy in screening for cases of Duchenne Muscular Dystrophy and may be a useful alternative in the early diagnosis of the disease followed by confirmatory genetic testing. --- Explanation: Systematic review confirms CK testing has good diagnostic accuracy for DMD screening.


MONDO:0010679

[PMID:37435300] [SUPPORT] Duchenne muscular dystrophy (DMD) is a severe, progressive, and ultimately fatal disease of skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. --- Explanation: Review confirms cardiomyopathy as a defining feature of DMD.

[PMID:22463839] [SUPPORT] Cardiomyopathy is a consequence of Duchenne muscular dystrophy (DMD). --- Explanation: Study confirms cardiomyopathy as a consequence of DMD.


MONDO:0010679

[PMID:37435300] [SUPPORT] Duchenne muscular dystrophy (DMD) is a severe, progressive, and ultimately fatal disease of skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. --- Explanation: Review confirms respiratory insufficiency as a defining feature of DMD.


MONDO:0010679

[PMID:37435300] [INDIRECT EVIDENCE] [SUPPORT] The identification of the dystrophin gene as central to DMD pathogenesis has led to the understanding of the muscle membrane and the proteins involved in membrane stability as the focal point of the disease. --- Explanation: Review confirms dystrophin gene mutations cause membrane instability as the central pathogenic mechanism.


MONDO:0010679

[PMID:37435300] [INDIRECT EVIDENCE] [SUPPORT] Duchenne muscular dystrophy (DMD) is a severe, progressive, and ultimately fatal disease of skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. --- Explanation: Review confirms progressive muscle wasting is a defining feature of DMD.


HGNC.SYMBOL:DMD


MONDO:0018276

[PMID:31311558] [SUPPORT] POMT1-related disorders belong to the group of dystroglycanopathies characterized by a proximally pronounced muscular dystrophy with structural or functional involvement of the brain and/or the eyes --- Explanation: Large clinical cohort confirms proximal muscular dystrophy as the cardinal feature across the dystroglycanopathy spectrum.


MONDO:0018276

[PMID:31311558] [SUPPORT] The milder LGMD phenotypes constantly show markedly elevated creatine kinase values in combination with microcephaly and cognitive impairment --- Explanation: Even in the mildest LGMD phenotypes, CK is markedly elevated, confirming this as a consistent feature across all severity types.


MONDO:0018276


MONDO:0018276

[DOI:10.7554/eLife.87965] [SUPPORT] these data show that inhibitory synaptic defects and elevated seizure susceptibility are hallmarks of severe dystroglycanopathy --- Explanation: Mouse models demonstrate that seizure susceptibility in dystroglycanopathy results from impaired inhibitory synapse formation.


MONDO:0018276

[PMID:31311558] [SUPPORT] patients with a severe WWS manifestation predominantly present with profound neonatal muscular hypotonia --- Explanation: Profound neonatal hypotonia is a defining feature of the severe WWS (type A) phenotype.


MONDO:0018276

[PMID:31311558] [SUPPORT] a severe and progressive hydrocephalus with involvement of brainstem and/or cerebellum --- Explanation: Progressive hydrocephalus with brainstem and cerebellar involvement is characteristic of type A (WWS).


MONDO:0018276

[PMID:29081423] [INDIRECT EVIDENCE] [SUPPORT] Abnormal glycosylation of alpha-dystroglycan reduces its binding activities to ligand proteins, including laminins --- Explanation: Review establishing that defective alpha-DG glycosylation reduces laminin binding as the common biochemical feature of all dystroglycanopathies.

[PMID:29081423] [INDIRECT EVIDENCE] [SUPPORT] The normal sugar chain contains tandem structures of ribitol-phosphate, a pentose alcohol that was previously unknown in humans. The dystroglycanopathy genes fukutin, fukutin-related protein (FKRP), and isoprenoid synthase domain-containing protein (ISPD) encode essential enzymes for the synthesis of this structure --- Explanation: Identifies the ribitol-phosphate pathway as a key component of the alpha-DG glycosylation machinery, with FKTN, FKRP, and ISPD/CRPPA as essential enzymes.

[DOI:10.7554/eLife.82811] [INDIRECT EVIDENCE] [SUPPORT] a shorter form of matriglycan reduce the size of α-DG and decrease laminin binding, leading to various forms of muscular dystrophy --- Explanation: Demonstrates that matriglycan length is the key functional parameter and that shortened matriglycan causes muscular dystrophy.

[PMID:34884967] [INDIRECT EVIDENCE] [SUPPORT] At least 18 causative genes of dystroglycanopathy have been identified, and its clinical symptoms are diverse, ranging from severe congenital to adult-onset limb-girdle types --- Explanation: Comprehensive review confirming 18+ causative genes and the continuous severity spectrum of dystroglycanopathy.


