HGNC.SYMBOL:EPCAM

[PMID:23411950] [SUPPORT] Germline mutations of 4 MMR genes, e.g., MLH1, MSH2, MSH6 and PMS2, had been identified as the cause of this disease, however, a novel mechanism, epigenetic inactivation of MSH2 gene due to hypermethylation of promotor region by the deletion of 3'part of epithelial cell adhesion molecule(EPCAM) gene which is located upstream of the MSH2 gene, has been reported in recent years.

[PMID:30461124] [SUPPORT] Monoallelic deletions of the 3' end of EPCAM that silence the downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer predisposition syndrome associated with loss of DNA mismatch repair.

[PMID:37088804] [SUPPORT] Four EO cases stood out: two with POLE/POLD1 variants in the key exonuclease domain, one with a BMPR1A duplication and one with an EPCAM deletion. --- Explanation: EPCAM deletion is mentioned as one of the variants related to Lynch Syndrome.


MONDO:0008721

[PMID:11263545] [SUPPORT] Clinical data on the probability of clinical disease indicates that MCADD patients are at risk for the following outcomes: hypoglycemia, vomiting, lethargy, encephalopathy, respiratory arrest, hepatomegaly, seizures, apnea, cardiac arrest, coma, and sudden and unexpected death. --- Explanation: This HuGE review of clinical data confirms hypoglycemia as a key clinical outcome in MCAD deficiency patients.


MONDO:0008721


MONDO:0008721

[PMID:11263545] [INDIRECT EVIDENCE] [SUPPORT] Medium chain acyl-CoA dehydrogenase (MCAD) is a tetrameric flavoprotein essential for the beta-oxidation of medium chain fatty acids. MCAD deficiency (MCADD) is an inherited error of fatty acid metabolism. --- Explanation: This epidemiological review confirms MCAD is essential for medium-chain fatty acid beta-oxidation and its deficiency causes a metabolic disorder.


MAXO:0000088

[PMID:18838415] [SUPPORT] The basic treatment is dietary: avoid fasting and ensure a high carbohydrate intake during any illness. --- Explanation: This clinical review confirms fasting avoidance and high carbohydrate intake as the basic treatment for MCAD deficiency.

[PMID:11263545] [SUPPORT] For those diagnosed, long-term management of the disease includes preventing stress caused by fasting and maintaining a high-carbohydrate, reduced-fat diet, and carnitine supplementation. --- Explanation: Confirms fasting avoidance and dietary management as key long-term management strategies for MCAD deficiency.


MAXO:0000058

[PMID:11263545] [SUPPORT] Acute attacks must be treated immediately with appropriate intravenous doses of glucose. --- Explanation: Confirms intravenous glucose as the immediate treatment for acute metabolic crises in MCAD deficiency.


MAXO:0000088

[PMID:11263545] [SUPPORT] long-term management of the disease includes preventing stress caused by fasting and maintaining a high-carbohydrate, reduced-fat diet, and carnitine supplementation. --- Explanation: Mentions carnitine supplementation as part of long-term management, though its routine use remains debated.


MAXO:0000088


HGNC.SYMBOL:ACADM variants

[PMID:11263545] [SUPPORT] One variant of the MCAD gene, G985A, a point mutation causing a change from lysine to glutamate at position 304 (K304E) in the mature MCAD protein, has been found in 90% of the alleles in MCADD patients identified retrospectively. --- Explanation: This epidemiological review documents that the K304E (G985A) mutation accounts for 90% of disease alleles in retrospectively identified patients.

[PMID:11263545] [SUPPORT] Of patients clinically diagnosed with MCADD, 81% who have been identified retrospectively are homozygous for K304E, and 18% are compound heterozygotes for K304E. --- Explanation: Provides genotype distribution showing 81% of patients are homozygous and 18% compound heterozygous for the common K304E variant.

[PMID:7904584] [SUPPORT] Approximately 90% of the disease-causing alleles in diagnosed patients are due to a single base mutation, an A (adenine) to G (guanine) transition at position 985 of MCAD cDNA (G985). --- Explanation: Confirms the predominance of the G985 mutation and documents the founder effect from northwestern Europe.

[PMID:23574375] [SUPPORT] The proportion of c.985A>G homozygotes was highest in Western Europe with 4.1 (95%CI: 2.8-5.6) per 100,000 individuals, then the New World (3.2, 95%CI: 2.0-4.7), Southern (1.2, 95%CI: 0.6-2.0) and Eastern European regions (0.9, 95%CI: 0.5-1.7). --- Explanation: Meta-analysis of 43 studies quantifies regional variation in c.985A>G frequency, supporting the northwestern European founder effect.


MONDO:0010436

[PMID:20425814] [SUPPORT] MECP2 duplication syndrome is 100% penetrant in affected males and is associated with infantile hypotonia, severe to profound mental retardation --- Explanation: Clinical review confirms severe to profound intellectual disability is a universal feature in affected males.


MONDO:0010436

[PMID:20301461] [SUPPORT] MECP2 duplication syndrome is a severe neurodevelopmental disorder characterized by early-onset hypotonia --- Explanation: GeneReviews entry identifies early-onset hypotonia as a characteristic feature.


MONDO:0010436

[PMID:20301461] [SUPPORT] recurrent respiratory infections (in ~75% of affected individuals) --- Explanation: GeneReviews entry provides frequency estimate for recurrent respiratory infections.

[PMID:28938254] [SUPPORT] Respiratory infections are the main cause of early death in patients with MECP2 duplication syndrome. --- Explanation: Documents that respiratory infections are the primary cause of mortality.


MONDO:0010436

[PMID:20301461] [SUPPORT] seizures (in ~50%) --- Explanation: GeneReviews provides frequency estimate for seizures.

[PMID:33170557] [SUPPORT] At baseline visit 28 participants had epilepsy. The average age of seizure onset was 8.96 years --- Explanation: Natural history study shows 28/69 participants had epilepsy with mean onset at 9 years.


MONDO:0010436

[PMID:33170557] [SUPPORT] Motor Dysfunction subscale (Figure 2) scores worsen with increasing age --- Explanation: Natural history study demonstrates progressive motor dysfunction including spasticity worsening with age.


MONDO:0010436

[PMID:20425814] [SUPPORT] poor speech development --- Explanation: Clinical review confirms poor speech development as a core feature.


MONDO:0010436

[PMID:20301461] [SUPPORT] gastrointestinal manifestations including gastroesophageal reflux and constipation --- Explanation: GeneReviews identifies GI manifestations as characteristic features.


MONDO:0010436

[PMID:20425814] [SUPPORT] autism or autistic features --- Explanation: Clinical review identifies autistic features as a common manifestation.


MONDO:0010436

[PMID:33170557] [SUPPORT] Twenty-two percent (n = 15 of 69 total) of the participants had regressed at the time of their visit, and average age of regression was 10.38 years --- Explanation: Natural history study documents regression in 22% of participants at baseline, likely underestimate given cross-sectional design.


MONDO:0010436

[PMID:20301461] [SUPPORT] early-onset hypotonia, feeding difficulty, gastrointestinal manifestations including gastroesophageal reflux and constipation --- Explanation: GeneReviews identifies feeding difficulty as a characteristic early feature.


MONDO:0010436

[PMID:20301461] [SUPPORT] delayed psychomotor development leading to severe intellectual disability --- Explanation: GeneReviews confirms global developmental delay as a core feature.

[PMID:35313898] [SUPPORT] The key features of MDS include intellectual disability, developmental delay, hypotonia, seizures, recurrent respiratory infections, gastrointestinal problems, behavioural features of autism and dysmorphic features --- Explanation: Comprehensive 20-year review confirms developmental delay as a key feature.


MONDO:0010436

[PMID:33638179] [INDIRECT EVIDENCE] [SUPPORT] MDS is a neurodegenerative disorder in which neurons die in specific parts of the central nervous system, including the cortex, hippocampus, cerebellum, and spinal cord. Neuronal death likely results from astrocytic dysfunction, including a breakdown of glutamate homeostatic mechanisms. --- Explanation: Review of cell culture and mouse models shows MECP2 overexpression causes region-specific neurodegeneration via astrocytic dysfunction.

[PMID:20425814] [INDIRECT EVIDENCE] [SUPPORT] MECP2 duplication syndrome is 100% penetrant in affected males and is associated with infantile hypotonia, severe to profound mental retardation, autism or autistic features, poor speech development, recurrent infections, epilepsy, progressive spasticity, and, in some cases, developmental regression. --- Explanation: Comprehensive clinical review confirms the core phenotype resulting from MECP2 overexpression.


MONDO:0010436


MONDO:0010436

[PMID:25721700] [INDIRECT EVIDENCE] [SUPPORT] increased susceptibility to infections in MECP2 duplication syndrome is associated with IgA/IgG2-deficiency, low antibody titers against pneumococci and elevated acute-phase responses --- Explanation: First systematic immunological characterization of 27 MECP2 duplication patients showing specific humoral immune defects.

