MONDO:0005045

[PMID:23124402] [SUPPORT] Hypertrophic cardiomyopathy is the most common genetic cardiovascular disorder and the leading cause of sudden cardiac death in the young. This article reviews the ventricular arrhythmias associated with hypertrophic cardiomyopathy. --- Explanation: The reference confirms that hypertrophic cardiomyopathy is associated with ventricular arrhythmias and is a leading cause of sudden cardiac death.

[PMID:28602671] [SUPPORT] Patients with HCM are predisposed to developing atrial fibrillation (AF) due primarily to advanced diastolic dysfunction and left atrial (LA) dilatation and remodelling. --- Explanation: The reference confirms that atrial fibrillation is common in patients with hypertrophic cardiomyopathy.

[PMID:29203161] [SUPPORT] Cardiac arrhythmias refer to any abnormality or disturbance in the normal activation sequence of the myocardium and may be indicative of structural heart disease and the cause of significant cardiovascular complications and sudden cardiac death. --- Explanation: The reference discusses the role of arrhythmias in structural heart disease, including hypertrophic cardiomyopathy, and their association with significant cardiovascular complications and sudden cardiac death.

[PMID:11174912] [SUPPORT] Ventricular arrhythmias in the athlete generally occur in the setting of structural heart disease that is genetically determined (hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, anomalous coronary arteries) or acquired (coronary artery disease, myocarditis, idiopathic dilated cardiomyopathies). --- Explanation: The reference confirms that ventricular arrhythmias are common in hypertrophic cardiomyopathy, particularly in athletes.


MONDO:0005045

[PMID:34533409] [SUPPORT] Common symptoms include chest pain, shortness of breath, palpitations, fatigue and syncope (fainting)... --- Explanation: The reference mentions fatigue as a common symptom of hypertrophic cardiomyopathy, supporting the statement that fatigue occurs occasionally in this condition.

[PMID:37715354] [SUPPORT] A 59-year-old man was referred for SSM as dyspnoea and low threshold muscle fatigue associated to severe left ventricular outflow obstruction... --- Explanation: The reference describes a patient with hypertrophic obstructive cardiomyopathy experiencing muscle fatigue, aligning with the statement that fatigue is occasionally observed due to reduced cardiac output and efficiency.


MONDO:0005045


MONDO:0005045

[PMID:16416046] [INDIRECT EVIDENCE] [SUPPORT] Hypertrophic Cardiomyopathy (HCM) is a relatively common primary cardiac disorder defined as the presence of a hypertrophied left ventricle... to date, 270 independent mutations in nine sarcomeric protein genes have been linked to Familial Hypertrophic Cardiomyopathy (FHC)... --- Explanation: The reference discusses how mutations in sarcomeric protein genes are linked to hypertrophic cardiomyopathy, which leads to heart muscle thickening.

[PMID:36797478] [INDIRECT EVIDENCE] [SUPPORT] The most common form of genetic heart disease is hypertrophic cardiomyopathy (HCM), which is caused by variants in cardiac sarcomeric genes and leads to abnormal heart muscle thickening. --- Explanation: This reference directly states that HCM is caused by variants in sarcomeric genes resulting in heart muscle thickening.

[PMID:28645928] [INDIRECT EVIDENCE] [SUPPORT] For example, increased myosin heavy chain (MHC) binding and ATP utilization lead to the hypercontractile sarcomere in HCM... --- Explanation: This reference explains how specific mutations in sarcomeric proteins lead to hypercontractility, a feature of muscle thickening in HCM.

[PMID:37060436] [INDIRECT EVIDENCE] [SUPPORT] Recent advances in our mechanistic understanding of sarcomere pathophysiology include high-resolution molecular models of sarcomere components and the identification of the myosin super-relaxed state. --- Explanation: This reference details how understanding sarcomere function and its pathophysiology relates to mutations leading to cardiomyopathy, thereby supporting the statement about genetic mutations affecting sarcomere proteins.


MONDO:0005045

[PMID:33447843] [INDIRECT EVIDENCE] [SUPPORT] Myocardial disarray is defined as disorganized cardiomyocyte spatial distribution, with loss of physiological fibre alignment and orientation. --- Explanation: The paper discusses how myocardial disarray is a typical feature of hypertrophic cardiomyopathy (HCM), implying its role in myocardial dysfunction.

[PMID:7665141] [INDIRECT EVIDENCE] [SUPPORT] Genes on five loci on separate chromosomes are responsible for a familial disease in which all or part of the ventricular muscle undergoes thickening with a histological picture of irregular hypertrophy and disorganized arrangement of myocytes (disarray). --- Explanation: This indicates that myocyte disarray is a feature of the disease, contributing to the thickening and impaired function of the myocardium.

[PMID:11040002] [INDIRECT EVIDENCE] [SUPPORT] Within an individual heart the magnitude of hypertrophy correlated with the severity of fibrosis (p = 0.006) and disarray (p = 0.0002). --- Explanation: The correlation between hypertrophy, fibrosis, and disarray supports the statement that myocyte disarray contributes to myocardial dysfunction.


MONDO:0005045

[PMID:1414892] [INDIRECT EVIDENCE] [SUPPORT] It appears that increased collagen production is mainly responsible for the functional consequences of structural remodelling --- Explanation: The increased collagen production discussed here is consistent with the contribution of interstitial cells to myocardial stiffness.

[PMID:25573453] [INDIRECT EVIDENCE] [SUPPORT] Tissue from cats with pre-clinical HCM also had a higher number of neutrophils and a greater collagen content than the myocardium of normal cats. --- Explanation: This study shows increased collagen deposition, contributing to myocardial stiffness, aligning with the statement.

[PMID:29522370] [INDIRECT EVIDENCE] [SUPPORT] We conclude that myocardial macrophages play an important role in the time-dependent increases in SPARC that enhance postsynthetic collagen processing, insoluble collagen content, and myocardial stiffness and contribute to the development of fibrosis. --- Explanation: The role of interstitial cells like macrophages in increasing collagen content supports the statement.

[PMID:12510171] [INDIRECT EVIDENCE] [SUPPORT] The myocardial collagen matrix consists of a network of fibrillar collagen which is intimately connected to the myocyte. --- Explanation: The mention of the collagen matrix supports the idea of increased collagen deposition by interstitial cells contributing to myocardial stiffness.


MAXO:0000186

[PMID:35450574] [SUPPORT] Beta-Blockers and Exercise Hemodynamics in Hypertrophic Cardiomyopathy. --- Explanation: This reference discusses the use of beta-blockers in the context of hypertrophic cardiomyopathy, which supports the statement that beta-blockers are used to improve symptoms in this condition, though details on heart rate reduction specifically may be implied but not detailed.

[PMID:21389910] [SUPPORT] Throughout the years, numerous medical treatments have been used to achieve symptom control in these patients, and include medications such as beta-blockers, calcium channel blockers, amiodarone, disopyramide, and angiotensin receptor blockers. --- Explanation: The abstract directly mentions the use of beta-blockers to control symptoms in hypertrophic cardiomyopathy, supporting the statement.

[PMID:37850394] [SUPPORT] beta-Adrenergic receptor antagonists (beta-blockers) are the first-line therapy for HCM. However, beta-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. --- Explanation: This reference confirms that beta-blockers are a first-line therapy for hypertrophic cardiomyopathy and are used for heart rate reduction, supporting the statement.

[PMID:25198737] [SUPPORT] Beta-blocker therapy is without doubt the treatment of choice for patients with heart failure caused by hypertrophic cardiomyopathy, but the dose needs to carefully titrated on an individual basis for maximum benefit. --- Explanation: The reference highlights the use of beta-blockers in hypertrophic cardiomyopathy to improve symptoms, aligning with the statement.


MAXO:0000434

[PMID:17162264] [SUPPORT] For symptomatic patients with non-obstructed disease medical treatment with calcium channel blockers and beta-blockers is aimed to improve heart failure symptoms, and ischemia. Verapamil is the most often used, with likely benefit of relieving ischemia. --- Explanation: The literature supports that calcium channel blockers are used to improve symptoms in hypertrophic cardiomyopathy patients, which implies relaxing the heart muscle and improving blood flow.

[PMID:3515244] [SUPPORT] The three approved calcium-channel blockers--nifedipine, verapamil and diltiazem--have offered new treatments for angina. --- Explanation: Even though the focus is on angina, the acknowledged use of calcium channel blockers reinforces their role in cardiovascular conditions including HCM.

[PMID:36044874] [SUPPORT] CCBs are effective antihypertensive drugs and a very good therapeutic option for HTN LVH as they can cause reverse LVH remodeling. --- Explanation: The review suggests the effectiveness of calcium channel blockers in treating hypertensive left ventricular hypertrophy (HTN LVH), indicating a role in remodeling heart muscle, which aligns with improving blood flow.

[PMID:7004293] [SUPPORT] The negative inotropic effects of verapamil are valuable in improving the symptoms and hemodynamic disturbances of hypertrophic cardiomyopathy. --- Explanation: This directly supports the use of calcium channel blockers (specifically verapamil) in hypertrophic cardiomyopathy by improving symptoms and hemodynamics, which implies relaxing the heart muscle and improving blood flow.


MAXO:0000004

[PMID:38368037] [SUPPORT] Septal myectomy is a well-established procedure for septal reduction in patients with obstructive hypertrophic cardiomyopathy (HCM) who have not responded to medical treatment. --- Explanation: The literature directly confirms that septal myectomy is used to surgically remove part of the thickened heart muscle in hypertrophic cardiomyopathy patients.

[PMID:31280832] [SUPPORT] Surgical myectomy was initially advocated only for patients with symptoms refractory to maximal tolerated medical therapy. --- Explanation: This supports the usage of septal myectomy for removing thickened muscle parts as a treatment for hypertrophic cardiomyopathy.

[PMID:22687587] [SUPPORT] Treatments for hypertrophic cardiomyopathy are largely selected based on patient symptoms and echocardiographic findings. --- Explanation: While this reference does not directly state septal myectomy, it mentions treatment selection based on symptoms, which aligns with the usage context of septal myectomy in other literature. Therefore, it indirectly supports the use.


MAXO:0000004

[PMID:35710280] [SUPPORT] Over the past several decades, alcohol septal ablation has become an established therapy for selected patients, in whom there is clinical improvement in symptoms as well as objective functional capacity. --- Explanation: This reference supports the use of alcohol septal ablation as a treatment for hypertrophic cardiomyopathy by describing improved clinical outcomes and functional capacity.

[PMID:36598161] [SUPPORT] There are several invasive therapies including proven therapies such as alcohol septal ablation and septal myectomy. --- Explanation: This reference supports the use of alcohol septal ablation as a proven therapy for hypertrophic cardiomyopathy.

[PMID:10980888] [SUPPORT] Following balloon inflation and intracoronary myocardial contrast echocardiography, ethyl alcohol is injected through the catheter lumen to cause proximal interventricular septum infarction and relief of outflow tract obstruction. --- Explanation: This reference supports the description of alcohol septal ablation as a minimally invasive procedure to reduce obstruction by injecting alcohol.

[PMID:20973822] [SUPPORT] Alcohol septal ablation (ASA) has been shown to be an effective treatment in patients with hypertrophic obstructive cardiomyopathy (HOCM) who are refractory to medical treatment. --- Explanation: This reference supports the effectiveness of alcohol septal ablation in treating hypertrophic cardiomyopathy by injecting alcohol into the septal artery.


MAXO:0000004

[PMID:26002383] [SUPPORT] Nevertheless, several observational clinical studies have shown that the ICD reliably terminates life-threatening ventricular tachyarrhythmias in HCM, and is largely responsible for reducing HCM mortality to 0.5% per year, by preventing SD and changing the natural course of the disease. --- Explanation: This excerpt supports the statement by showing that ICDs prevent sudden cardiac death in high-risk patients with hypertrophic cardiomyopathy.