MONDO:0018276

[DOI:10.7554/eLife.82811] [INDIRECT EVIDENCE] [SUPPORT] This smaller form of α-DG binds laminin and maintains specific force but does not prevent muscle pathophysiology, including reduced force production after eccentric contractions (ECs) or abnormalities in the neuromuscular junctions --- Explanation: Mouse model demonstrates that shortened matriglycan preserves baseline force but fails to protect against eccentric contraction-induced damage.

[DOI:10.3389/fmolb.2023.1325284] [INDIRECT EVIDENCE] [SUPPORT] represents a molecular bridge between the outside and the inside of the cell, which is essential for the mechanical and structural stability of the plasma membrane --- Explanation: Review establishing dystroglycan as the critical mechanical link between ECM and cytoskeleton for sarcolemmal stability.


MONDO:0018276

[DOI:10.7554/eLife.87965] [INDIRECT EVIDENCE] [SUPPORT] a type of congenital muscular dystrophy characterized by a wide range of phenotypes including muscle weakness, brain defects, and cognitive impairment --- Explanation: Mouse models of dystroglycanopathy confirm brain involvement including cortical malformations in severe forms.


MONDO:0018276

[DOI:10.7554/eLife.87965] [INDIRECT EVIDENCE] [SUPPORT] these data show that inhibitory synaptic defects and elevated seizure susceptibility are hallmarks of severe dystroglycanopathy, and show that Dystroglycan plays an important role in organizing functional inhibitory synapse assembly --- Explanation: Establishes that inhibitory synapse dysfunction and seizure susceptibility are core features of severe dystroglycanopathy pathophysiology.


MONDO:0018276

[DOI:10.3389/fmolb.2023.1325284] [INDIRECT EVIDENCE] [SUPPORT] DG is a versatile molecule acting not only as a mechanical building block but also as a modulator of outside–inside signaling events --- Explanation: Review establishing the dual adhesion and signaling role of dystroglycan.


MAXO:0000950


MAXO:0000011


MAXO:0000079


MAXO:0000058


MAXO:0001001


hgnc:9202

[PMID:31311558] [SUPPORT] The phenotypic severity of POMT1-related dystroglycanopathies depends on the residual enzyme activity. A genotype-phenotype correlation can be assumed --- Explanation: Large clinical cohort demonstrating genotype-phenotype correlation based on residual POMT1 enzyme activity.

[PMID:31311558] [SUPPORT] Patients with two mutations leading to premature protein termination had a WWS phenotype, while the presence of at least one missense mutation was associated with milder phenotypes --- Explanation: Two truncating mutations cause severe WWS, while missense mutations with residual activity cause milder phenotypes.


hgnc:19743


hgnc:19139


hgnc:3622

[PMID:29081423] [SUPPORT] fukutin and FKRP transfer ribitol-phosphate onto sugar chains of alpha-dystroglycan, and ISPD synthesizes CDP-ribitol, a donor substrate for fukutin and FKRP --- Explanation: Establishes the enzymatic function of fukutin as a ribitol-phosphate transferase in the alpha-DG glycosylation pathway.


hgnc:17997

[DOI:10.3233/jnd-230205] [SUPPORT] Missense point mutations in the Fukutin-related protein (FKRP) gene cause variable reduction in the synthesis of matriglycan on alpha-dystroglycan (α-DG) and a wide range of disease severity --- Explanation: FKRP mutations cause variable matriglycan reduction and a wide severity spectrum.


hgnc:6511

[DOI:10.7554/eLife.82811] [SUPPORT] is uniquely synthesized on α-dystroglycan (α-DG) by like-acetylglucosaminyltransferase-1 (LARGE1) --- Explanation: Identifies LARGE1 as the enzyme that synthesizes matriglycan on alpha-DG.


hgnc:37276

[PMID:29081423] [SUPPORT] ISPD synthesizes CDP-ribitol, a donor substrate for fukutin and FKRP --- Explanation: Identifies CRPPA/ISPD as the CDP-ribitol synthase.


hgnc:25902


hgnc:26267

[DOI:10.7554/eLife.82811] [SUPPORT] -mannose kinase (POMK) is required for LARGE1 to generate full-length matriglycan on α-DG (~150–250 kDa) --- Explanation: Demonstrates that POMK-mediated phosphorylation is a prerequisite for full matriglycan extension by LARGE1.


hgnc:28596


hgnc:15685


hgnc:13530


hgnc:22932


hgnc:2666


hgnc:3005


hgnc:3006


hgnc:3007


MONDO:0018276


MONDO:0006543

[PMID:32973163] [SUPPORT] mucocutaneous fragility and blister formation, inducible by often minimal trauma --- Explanation: Confirms skin blistering induced by minimal trauma as the defining feature of EB.