[PMID:25721700] [INDIRECT EVIDENCE] [SUPPORT] 17/27 analyzed patients suffered from pneumonia, 5/27 from at least one episode of sepsis. Encapsulated bacteria (S.pneumoniae, H.influenzae) were frequently isolated. --- Explanation: Documents the infectious phenotype with predominance of encapsulated bacterial infections.

[PMID:36319802] [INDIRECT EVIDENCE] [SUPPORT] most patients with MECP2/IRAK1 duplication syndrome present with recurrent and severe infections, accompanied by strong inflammation. Respiratory infections are the most common cause of death. --- Explanation: Confirms recurrent severe infections and strong inflammatory responses in MECP2/IRAK1 duplication patients.

[PMID:36319802] [INDIRECT EVIDENCE] [REFUTE] Patients with MECP2/IRAK1 duplication syndrome do not show increased canonical NF-κB signaling in immortalized fibroblasts, PBMCs, and whole blood. --- Explanation: Despite IRAK1 co-duplication, canonical NF-kB pathway is not hyperactivated, suggesting immune dysfunction mechanism is more complex than simple innate immune overactivation.


MAXO:0000167

[PMID:20301461] [SUPPORT] Routine management of feeding difficulties, constipation, developmental and speech delays, spasticity, and seizures. --- Explanation: GeneReviews recommends routine seizure management as part of standard care.


MAXO:0000058

[PMID:28938254] [SUPPORT] Immunoglobulin substitution, daily antibiotic prophylaxis with two agents and supportive measures reduced occurrence of pneumonia to four episodes in the following 6 2/12 years of life. --- Explanation: Case report demonstrates effectiveness of combined immunoglobulin replacement and antibiotic prophylaxis in reducing pneumonia episodes.


NCIT:C258

[PMID:28938254] [INDIRECT EVIDENCE] [SUPPORT] Immunoglobulin substitution, daily antibiotic prophylaxis with two agents and supportive measures reduced occurrence of pneumonia to four episodes in the following 6 2/12 years of life. --- Explanation: Case report demonstrates effectiveness of combined immunoglobulin replacement and antibiotic prophylaxis in reducing pneumonia episodes.


MAXO:0000011

[PMID:20301461] [SUPPORT] Physical therapy to maintain range of motion to reduce likelihood of contractures. --- Explanation: GeneReviews recommends physical therapy for spasticity management.


MAXO:0000079

[PMID:20301461] [SUPPORT] Once the MECP2 duplication has been identified in an affected family member (and/or the mother of the proband is found to be a carrier of a balanced translocation), prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. --- Explanation: GeneReviews details genetic counseling approach including prenatal and preimplantation testing options.


hgnc:6990

[PMID:35313898] [SUPPORT] MECP2 duplication syndrome (MDS) is a rare, X-linked, neurodevelopmental disorder caused by a duplication of the methyl-CpG-binding protein 2 (MECP2) gene --- Explanation: Comprehensive review confirms MECP2 duplication as the causative genetic alteration.

[PMID:20425814] [SUPPORT] Most of the reported cases are inherited, however, de novo cases have been documented. While carrier females have been reported to be unaffected, more recent research demonstrates that despite normal intelligence, female carriers display a range of neuropsychiatric phenotypes --- Explanation: Documents inheritance pattern and carrier female phenotype.

[PMID:39696717] [SUPPORT] Duplication sizes in the cohort ranging from 64.6 kb to 16.5 Mb were classified into four categories comprising of tandem duplications (48%), terminal duplications (22%), inverted triplications (20%), and other CGRs (10%). --- Explanation: Largest genotype-phenotype study of 137 individuals characterizes structural variant heterogeneity.

[PMID:39696717] [SUPPORT] Genotype-phenotype analyses indicated a gradual worsening of phenotypic features, including overall survival, developmental levels, microcephaly, epilepsy, and genitourinary/eye abnormalities in the following order: Tandem duplications, Other complex duplications, Terminal duplications/Translocations, and Triplications encompassing MECP2. --- Explanation: Demonstrates that clinical severity correlates with rearrangement structure and MECP2 dosage.


hgnc:6112

[PMID:36319802] [SUPPORT] most patients with MECP2/IRAK1 duplication syndrome present with recurrent and severe infections, accompanied by strong inflammation. Respiratory infections are the most common cause of death. --- Explanation: Confirms IRAK1 co-duplication is a consistent feature and that immune dysfunction accompanies the duplication.

[PMID:36319802] [REFUTE] Patients with MECP2/IRAK1 duplication syndrome do not show increased canonical NF-κB signaling in immortalized fibroblasts, PBMCs, and whole blood. --- Explanation: Despite IRAK1 duplication, canonical NF-kB pathway activation is not increased, ruling out simple innate immune pathway overactivation as the mechanism.


MONDO:0005061


MONDO:0005061

[PMID:26729443] [INDIRECT EVIDENCE] [PARTIAL] MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs (3.0%) and were not seen in other cancer types in this study. --- Explanation: This abstract documents MET exon 14 mutations in NSCLC, supporting the presence of exon 14 alterations in this subtype.


MAXO:0000058


CHEBI:231693


NCIT:C88314


CHEBI:64310


MAXO:0000647


HGNC.SYMBOL:MET


MONDO:0005061

[PMID:32657049] [PARTIAL] Of 256 patients with NSCLC, 219 were adenocarcinoma --- Explanation: Abstract reports a NSCLC cohort dominated by adenocarcinoma.


MONDO:0018094

[PMID:8659547] [SUPPORT] Waardenburg syndrome type 2 (WS2) is a dominantly inherited disorder characterized by a pigmentation anomaly and hearing impairment due to lack of melanocyte --- Explanation: Confirms pigmentation anomalies including depigmented hair patches as characteristic of WS2A.


MONDO:0018094

[PMID:10851256] [SUPPORT] Patients with Tietz syndrome have congenital profound deafness and generalised hypopigmentation, inherited in a fully penetrant autosomal dominant fashion --- Explanation: Confirms generalized hypopigmentation as a cardinal feature of Tietz syndrome.


MONDO:0018094

[PMID:7874167] [SUPPORT] Waardenburg syndrome type 2 (WS2) is a dominantly inherited syndrome of hearing loss and pigmentary disturbances --- Explanation: Pigmentary disturbances in WS2 include heterochromia iridis as a common ophthalmologic finding.


MONDO:0018094

[PMID:8659547] [SUPPORT] Waardenburg syndrome type 2 (WS2) is a dominantly inherited disorder characterized by a pigmentation anomaly and hearing impairment due to lack of melanocyte --- Explanation: Establishes that hearing impairment in WS2 is due to absence of melanocytes, which are required for cochlear function.

[PMID:10851256] [SUPPORT] Patients with Tietz syndrome have congenital profound deafness and generalised hypopigmentation, inherited in a fully penetrant autosomal dominant fashion --- Explanation: Confirms profound deafness is fully penetrant in Tietz syndrome.


MONDO:0018094

[PMID:27889061] [SUPPORT] characterized by coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness --- Explanation: Albinism is a defining feature of COMMAD syndrome.


MONDO:0018094

[PMID:27889061] [SUPPORT] Human MITF is, by convention, called the "microphthalmia-associated transcription factor" because of previously published seminal mouse genetic studies; however, mutations in MITF have never been associated with microphthalmia in humans --- Explanation: COMMAD was the first human syndrome demonstrating MITF-associated microphthalmia.


MONDO:0018094

[PMID:27889061] [SUPPORT] COMMAD is associated with biallelic MITF mutant alleles and hence suggests a role for MITF in regulating processes such as optic-fissure closure and bone development or homeostasis --- Explanation: Demonstrates MITF role in optic fissure closure.


MONDO:0018094

[PMID:27889061] [SUPPORT] COMMAD is associated with biallelic MITF mutant alleles and hence suggests a role for MITF in regulating processes such as optic-fissure closure and bone development or homeostasis --- Explanation: Biallelic MITF loss causes osteopetrosis, consistent with mouse mi/mi phenotype.


MONDO:0018094

[PMID:27889061] [SUPPORT] characterized by coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness --- Explanation: Macrocephaly is a defining feature of COMMAD syndrome.


MONDO:0018094

[PMID:8659547] [INDIRECT EVIDENCE] [SUPPORT] the phenotypes of the two families with WS2A in the present study are caused by loss-of-function mutations in one of the two alleles of the MITF gene, resulting in haploinsufficiency of the MITF protein, the protein necessary for normal development of melanocytes --- Explanation: Demonstrates haploinsufficiency mechanism for WS2A.

[PMID:7874167] [INDIRECT EVIDENCE] [SUPPORT] This encodes a putative basic-helix-loop-helix-leucine zipper transcription factor expressed in adult skin and in embryonic retina, otic vesicle and hair follicles --- Explanation: MITF expression pattern in melanocyte-containing tissues explains the pigmentary and auditory phenotype.