[PMID:36396186] [SUPPORT] Implantable cardioverter-defibrillators are the mainstay of therapy for prevention of sudden cardiac death in high-risk patients with hypertrophic cardiomyopathy (HCM). --- Explanation: This excerpt also supports the statement by confirming that ICDs are a primary treatment used to prevent sudden cardiac death in high-risk HCM patients.

[PMID:22687587] [SUPPORT] Risk of sudden death correlates with maximum left ventricular (LV) wall thickness. Massive LV thickening of 30 mm or more is an indication for primary prevention of sudden death with an implanted defibrillator. --- Explanation: This excerpt provides specific criteria for using ICDs as a preventative measure in patients with significant hypertrophic cardiomyopathy, further supporting the statement.

[PMID:36134835] [SUPPORT] During follow-up of 4.8+/-3.4 years, there was no sudden cardiac death, but 20.6% patients with implantable cardioverter-defibrillator had at least one appropriate shock. --- Explanation: While the focus is on the outcome of ICD shocks, the lack of sudden cardiac deaths among ICD patients aligns with the notion that ICDs prevent sudden cardiac death in high-risk HCM patients.


HGNC.SYMBOL:MYH7

[PMID:38423942] [SUPPORT] Hypertrophic cardiomyopathy: New pathogenic variant in MYH7. --- Explanation: The title of the referenced article explicitly indicates the association of a pathogenic variant in MYH7 with hypertrophic cardiomyopathy.

[PMID:23905887] [SUPPORT] Genetic mutations can be identified in approximately 60% of patients; these are commonest in genes that encode proteins of the cardiac sarcomere. --- Explanation: While the specific mutations in MYH7 are not detailed in this snippet, the article supports the general assertion that genetic mutations, particularly in sarcomeric genes like MYH7, are common in hypertrophic cardiomyopathy.

[PMID:31735781] [SUPPORT] By NGS, we determined that these subjects with HCM symptoms carried a missense heterozygous genetic mutation c.2632C>A (p.V878L) in the myosin heavy chain 7 (MYH7) gene with an autosomal dominant pattern of inheritance. --- Explanation: The article details a specific pathogenic variant (p.V878L) in the MYH7 gene associated with hypertrophic cardiomyopathy.

[PMID:36797478] [SUPPORT] The dominant-negative c.1208G>A (p.R403Q) pathogenic variant (PV) in beta-myosin (MYH7) is a common and well-studied PV that leads to increased cardiac contractility and HCM onset. --- Explanation: The article identifies the commonly studied pathogenic variant (p.R403Q) in MYH7 which leads to hypertrophic cardiomyopathy.

[PMID:30681346] [SUPPORT] Of 33 HCM genes, only 8 (24%) were categorized as definitive (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3). --- Explanation: The article categorizes MYH7 as one of the 'definitive' genes associated with hypertrophic cardiomyopathy.

[PMID:37565978] [SUPPORT] MYH7 variants cause hypertrophic cardiomyopathy (HCM), noncompaction cardiomyopathy (NCCM), and dilated cardiomyopathy (DCM). --- Explanation: The article explicitly states that MYH7 variants cause hypertrophic cardiomyopathy, reinforcing the genetic association.


HGNC.SYMBOL:MYBPC3

[PMID:34180388] [SUPPORT] The proband carries a novel heterozygous nonsense variant of MYBPC3:c.2731G > T (p.E911X) ... suggesting the functional damages to the protein of MYBPC3. --- Explanation: The study identifies a novel pathogenic variant in MYBPC3 associated with hypertrophic cardiomyopathy.

[PMID:24240729] [SUPPORT] The second wave started in 1995 by the discovery that mutations in the gene encoding cMyBP-C cause hypertrophic cardiomyopathy (HCM). --- Explanation: This review discusses that mutations in MYBPC3 (which encodes cMyBP-C) cause HCM.

[PMID:37409452] [SUPPORT] The 2 sarcomere genes most commonly associated with hypertrophic cardiomyopathy (HCM), MYBPC3 (myosin-binding protein C3)... --- Explanation: Study identifies MYBPC3 as a common gene associated with hypertrophic cardiomyopathy.

[PMID:35544052] [SUPPORT] Pathogenic variants associated with inherited cardiomyopathy ... MYBPC3 ... were classified ... --- Explanation: This study includes MYBPC3 as one of the genes with pathogenic variants associated with inherited cardiomyopathy.


HGNC.SYMBOL:TNNT2

[PMID:33588347] [SUPPORT] Variants were identified and annotated using in silico tools, and further classified as pathogenic or benign according to the American College of Medical Genetics and Genomics guidelines. Variants with functional effects were identified...and TNNT2... --- Explanation: The study identifies pathogenic variants in TNNT2 among patients with hypertrophic cardiomyopathy, supporting the genetic association.

[PMID:7665141] [SUPPORT] Genes on five loci on separate chromosomes are responsible for a familial disease in which all or part of the ventricular muscle undergoes thickening with a histological picture of irregular hypertrophy and disorganized arrangement of myocytes (disarray). The three genes identified so far encode for beta heavy chain myosin (chromosome 14), troponin T (chromosome 1) and alpha tropomyosin (chromosome 15). --- Explanation: The study reveals that the troponin T gene (TNNT2) is one of the implicated genes in hypertrophic cardiomyopathy.


HGNC.SYMBOL:ALPK3


HGNC.SYMBOL:FHOD3


HGNC.SYMBOL:TRIM63


HGNC.SYMBOL:SVIL


MONDO:0019669

[PMID:6641761] [SUPPORT] The roentgenological signs were less severe than those of type II achondrogenesis. --- Explanation: Confirms that hypochondrogenesis represents a less severe form of short-limbed dwarfism compared to achondrogenesis type II.

[PMID:3717210] [SUPPORT] Review of the radiographic findings in these cases show a fairly continuous spectrum of bony defects, rather than two distinct radiographic syndromes. --- Explanation: Confirms the spectrum of skeletal severity in the achondrogenesis II-hypochondrogenesis continuum.


MONDO:0019669

[PMID:6641761] [SUPPORT] The delay in vertebral ossification, the absence of all the epiphyseal nuclei and of the tarsal bones might suggest the diagnosis of hypochondrogenesis, rather than that of spondyloepiphyseal dysplasia. --- Explanation: Confirms delayed vertebral ossification as a diagnostic feature of hypochondrogenesis.


MONDO:0019669

[PMID:3057886] [SUPPORT] radiographs revealed short ribs, hypoplastic ilia, absence of ossification of sacrum, pubis, ischia, tali, calcanei, and many vertebral bodies; the long bones were short with mild metaphyseal flaring --- Explanation: Detailed radiographic description confirms short ribs as a defining feature in a case of achondrogenesis II-hypochondrogenesis.


MONDO:0019669

[PMID:11956729] [SUPPORT] ill-defined ossification of the cervical vertebral bodies, hypoplastic thorax, retarded ossification of the pubic bones, and broad, short long bones --- Explanation: MRI-based prenatal diagnosis confirms hypoplastic (narrow) thorax as a key finding in hypochondrogenesis.


MONDO:0019669

[PMID:6641761] [SUPPORT] The delay in vertebral ossification, the absence of all the epiphyseal nuclei and of the tarsal bones might suggest the diagnosis of hypochondrogenesis --- Explanation: Original description confirms absent epiphyseal nuclei as a diagnostic feature.


MONDO:0019669

[PMID:11956729] [SUPPORT] ill-defined ossification of the cervical vertebral bodies, hypoplastic thorax, retarded ossification of the pubic bones, and broad, short long bones --- Explanation: Hypoplastic thorax documented on prenatal imaging implies pulmonary hypoplasia as a secondary consequence of thoracic restriction.


MONDO:0019669

[PMID:25823796] [SUPPORT] a fetus who presented with generalized hydrops fetalis and severe micromelia during prenatal sonographic examinations --- Explanation: Confirms hydrops fetalis as a presenting feature in a COL2A1-mutant fetus in the achondrogenesis II-hypochondrogenesis spectrum.


MONDO:0019669


MONDO:0019669

[PMID:11956729] [SUPPORT] ill-defined ossification of the cervical vertebral bodies, hypoplastic thorax, retarded ossification of the pubic bones, and broad, short long bones --- Explanation: Ill-defined cervical vertebral ossification contributes to the short neck phenotype observed in hypochondrogenesis.


MONDO:0019669

[PMID:2572591] [INDIRECT EVIDENCE] [SUPPORT] The substitution disrupts the invariant Gly-X-Y structural motif necessary for perfect triple helix formation and leads to extensive overmodification, intracellular retention, and reduced secretion of type II collagen. --- Explanation: Demonstrates that glycine substitutions in COL2A1 disrupt collagen triple helix formation, causing intracellular retention and reduced secretion.

[PMID:8175802] [INDIRECT EVIDENCE] [SUPPORT] Microscopic examination of cartilage showed that the mutation altered the organization of the growth plate. Also, articular chondrocytes contained large cisternae of rough endoplasmic reticulum. The density of the extracellular matrix was reduced, and the intensity of the staining with an antibody to type II collagen was diminished. --- Explanation: Confirms that COL2A1 mutations cause ER retention of misfolded collagen and reduced extracellular matrix density in hypochondrogenesis patients.

[PMID:10797431] [INDIRECT EVIDENCE] [SUPPORT] Ten of the mutations were single base substitutions that converted a codon for an obligate glycine to a codon for an amino acid with a bulkier side chain. --- Explanation: Confirms that glycine substitutions in the triple-helical domain are the predominant mutation class in the achondrogenesis II/hypochondrogenesis spectrum.

[PMID:38076483] [INDIRECT EVIDENCE] [SUPPORT] Functional studies on father's cutaneous fibroblasts, along with in silico protein modeling and in vitro chondrocytes differentiation, showed intracellular accumulation of collagen-II, its localization in external Golgi vesicles and nuclear morphological alterations. --- Explanation: Patient-derived functional studies confirm intracellular collagen II accumulation and trafficking disruption for a COL2A1 glycine substitution.


MONDO:0019669

[PMID:3717210] [INDIRECT EVIDENCE] [SUPPORT] Chondro-osseous histology and ultrastructure was similar in all cases regardless of severity and was characterized by hypervascularity and hypercellularity of the cartilage with multiple small, round dilated cysternae of rough endoplasmic reticulum. --- Explanation: Confirms dilated ER cisternae in chondrocytes from hypochondrogenesis/achondrogenesis II patients, indicating ER stress from collagen misfolding.

[PMID:35225118] [INDIRECT EVIDENCE] [PARTIAL] While there is strong evidence that the UPR contributes to the pathology for collagen X misfolding mutations, the evidence that misfolding mutations in other collagen types induce a canonical, cytotoxic UPR is incomplete. --- Explanation: Authoritative review confirms UPR is plausible in collagenopathies but notes evidence for canonical cytotoxic UPR varies across collagen types and alleles.

[PMID:32399188] [INDIRECT EVIDENCE] [SUPPORT] As professionally secreting cells, chondrocytes are particularly susceptible to endoplasmic reticulum (ER) stress and this has been identified as a core disease mechanism in a group of clinically and pathologically related GSDs. --- Explanation: Review identifies chondrocyte ER stress as a core disease mechanism in genetic skeletal diseases.


MONDO:0019669

[PMID:25187577] [INDIRECT EVIDENCE] [SUPPORT] The COL2pathy-iChon cells showed suppressed expression of COL2A1 and significant apoptosis. A distended endoplasmic reticulum (ER) was detected, thus suggesting the adaptation of gene expression and cell death caused by excess ER stress. --- Explanation: Demonstrates that type II collagenopathy chondrocytes exhibit apoptosis linked to ER stress from misfolded collagen accumulation.


MONDO:0019669

[PMID:8175802] [INDIRECT EVIDENCE] [SUPPORT] In situ hybridization with cRNA probes revealed a significant level of alpha 1(I) mRNA in the cytoplasm of the patient's chondrocytes. --- Explanation: Demonstrates that chondrocytes in hypochondrogenesis aberrantly express type I collagen genes alongside type II collagen.