[PMID:20301481] [SUPPORT] skin fragility manifested by blistering and erosions with minimal trauma --- Explanation: GeneReviews confirms blistering and erosions as cardinal features.


MONDO:0006543

[PMID:20301481] [SUPPORT] skin fragility manifested by blistering and erosions with minimal trauma that heals with milia and scarring --- Explanation: GeneReviews confirms healing with scarring as a defining DEB feature.


MONDO:0006543

[PMID:20301481] [SUPPORT] blistering and erosions with minimal trauma that heals with milia and scarring --- Explanation: GeneReviews confirms milia formation at healed blister sites.


MONDO:0006543

[PMID:20301481] [SUPPORT] Dystrophic nails, especially toenails, are common and may be the only manifestation of DDEB --- Explanation: GeneReviews confirms nail dystrophy as a very common DEB feature.


MONDO:0006543

[PMID:20301481] [SUPPORT] Blistering of the hands and feet followed by scarring results in contractures and pseudosyndactyly --- Explanation: GeneReviews confirms pseudosyndactyly from progressive scarring.


MONDO:0006543

[PMID:20301481] [SUPPORT] Esophageal erosions can lead to webs and strictures that can cause severe dysphagia --- Explanation: GeneReviews confirms esophageal stricture formation in DEB.


MONDO:0006543

[PMID:20301481] [SUPPORT] Esophageal erosions can lead to webs and strictures that can cause severe dysphagia --- Explanation: Confirms dysphagia as a consequence of esophageal strictures.


MONDO:0006543

[PMID:20301481] [SUPPORT] Oral involvement may lead to mouth blistering, fusion of the tongue to the floor of the mouth, and progressive diminution of the size of the oral cavity and mouth opening --- Explanation: GeneReviews confirms microstomia from progressive oral scarring.


MONDO:0006543

[PMID:20301481] [SUPPORT] Malnutrition with vitamin and mineral deficiency may lead to growth deficiency in young children --- Explanation: GeneReviews confirms growth deficiency from malnutrition in DEB.


MONDO:0006543

[PMID:20301481] [SUPPORT] Anemia is treated with iron supplements and transfusions as needed --- Explanation: GeneReviews confirms anemia requiring treatment in DEB.


MONDO:0006543

[PMID:19026465] [SUPPORT] Cumulative risks rose steeply in RDEB-HS, from 7.5% by age 20 to 67.8%, 80.2%, and 90.1% by ages 35, 45, and 55, respectively --- Explanation: National EB Registry documents extremely high lifetime SCC risk in severe RDEB.

[PMID:19026465] [SUPPORT] nearly 80% will have died of metastatic SCC despite aggressive surgical resection --- Explanation: Confirms high mortality from metastatic SCC in RDEB.


MONDO:0006543

[PMID:20301481] [SUPPORT] Corneal erosions can lead to scarring and loss of vision --- Explanation: GeneReviews confirms corneal erosions as a DEB complication.


MONDO:0006543

[PMID:20301481] [SUPPORT] good dental care --- Explanation: GeneReviews recommends dental care as part of DEB management, indicating dental complications including caries from enamel involvement.

[PMID:19700011] [SUPPORT] Some epidermolysis bullosa subtypes are at risk for severe injury of the bone marrow, musculoskeletal system, heart, kidney, and teeth --- Explanation: Confirms dental/teeth involvement as an extracutaneous EB complication requiring surveillance.


MONDO:0006543

[PMID:20301481] [SUPPORT] Calcium and vitamin D supplementation and bisphosphonates as needed for osteoporosis --- Explanation: GeneReviews confirms osteoporosis requiring treatment in DEB.


MONDO:0006543

[PMID:20301481] [SUPPORT] management of constipation --- Explanation: GeneReviews mentions constipation management as part of DEB care.


MONDO:0006543

[PMID:36516090] [INDIRECT EVIDENCE] [SUPPORT] Dystrophic epidermolysis bullosa is a rare genetic blistering skin disease caused by mutations in COL7A1, which encodes type VII collagen (C7) --- Explanation: Confirms COL7A1 mutations as the cause of DEB.

[PMID:32973163] [INDIRECT EVIDENCE] [SUPPORT] pathogenetic mutations in 16 distinct genes have been implicated in EB, encoding proteins influencing cellular integrity and adhesion --- Explanation: Confirms that EB is caused by mutations in genes encoding structural proteins critical for cell adhesion.

[PMID:20301481] [INDIRECT EVIDENCE] [SUPPORT] biallelic COL7A1 pathogenic variants (for RDEB) or a heterozygous pathogenic variant in COL7A1 (for DDEB) --- Explanation: GeneReviews confirms the genetic basis of both RDEB and DDEB in COL7A1.


MONDO:0006543