MONDO:0018094


MONDO:0018094

[PMID:8659547] [INDIRECT EVIDENCE] [SUPPORT] Waardenburg syndrome type 2 (WS2) is a dominantly inherited disorder characterized by a pigmentation anomaly and hearing impairment due to lack of melanocyte --- Explanation: Pigmentation anomalies result from melanocyte absence.


MONDO:0018094

[PMID:8659547] [INDIRECT EVIDENCE] [SUPPORT] hearing impairment due to lack of melanocyte --- Explanation: Hearing impairment in WS2 is directly attributed to melanocyte absence in the cochlea.


hgnc:7105

[PMID:8659547] [SUPPORT] The two mutations (C760--> T and C895--> T) create stop codons in exons 7 and 8, respectively --- Explanation: Describes specific nonsense mutations causing WS2A through haploinsufficiency.

[PMID:7874167] [SUPPORT] affected individuals in two WS2 families have mutations affecting splice sites in the MITF gene --- Explanation: First demonstration that MITF splice-site mutations cause WS2.


hgnc:7105

[PMID:10851256] [SUPPORT] a missense mutation was found in the basic region of the MITF gene in family members with Tietz syndrome --- Explanation: Identifies the causative MITF missense mutation in Tietz syndrome.


hgnc:7105

[PMID:27889061] [SUPPORT] COMMAD is associated with biallelic MITF mutant alleles and hence suggests a role for MITF in regulating processes such as optic-fissure closure and bone development or homeostasis --- Explanation: Biallelic MITF mutations cause COMMAD with features beyond the monoallelic spectrum.


MONDO:0005575


MONDO:0005575

[PMID:41113075] [INDIRECT EVIDENCE] [PARTIAL] High microsatellite instability (MSI-H) colorectal cancer (CRC), caused by deficient mismatch repair, accounts for about 15% of all CRC cases and is more common in right-sided tumors. --- Explanation: This abstract explicitly links MSI-H CRC to deficient mismatch repair, supporting the core disease mechanism described.


MONDO:0005575

[PMID:36115290] [INDIRECT EVIDENCE] [PARTIAL] Microsatellite unstable (MSI) colorectal cancers (CRCs) are due to DNA mismatch repair (MMR) deficiency --- Explanation: Abstract links MSI CRC to MMR deficiency, supporting the MSI mechanism.


MAXO:0000058

[PMID:33264544] [SUPPORT] Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer --- Explanation: KEYNOTE-177 abstract reports improved progression-free survival with first-line pembrolizumab versus chemotherapy.


NCIT:C106432

[PMID:33264544] [INDIRECT EVIDENCE] [SUPPORT] Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer --- Explanation: KEYNOTE-177 abstract reports improved progression-free survival with first-line pembrolizumab versus chemotherapy.


MAXO:0000058

[PMID:29355075] [SUPPORT] investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80% --- Explanation: CheckMate-142 trial demonstrated high objective response rate (55%) and disease control rate (80%) with nivolumab plus ipilimumab in dMMR/MSI-H mCRC.


NCIT:C68814

[PMID:29355075] [INDIRECT EVIDENCE] [SUPPORT] investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80% --- Explanation: CheckMate-142 trial demonstrated high objective response rate (55%) and disease control rate (80%) with nivolumab plus ipilimumab in dMMR/MSI-H mCRC.


CHEBI:231679


MAXO:0000058

[PMID:35660797] [PARTIAL] All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. --- Explanation: Phase 2 study showed 100% clinical complete response rate with dostarlimab monotherapy in mismatch repair-deficient locally advanced rectal cancer.


NCIT:C126799

[PMID:35660797] [INDIRECT EVIDENCE] [PARTIAL] All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. --- Explanation: Phase 2 study showed 100% clinical complete response rate with dostarlimab monotherapy in mismatch repair-deficient locally advanced rectal cancer.


MAXO:0000004

[PMID:35660797] [PARTIAL] Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. --- Explanation: The study confirms surgical resection is standard treatment for locally advanced rectal cancer, supporting the role of surgery in MSI-H CRC.


HGNC.SYMBOL:MLH1


HGNC.SYMBOL:MSH2


HGNC.SYMBOL:MSH6


HGNC.SYMBOL:PMS2


HGNC.SYMBOL:BRAF V600E


MONDO:0005575

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


MONDO:0011962


MONDO:0011962

[PMID:39860407] [INDIRECT EVIDENCE] [PARTIAL] Cancer immunotherapy through the use of PD-1/PD-L1 inhibitors have shown significant promise in endometrial carcinoma (EC), particularly in tumors with microsatellite instability (MSI) or mismatch repair deficiency (dMMR), present in approximately 30% of cases. --- Explanation: Supports the frequency of MSI/dMMR in endometrial carcinoma.


MONDO:0011962

[PMID:19620942] [INDIRECT EVIDENCE] [PARTIAL] Microsatellite instability (MSI) is the hallmark of a molecular pathway to carcinogenesis due to sporadic or inherited abnormalities of DNA mismatch repair genes. --- Explanation: Abstract links MSI to mismatch repair abnormalities, supporting this mechanism.


MAXO:0000058

[PMID:35045221] [PARTIAL] Lenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival than chemotherapy among patients with advanced endometrial cancer. --- Explanation: KEYNOTE-775 demonstrated significant PFS and OS benefit with lenvatinib plus pembrolizumab versus chemotherapy in advanced endometrial cancer.


CHEBI:85994

[PMID:35045221] [INDIRECT EVIDENCE] [PARTIAL] Lenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival than chemotherapy among patients with advanced endometrial cancer. --- Explanation: KEYNOTE-775 demonstrated significant PFS and OS benefit with lenvatinib plus pembrolizumab versus chemotherapy in advanced endometrial cancer.


MAXO:0000058

[PMID:34990208] [SUPPORT] The objective response rate was 48% (95% CI, 37 to 60) --- Explanation: KEYNOTE-158 abstract reports response rate for pembrolizumab in MSI-H/dMMR endometrial cancer.


NCIT:C106432

[PMID:34990208] [INDIRECT EVIDENCE] [SUPPORT] The objective response rate was 48% (95% CI, 37 to 60) --- Explanation: KEYNOTE-158 abstract reports response rate for pembrolizumab in MSI-H/dMMR endometrial cancer.


MAXO:0000058

[PMID:35064011] [SUPPORT] In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. --- Explanation: GARNET trial demonstrated 43.5% objective response rate with dostarlimab in dMMR/MSI-H endometrial cancer.


NCIT:C126799

[PMID:35064011] [INDIRECT EVIDENCE] [SUPPORT] In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. --- Explanation: GARNET trial demonstrated 43.5% objective response rate with dostarlimab in dMMR/MSI-H endometrial cancer.


MAXO:0000004

[PMID:35045221] [NO_EVIDENCE] Standard therapy for advanced endometrial cancer after failure of platinum-based chemotherapy remains unclear. --- Explanation: While the study focuses on advanced disease after chemotherapy failure, it implies surgery (hysterectomy) and platinum chemotherapy are standard initial therapies.


MONDO:0011962

[PMID:26354523] [PARTIAL] histological subtype is endometrioid adenocarcinoma. --- Explanation: Abstract notes endometrioid adenocarcinoma as the most frequent histological subtype.


MONDO:0019497

[PMID:32143290] [SUPPORT] most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age --- Explanation: Characterizes the progressive sensorineural hearing loss pattern in MYO6 DFNA22 patients.


MONDO:0019497

[PMID:32143290] [SUPPORT] The estimated hearing deterioration was found to be 0.57 dB per year; when restricted to change after 40 years of age, the deterioration speed was accelerated to 1.07 dB per year. --- Explanation: Quantifies the progressive nature of MYO6-related hearing loss with age-dependent acceleration.


MONDO:0019497

[PMID:26265212] [SUPPORT] In mice and humans, loss of myosin VI (Myo6) function results in deafness, and certain Myo6 mutations also result in cardiomyopathies in humans. --- Explanation: Confirms the association of MYO6 mutations with cardiomyopathy in humans and animal models.

[PMID:15060111] [SUPPORT] Novel association of hypertrophic cardiomyopathy, sensorineural deafness, and a mutation in unconventional myosin VI (MYO6). --- Explanation: Human family study that first reported hypertrophic cardiomyopathy with the MYO6 H246R variant.


MONDO:0019497

[PMID:26265212] [SUPPORT] Sv/sv heart mass is significantly greater than that of sv/+ littermates, a result of left ventricle hypertrophy. --- Explanation: Demonstrates left ventricular hypertrophy in the MYO6-null Snell's waltzer mouse model.

[PMID:15060111] [SUPPORT] Novel association of hypertrophic cardiomyopathy, sensorineural deafness, and a mutation in unconventional myosin VI (MYO6). --- Explanation: Human clinical evidence linking MYO6 mutation to ventricular hypertrophy in the reported kindred.