MONDO:0019669

[PMID:6641761] [INDIRECT EVIDENCE] [SUPPORT] high cellularity with poor matrix development; irregular columnization and vascular penetration; large chondrocytes and even more enlarged lacunae; large sclerotic cartilage canals --- Explanation: Original description of hypochondrogenesis confirming growth plate disorganization with hypercellularity, poor matrix, and irregular vascular penetration.

[PMID:3717210] [INDIRECT EVIDENCE] [SUPPORT] Chondro-osseous histology and ultrastructure was similar in all cases regardless of severity and was characterized by hypervascularity and hypercellularity of the cartilage --- Explanation: Confirms uniform growth plate pathology across the achondrogenesis II-hypochondrogenesis spectrum.


MONDO:0019669

[PMID:8175802] [INDIRECT EVIDENCE] [SUPPORT] Microscopic examination of cartilage showed that the mutation altered the organization of the growth plate. --- Explanation: Direct histological evidence of growth plate disorganization leading to ossification failure in a COL2A1-mutant hypochondrogenesis patient.

[PMID:3057886] [INDIRECT EVIDENCE] [SUPPORT] radiographs revealed short ribs, hypoplastic ilia, absence of ossification of sacrum, pubis, ischia, tali, calcanei, and many vertebral bodies; the long bones were short with mild metaphyseal flaring --- Explanation: Radiographic documentation of widespread ossification failure across multiple skeletal elements.


MAXO:0000950


MAXO:0000079


HGNC.SYMBOL:COL2A1 Mutations

[PMID:2572591] [SUPPORT] Here we demonstrate that the mutation in the type II procollagen gene is a single base change that converts the codon for glycine (GGC) at amino acid 943 of the alpha 1 (II) chain to a codon for serine (AGC). --- Explanation: Identifies a specific glycine-to-serine substitution in COL2A1 as causative of achondrogenesis II-hypochondrogenesis.

[PMID:8175802] [SUPPORT] Sequencing of exon 35 demonstrated a single base mutation that converted the codon for glycine at position 604 to a codon for alanine. --- Explanation: Identifies another specific COL2A1 glycine substitution mutation in a hypochondrogenesis patient.

[PMID:10797431] [SUPPORT] Mutations in the COL2A1 gene were found in all 12 patients. Ten of the mutations were single base substitutions that converted a codon for an obligate glycine to a codon for an amino acid with a bulkier side chain. --- Explanation: Confirms that virtually all achondrogenesis II/hypochondrogenesis patients carry COL2A1 mutations, predominantly glycine substitutions.


MONDO:0007793

[PMID:36442838] [SUPPORT] The patients presented with a short stature and/or short limbs. --- Explanation: All 20 Korean patients with confirmed FGFR3 N540K presented with short stature and/or short limbs as the primary clinical feature.

[PMID:41762373] [SUPPORT] HCH should be considered in the differential diagnosis of idiopathic or isolated short stature. --- Explanation: Expert consensus panel notes that HCH is an important differential for children with unexplained short stature.


MONDO:0007793

[PMID:41762373] [SUPPORT] Between ages 2-3 years, a characteristic growth pattern including limb shortening and body disproportion may become evident. --- Explanation: Expert diagnostic pathway review identifies limb shortening and body disproportion as a characteristic growth pattern becoming evident at ages 2-3 years.


MONDO:0007793

[PMID:36442838] [SUPPORT] Genu varum, macrocephaly, and developmental delay were observed in 11 (55.0%), 9 (45.0%), and 5 (25.0%) patients, respectively. --- Explanation: Macrocephaly was observed in 45% of 20 Korean patients with FGFR3 N540K-related hypochondroplasia.

[PMID:41762373] [SUPPORT] features suggestive of HCH include a sustained fall in length/height centiles over the first 2 years of life, relative macrocephaly, neonatal seizures, and specific radiographic and neuroimaging findings. --- Explanation: Expert consensus identifies relative macrocephaly as one of the key features suggestive of HCH diagnosis.


MONDO:0007793


MONDO:0007793

[PMID:36442838] [SUPPORT] Genu varum, macrocephaly, and developmental delay were observed in 11 (55.0%), 9 (45.0%), and 5 (25.0%) patients, respectively. --- Explanation: Genu varum was the most common skeletal feature in this cohort, observed in 55% of patients.


MONDO:0007793

[PMID:23165795] [SUPPORT] Eight patients had neurocognitive difficulties, ranging from specific learning disorder (2/13) to mild intellectual disability (5/13) or global developmental delay (1/13). --- Explanation: A retrospective study of 13 Finnish patients with confirmed FGFR3 N540K found that 8 (62%) had neurocognitive difficulties, a higher prevalence than previously appreciated.

[PMID:36442838] [SUPPORT] Genu varum, macrocephaly, and developmental delay were observed in 11 (55.0%), 9 (45.0%), and 5 (25.0%) patients, respectively. --- Explanation: Developmental delay was observed in 25% of Korean HCH patients with FGFR3 N540K.


MONDO:0007793

[PMID:23165795] [SUPPORT] Six of 13 patients had a history of seizures or epilepsy. --- Explanation: Seizures or epilepsy were present in 46% of Finnish HCH patients, though this cohort was selected for neurological workup and may overestimate true prevalence.

[PMID:41762373] [SUPPORT] features suggestive of HCH include a sustained fall in length/height centiles over the first 2 years of life, relative macrocephaly, neonatal seizures, and specific radiographic and neuroimaging findings. --- Explanation: Expert diagnostic consensus identifies neonatal seizures as a feature suggestive of HCH.


MONDO:0007793

[PMID:23165795] [SUPPORT] Eight patients had undergone MRI. They all had structural abnormalities consistent with temporal lobe dysgenesis. --- Explanation: All 8 HCH patients who underwent brain MRI showed temporal lobe dysgenesis in this neurologically selected cohort. True population frequency is likely lower.

[PMID:36442838] [SUPPORT] Of the 12 patients who underwent neuroimaging, five (41.7%) showed abnormal findings (one required operation for obstructive hydrocephalus). --- Explanation: In an unselected Korean cohort, 42% of neuroimaged patients had abnormal findings, providing a less biased estimate of neuroimaging abnormalities.


MONDO:0007793

[PMID:23165795] [SUPPORT] Six patients had peritrigonal white matter reduction, and 4 had abnormally shaped lateral ventricles. --- Explanation: Abnormally shaped lateral ventricles were found in 4 of 8 HCH patients who underwent MRI, alongside white matter changes.


MONDO:0007793

[PMID:29063142] [INDIRECT EVIDENCE] [SUPPORT] The FGFR3 gene encodes fibroblast growth factor receptor 3 protein, a negative regulator of chondrogenesis. Gain-of-function mutations result in constitutively activated FGFR3, leading to aberrant signal transduction, and accounting for inhibition of chondrocyte proliferation and differentiation. --- Explanation: Comprehensive review of FGFR3 molecular pathology establishing that gain-of-function mutations cause constitutive activation leading to impaired chondrocyte proliferation and differentiation.

[PMID:37345656] [INDIRECT EVIDENCE] [SUPPORT] Hypochondroplasia (HCH) is a mild dwarfism caused by missense mutations in fibroblast growth factor receptor 3 (FGFR3), with the majority of cases resulting from a heterozygous p.Asn540Lys gain-of-function mutation. --- Explanation: The first HCH mouse model confirms that the Asn540Lys gain-of-function mutation is sufficient to cause progressive dwarfism via FGFR3 activation.


MONDO:0007793

[PMID:29063142] [INDIRECT EVIDENCE] [SUPPORT] Gain-of-function mutations result in constitutively activated FGFR3, leading to aberrant signal transduction, and accounting for inhibition of chondrocyte proliferation and differentiation. --- Explanation: The FGFR3 therapeutic review establishes that aberrant MAPK/ERK signal transduction downstream of activated FGFR3 inhibits chondrocyte proliferation and differentiation.


MONDO:0007793

[PMID:37345656] [INDIRECT EVIDENCE] [SUPPORT] Fgfr3Asn534Lys/+ mice exhibited progressive dwarfism and impairment of the synchondroses of the cranial base, resulting in defective formation of the foramen magnum. --- Explanation: The HCH mouse model demonstrates that FGFR3 gain-of-function causes progressive dwarfism through impaired endochondral ossification.


MONDO:0007793

[PMID:37345656] [INDIRECT EVIDENCE] [SUPPORT] Trabecular bone mineral density (BMD) of long bones and vertebral bodies was decreased, but cortical BMD increased with age in both tibiae and femurs. These results demonstrate that bones in Fgfr3Asn534Lys/+ mice, due to FGFR3 activation, exhibit some characteristics of osteoporosis. --- Explanation: The HCH mouse model reveals a complex bone mineralization phenotype with decreased trabecular BMD and paradoxically increased cortical BMD with reduced mechanical toughness, suggesting osteoporosis risk in aging HCH patients.


MONDO:0007793

[PMID:37345656] [INDIRECT EVIDENCE] [SUPPORT] Fgfr3Asn534Lys/+ mice exhibited progressive dwarfism and impairment of the synchondroses of the cranial base, resulting in defective formation of the foramen magnum. --- Explanation: Mouse model demonstrates that FGFR3 gain-of-function directly disrupts cranial base synchondrosis development and foramen magnum formation, explaining the craniofacial features of HCH.


MAXO:0000058

[PMID:38813446] [SUPPORT] Vosoritide was well tolerated with no treatment-related serious adverse events. Injection site reactions occurred in 83.3% of participants. No participants discontinued therapy due to an adverse event. Annualized growth velocity increased by 2.26 standard deviations (SD) and height SDS increased by 0.36 SD during the treatment period versus the observation period. --- Explanation: Phase 2 trial in 24 children with HCH demonstrated that vosoritide significantly increased growth velocity with a favorable safety profile.


MAXO:0000058

[PMID:36442838] [SUPPORT] Among 16 growth-hormone-treated patients (two were growth-hormone deficient), the increase in height standard deviation scores was significant after a mean 5.4±0.7 years of treatment (+0.6 and+1.8 using growth references for healthy controls and achondroplasia children, respectively). --- Explanation: Korean cohort data shows statistically significant height gains with GH therapy in HCH, though the magnitude of improvement is modest.


MAXO:0000004

[PMID:36442838] [SUPPORT] Four patients underwent surgical limb lengthening at a mean age of 8.8±3.3 years. --- Explanation: Surgical limb lengthening was performed in 4 of 20 Korean HCH patients, typically in mid-childhood.


HGNC.SYMBOL:FGFR3 N540K mutation

[PMID:7670477] [SUPPORT] We now report a single FGFR3 mutation found in 8 out of 14 unrelated patients with hypochondroplasia. This mutation causes a C to A transversion at nucleotide 1620, resulting in an Asn540Lys substitution in the proximal tyrosine kinase domain. --- Explanation: Landmark Nature Genetics paper identifying the recurrent FGFR3 N540K mutation as the cause of hypochondroplasia in the majority of genetically confirmed cases.

[PMID:36442838] [SUPPORT] The N540K variant accounts for 60-70% of reported cases and is associated with severe manifestations. --- Explanation: Korean clinical series confirms the high frequency of the N540K variant among genetically confirmed HCH cases.

[PMID:41184854] [SUPPORT] Overall, 85.5% of ACH cases and 57.2% of HCH cases were related to de novo genetic variants --- Explanation: French nationwide data confirms that the majority of HCH cases arise from de novo FGFR3 variants.


MONDO:0018570

[PMID:26590809] [SUPPORT] HPP features rickets or osteomalacia and hypomineralization of teeth --- Explanation: Rickets and osteomalacia are the hallmark skeletal manifestations of HPP.

[PMID:20392236] [SUPPORT] Hypophosphatasia (HPP) is the instructive rickets or osteomalacia caused by loss-of-function mutation(s) within TNSALP --- Explanation: Defines HPP as a form of rickets/osteomalacia caused by TNSALP mutations.