MONDO:0019497

[PMID:32143290] [INDIRECT EVIDENCE] [SUPPORT] In conclusion, the present data clearly showed that MYO6 is one of the genes to keep in mind with regard to ADSNHL, and the molecular characteristics of the identified gene variants suggest that a possible pathology seems to result from malformed stereocilia of the cochlear hair cells. --- Explanation: Links MYO6 variants to stereocilia malformation as the mechanism underlying hearing loss.

[PMID:31103816] [INDIRECT EVIDENCE] [SUPPORT] We also observed disorganized stereocilia with irregular morphological features by immunohistochemistry and scanning electron microscopy. --- Explanation: Mouse model confirms that MYO6 mutation causes stereocilia disorganization in vivo.


MONDO:0019497


hgnc:7605

[PMID:32451864] [SUPPORT] The evidence that pathogenic variants of human MYO3A, MYO6, MYO7A, MYO15A, MYH14 and MYH9 are associated with deafness ranges from moderate to definitive. --- Explanation: Review confirms definitive evidence for MYO6 as a deafness gene.

[PMID:11468689] [SUPPORT] Mutations in the unconventional myosin VI gene, Myo6, are associated with deafness and vestibular dysfunction in the Snell's waltzer (sv) mouse. The corresponding human gene, MYO6, is located on chromosome 6q13. --- Explanation: First identification of MYO6 as the causative gene for DFNA22.


MONDO:0019497

[PMID:11468689] [SUPPORT] We describe the mapping of a new deafness locus, DFNA22, on chromosome 6q13 in a family affected by a nonsyndromic dominant form of deafness (NSAD), and the subsequent identification of a missense mutation in the MYO6 gene in all members of the family with hearing loss. --- Explanation: Original identification of DFNA22 locus with autosomal dominant inheritance linked to MYO6 mutation.


MONDO:0019497

[PMID:12687499] [SUPPORT] Cosegregation of profound, congenital deafness with markers on chromosome 6q13 in three Pakistani families defines a new recessive deafness locus, DFNB37. --- Explanation: Establishes DFNB37 as an autosomal recessive deafness locus mapping to MYO6 on chromosome 6q13.


MONDO:0002009


MONDO:0002009

[PMID:38331979] [INDIRECT EVIDENCE] [SUPPORT] The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis --- Explanation: This review confirms the neurotransmitter hypothesis as a foundational theory of MDD pathogenesis, though it notes that multiple hypotheses are needed to fully explain the disorder.

[PMID:39150594] [INDIRECT EVIDENCE] [SUPPORT] MDD is especially burdensome as approved monoamine antidepressant treatments have weeks-long delays before clinical benefit and low remission rates. --- Explanation: This highlights the clinical reality of monoamine-based treatments, confirming their use while acknowledging their limitations in achieving remission.

[PMID:38474387] [INDIRECT EVIDENCE] [SUPPORT] neuroinflammation and gut dysbiosis induce alterations in tryptophan metabolism, culminating in decreased serotonin synthesis, impairments in neuroplasticity-related mechanisms, and glutamate-mediated excitotoxicity. --- Explanation: This demonstrates how inflammatory mechanisms contribute to decreased serotonin synthesis, supporting the monoamine deficiency theory while connecting it to broader pathophysiological processes.


MONDO:0002009

[PMID:38331979] [INDIRECT EVIDENCE] [SUPPORT] The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis --- Explanation: This review identifies the HPA axis hypothesis as one of the widely accepted core pathophysiological mechanisms in MDD.


MONDO:0002009

[PMID:38331979] [INDIRECT EVIDENCE] [SUPPORT] The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis --- Explanation: This comprehensive review identifies the neuroplasticity hypothesis as one of the core accepted mechanisms in MDD pathogenesis.

[PMID:39150594] [INDIRECT EVIDENCE] [SUPPORT] This narrative review provides a high-level overview of glutamate signaling in synaptogenesis and neural plasticity and the implications of glutamate dysregulation in depression. --- Explanation: This demonstrates the link between glutamate signaling, synaptogenesis, and neural plasticity deficits in depression, supporting the neuroplasticity deficit mechanism.

[PMID:38474387] [INDIRECT EVIDENCE] [SUPPORT] neuroinflammation and gut dysbiosis induce alterations in tryptophan metabolism, culminating in decreased serotonin synthesis, impairments in neuroplasticity-related mechanisms, and glutamate-mediated excitotoxicity. --- Explanation: This shows how inflammatory processes lead to impairments in neuroplasticity-related mechanisms, connecting inflammation to neuroplasticity deficits in MDD.


MONDO:0002009

[PMID:38331979] [INDIRECT EVIDENCE] [SUPPORT] The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis --- Explanation: This review identifies the cytokine hypothesis as one of the widely accepted theories of MDD pathogenesis, supporting the role of inflammatory mechanisms.

[PMID:38474387] [INDIRECT EVIDENCE] [SUPPORT] The involvement of central and peripheral inflammation in the pathogenesis and prognosis of major depressive disorder (MDD) has been demonstrated. The increase of pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-18, and TNF-α) in individuals with depression may elicit neuroinflammatory processes and peripheral inflammation --- Explanation: This provides direct evidence for elevated pro-inflammatory cytokines in MDD and their role in eliciting neuroinflammatory processes.

[PMID:38474387] [INDIRECT EVIDENCE] [SUPPORT] mechanisms that, in turn, can contribute to gut microbiota dysbiosis. Together, neuroinflammation and gut dysbiosis induce alterations in tryptophan metabolism, culminating in decreased serotonin synthesis, impairments in neuroplasticity-related mechanisms, and glutamate-mediated excitotoxicity. --- Explanation: This demonstrates how neuroinflammation contributes to both monoamine depletion (decreased serotonin) and neuroplasticity deficits, confirming the description's mechanistic links.

[PMID:20015486] [INDIRECT EVIDENCE] [SUPPORT] This meta-analysis reports significantly higher concentrations of the proinflammatory cytokines TNF-alpha and IL-6 in depressed subjects compared with control subjects. --- Explanation: Meta-analysis evidence shows elevated proinflammatory cytokines in major depression, supporting neuroinflammatory mechanisms.


HGNC.SYMBOL:SLC6A4


HGNC.SYMBOL:BDNF


HGNC.SYMBOL:FKBP5


HGNC.SYMBOL:HTR2A


MONDO:0005136

[PMID:8644955] [SUPPORT] The most common documented symptoms were fever (100%), chills (65%), vomiting (60%), anorexia (45%), and headache (45%). --- Explanation: Clinical case-series data show fever as the most frequent presenting feature.


MONDO:0005136

[PMID:8644955] [SUPPORT] The most common documented symptoms were fever (100%), chills (65%), vomiting (60%), anorexia (45%), and headache (45%). --- Explanation: Clinical series directly reports chills as a frequent presenting symptom.


MONDO:0005136

[PMID:8644955] [SUPPORT] The most common documented symptoms were fever (100%), chills (65%), vomiting (60%), anorexia (45%), and headache (45%). --- Explanation: Reported headache prevalence supports inclusion as a common malaria phenotype.


MONDO:0005136

[PMID:8644955] [SUPPORT] The most common documented symptoms were fever (100%), chills (65%), vomiting (60%), anorexia (45%), and headache (45%). --- Explanation: Case-series symptom profile supports vomiting as a frequent manifestation.


MONDO:0005136

[PMID:17568940] [SUPPORT] Headache (59.8%), fever (57.1%), and myalgia (48.4%) were the most frequent symptoms. --- Explanation: Prospective cohort data identifies myalgia among the most frequent malaria symptoms.


MONDO:0005136

[PMID:8644955] [SUPPORT] There were no deaths, and complications were limited to thrombocytopenia and anemia. --- Explanation: Clinical complications in falciparum malaria include anemia.


MONDO:0005136

[PMID:8644955] [SUPPORT] There were no deaths, and complications were limited to thrombocytopenia and anemia. --- Explanation: Directly supports thrombocytopenia as a clinical complication.


MONDO:0005136

[PMID:25889074] [SUPPORT] Fever, tachycardia, pallor and abdominal pain on palpation were more frequent in P. falciparum patients, whereas mild hepatomegaly and splenomegaly were mostly observed with P. vivax. --- Explanation: Large Colombian clinical surveillance cohort documents splenomegaly, especially in vivax infection.


MONDO:0005136

[PMID:40701686] [SUPPORT] The disease is defined clinically as an otherwise unexplained coma in someone with malaria parasitemia. --- Explanation: Human clinical neurology review defines coma as the core phenotype of cerebral malaria.


MONDO:0005136

[PMID:40701686] [SUPPORT] Acute seizures are common and increasing numbers of them during the index illness are associated with a greater likelihood of adverse outcomes. --- Explanation: Human clinical evidence supports seizures as common, prognostically relevant cerebral-malaria manifestations.


MONDO:0005136

[PMID:27939609] [INDIRECT EVIDENCE] [SUPPORT] Infected erythrocyte sequestration in the microvasculature plays a critical role in the development of severe disease --- Explanation: Directly supports sequestration as a central severe-malaria mechanism.


MONDO:0005136


MONDO:0005136

[DOI:10.1186/s12987-024-00541-9] [INDIRECT EVIDENCE] [SUPPORT] Blood–brain barrier (BBB) disruption is a central feature of cerebral malaria (CM), a severe complication of Plasmodium falciparum (Pf) infections. --- Explanation: Establishes BBB disruption as a core pathophysiologic feature of cerebral malaria.

[DOI:10.1186/s12987-024-00541-9] [INDIRECT EVIDENCE] [SUPPORT] After 6-h of co-culture with Pf-iRBCs, hiPSC-BMECs showed reduced TEER and increased sodium fluorescein permeability compared to co-culture with uninfected RBCs, indicative of a leaky barrier. --- Explanation: Demonstrates mechanistic endothelial barrier failure in an in vitro CM model.


MONDO:0005136

[PMID:27939609] [INDIRECT EVIDENCE] [SUPPORT] The recent discovery that parasite binding to endothelial protein C receptor (EPCR) is associated with severe disease has suggested new mechanisms of pathology and provided new avenues for severe malaria adjunctive therapy research. --- Explanation: Supports EPCR-linked endothelial pathology as a severity mechanism.


MONDO:0005136

[PMID:31821175] [INDIRECT EVIDENCE] [SUPPORT] We identified effector CD3+CD8+ T cells engaged on the cerebrovasculature in 69% of CM+ HIV- children. --- Explanation: Provides direct human tissue evidence for cerebrovascular CD8-positive T-cell involvement.

[PMID:31821175] [INDIRECT EVIDENCE] [SUPPORT] Within the studied cohort, CM is associated with cerebrovascular engagement of CD3+CD8+ T cells, which is exacerbated by HIV coinfection. --- Explanation: Confirms association between cerebral malaria and cerebrovascular CD8-positive T-cell activity.


MONDO:0005136

[PMID:37708213] [INDIRECT EVIDENCE] [SUPPORT] Blood group O is associated with protection against severe malaria and reduced size and stability of P. falciparum-host red blood cell (RBC) rosettes compared to non-O blood groups. --- Explanation: Supports RBC rosetting and host blood-group dependence in severe malaria risk.

[PMID:37708213] [INDIRECT EVIDENCE] [SUPPORT] In the case-control study, compared to OO, the double dose genotypes consistently had higher odds ratios (OR) for severe malaria than single dose genotypes, with AB (OR 1.93) and AO (OR 1.27) showing most marked difference (p = 0.02, Wald test). --- Explanation: Restricts this evidence item to human case-control findings on genotype-specific severe-malaria risk.


MONDO:0005136

[PMID:37748496] [INDIRECT EVIDENCE] [SUPPORT] Primaquine is used to eliminate Plasmodium vivax hypnozoites, but its optimal dosing regimen remains unclear. --- Explanation: Directly links dormant hypnozoites to the need for radical cure in recurrent vivax malaria.


MAXO:0000058

[PMID:37924827] [SUPPORT] Parasitological diagnosis and treatment with oral or parenteral artemisinin-based therapy is the mainstay of patient management. --- Explanation: Directly supports frontline antimalarial pharmacotherapy.


MAXO:0000058

[PMID:37748496] [SUPPORT] Compared with treatment without primaquine, the rate of P vivax recurrence was lower after treatment with low-dose primaquine (adjusted hazard ratio 0·21, 95% CI 0·17-0·27; p<0·0001) and high-dose primaquine (0·10, 0·08-0·12; p<0·0001). --- Explanation: Demonstrates major recurrence-risk reduction with primaquine.


MAXO:0000950

[PMID:37924827] [SUPPORT] Timely blood transfusion, renal replacement therapy, and restrictive fluid therapy can improve survival in severe malaria. --- Explanation: Supports critical-care supportive interventions in severe disease.


MAXO:0000001

[PMID:22445352] [SUPPORT] including intermittent preventive antimalarial therapy in children (87% to 69%)74,75 or infants (38%)76 and the use of insecticide-treated bed nets (45%).77 --- Explanation: Human epidemiologic synthesis identifies insecticide-treated bed nets as a major malaria-control intervention.


MAXO:0000058

[PMID:37924827] [SUPPORT] Rigorous use of intermittent preventive treatment in pregnancy and infancy and seasonal chemoprevention, potentially combined with pre-erythrocytic vaccines endorsed by WHO in 2021 and 2023, can substantially reduce malaria morbidity. --- Explanation: Directly supports IPTp/infancy preventive treatment and seasonal chemoprevention as morbidity-reducing strategies.


MAXO:0001017

[PMID:37924827] [SUPPORT] Rigorous use of intermittent preventive treatment in pregnancy and infancy and seasonal chemoprevention, potentially combined with pre-erythrocytic vaccines endorsed by WHO in 2021 and 2023, can substantially reduce malaria morbidity. --- Explanation: Supports clinical deployment of RTS,S (2021) and R21 (2023) era malaria vaccines as morbidity-reduction interventions.


HGNC.SYMBOL:HBB (HbS trait)

[PMID:22445352] [SUPPORT] Meta-analysis of case-control studies showed a decreased risk of severe P. falciparum malaria in individuals with haemoglobin AS (OR 0·09, 95% CI 0·06-0·12), haemoglobin CC (0·27, 0·11-0·63), haemoglobin AC (0·83, 0·67-0·96), homozygous α-thalassaemia (0·63, 0·48-0·83), and heterozygous α-thalassaemia (0·83, 0·74-0·92). --- Explanation: Meta-analysis provides strong human clinical evidence for marked severe-malaria protection in HbAS.

[PMID:23035141] [SUPPORT] Although sickle cell trait protects against severe disease due to Plasmodium falciparum, it has not been clear whether sickle trait also protects against asymptomatic infection (parasitemia). --- Explanation: Confirms HbAS as a major protective modifier in falciparum malaria.


HGNC.SYMBOL:G6PD

[PMID:17355169] [SUPPORT] Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. --- Explanation: Case-control evidence supports genotype-specific protection from severe malaria.

[PMID:24372186] [SUPPORT] It is now clear that it is not good practice to give one of these drugs before testing a person for his/her G6PD status, especially in populations in whom G6PD deficiency is common. --- Explanation: Supports clinically important pharmacogenomic implications for primaquine safety.


HGNC.SYMBOL:ACKR1 (Duffy antigen receptor for chemokines)

[PMID:30218021] [SUPPORT] The variants of the Duffy Antigen/Receptor for Chemokines (DARC) gene have probably been selected by malaria parasites, particularly the FY*O allele, which is fixed in sub-Saharan Africa and confers resistance to Plasmodium vivax infection. --- Explanation: Human population genetics evidence supports Duffy-null resistance against vivax malaria.

[PMID:37399221] [PARTIAL] This study confirms that Duffy-negativity does not provide complete protection against P. vivax infection. --- Explanation: Adds modern nuance that protection is strong but not absolute in all endemic contexts.


HGNC.SYMBOL:HBB (HbC)

[PMID:15295709] [SUPPORT] HbAC did not prevent infection but reduced the odds of developing severe malaria and severe anemia. --- Explanation: Case-control data supports protection from severe outcomes despite ongoing infection risk.


HGNC.SYMBOL:HBA1/HBA2 (alpha-thalassemia)

[PMID:22445352] [SUPPORT] Meta-analysis of case-control studies showed a decreased risk of severe P. falciparum malaria in individuals with haemoglobin AS (OR 0·09, 95% CI 0·06-0·12), haemoglobin CC (0·27, 0·11-0·63), haemoglobin AC (0·83, 0·67-0·96), homozygous α-thalassaemia (0·63, 0·48-0·83), and heterozygous α-thalassaemia (0·83, 0·74-0·92). --- Explanation: Meta-analysis shows significant protective effects for alpha-thalassemia genotypes.


HGNC.SYMBOL:HBB (beta-thalassemia trait)

[PMID:8846492] [SUPPORT] The mean parasitaemia levels of patients with alpha- or beta-thalassaemia trait or with severe glucose-6-phosphate dehydrogenase (G6PD) deficiency were lower than those of individuals with normal haemoglobin AA or with heterozygous haemoglobin E. --- Explanation: Human observational data supports reduced parasitemia in beta-thalassemia trait.

[PMID:22445352] [PARTIAL] Few clinical studies have investigated β-thalassaemia, haemoglobin E, P. vivax malaria, or pregnancy-associated malaria. --- Explanation: Indicates supporting literature is more limited than for other major malaria-protective polymorphisms.


HGNC.SYMBOL:ABO

[PMID:37708213] [SUPPORT] In the case-control study, compared to OO, the double dose genotypes consistently had higher odds ratios (OR) for severe malaria than single dose genotypes, with AB (OR 1.93) and AO (OR 1.27) showing most marked difference (p = 0.02, Wald test). --- Explanation: Human case-control data support increased severe-malaria risk in double-dose non-O genotypes.