MONDO:0018570

[PMID:26590809] [SUPPORT] HPP features rickets or osteomalacia and hypomineralization of teeth --- Explanation: Dental hypomineralization leading to premature tooth loss is a cardinal HPP feature.


MONDO:0018570

[PMID:32973344] [SUPPORT] mild HPP, characterized by low alkaline phosphatase and unspecific clinical signs, is dominantly inherited and very common --- Explanation: Low ALP is the defining biochemical feature, present even in the mildest HPP form.


MONDO:0018570


MONDO:0018570

[PMID:26590809] [SUPPORT] craniosynostosis and muscle weakness when HPP is severe --- Explanation: Craniosynostosis is a recognized complication of severe HPP, with mechanism not yet fully understood.


MONDO:0018570

[PMID:20392236] [SUPPORT] Aberrations of vitamin B(6) metabolism in HPP revealed that TNSALP is an ectoenzyme --- Explanation: Vitamin B6 metabolism defects explain pyridoxine-responsive seizures in severe HPP.


MONDO:0018570

[PMID:26529632] [SUPPORT] in its most severe perinatal and infantile forms, results in 50-100% mortality, typically from respiratory complications --- Explanation: Respiratory complications are the primary cause of death in severe perinatal/infantile HPP.


MONDO:0018570

[PMID:26590809] [INDIRECT EVIDENCE] [PARTIAL] ALPL mutations leading to deficient activity of the tissue-non-specific alkaline phosphatase isozyme (TNAP) and thereby extracellular accumulation of inorganic pyrophosphate (PPi), a natural substrate of TNAP and potent inhibitor of mineralization --- Explanation: Concise summary of the core HPP pathophysiology: ALPL mutations cause TNAP deficiency, PPi accumulation, and mineralization failure.

[PMID:20392236] [INDIRECT EVIDENCE] [SUPPORT] PP(i) inhibition of hydroxyapatite crystal growth extracellularly so that crystals form within matrix vesicles but fail to enlarge after these structures rupture --- Explanation: Explains the precise mineralization defect: hydroxyapatite crystals form in matrix vesicles but cannot grow after vesicle rupture due to PPi inhibition.

[PMID:20392236] [INDIRECT EVIDENCE] [SUPPORT] TNSALP is a phosphomonoester phosphohydrolase and a pyrophosphatase that hydrolyzes much lower concentrations of natural substrates than the artificial substrates of laboratory assays --- Explanation: Clarifies that TNSALP acts on natural substrates at physiological pH despite the misleading 'alkaline phosphatase' name.

[PMID:26590809] [INDIRECT EVIDENCE] [PARTIAL] Enzyme replacement using mineral-targeted TNAP from birth prevented severe HPP in TNAP-knockout mice and was then shown to rescue and substantially treat infants and young children with life-threatening HPP --- Explanation: Demonstrates that the mineralization defect is reversible with enzyme replacement, confirming the causal mechanism.


MONDO:0018570

[PMID:20392236] [INDIRECT EVIDENCE] [PARTIAL] Aberrations of vitamin B(6) metabolism in HPP revealed that TNSALP is an ectoenzyme --- Explanation: Vitamin B6 metabolism abnormalities in HPP demonstrated TNSALP's ectoenzyme nature.

[PMID:20392236] [INDIRECT EVIDENCE] [SUPPORT] Increased extracellular levels of pyridoxal 5'-phosphate and inorganic pyrophosphate (PP(i)) demonstrate that TNSALP is a phosphomonoester phosphohydrolase and a pyrophosphatase --- Explanation: Elevated PLP levels confirm TNSALP's role in PLP dephosphorylation.


HGNC.SYMBOL:ALPL Mutations

[PMID:32973344] [SUPPORT] We analyzed a cohort of 424 HPP patients from European geographic origin or ancestry. Using 3D modeling and results of functional tests we classified ALPL pathogenic variants according to their dominant negative effect (DNE) and their severity --- Explanation: Large cohort study of 424 patients classifying ALPL variants by severity and dominant negative effect.

[PMID:32973344] [SUPPORT] Pathogenic variants with DNE were found in both recessive and dominant HPP --- Explanation: Dominant negative variants can cause disease in both heterozygous (dominant) and homozygous (recessive) states.

[PMID:32973344] [SUPPORT] Homozygosity was an aggravating factor of the severity and moderate alleles were rare both in number and frequency --- Explanation: Homozygosity worsens phenotype; moderate alleles are uncommon.

[PMID:32973344] [SUPPORT] Adults with dominant HPP without DNE were found statistically less severely affected than adults with DNE variants --- Explanation: Genotype-phenotype correlation: dominant negative variants cause more severe disease than haploinsufficiency.


MONDO:0018874


MONDO:0018874

[PMID:37526143] [INDIRECT EVIDENCE] [SUPPORT] Mutations in isocitrate dehydrogenase (IDH) 1 and -2 increase the capacity of cancer cells to produce a normally scarce metabolite, D-2-hydroxyglutarate (2-HG), by several orders of magnitude. --- Explanation: This abstract links IDH1/2 mutations to increased 2-HG production, supporting the neomorphic IDH activity described.


MAXO:0000058


CHEBI:145430


CHEBI:145374


CHEBI:133021


MAXO:0000647


MAXO:0000747


HGNC.SYMBOL:IDH1


HGNC.SYMBOL:IDH2


MONDO:0018874

[PMID:23590662] [SUPPORT] myeloblasts in the blood or bone marrow. --- Explanation: Abstract notes myeloblasts in the blood or bone marrow in AML.


MONDO:0956994


MONDO:0956994

[PMID:40916936] [INDIRECT EVIDENCE] [SUPPORT] This unique immune microenvironment is shaped by 2-hydroxyglutarate (2-HG), an oncometabolite produced by mutant IDH. --- Explanation: This abstract directly states that mutant IDH produces 2-HG, supporting the neomorphic IDH activity described.


MAXO:0000004


MAXO:0000014


NCIT:C152914


HGNC.SYMBOL:IDH1

[PMID:26061751] [SUPPORT] three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class --- Explanation: TCGA data establishes IDH mutation status as a fundamental molecular classifier of lower-grade gliomas, more accurate than histologic class.


HGNC.SYMBOL:TP53

[PMID:26061751] [SUPPORT] Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). --- Explanation: TCGA data shows TP53 mutations in 94% of IDH-mutant non-codeleted (astrocytic) lower-grade gliomas.


HGNC.SYMBOL:ATRX

[PMID:26061751] [SUPPORT] Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). --- Explanation: TCGA data shows ATRX inactivation in 86% of IDH-mutant non-codeleted (astrocytic) lower-grade gliomas.


HGNC.SYMBOL:CDKN2A


MONDO:0956994

[PMID:36651583] [SUPPORT] oligodendroglioma IDH-mutant and 1p/19q codeleted, astrocytoma IDH-mutant, and --- Explanation: Abstract lists IDH-mutant oligodendroglioma and astrocytoma among diffuse gliomas.


MONDO:0003210


MONDO:0003210

[PMID:25536104] [INDIRECT EVIDENCE] [PARTIAL] Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). --- Explanation: Supports the presence of IDH1 mutations in intrahepatic cholangiocarcinoma.


MAXO:0000058


CHEBI:145430


MAXO:0000647


NCIT:C103194


CHEBI:27899


HGNC.SYMBOL:IDH1

[PMID:24569570] [PARTIAL] Hotspot mutations in IDH isoforms 1 or 2 occur in approximately 15% of intrahepatic cholangiocarcinomas. --- Explanation: Abstract reports IDH1/2 hotspot mutations in intrahepatic cholangiocarcinoma.


HGNC.SYMBOL:IDH2


HGNC.SYMBOL:ARID1A


HGNC.SYMBOL:BAP1


MONDO:0003210

[PMID:12901270] [PARTIAL] Histologically, 90-95% of CC are well differentiated --- Explanation: Abstract notes that the majority of cholangiocarcinomas are well differentiated.


MONDO:0859592

[PMID:26478444] [SUPPORT] Epilepsy develops in more than 70-90% of oligodendroglial tumors and represents a favorable indicator for long-term survival if present as the first clinical sign. --- Explanation: Documents the high frequency (70-90%) of seizures in oligodendroglial tumors and their prognostic significance.


MONDO:0859592


MONDO:0859592

[PMID:40916936] [INDIRECT EVIDENCE] [SUPPORT] This unique immune microenvironment is shaped by 2-hydroxyglutarate (2-HG), an oncometabolite produced by mutant IDH. --- Explanation: This abstract explicitly links mutant IDH to 2-HG production, supporting the neomorphic IDH mechanism.


MONDO:0859592

[PMID:37743332] [INDIRECT EVIDENCE] [SUPPORT] Oligodendrogliomas were clearly defined as tumors with IDH mutations and 1p/19q codeletion by the World Health Organization(WHO)in 2016. --- Explanation: Abstract defines oligodendrogliomas by IDH mutation and 1p/19q codeletion.


MAXO:0000004


MAXO:0000014


MAXO:0000647

[PMID:23071247] [SUPPORT] the median survival of those with codeleted tumors treated with PCV plus RT was twice that of patients receiving RT (14.7 v 7.3 years; HR = 0.59; 95% CI, 0.37 to 0.95; P = .03) --- Explanation: Landmark RTOG 9402 phase III trial demonstrating that PCV plus radiation doubles median survival compared to radiation alone in 1p/19q-codeleted anaplastic oligodendroglioma.

[PMID:23071237] [SUPPORT] The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors. --- Explanation: EORTC 26951 phase III trial confirming survival benefit of adjuvant PCV chemotherapy with preferential benefit in 1p/19q-codeleted tumors.


HGNC.SYMBOL:IDH1


HGNC.SYMBOL:CIC

[PMID:22072542] [SUPPORT] overall mutation rate in oligodendrogliomas in this study to 20/29 (69%) --- Explanation: Documents CIC mutation frequency of 69% in 1p/19q-codeleted oligodendrogliomas through exome sequencing.

[PMID:22072542] [SUPPORT] CIC mutations were highly associated with oligodendroglioma histology, 1p/19q co-deletion, and IDH1/2 mutation (p < 0.001) --- Explanation: Establishes strong association between CIC mutations and the defining features of oligodendroglioma.


HGNC.SYMBOL:FUBP1


HGNC.SYMBOL:TERT


HGNC.SYMBOL:NOTCH1


MONDO:0005342


MONDO:0005342

[PMID:39124764] [INDIRECT EVIDENCE] [PARTIAL] The pathogenesis of IgAN is considered a multifactorial process involving the formation of immune complexes wherein aberrantly O-glycosylated IgA1 is recognized as an autoantigen. --- Explanation: This 2024 review confirms that aberrantly O-glycosylated IgA1 is central to IgAN pathogenesis and serves as the autoantigen triggering immune complex formation.

[PMID:22904352] [INDIRECT EVIDENCE] [PARTIAL] Mesangial and circulating IgA1 with aberrantly glycosylated hinge region O-glycans characterize IgA nephropathy (IgAN). Unlike healthy individuals, some IgA1 is galactose deficient in patients with IgAN, leaving terminal N-acetylgalactosamine residues in the hinge region exposed. --- Explanation: This landmark study establishes that galactose-deficient IgA1 with exposed N-acetylgalactosamine residues is the characteristic molecular abnormality in IgAN.


MONDO:0005342

[PMID:22904352] [INDIRECT EVIDENCE] [SUPPORT] Circulating autoantibodies that recognize such galactose-deficient IgA1 as an autoantigen, or the levels of the autoantigen itself, may allow prediction of disease progression. --- Explanation: This study demonstrates that autoantibodies targeting galactose-deficient IgA1 are pathogenic in IgAN and correlate with disease progression.

[PMID:38427309] [INDIRECT EVIDENCE] [PARTIAL] The O-glycosylation status of IgA1 plays a crucial role in disease pathophysiology. The level of poorly-O-galactosylated IgA1, or galactose-deficient IgA1 (Gd-IgA1), has also been identified as a potential biomarker in IgAN. --- Explanation: This 2024 systematic review confirms that Gd-IgA1 is central to IgAN pathophysiology and serves as the target for autoantibody formation.


MONDO:0005342

[PMID:38182298] [INDIRECT EVIDENCE] [PARTIAL] Mesangial complement C3 deposits, reflecting alternative and possibly lectin pathway activation, are characteristic in biopsies of patients with IgA nephropathy (IgAN). --- Explanation: This 2024 study confirms that mesangial C3 deposition is a hallmark of IgAN, indicating complement activation triggered by immune complex deposition in the mesangium.

[PMID:38053977] [INDIRECT EVIDENCE] [PARTIAL] The alternative complement pathway is the major complement cascade activator in IgAN, and glomerular C3 deposition has been shown to correlate with disease progression. --- Explanation: This comprehensive 2023 review establishes that alternative complement pathway activation in the mesangium drives IgAN progression.

[PMID:35781866] [INDIRECT EVIDENCE] [PARTIAL] Patients with positive glomerular C3 deposition presented with more severe clinical and histopathological characteristics and a higher score on the Oxford scoring system. With the increasing intensity of C3 deposition, IgAN patients were more likely to present with high level of microscopic hematuria, fibrous crescents, interstitial inflammatory cell infiltration, and a higher score on segmental sclerosis lesions. --- Explanation: This study demonstrates that C3 deposition intensity in the mesangium correlates with disease severity and progression, supporting the role of complement-mediated mesangial injury in IgAN pathophysiology.


HGNC.SYMBOL:CFHR1/CFHR3 Deletion


HGNC.SYMBOL:HLA-DQB1


HGNC.SYMBOL:DEFA


MONDO:0017287


MONDO:0017287

[PMID:25988916] [INDIRECT EVIDENCE] [SUPPORT] IgG4-related disease (IgG4-RD) has emerged over the last decade as a unique immune-mediated condition that links multiple fibro-inflammatory disorders previously regarded as separate entities --- Explanation: Establishes IgG4-RD as a unified immune-mediated fibroinflammatory condition.

[PMID:25988916] [INDIRECT EVIDENCE] [SUPPORT] The gold-standard for the diagnosis of IgG4-RD, regardless of the organ(s) involved, is the identification of typical histopathology features (e.g., lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis) in the context of a significant IgG4+ plasma cell infiltrate --- Explanation: Confirms lymphoplasmacytic infiltrate with IgG4+ plasma cells as the histopathological hallmark.


MONDO:0017287

[PMID:25988916] [INDIRECT EVIDENCE] [SUPPORT] The major histopathologic features include a dense lymphoplasmacytic infiltrate, fibrosis that has a storiform pattern in focal (or diffuse) areas, and obliterative phlebitis. --- Explanation: Storiform fibrosis identified as one of the three major histopathological features of IgG4-RD.


MAXO:0000058

[PMID:25988916] [SUPPORT] Treatment with glucocorticoids failed to produce sustained remission in 77% of patients. --- Explanation: While glucocorticoids are first-line, they fail to produce sustained remission in the majority of patients.

[PMID:25809420] [SUPPORT] International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. --- Explanation: International consensus guidelines established for IgG4-RD management.


MAXO:0000058


MONDO:0008558

[PMID:38396839] [SUPPORT] Although the pathogenesis of ITP is currently better known and its etiology has been extensively studied, up to 75% of adult patients with ITP may develop chronicity, which represents a significant burden on patients' quality of life. A major risk of ITP is bleeding, but knowledge on the exact relationship between the degree of thrombocytopenia and bleeding symptoms, especially at a lower platelet count, is lacking. --- Explanation: This review highlights that thrombocytopenia is the cardinal feature of ITP, with up to 75% of adult patients developing chronic thrombocytopenia, and bleeding risk correlates with platelet count severity.


MONDO:0008558


MONDO:0008558

[PMID:38396839] [INDIRECT EVIDENCE] [NO_EVIDENCE] A better understanding of the underlying pathology has facilitated the development of a number of new targeted therapies (Bruton's tyrosine kinase inhibitors, neonatal Fc receptors, strategies targeting B and plasma cells, strategies targeting T cells, complement inhibitors, and newer TPO-RAs for improving megakaryopoiesis), which seem to be highly effective and well tolerated and result in a significant improvement in patients' quality of life. --- Explanation: This review confirms that autoantibody-mediated platelet destruction is central to ITP pathogenesis, with therapeutic strategies targeting Fc receptors and B cells showing efficacy.


MONDO:0008558

[PMID:38525349] [INDIRECT EVIDENCE] [SUPPORT] In vitro studies using ITP sera or monoclonal antibodies against platelet and megakaryocyte surface glycoproteins have shown an impairment of many steps of megakaryopoiesis and thrombopoiesis, such as megakaryocyte differentiation and maturation, migration from the osteoblastic to the vascular niche, adhesion to extracellular matrix proteins, and proplatelet formation, resulting in impaired and ectopic platelet production in the bone marrow and diminished platelet release in the bloodstream. --- Explanation: This study demonstrates that ITP autoantibodies directly impair multiple steps of megakaryocyte maturation and platelet production, contributing to thrombocytopenia beyond peripheral destruction.

[PMID:38525349] [INDIRECT EVIDENCE] [SUPPORT] Moreover, cytotoxic T cells may target bone marrow megakaryocytes, resulting in megakaryocyte destruction. --- Explanation: Evidence that cellular immunity, specifically cytotoxic T cells, can directly attack megakaryocytes in the bone marrow, providing a T cell-mediated mechanism for impaired platelet production.


MONDO:0008558

[PMID:37062251] [INDIRECT EVIDENCE] [SUPPORT] Studies have shown that an imbalance between T helper 17 (Th17) and Regulatory T (Treg) cells differentiated from CD4+T-cells is a key factor influencing the development and pathogenesis of immune thrombocytopenia. Th17 cells promote the development of chronic inflammatory disorders and induce autoimmune diseases, whereas Treg cells regulate immune homeostasis and prevent autoimmune diseases. --- Explanation: This review establishes that Th17/Treg imbalance is a key pathogenic factor in ITP, with Th17 cells promoting autoimmunity and Treg dysfunction leading to loss of tolerance.


MONDO:0008558

[PMID:32515487] [INDIRECT EVIDENCE] [SUPPORT] Statistical analyses showed that acute ITP patients had higher plasma levels of sC5b-9 and C1q than CR or PR patients (median = sC5b-9: 200 versus 98 mg/dl, P-value < 0·001) (median C1q = 2·11 versus 1·00 mg/dl, P-value < 0·001). CR and PR ITP patients had sC5b-9 and C1q plasma levels comparable to those observed in healthy volunteers. --- Explanation: This study demonstrates that complement activation markers (sC5b-9 and C1q) are significantly elevated in acute ITP patients compared to patients in remission, and that sC5b-9 levels inversely correlate with platelet count, supporting complement's role in ITP pathogenesis.

[PMID:32515487] [INDIRECT EVIDENCE] [SUPPORT] The pathogenesis involves antibody production, cytokine release, T cell impairment, complement activation and clearance of platelets. --- Explanation: This research explicitly identifies complement activation as one of the key pathogenic mechanisms in ITP alongside antibodies and T cell dysfunction.


MONDO:0009227

[PMID:28334876] [SUPPORT] Infantile myofibromatosis is one of the most prevalent soft tissue tumors of infancy and childhood. --- Explanation: Defines myofibromatosis as the hallmark feature.


MONDO:0009227

[PMID:28334876] [SUPPORT] Multifocal nodules with visceral lesions are associated with a poor prognosis. --- Explanation: Subcutaneous nodules are a characteristic presentation.


MAXO:0000058

[PMID:31017643] [SUPPORT] All of the PDGFRB mutations were associated with ligand-independent receptor activation, and all but one were sensitive to imatinib at clinically relevant concentrations. --- Explanation: Demonstrates sensitivity of PDGFRB mutants to imatinib.

[PMID:32500973] [SUPPORT] Three patients were treated with imatinib and had robust and rapid response, including the first two reported infants with multicentric myofibromas treated with imatinib monotherapy --- Explanation: Clinical evidence of imatinib response in infantile myofibromatosis.


hgnc:8804

[PMID:28334876] [SUPPORT] Mutations in the coding sequence of PDGFRB were identified in 6 out of 8 patients with the sporadic multicentric form of the disease and in 1 out of 8 patients with isolated myofibroma. --- Explanation: Demonstrates high frequency of PDGFRB mutations in sporadic multicentric myofibromatosis.

[PMID:31017643] [SUPPORT] Gain-of-function PDGFRB mutations were found in samples from 25 children, with no mutation found in samples from adults. --- Explanation: Largest cohort study confirming PDGFRB mutations in pediatric myofibromatosis.


MONDO:0009227


MONDO:0005550

[PMID:10884944] [INDIRECT EVIDENCE] [SUPPORT] On exposure to a pathogen, a host may resist infection, become subclinically infected, or progress through several stages from mild to severe infection. Chronic sequelae may or may not occur. Host factors, particularly host genes, influence many of these stages. --- Explanation: The abstract describes staged progression and host genetic influence on infectious disease outcomes.


MAXO:0001017

[PMID:10884944] [SUPPORT] Priorities for prevention and control of these pathogens include vaccines and antimicrobial drugs. --- Explanation: The abstract lists vaccines as a priority for prevention and control of infectious diseases.


MAXO:0000058

[PMID:10884944] [SUPPORT] Priorities for prevention and control of these pathogens include vaccines and antimicrobial drugs. --- Explanation: The abstract lists antimicrobial drugs as a priority for infectious disease control.


MONDO:0005812


MONDO:0005812

[DOI:10.3390/pathogens13070561] [SUPPORT] In some individuals, flu can lead to pneumonia and acute respiratory distress syndrome. --- Explanation: Confirms pneumonia as a serious complication of influenza.


MONDO:0005812

[DOI:10.3390/pathogens13070561] [INDIRECT EVIDENCE] [SUPPORT] Influenza virus possesses an RNA genome of single-stranded, negative-sensed, and segmented configuration. Influenza virus causes an acute respiratory disease, commonly known as the "flu" in humans. In some individuals, flu can lead to pneumonia and acute respiratory distress syndrome. --- Explanation: Describes influenza as an acute respiratory disease caused by viral infection of the respiratory tract.


MONDO:0005812

[DOI:10.3390/ijms25115909] [INDIRECT EVIDENCE] [SUPPORT] Because TLRs may act as a double-edged sword, a balanced TLR response is critical for the overall benefit of the host. --- Explanation: Confirms the dual role of TLR signaling in both antiviral defense and immunopathology during influenza.

[DOI:10.3390/pathogens13070561] [INDIRECT EVIDENCE] [SUPPORT] Host cells sense IAV infection through multiple receptors and mechanisms, which culminate in the induction of a concerted innate antiviral response and the creation of an antiviral state, which inhibits and clears the infection from host cells. --- Explanation: Describes innate antiviral sensing mechanisms including TLR pathways.


MONDO:0005812

[DOI:10.3390/v16101535] [INDIRECT EVIDENCE] [SUPPORT] Paradoxically, AIM2 deficiency has been linked to both enhanced and reduced vulnerability to IAV infection. --- Explanation: Describes the complex role of AIM2 inflammasome in influenza pathogenesis.

[DOI:10.3390/v16101535] [INDIRECT EVIDENCE] [SUPPORT] While a strong response is necessary for early viral control, overactivation of inflammasomes can precipitate harmful hyperinflammatory responses, a defining characteristic observed during severe influenza infections. --- Explanation: Confirms that inflammasome overactivation drives hyperinflammation in severe influenza.