NCBITaxon:5833

[DOI:10.1186/s12987-024-00541-9] [SUPPORT] Blood–brain barrier (BBB) disruption is a central feature of cerebral malaria (CM), a severe complication of Plasmodium falciparum (Pf) infections. --- Explanation: Identifies P. falciparum as a major causative agent linked to severe pathophysiology.


NCBITaxon:5855

[PMID:37748496] [SUPPORT] Primaquine is used to eliminate Plasmodium vivax hypnozoites, but its optimal dosing regimen remains unclear. --- Explanation: Confirms P. vivax pathobiology and therapeutic implications.


MONDO:0006292


MONDO:0006292

[PMID:25889843] [INDIRECT EVIDENCE] [SUPPORT] pleural MMs have been genetically characterized by the loss of BAP1 (40-60%) --- Explanation: Abstract reports frequent BAP1 loss in pleural mesothelioma.


MAXO:0000647


CHEBI:27899


CHEBI:63616


MAXO:0000058


MAXO:0000004


MAXO:0000014


HGNC.SYMBOL:BAP1


HGNC.SYMBOL:NF2


HGNC.SYMBOL:CDKN2A


ECTO:9000033

[PMID:23743993] [SUPPORT] Malignant pleural mesothelioma (MPM) is an aggressive, malignant tumor of the pleural surface and is strongly associated with asbestos exposure. --- Explanation: Supports the strong association between mesothelioma and asbestos exposure.


MONDO:0006292

[PMID:21412769] [SUPPORT] Malignant mesothelioma (MM) is a neoplasm arising from mesothelial cells lining --- Explanation: Abstract defines malignant mesothelioma as arising from mesothelial cells.


MONDO:0005015

[PMID:32922057] [PARTIAL] thin, severely hyperglycemic and ketone resistant teenager with history and signs of chronic under-nutrition --- Explanation: The case report describes hyperglycemia with ketosis resistance in a malnourished patient.


MONDO:0005015

[PMID:40049652] [INDIRECT EVIDENCE] [PARTIAL] Studies have shown that insulin deficiency due to pancreatic β-cell impairment is likely to contribute to the development of undernutrition-associated diabetes. --- Explanation: The review links undernutrition-associated diabetes to beta-cell impairment and insulin deficiency.


MONDO:0005015


MONDO:0018876

[PMID:9178843] [SUPPORT] Initial parameters in all published series are advanced disease with generalized lymphadenopathy in 90% --- Explanation: This review supports generalized lymphadenopathy as the dominant presenting clinical phenotype of mantle cell lymphoma.


MONDO:0018876

[PMID:15370245] [SUPPORT] Presenting features included splenomegaly (74%), lymphadenopathy (45%), hepatomegaly (17%) --- Explanation: This leukemic-presentation cohort directly supports splenomegaly as a common presenting manifestation of mantle cell lymphoma.


MONDO:0018876

[PMID:9178843] [SUPPORT] Initial parameters in all published series are advanced disease with generalized lymphadenopathy in 90%, bone marrow infiltration in 60-75%, splenomegaly in 55%, hepatomegaly in 35%, gastrointestinal involvement in about 25% and peripheral blood lymphocytosis in 20-30% of patients. --- Explanation: This clinical review supports hepatomegaly as a recurrent though less dominant manifestation of mantle cell lymphoma.


MONDO:0018876

[PMID:17001159] [SUPPORT] As a whole, 92% of patients showed upper or lower GI tract infiltration by MCL. --- Explanation: This prospective endoscopic study demonstrates that GI tract involvement is extremely common in MCL when systematically evaluated.


MONDO:0018876

[PMID:38222137] [SUPPORT] Mantle cell lymphoma (MCL) most commonly presents as lymphadenopathy (LAD), fevers, night sweats, weight loss, splenomegaly, and blood count abnormalities. --- Explanation: This clinical report explicitly lists fever among the common presenting manifestations of mantle cell lymphoma.


MONDO:0018876

[PMID:38222137] [SUPPORT] Mantle cell lymphoma (MCL) most commonly presents as lymphadenopathy (LAD), fevers, night sweats, weight loss, splenomegaly, and blood count abnormalities. --- Explanation: This clinical report explicitly lists night sweats among the common presenting manifestations of mantle cell lymphoma.


MONDO:0018876

[PMID:38222137] [SUPPORT] Mantle cell lymphoma (MCL) most commonly presents as lymphadenopathy (LAD), fevers, night sweats, weight loss, splenomegaly, and blood count abnormalities. --- Explanation: This clinical report explicitly includes weight loss among the common presenting features of mantle cell lymphoma.


MONDO:0018876

[PMID:15914363] [SUPPORT] We encountered a 53-year-old man with general fatigue. --- Explanation: This case report supports fatigue as a clinically relevant presenting symptom in mantle cell lymphoma, although it does not establish frequency.


MONDO:0018876

[PMID:15370245] [SUPPORT] Median lymphocyte count was 58 x 10(9)/l, 55% had anemia and 17% had thrombocytopenia. --- Explanation: This leukemic mantle cell lymphoma cohort directly supports anemia as a common hematologic manifestation.


MONDO:0018876

[PMID:9178843] [SUPPORT] Initial parameters in all published series are advanced disease with generalized lymphadenopathy in 90%, bone marrow infiltration in 60-75%, splenomegaly in 55%, hepatomegaly in 35%, gastrointestinal involvement in about 25% and peripheral blood lymphocytosis in 20-30% of patients. --- Explanation: This review supports peripheral blood lymphocytosis as a recognized hematologic manifestation in a subset of mantle cell lymphoma patients.


MONDO:0018876

[PMID:15370245] [SUPPORT] Median lymphocyte count was 58 x 10(9)/l, 55% had anemia and 17% had thrombocytopenia. --- Explanation: This leukemic mantle cell lymphoma cohort directly supports thrombocytopenia as an associated hematologic manifestation.


MONDO:0018876

[PMID:16155021] [INDIRECT EVIDENCE] [SUPPORT] The genetic hallmark of MCL is the chromosomal translocation t(11;14)(q13;q32) that leads to deregulation and upregulation of Cyclin D1, an important regulator of the G1 phase of the cell cycle. --- Explanation: This review defines t(11;14) as the hallmark initiating genetic lesion in mantle cell lymphoma.


MONDO:0018876

[PMID:16155021] [INDIRECT EVIDENCE] [SUPPORT] The genetic hallmark of MCL is the chromosomal translocation t(11;14)(q13;q32) that leads to deregulation and upregulation of Cyclin D1, an important regulator of the G1 phase of the cell cycle. --- Explanation: This supports accelerated G1/S control as a core cell-cycle consequence of the mantle cell lymphoma genetic hallmark.


MONDO:0018876

[PMID:41219853] [INDIRECT EVIDENCE] [SUPPORT] MCL cells develop in specialized tissue microenvironments such as bone marrow and secondary lymphoid organs, where the pathological cells interact with several microenvironmental components through a complex network of soluble factors and adhesion molecules. --- Explanation: This supports a distinct microenvironmental mechanism operating in marrow and lymphoid tissue niches.


MONDO:0018876


MONDO:0018876

[PMID:41219853] [INDIRECT EVIDENCE] [SUPPORT] This dynamic and complex system, including the activation of B-cell receptor signaling (BCR), promotes survival, immune evasion, and therapeutic resistance. --- Explanation: This supports ongoing BCR pathway activation as a central mantle cell lymphoma mechanism.


MONDO:0018876

[PMID:41219853] [INDIRECT EVIDENCE] [SUPPORT] Given the central role of the BCR signaling pathway in proliferation and survival of neoplastic B lymphocytes, in the last decades several biological agents against the key BCR proteins, i.e. Bruton Tyrosine Kinase inhibitors (BTKi), have been developed, and they represent the most effective treatment for MCL management. --- Explanation: This supports a discrete survival-advantage state downstream of BCR signaling.


MONDO:0018876

[PMID:41219853] [INDIRECT EVIDENCE] [SUPPORT] Given the central role of the BCR signaling pathway in proliferation and survival of neoplastic B lymphocytes, in the last decades several biological agents against the key BCR proteins, i.e. Bruton Tyrosine Kinase inhibitors (BTKi), have been developed, and they represent the most effective treatment for MCL management. --- Explanation: This supports proliferative expansion of neoplastic B lymphocytes as a central downstream state in MCL.


MONDO:0018876

[PMID:19863180] [INDIRECT EVIDENCE] [SUPPORT] Most patients present with advanced stage disease, often with extranodal dissemination, and typically pursue an aggressive clinical course. --- Explanation: This supports advanced-stage disseminated disease as a characteristic downstream pathobiologic state in mantle cell lymphoma.

[PMID:19556426] [INDIRECT EVIDENCE] [SUPPORT] The clinical presentation often includes extranodal involvement, particularly of the bone marrow and gut. --- Explanation: This review specifically supports bone marrow and gastrointestinal involvement as common sites of mantle cell lymphoma dissemination.