MONDO:0005812

[DOI:10.3390/vetsci11110555] [INDIRECT EVIDENCE] [SUPPORT] Influenza A virus (IAV) infection initiates a complex interplay of cell death modalities, including apoptosis, necroptosis, pyroptosis, and their integration, known as PANoptosis, which significantly impacts host immune responses and tissue integrity. --- Explanation: Directly describes PANoptosis as integrated cell death modalities in IAV infection.


MAXO:0000058

[PMID:29955068] [SUPPORT] Antiviral agents that target the influenza virus enzyme neuraminidase have been developed for prophylaxis and therapy. --- Explanation: Confirms neuraminidase inhibitors as established influenza antivirals.


MAXO:0000058


MAXO:0001017

[PMID:29955068] [SUPPORT] Influenza vaccines are formulated every year to match the circulating strains, as they evolve antigenically owing to antigenic drift. --- Explanation: Describes the rationale for annual influenza vaccination.


MAXO:0000950


NCBITaxon:11320

[PMID:29955068] [SUPPORT] Influenza is an infectious respiratory disease that, in humans, is caused by influenza A and influenza B viruses. Typically characterized by annual seasonal epidemics, sporadic pandemic outbreaks involve influenza A virus strains of zoonotic origin. --- Explanation: Confirms influenza A causes seasonal epidemics and pandemic outbreaks of zoonotic origin.


NCBITaxon:11520

[PMID:29955068] [SUPPORT] Influenza is an infectious respiratory disease that, in humans, is caused by influenza A and influenza B viruses. --- Explanation: Confirms influenza B as a causative agent of human influenza.


MONDO:0010118

[PMID:3083684] [SUPPORT] Her serum threonine level was increased (2.0 to 5.3 mg/dl; normal, 0.78 to 1.82 mg/dl).
 --- Explanation: Documents elevated serum threonine levels in a patient with hyperthreoninemia, with quantitative values and normal range.


MONDO:0010118

[PMID:3083684] [SUPPORT] He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation.
 --- Explanation: Directly reports hyperthreoninuria in a patient with hyperthreoninemia.


MONDO:0010118

[PMID:6434824] [SUPPORT] A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH) is presented.
 --- Explanation: The index patient for threonine dehydratase deficiency presented with classical NKH symptoms alongside threoninemia.


MONDO:0010118

[PMID:6434824] [PARTIAL] A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH) is presented.
 --- Explanation: The abstract describes classical NKH symptoms without enumerating them individually. Seizures are a hallmark of NKH and are inferred from this presentation.


MONDO:0010118

[PMID:3083684] [SUPPORT] He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation.
 --- Explanation: Reports mental retardation in a patient with hyperthreoninemia.

[PMID:15168722] [SUPPORT] A screening program was carried out for amino acid disorders in children with mental handicaps from the state of Andhra Pradesh (India) during the last two decades.
 --- Explanation: Threoninemia was detected in the context of screening children with mental handicaps, supporting the association between threoninemia and intellectual disability.


MONDO:0010118

[PMID:3083684] [SUPPORT] He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation.
 --- Explanation: Directly reports hepatomegaly in a patient with hyperthreoninemia.


MONDO:0010118

[PMID:6434824] [PARTIAL] A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH) is presented.
 --- Explanation: The abstract describes classical NKH symptoms without enumerating them individually. Lethargy is a hallmark of NKH and is inferred from this presentation.


MONDO:0010118

[PMID:6434824] [PARTIAL] A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH) is presented.
 --- Explanation: The abstract describes classical NKH symptoms without enumerating them individually. Poor suck is a hallmark neonatal NKH symptom and is inferred from this presentation.


MONDO:0010118

[PMID:3083684] [SUPPORT] He also had hyperthreoninemia, hyperthreoninuria, hepatomegaly, and mental and physical retardation.
 --- Explanation: Physical retardation reported in a patient with hyperthreoninemia is consistent with failure to thrive.


MONDO:0010118

[PMID:3083684] [PARTIAL] Two siblings had Leber's congenital amaurosis. The girl (Patient 1) showed blindness shortly after birth, absent pupillary light reflex, and multiple round, white spots in both fundi.
 --- Explanation: Reports Leber congenital amaurosis in two siblings with hyperthreoninemia. Classified as PARTIAL because the causal relationship between hyperthreoninemia and LCA is not established.

[PMID:3083684] [PARTIAL] We suspect a close relationship between hyperthreoninemia and Leber's congenital amaurosis in these siblings.
 --- Explanation: The authors suggest a relationship but do not demonstrate causality.


MONDO:0010118

[PMID:6434824] [INDIRECT EVIDENCE] [SUPPORT] Threonine dehydratase was undetectable in a liver autopsy specimen, which was obtained within 1 h of death and immediately frozen at -70 degrees C. Activities of four marker enzymes were normal.
 --- Explanation: Direct demonstration of undetectable threonine dehydratase in liver tissue from a patient with threoninemia and NKH symptoms, establishing the enzyme deficiency as the primary metabolic block.

[PMID:6434824] [INDIRECT EVIDENCE] [SUPPORT] This represents the first documentation of an inborn error of threonine metabolism and a new explanation of NKH.
 --- Explanation: The authors explicitly frame this as the first documented inborn error of threonine metabolism.


MONDO:0010118


MONDO:0010118

[PMID:6434824] [INDIRECT EVIDENCE] [SUPPORT] A patient with classical symptoms of non-ketotic hyperglycinaemia (NKH) is presented.
 --- Explanation: The patient presented with classical NKH symptoms, consistent with the proposed mechanism of secondary hyperglycinemia from disrupted glycine-serine-threonine interconversion caused by excess threonine.


MAXO:0000088


MAXO:0000167


HGNC.SYMBOL:Threonine dehydratase (enzyme level)

[PMID:6434824] [SUPPORT] Threonine dehydratase was undetectable in a liver autopsy specimen, which was obtained within 1 h of death and immediately frozen at -70 degrees C.
 --- Explanation: Direct enzyme assay demonstrating undetectable threonine dehydratase activity in the index patient.


MONDO:0005052

[PMID:18252749] [SUPPORT] Increased TRPV1 nerve fibres are observed in IBS, together with a low-grade inflammatory response. The increased TRPV1 nerve fibres may contribute to visceral hypersensitivity and pain in IBS, and provide a novel therapeutic target. --- Explanation: TRPV1-expressing nerve fibers are increased in IBS and directly linked to abdominal pain severity.

[PMID:17241857] [SUPPORT] IBS-dependent excitation of dorsal root ganglia was inhibited by histamine H(1) receptor blockade and serine protease inactivation (inhibition of 51.7%; P < .05 and 74.5%; P < .05; respectively). --- Explanation: Mast cell mediators, particularly histamine and proteases, directly excite nociceptive neurons to produce abdominal pain in IBS.


MONDO:0005052


MONDO:0005052

[PMID:19595511] [SUPPORT] Approximately 39% of diarrhea-predominant IBS patients had increased intestinal membrane permeability as measured by the lactulose/mannitol ratio. --- Explanation: Increased intestinal permeability is present in a substantial proportion of IBS-D patients and may contribute to diarrheal symptoms.

[PMID:15100164] [SUPPORT] 5-HT directly and indirectly affects intestinal motor and secretory function and abnormalities may lead to either constipation or diarrhea. --- Explanation: Dysregulated serotonin signaling affects secretion and motility, contributing to diarrhea in IBS-D.


MONDO:0005052

[PMID:18252749] [INDIRECT EVIDENCE] [SUPPORT] A significant 3.5-fold increase in median numbers of TRPV1-immunoreactive fibres was found in biopsies from IBS patients compared with controls (p<0.0001). --- Explanation: TRPV1-expressing sensory nerve fibers are significantly increased in IBS, providing a molecular basis for visceral hypersensitivity.

[PMID:18252749] [INDIRECT EVIDENCE] [SUPPORT] In multivariate regression analysis, only TRPV1-immuno-reactive fibres (p = 0.005) and mast cells (p = 0.008) were significantly related to the abdominal pain score. --- Explanation: TRPV1 nerve fiber density directly correlates with abdominal pain severity in IBS patients.

[PMID:17241857] [INDIRECT EVIDENCE] [SUPPORT] Mediators from IBS patients, but not controls, markedly enhanced the firing of mesenteric nerves (14.7 +/- 3.2 imp/sec vs 2.8 +/- 1.5 imp/sec; P < .05) and stimulated mobilization of Ca(2+) in dorsal root ganglia neurons (29% +/- 4% vs 11% +/- 4%; P < .05). --- Explanation: Mucosal mediators from IBS patients directly excite visceral sensory neurons, demonstrating a mechanism for visceral hypersensitivity.

[PMID:17241857] [INDIRECT EVIDENCE] [SUPPORT] On average, 64% of dorsal root ganglia responsive to mediators were capsaicin-sensitive, known to mediate nociception. --- Explanation: The majority of sensory neurons activated by IBS mucosal mediators are nociceptive, explaining the pain phenotype.


MONDO:0005052

[PMID:15100164] [INDIRECT EVIDENCE] [SUPPORT] 5-HT release from enterochromaffin (EC) cells initiates peristaltic, secretory, vasodilatory, vagal and nociceptive reflexes. --- Explanation: Serotonin from enterochromaffin cells is a key regulator of intestinal motility and peristaltic reflexes.

[PMID:15100164] [INDIRECT EVIDENCE] [SUPPORT] 5-HT directly and indirectly affects intestinal motor and secretory function and abnormalities may lead to either constipation or diarrhea. --- Explanation: Dysregulated serotonin signaling can account for both IBS-D and IBS-C subtypes through effects on motility.


MONDO:0005052

[PMID:37048642] [INDIRECT EVIDENCE] [SUPPORT] Although the pathophysiology of IBS has not been fully elucidated, it involves dysregulation of communication between the brain and gut (brain-gut axis) which is associated with alterations in intestinal motility, gut permeability, visceral hypersensitivity and gut microbiota composition. --- Explanation: The gut-brain axis is a central organizing principle in IBS pathophysiology, integrating multiple dysfunctional mechanisms.

[PMID:15100164] [INDIRECT EVIDENCE] [SUPPORT] Ongoing, bidirectional brain-gut interactions involving 5-HT pathways occur that significantly influence the effector systems. --- Explanation: Serotonin pathways mediate bidirectional brain-gut communication in IBS.


MONDO:0005052

[PMID:17241857] [INDIRECT EVIDENCE] [SUPPORT] IBS-dependent nerve firing and Ca(2+) mobilization were correlated with the area of the colonic lamina propria occupied by mast cells (r = 0.74; P < .01, and r = 0.78; P < .01, respectively). --- Explanation: Mast cell density directly correlates with sensory neuron activation in IBS, establishing a quantitative relationship.

[PMID:17241857] [INDIRECT EVIDENCE] [SUPPORT] Mucosal mast cell mediators from IBS patients excite rat nociceptive visceral sensory nerves. These results provide new insights into the mechanism underlying visceral hypersensitivity in IBS. --- Explanation: Mast cell mediators from IBS patients directly activate nociceptive neurons, providing a mechanistic link to pain.

[PMID:18252749] [INDIRECT EVIDENCE] [SUPPORT] Substance P-immunoreactive fibres (p = 0.01), total nerve fibres (PGP9.5) (p = 0.002), mast cells (c-kit) (p = 0.02) and lymphocytes (CD3) (p = 0.03) were also significantly increased in the IBS group. --- Explanation: Both mast cells and immune cells are increased in IBS mucosa, indicating low-grade immune activation.


MONDO:0005052

[PMID:37048642] [INDIRECT EVIDENCE] [SUPPORT] It has a prevalence of 10 to 25% in the United States and has a high disease burden, as evidenced by reduced quality of life, decreased work productivity and increased healthcare utilization and costs. --- Explanation: IBS is a common disorder with substantial public health impact, emphasizing the importance of understanding pathophysiological mechanisms including microbiome alterations.