MAXO:0000058

[PMID:26059948] [SUPPORT] Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. --- Explanation: This directly supports ibrutinib as an approved treatment for relapsed mantle cell lymphoma.

[PMID:26059948] [SUPPORT] The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. --- Explanation: This phase 2 trial supports the stated high single-agent activity of ibrutinib in relapsed or refractory mantle cell lymphoma.


CHEBI:76612

[PMID:26059948] [INDIRECT EVIDENCE] [SUPPORT] Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. --- Explanation: This directly supports ibrutinib as an approved treatment for relapsed mantle cell lymphoma.

[PMID:26059948] [INDIRECT EVIDENCE] [SUPPORT] The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. --- Explanation: This phase 2 trial supports the stated high single-agent activity of ibrutinib in relapsed or refractory mantle cell lymphoma.


MAXO:0000058

[clinicaltrials:NCT02213926] [SUPPORT] The purpose of this study is to characterize the safety and efficacy profile of ACP-196 (acalabrutinib) in subjects with relapsed or refractory Mantle Cell Lymphoma (MCL). --- Explanation: This phase 2 mantle cell lymphoma trial directly supports acalabrutinib as a disease-relevant therapeutic agent in relapsed or refractory MCL.


CHEBI:167707

[clinicaltrials:NCT02213926] [INDIRECT EVIDENCE] [SUPPORT] The purpose of this study is to characterize the safety and efficacy profile of ACP-196 (acalabrutinib) in subjects with relapsed or refractory Mantle Cell Lymphoma (MCL). --- Explanation: This phase 2 mantle cell lymphoma trial directly supports acalabrutinib as a disease-relevant therapeutic agent in relapsed or refractory MCL.


MAXO:0000747

[PMID:19556426] [SUPPORT] Very intensive regimens, including autologous and allogeneic stem cell transplantation, seem required to improve the outcome --- Explanation: This treatment review supports intensive regimens incorporating stem cell transplantation as an outcome-improving strategy in mantle cell lymphoma.


MAXO:0000058

[PMID:26411584] [SUPPORT] bendamustine-rituximab is an effective therapy with manageable toxicity in relapsed/refractory MCL. --- Explanation: This phase 2 study directly supports bendamustine plus rituximab as an active mantle cell lymphoma regimen with a high response rate in relapsed or refractory disease.

[clinicaltrials:NCT01415752] [PARTIAL] PURPOSE: This randomized phase II trial studies rituximab, bortezomib, bendamustine, and lenalidomide in treating previously untreated older patients with mantle cell lymphoma. --- Explanation: This directly supports bendamustine-rituximab as a frontline regimen under formal study in older patients with previously untreated mantle cell lymphoma, although the abstract summary does not report the regimen-specific outcomes.


CHEBI:135515

[PMID:26411584] [INDIRECT EVIDENCE] [SUPPORT] bendamustine-rituximab is an effective therapy with manageable toxicity in relapsed/refractory MCL. --- Explanation: This phase 2 study directly supports bendamustine plus rituximab as an active mantle cell lymphoma regimen with a high response rate in relapsed or refractory disease.

[clinicaltrials:NCT01415752] [INDIRECT EVIDENCE] [PARTIAL] PURPOSE: This randomized phase II trial studies rituximab, bortezomib, bendamustine, and lenalidomide in treating previously untreated older patients with mantle cell lymphoma. --- Explanation: This directly supports bendamustine-rituximab as a frontline regimen under formal study in older patients with previously untreated mantle cell lymphoma, although the abstract summary does not report the regimen-specific outcomes.


NCIT:C1702


MAXO:0001002

[clinicaltrials:NCT02601313] [SUPPORT] The goal of this clinical study is to test how well the study drug, brexucabtagene autoleucel (KTE-X19), works in participants with relapsed/refractory (r/r) mantle cell lymphoma (MCL). --- Explanation: This phase 2 trial directly supports CD19-directed CAR-T therapy as a disease-specific treatment strategy for relapsed or refractory mantle cell lymphoma.


MAXO:0000058

[DOI:10.1002/ajh.25487] [SUPPORT] The therapeutic options in MCL are constantly evolving, with dramatic responses from nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). --- Explanation: This 2019 clinical review supports venetoclax as one of the nonchemotherapeutic agents producing notable responses in mantle cell lymphoma.

[clinicaltrials:NCT03112174] [SUPPORT] This Phase 3 multinational, randomized, double-blind study is designed to compare the efficacy and safety of the combination of ibrutinib and venetoclax vs. ibrutinib and placebo in subjects with MCL. --- Explanation: This confirms active phase 3 evaluation of venetoclax in rational BTK-inhibitor combination therapy for mantle cell lymphoma.


CHEBI:133021

[DOI:10.1002/ajh.25487] [INDIRECT EVIDENCE] [SUPPORT] The therapeutic options in MCL are constantly evolving, with dramatic responses from nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). --- Explanation: This 2019 clinical review supports venetoclax as one of the nonchemotherapeutic agents producing notable responses in mantle cell lymphoma.

[clinicaltrials:NCT03112174] [INDIRECT EVIDENCE] [SUPPORT] This Phase 3 multinational, randomized, double-blind study is designed to compare the efficacy and safety of the combination of ibrutinib and venetoclax vs. ibrutinib and placebo in subjects with MCL. --- Explanation: This confirms active phase 3 evaluation of venetoclax in rational BTK-inhibitor combination therapy for mantle cell lymphoma.


hgnc:1582

[PMID:16155021] [SUPPORT] The genetic hallmark of MCL is the chromosomal translocation t(11;14)(q13;q32) that leads to deregulation and upregulation of Cyclin D1, an important regulator of the G1 phase of the cell cycle. --- Explanation: This directly supports CCND1/IGH translocation as the defining genetic lesion of mantle cell lymphoma.


hgnc:11998

[PMID:32584970] [SUPPORT] Several drivers had prognostic impact, but only TP53 and MYC aberrations added value independently of genomic complexity. --- Explanation: This supports TP53 aberration as an adverse prognostic marker with independent impact in mantle cell lymphoma.


hgnc:795

[PMID:32584970] [SUPPORT] cMCL carried significant higher numbers of structural variants, copy number alterations, and driver changes than nnMCL, with exclusive alterations of ATM in cMCL --- Explanation: This supports ATM alteration as a recurrent genomic event in conventional mantle cell lymphoma linked to genomic instability.


MONDO:0018876

[PMID:34114641] [SUPPORT] Mantle cell lymphoma (MCL) is a mature B-cell non-Hodgkin lymphoma usually --- Explanation: Abstract describes mantle cell lymphoma as a mature B-cell non-Hodgkin lymphoma.


MONDO:0009563

[PMID:28919799] [SUPPORT] The classic presentation occurs in the neonatal period with developmental delay, failure to thrive, feeding difficulties, and maple syrup odor in the cerumen and urine --- Explanation: Confirms characteristic maple syrup odor in urine and cerumen as a classic presentation.


MONDO:0009563

[PMID:28919799] [SUPPORT] The classic presentation occurs in the neonatal period with developmental delay, failure to thrive, feeding difficulties, and maple syrup odor in the cerumen and urine --- Explanation: Confirms feeding difficulties as a classic neonatal presentation of MSUD.


MONDO:0009563

[PMID:32491705] [SUPPORT] It classically manifests in the neonatal period with failure to thrive, delayed developmental milestones, feeding difficulties, lethargy, irritability, and a maple syrup odor first noticeable in the cerumen and then the urine. --- Explanation: Confirms lethargy as a classic neonatal manifestation of MSUD.


MONDO:0009563

[PMID:23478409] [SUPPORT] Maple syrup urine disease (MSUD) is an inherited disorder of branched chain amino acid metabolism presenting with neonatal encephalopathy, episodic metabolic decompensation, and chronic amino acid imbalances. --- Explanation: Confirms neonatal encephalopathy as a presenting feature of MSUD.


MONDO:0009563

[PMID:32491705] [SUPPORT] If left untreated, the most severe, classic form of MSUD can quickly lead to irreversible neurological injury manifesting as brain damage, seizures, a coma, or central respiratory failure within just 7 to 10 days after birth. --- Explanation: Confirms seizures as a neurological manifestation of untreated classic MSUD.


MONDO:0009563

[PMID:31559730] [SUPPORT] Physical examination of the neonates were similar having stupor, hypotonia and depressed newborn reflexes. --- Explanation: Confirms hypotonia as a neurological finding on examination of neonates with MSUD metabolic decompensation.


MONDO:0009563

[PMID:21839471] [SUPPORT] One-third of our patients were mentally impaired (IQ ≤ 70) before transplantation, with no statistically significant change 1 year later. --- Explanation: Confirms intellectual impairment occurs in MSUD and is not reversed by liver transplantation.

[PMID:23478409] [SUPPORT] Compared with 26 age-matched controls, MSUD patients were at higher risk for disorders of cognition, attention, and mood. --- Explanation: Demonstrates cognitive impairment in MSUD patients compared to controls.