HGNC.SYMBOL:HTR3E


HGNC.SYMBOL:SCN5A


MONDO:0012648

[PMID:34544473] [SUPPORT] All patients presented continuously elevated C4-acylcarnitine levels with higher ratios of C4/C2 and C4/C3. --- Explanation: All 40 patients in the cohort showed persistent C4-acylcarnitine elevation.

[PMID:17304052] [SUPPORT] We identified 13 isobutyryl-CoA dehydrogenase-deficient patients through newborn screening due to an elevation of C4-acylcarnitine in dried blood spots. --- Explanation: Confirms C4-acylcarnitine elevation as the screening marker for IBDD.


MONDO:0012648

[PMID:17304052] [SUPPORT] Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. --- Explanation: The index case presented with anemia alongside cardiomyopathy.

[PMID:33432785] [SUPPORT] Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis. --- Explanation: Review of IBDD symptoms reported across published cases.


MONDO:0012648

[PMID:34544473] [SUPPORT] During follow-up, four patients had a transient motor delay, and two patients had growth delay. --- Explanation: Quantifies transient motor delay in 4 of 40 patients.


MONDO:0012648

[PMID:34544473] [SUPPORT] During follow-up, four patients had a transient motor delay, and two patients had growth delay. --- Explanation: Growth delay reported in 2 of 40 patients in the Chinese cohort.

[PMID:33432785] [SUPPORT] Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis. --- Explanation: Failure to thrive listed among reported IBDD symptoms.


MONDO:0012648

[PMID:30253142] [SUPPORT] Five patients remained asymptomatic during follow-up, whereas one juvenile had speech delay and one newborn exhibited clinical symptoms. --- Explanation: Speech delay reported in one of seven Chinese IBDD patients.

[PMID:33432785] [SUPPORT] Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis. --- Explanation: Speech delay is listed among reported symptoms in IBDD review.


MONDO:0012648

[PMID:33432785] [SUPPORT] Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis. --- Explanation: Hypotonia listed among symptoms reported in IBDD patients.


MONDO:0012648

[PMID:21659959] [SUPPORT] The mutant mice grew normally but demonstrated cold intolerance at young age with a progressive hepatic steatosis. --- Explanation: Mouse model demonstrates hepatic pathology consistent with reported human transaminase elevations.


MONDO:0012648

[PMID:17304052] [SUPPORT] Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. --- Explanation: The index IBDD case had cardiomyopathy as a presenting feature.

[PMID:28053874] [SUPPORT] One reported non-screened patient had dilated cardiomyopathy and anaemia at the age of two years. --- Explanation: Confirms dilated cardiomyopathy in the historically reported symptomatic case.


MONDO:0012648

[PMID:28053874] [PARTIAL] We report a 13 month old girl diagnosed with IBDD after developing hypoglycaemic encephalopathy (blood glucose 1.9 mmol/l) during an episode of rotavirus-induced gastroenteritis. --- Explanation: Single case presenting with hypoglycemia; causality uncertain.

[PMID:28053874] [PARTIAL] Though we suspect IBDD did not contribute to hypoglycaemia in this patient, patients should be followed-up carefully --- Explanation: Authors suspect IBDD did not cause the hypoglycemia episode.


MONDO:0012648

[PMID:33432785] [PARTIAL] trio whole exome sequencing did not establish an alternative secondary genetic diagnosis for autism, and reported long-term follow-up of IBDD patients is limited, it is possible that autism spectrum disorders could be one of the disease-associated features. --- Explanation: Single case report suggesting possible IBDD-autism association but causality uncertain.


MONDO:0012648

[PMID:33432785] [SUPPORT] Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis. --- Explanation: Emesis listed among reported IBDD symptoms.


MONDO:0012648

[PMID:21659959] [SUPPORT] The mutant mice grew normally but demonstrated cold intolerance at young age with a progressive hepatic steatosis. --- Explanation: Progressive hepatic steatosis demonstrated in ACAD8-deficient mouse model.

[PMID:21659959] [SUPPORT] This mouse model of isobutyryl-CoA dehydrogenase deficiency could provide us a better understanding of the possible role of IBD deficiency in mitochondriopathy and fatty liver. --- Explanation: Authors propose the mouse model supports investigating fatty liver in IBDD.


MONDO:0012648

[PMID:34544473] [INDIRECT EVIDENCE] [SUPPORT] Isobutyryl-CoA dehydrogenase deficiency (IBDD) is a rare autosomal recessive metabolic disorder resulting from variants in ACAD8 --- Explanation: Supports ACAD8 molecular dysfunction as the initiating defect.


MONDO:0012648


MONDO:0012648

[PMID:21104317] [INDIRECT EVIDENCE] [SUPPORT] Valine is one of the three branched-chain amino acids which undergoes oxidation within mitochondria. --- Explanation: Review confirming valine oxidation occurs in mitochondria via the ACAD8-dependent pathway.


MONDO:0012648

[PMID:34544473] [INDIRECT EVIDENCE] [SUPPORT] All patients presented continuously elevated C4-acylcarnitine levels with higher ratios of C4/C2 and C4/C3. Isobutyrylglycine occurred in only 8 patients. --- Explanation: Demonstrates the characteristic biomarker pattern including variable isobutyrylglycine.

[PMID:15505379] [INDIRECT EVIDENCE] [SUPPORT] It is as yet uncertain whether IBD deficiency may cause significant morbidity in affected children and whether treatment is necessary. --- Explanation: Early report confirming IBD deficiency detected by metabolite accumulation in newborn screening.


MONDO:0012648

[PMID:21659959] [INDIRECT EVIDENCE] [SUPPORT] The mutant mice grew normally but demonstrated cold intolerance at young age with a progressive hepatic steatosis. --- Explanation: Mouse model of IBDD showing progressive hepatic steatosis and mitochondrial abnormalities.

[PMID:21659959] [INDIRECT EVIDENCE] [SUPPORT] Homozygous mutant mice hepatocytes had abnormal mitochondria with crystalline inclusions, suggestive of mitochondriopathy. --- Explanation: Demonstrates mitochondrial pathology in hepatocytes of ACAD8-deficient mice.


MAXO:0000950

[PMID:34544473] [SUPPORT] All patients were regularly monitored once they were diagnosed, and each patient gradually had a normal diet after 6 months of age. --- Explanation: Describes conservative monitoring approach with gradual diet normalization.

[PMID:28053874] [SUPPORT] Though we suspect IBDD did not contribute to hypoglycaemia in this patient, patients should be followed-up carefully --- Explanation: Supports careful monitoring due to uncertain clinical significance.


MAXO:0000088

[PMID:34544473] [SUPPORT] All patients were regularly monitored once they were diagnosed, and each patient gradually had a normal diet after 6 months of age. --- Explanation: Describes gradual normalization of diet in monitored IBDD patients.


MAXO:0000058

[PMID:17304052] [SUPPORT] Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. --- Explanation: The index case had secondary carnitine deficiency, supporting supplementation when deficient.

[PMID:28053874] [PARTIAL] Free carnitine was normal in all acylcarnitine samples. --- Explanation: Carnitine supplementation was not needed in this case as free carnitine remained normal.


MAXO:0000950

[PMID:28053874] [PARTIAL] The patient was given, but has not used, a glucose polymer emergency regimen --- Explanation: Emergency regimen provided as precaution but never required in 10 years of follow-up.


MAXO:0000124

[PMID:34544473] [SUPPORT] The concentration of C4-acylcarnitine in NBS plus subsequent genetic testing is necessary for IBDD diagnosis. --- Explanation: Confirms NBS combined with genetic testing as the diagnostic pathway.


MAXO:0000124

[PMID:38137468] [SUPPORT] Our results suggest that the new ratios are optimal indicators for identifying true positives, distinguishing between two rare diseases that share the same primary biomarker, improving the predictive positive value (PPV). --- Explanation: Novel ratios demonstrated statistical robustness for screening discrimination.


MAXO:0000079

[PMID:34544473] [SUPPORT] Isobutyryl-CoA dehydrogenase deficiency (IBDD) is a rare autosomal recessive metabolic disorder resulting from variants in ACAD8 --- Explanation: Autosomal recessive inheritance supports the role of genetic counseling.

[PMID:15505379] [SUPPORT] In view of the limited experience worldwide, careful monitoring of the children is recommended. --- Explanation: Uncertainty about clinical significance supports counseling for informed family decision-making.


MAXO:0000124

[PMID:34869113] [SUPPORT] the application of second-tier tests before the release of neonatal screening results reduced referrals by over 91.89% and improved the positive predictive value (PPV) for short-chain acyl-CoA dehydrogenase deficiency/isobutyryl-CoA dehydrogenase deficiency (SCADD/IBDD) screening. --- Explanation: Demonstrates that second-tier testing greatly reduces unnecessary referrals.


HGNC.SYMBOL:ACAD8 pathogenic variants

[PMID:34544473] [SUPPORT] Both the genotypes and ACAD8 variants in IBDD are highly heterogeneous, and no significant correlations between genotype and phenotype are present here in patients with IBDD. --- Explanation: Confirms high genetic heterogeneity and absence of genotype-phenotype correlation.

[PMID:33432785] [SUPPORT] Statistical analysis of these parameters did not establish significant differences amongst both groups. --- Explanation: No significant genotype-phenotype correlation found when comparing symptomatic and asymptomatic groups.


MONDO:0009475

[PMID:38344522] [SUPPORT] Laboratory results showed acidosis (81%), hyperammonemia (71.4%), and hypoglycemia (14.3%). --- Explanation: Directly quantifies acidosis at 81% in an IVA cohort.

[PMID:41133704] [SUPPORT] The clinical presentation is highly variable, ranging from life-threatening metabolic crises with metabolic acidosis and hyperammonemia to a clinically asymptomatic only biochemical phenotype. --- Explanation: Supports metabolic acidosis as a key crisis phenotype.


MONDO:0009475

[PMID:38344522] [SUPPORT] Laboratory results showed acidosis (81%), hyperammonemia (71.4%), and hypoglycemia (14.3%). --- Explanation: Directly quantifies hyperammonemia at 71.4% in an IVA cohort.

[PMID:30522498] [SUPPORT] Repeated and frequent episodes of hyperammonaemia (alongside metabolic decompensations) can result in impaired growth and intellectual disability, the severity of which increase with longer duration of hyperammonaemia. --- Explanation: Supports hyperammonemia as contributing to neurological sequelae.


MONDO:0009475

[PMID:38344522] [SUPPORT] Vomiting was the most prevalent symptom (57.1%), and encephalopathy occurred in 33.3%. --- Explanation: Directly quantifies vomiting as the most common symptom.


MONDO:0009475

[PMID:38344522] [SUPPORT] Vomiting was the most prevalent symptom (57.1%), and encephalopathy occurred in 33.3%. --- Explanation: Directly quantifies encephalopathy at 33.3% in an IVA cohort.

[PMID:19210957] [SUPPORT] Patients affected by IVAcidemia suffer from acute episodes of encephalopathy, whose underlying mechanisms are poorly known. --- Explanation: Confirms encephalopathy as a recognized acute manifestation of IVA.


MONDO:0009475

[PMID:30522498] [SUPPORT] The 'classic' organic acidaemias (OAs) (propionic, methylmalonic and isovaleric) typically present in neonates or infants as acute metabolic decompensation with encephalopathy. --- Explanation: Acute metabolic decompensation with encephalopathy encompasses lethargy as a presenting feature.


MONDO:0009475

[PMID:38344522] [SUPPORT] Laboratory results showed acidosis (81%), hyperammonemia (71.4%), and hypoglycemia (14.3%). --- Explanation: Directly quantifies hypoglycemia at 14.3% in an IVA cohort.


MONDO:0009475

[PMID:30522498] [SUPPORT] This is frequently accompanied by severe hyperammonaemia and constitutes a metabolic emergency, as increased ammonia levels and accumulating toxic metabolites are associated with life-threatening neurological complications. --- Explanation: Severe neurological complications from hyperammonemia include seizures during metabolic crises.


MONDO:0009475

[PMID:30522498] [SUPPORT] Repeated and frequent episodes of hyperammonaemia (alongside metabolic decompensations) can result in impaired growth and intellectual disability, the severity of which increase with longer duration of hyperammonaemia. --- Explanation: Supports developmental compromise from repeated hyperammonemic episodes.


MONDO:0009475

[PMID:30522498] [SUPPORT] Repeated and frequent episodes of hyperammonaemia (alongside metabolic decompensations) can result in impaired growth and intellectual disability, the severity of which increase with longer duration of hyperammonaemia. --- Explanation: Directly supports intellectual disability as outcome of repeated hyperammonemic episodes in organic acidaemias.


MONDO:0009475

[PMID:30522498] [SUPPORT] Repeated and frequent episodes of hyperammonaemia (alongside metabolic decompensations) can result in impaired growth and intellectual disability --- Explanation: Supports impaired growth as a consequence of recurrent metabolic instability.


MONDO:0009475


MONDO:0009475

[PMID:27613073] [SUPPORT] Among these disorders, methyl malonic aciduria, propionic aciduria, maple syrup urine disease and isovaleric aciduria are sometimes referred to as classical organic acidurias. --- Explanation: IVA is a classical organic aciduria characterized by distinct volatile acid accumulation producing the sweaty feet odor.


MONDO:0009475

[PMID:41133704] [INDIRECT EVIDENCE] [SUPPORT] Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading to an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids. --- Explanation: Supports IVD molecular dysfunction as the initiating defect.


MONDO:0009475

[PMID:30740403] [INDIRECT EVIDENCE] [SUPPORT] Organic acids (OAs) are intermediary products of several amino acid catabolism or degradation via multiple biochemical pathways for energy production. --- Explanation: Supports organic acid disorders as defects in amino acid catabolic pathways.


MONDO:0009475

[PMID:30740403] [INDIRECT EVIDENCE] [SUPPORT] High anion gap metabolic acidosis with hyperammonemia is a characteristic OA biochemical finding. --- Explanation: Supports hyperammonemia as characteristic of organic acid disorders.

[PMID:41133704] [INDIRECT EVIDENCE] [SUPPORT] The clinical presentation is highly variable, ranging from life-threatening metabolic crises with metabolic acidosis and hyperammonemia to a clinically asymptomatic only biochemical phenotype. --- Explanation: Directly supports hyperammonemia as a key crisis feature of IVA.


MONDO:0009475

[PMID:19210957] [INDIRECT EVIDENCE] [SUPPORT] IVA administration significantly inhibited (14)CO(2) production from acetate (22%) and citrate synthase activity (20%) in cerebral cortex homogenates prepared 24 h after injection. --- Explanation: Demonstrates TCA cycle impairment in cerebral cortex from isovaleric acid exposure in vivo.

[PMID:27613073] [INDIRECT EVIDENCE] [SUPPORT] More than 65 organic acidurias have been described --- Explanation: Review providing pathogenetic basis for oxidative stress and mitochondrial dysfunction in classical organic acidurias including IVA.


MONDO:0009475

[PMID:19210957] [INDIRECT EVIDENCE] [SUPPORT] IVA injection significantly inhibited Na(+),K(+)-ATPase activity (25%) in cerebral cortex of rats 2 or 24 h after IVA administration, while pre-treatment of rats with creatine completely prevented the inhibitory effects of IVA on Na(+),K(+)-ATPase. --- Explanation: Demonstrates direct inhibition of Na+,K+-ATPase by isovaleric acid in cerebral cortex and prevention by creatine.


MAXO:0000088

[PMID:41133704] [SUPPORT] Treatment consists of a protein-restricted diet combined with supplementation of carnitine and/or glycine and emergency treatment in catabolic episodes. --- Explanation: Directly supports protein-restricted diet as the primary chronic treatment.

[PMID:38344522] [SUPPORT] The early initiation of treatment for organic acid disorders carries a more favorable prognosis. --- Explanation: Supports early treatment initiation including dietary management for better outcomes.


MAXO:0000058

[PMID:41133704] [SUPPORT] Treatment consists of a protein-restricted diet combined with supplementation of carnitine and/or glycine and emergency treatment in catabolic episodes. --- Explanation: Directly supports carnitine supplementation as part of standard IVA treatment.


MAXO:0000058

[PMID:41133704] [SUPPORT] Treatment consists of a protein-restricted diet combined with supplementation of carnitine and/or glycine and emergency treatment in catabolic episodes. --- Explanation: Directly supports glycine supplementation as part of standard treatment.


MAXO:0000058

[PMID:30522498] [SUPPORT] Treatment with N-carbamyl-L-glutamate can rapidly normalise ammonia levels by stimulating the first step of the urea cycle. --- Explanation: Directly supports N-carbamylglutamate as an effective treatment for hyperammonemia in organic acidaemias.


MAXO:0000950

[PMID:41133704] [SUPPORT] Treatment consists of a protein-restricted diet combined with supplementation of carnitine and/or glycine and emergency treatment in catabolic episodes. --- Explanation: Directly supports emergency treatment during catabolic episodes.

[PMID:30522498] [SUPPORT] The acute management of hyperammonaemia in organic acidaemias requires administration of intravenous calories as glucose and lipids to promote anabolism, carnitine to promote urinary excretion of urinary organic acid esters, and correction of metabolic acidosis --- Explanation: Provides detailed acute management protocol for hyperammonemia in organic acidaemias.


MAXO:0000124

[PMID:36636590] [SUPPORT] Out of 156 772 newborns tested, one turned out to have genetically proven IVA while 99 were false positive (C5: 0.5-8.2 μmol/L) due to the presence of pivaloylcarnitine. --- Explanation: Documents NBS implementation and the high false-positive rate from pivaloylcarnitine interference.

[PMID:36837923] [SUPPORT] Our results show that this reduces the false positive rate by 69.9% from 103 to 31 while maintaining 100% sensitivity in cross-validation. --- Explanation: Demonstrates machine learning approach to improve NBS specificity for IVA.


MAXO:0000079

[PMID:41133704] [SUPPORT] Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD) --- Explanation: Inherited genetic etiology supports the role of genetic counseling for affected families.


hgnc:6186

[PMID:41133704] [SUPPORT] Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading to an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids. --- Explanation: Directly supports IVD as the causal gene with characteristic metabolite accumulation.

[PMID:27613073] [SUPPORT] Among these disorders, methyl malonic aciduria, propionic aciduria, maple syrup urine disease and isovaleric aciduria are sometimes referred to as classical organic acidurias. --- Explanation: Supports IVA as a classical organic aciduria with well-defined genetic basis.


MONDO:0007400

[PMID:7874170] [SUPPORT] Jackson-Weiss syndrome is an autosomal dominant condition characterized by craniosynostosis, foot anomalies and great phenotypic variability. --- Explanation: Confirms craniosynostosis as a key feature of Jackson-Weiss syndrome.


MONDO:0007400

[PMID:1271196] [PARTIAL] An unusual spectrum of craniofacial and foot abnormalities has been detected within a large midwestern Amish kindred. --- Explanation: Provides partial support for recurrent craniofacial abnormality in the original Jackson-Weiss kindred, although the abstract does not localize the defect specifically to the midface.


MONDO:0007400

[PMID:1271196] [PARTIAL] All affected individuals had some clinical or radiologic abnormality of the feet. --- Explanation: Original description establishing foot abnormalities as universal in affected individuals.


MONDO:0007400

[PMID:1271196] [SUPPORT] All affected individuals had some clinical or radiologic abnormality of the feet. --- Explanation: The original description noted characteristic foot abnormalities including tarsal/metatarsal involvement.


MONDO:0007400


MONDO:0007400

[PMID:1271196] [SUPPORT] Enlarged great toes and craniofacial abnormalities suggested Pfeiffer acrocephalosynadactyly type V; however, thumb abnormalities were not present. --- Explanation: The original description explicitly notes absence of thumb/hand abnormalities, distinguishing JWS from Pfeiffer syndrome.


MONDO:0007400

[PMID:7874170] [INDIRECT EVIDENCE] [PARTIAL] We now report an FGFR2 mutation in the conserved region of the immunoglobulin IIIc domain in the Jackson-Weiss syndrome family in which the syndrome was originally described. --- Explanation: Landmark paper identifying FGFR2 mutations as the cause of Jackson-Weiss syndrome in the original Amish kindred.

[PMID:9385368] [INDIRECT EVIDENCE] [PARTIAL] Both nucleotide changes predict a serine for cysteine-342 substitution in the second half of the third immunoglobulin-like domain. --- Explanation: Identifies specific FGFR2 mutations in JWS patients affecting the immunoglobulin-like domain critical for receptor function.


MAXO:0000004


HGNC.SYMBOL:FGFR2 Mutations

[PMID:7874170] [SUPPORT] We now report an FGFR2 mutation in the conserved region of the immunoglobulin IIIc domain in the Jackson-Weiss syndrome family in which the syndrome was originally described. --- Explanation: First identification of FGFR2 mutation in JWS, establishing FGFR2 as the causative gene.

[PMID:8644708] [SUPPORT] Fibroblast growth factor receptor 2 (FGFR2) mutations have been associated with the craniosynostotic conditions Crouzon, Jackson-Weiss, and Pfeiffer syndromes. --- Explanation: Confirms FGFR2 mutations cause JWS along with related craniosynostosis syndromes.

[PMID:8528214] [SUPPORT] In addition, the Jackson-Weiss syndrome mutation, C342R, in exon IIIc was observed previously in other craniosynostotic syndromes, Crouzon and Pfeiffer. --- Explanation: This directly shows that a Jackson-Weiss-associated FGFR2 allele is shared with Crouzon and Pfeiffer syndrome rather than being syndrome-private.

[PMID:9385368] [SUPPORT] Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been recently identified as causes of this syndrome and of at least four other craniosynostotic disorders, namely the Apert, Beare-Stevenson cutis gyrata, Crouzon and Pfeiffer syndromes. --- Explanation: Identifies novel FGFR2 mutations specific to JWS that overlap with Crouzon syndrome mutations.


MONDO:0015346

[PMID:32554361] [SUPPORT] Jeavons syndrome (JS) is mainly characterized by eyelid myoclonia with or without absences. --- Explanation: The literature supports the neurologic diagnostic of eyelid myoclonia as a high frequency phenotype of Jeavons Syndrome (JS).

[PMID:30685520] [SUPPORT] Eyelid myoclonia, the most common seizure type in all 8 patients, were typically initiated by eating or other simple orofacial stimuli. --- Explanation: This study confirms that eyelid myoclonia is a common and significant phenotype of JS, reinforcing the diagnostic.

[PMID:36216271] [SUPPORT] To the best of our knowledge, this is the first case of STAG2 encephalopathy fulfilling all electroclinical criteria for epilepsy with eyelid myoclonia and absences (EMA), formally named Jeavons syndrome (JS). --- Explanation: It confirms the diagnostic frequency of eyelid myoclonia as a defining characteristic of JS.

[PMID:14706039] [PARTIAL] Seizures induced by photic (or visual) stimuli or photosensitive seizures can be observed in generalized or focal, idiopathic, or symptomatic epilepsies... --- Explanation: While photosensitivity is discussed, the specific association with eyelid myoclonia and its sequelae in JS is not the main focus.


MONDO:0015346

[PMID:15508923] [SUPPORT] Eyelid myoclonia and absence. --- Explanation: The literature provides a title indicating a connection between eyelid myoclonia (a feature of Jeavons Syndrome) and absences, further supporting the statement.


MONDO:0015346

[PMID:30082241] [PARTIAL] After a median follow-up of two years, 80% of patients had drug-resistant epilepsy and 70% experienced generalized tonic-clonic seizures. --- Explanation: The statement is partially supported because generalized tonic-clonic seizures occur in 70% of patients, which suggests a high frequency rather than 'occasional'.