MONDO:0009563

[PMID:35578286] [SUPPORT] In some patients, enteral administration is not possible, either because the patient presents with vomiting, coma, or refuses nasogastric administration --- Explanation: Vomiting is a recognized presentation during MSUD decompensation episodes.


MONDO:0009563

[PMID:35578286] [SUPPORT] In some patients, enteral administration is not possible, either because the patient presents with vomiting, coma, or refuses nasogastric administration --- Explanation: Coma is recognized as a presentation during severe MSUD decompensation.


MONDO:0009563

[PMID:28919799] [SUPPORT] The classic presentation occurs in the neonatal period with developmental delay, failure to thrive, feeding difficulties, and maple syrup odor in the cerumen and urine --- Explanation: Confirms developmental delay as a classic presentation of MSUD.


MONDO:0009563

[PMID:27373929] [SUPPORT] The concentrations of leucine and BCAAs in the blood range from approximately 1 to 5 mM in MSUD patients --- Explanation: Confirms marked elevation of branched chain amino acids in MSUD patients.


MONDO:0009563

[PMID:28919799] [SUPPORT] The classic presentation occurs in the neonatal period with developmental delay, failure to thrive, feeding difficulties, and maple syrup odor in the cerumen and urine --- Explanation: Confirms failure to thrive as a classic neonatal presentation of MSUD.


MONDO:0009563

[PMID:36550798] [SUPPORT] The main clinical symptoms of maple syrup urine disease (MSUD) are dehydration, acidosis, nervous system symptoms and intellectual disability. --- Explanation: Confirms acidosis as a main clinical symptom of MSUD.


MONDO:0009563

[PMID:20301495] [SUPPORT] Severe intoxication culminates in critical cerebral edema, coma, and central respiratory failure. --- Explanation: Confirms cerebral edema as a critical complication of severe MSUD metabolic intoxication.


MONDO:0009563

[PMID:35672312] [INDIRECT EVIDENCE] [SUPPORT] Maple syrup urine disease (MSUD) is a rare recessively inherited metabolic disorder causing accumulation of branched chain amino acids leading to neonatal death, if untreated. --- Explanation: Confirms MSUD causes BCAA accumulation due to enzyme deficiency.

[PMID:27373929] [INDIRECT EVIDENCE] [SUPPORT] Maple Syrup Urine Disease (MSUD) is an inherited disorder caused by the dysfunction in the branched chain keto-acid dehydrogenase (BCKDH) enzyme. --- Explanation: Confirms BCKDH enzyme dysfunction is the core defect in MSUD.


MONDO:0009563


MONDO:0009563

[PMID:27373929] [INDIRECT EVIDENCE] [SUPPORT] BCKDH dysfunction results in the accumulation of the keto-acids ketoisocaproic acid (KIC) from leucine, ketoisovaleric acid (KIV) from valine and ketomethylvaleric acid (KMV) from isoleucine --- Explanation: Confirms accumulation of all three BCKAs due to BCKDH dysfunction.

[PMID:28919799] [INDIRECT EVIDENCE] [SUPPORT] Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by defects in the branched-chain α-ketoacid dehydrogenase complex, which results in elevations of the branched-chain amino acids (BCAAs) in plasma, α-ketoacids in urine, and production of the pathognomonic disease marker, alloisoleucine. --- Explanation: Confirms elevation of BCAAs, ketoacids, and alloisoleucine in MSUD.


MONDO:0009563

[PMID:23478409] [INDIRECT EVIDENCE] [SUPPORT] amino acid dysregulation results in aberrant neural networks with neurochemical deficiencies that persist after transplant and correlate with neuropsychiatric morbidities --- Explanation: Demonstrates that amino acid dysregulation, including transport competition at the BBB, leads to neurochemical deficiencies in MSUD patients.


MONDO:0009563

[PMID:23478409] [INDIRECT EVIDENCE] [SUPPORT] Using quantitative proton magnetic resonance spectroscopy, we found lower brain glutamate, N-acetylaspartate (NAA), and creatine concentrations in MSUD patients, which correlated with specific neuropsychiatric outcomes. --- Explanation: Direct demonstration of depleted glutamate and NAA in MSUD patient brains correlating with neuropsychiatric illness.


MONDO:0009563

[PMID:27373929] [INDIRECT EVIDENCE] [SUPPORT] KIC is an inhibitor of mitochondrial function at disease relevant concentrations. --- Explanation: Confirms KIC directly inhibits mitochondrial function.

[DOI:10.1091/mbc.11.5.1919] [INDIRECT EVIDENCE] [SUPPORT] increased concentrations of MSUD metabolites, in particular α-keto isocaproic acid, specifically induced apoptosis in glial and neuronal cells in culture --- Explanation: Demonstrates KIC-specific neurotoxicity inducing apoptosis in neural cell cultures.


MONDO:0009563

[PMID:23478409] [INDIRECT EVIDENCE] [SUPPORT] we found lower brain glutamate, N-acetylaspartate (NAA), and creatine concentrations in MSUD patients, which correlated with specific neuropsychiatric outcomes --- Explanation: Low NAA and creatine in MSUD brains reflects cerebral energy failure and neuronal compromise.


MONDO:0009563

[DOI:10.1091/mbc.11.5.1919] [INDIRECT EVIDENCE] [SUPPORT] Apoptosis was associated with a reduction in cell respiration but without impairment of respiratory chain function, without early changes in mitochondrial membrane potential and without cytochrome c release into the cytosol --- Explanation: Demonstrates apoptosis via cytochrome c-independent pathway in neural cells exposed to MSUD metabolites.

[DOI:10.1091/mbc.11.5.1919] [INDIRECT EVIDENCE] [SUPPORT] α-keto isocaproic acid also triggered neuronal apoptosis in vivo after intracerebral injection into the developing rat brain --- Explanation: Confirms KIC triggers neuronal apoptosis in vivo in developing brain tissue.

[DOI:10.1007/s11011-022-01109-y] [INDIRECT EVIDENCE] [SUPPORT] BCAA significantly increased the levels of Beclin-1, ATG7, and ATG5 in the cerebral cortex of rats --- Explanation: Demonstrates that BCAA administration increases autophagy markers in brain tissue of rats in an MSUD model, supporting the role of autophagy in neural cell death.


MONDO:0009563

[PMID:27373929] [INDIRECT EVIDENCE] [SUPPORT] iMSUD mice displayed a significant reduction in muscle fiber size, suggesting muscle atrophy. --- Explanation: Animal model demonstrates skeletal muscle atrophy in MSUD.

[PMID:27373929] [INDIRECT EVIDENCE] [SUPPORT] Metformin-treatment significantly reduced levels of KIC in the muscle (by 69%) and serum (by 56%) isolated from iMSUD mice, and restored levels of mitochondrial metabolites --- Explanation: Confirms KIC accumulation in muscle disrupts mitochondrial metabolism, reversible with metformin.


MAXO:0000088

[PMID:35672312] [SUPPORT] Treatment for MSUD represents an unmet need because the current treatment with life-long low-protein diet is challenging to maintain, and despite treatment the risk of acute decompensations and neuropsychiatric symptoms remains. --- Explanation: Confirms lifelong dietary treatment is the current standard of care but has limitations.


MAXO:0000088

[PMID:35578286] [SUPPORT] Patients with maple syrup urine disease (MSUD) experiencing metabolic decompensations have traditionally been treated with branched-chain amino acid (BCAA)-free mixture via oral or nasogastric administration routes. --- Explanation: Confirms BCAA-free amino acid mixtures are standard treatment.


MAXO:0000058

[PMID:27373929] [SUPPORT] Thiamine responsivity is associated with a specific mutation in the thiamine binding site in the E1b subunit, or due to the stabilization of BCKDH via an allosteric interaction --- Explanation: Confirms thiamine supplementation is effective for patients with specific mutations.


MAXO:0001175

[PMID:21839471] [SUPPORT] Patient and graft survival were 100% at 4.5 ± 2.2 years of follow-up. Liver function was normal in all patients. Branched-chain amino acid levels were corrected within hours after surgery and remained stable, with leucine tolerance increasing more than 10-fold. --- Explanation: Demonstrates excellent outcomes with liver transplantation for MSUD.

[PMID:23478409] [SUPPORT] Liver transplantation has emerged as an effective way to eliminate acute decompensation risk. --- Explanation: Confirms liver transplantation eliminates risk of acute metabolic crises.


MAXO:0000058

[PMID:35578286] [SUPPORT] The IV BCAA-free solution is safe and effective in normalising leucine concentrations during MSUD decompensation episodes in both children and adults --- Explanation: Demonstrates safety and efficacy of IV BCAA-free solutions for acute decompensation.


MAXO:0000058

[PMID:20301495] [SUPPORT] Acute metabolic decompensation is corrected by treating the precipitating stress while delivering sufficient calories, insulin, free amino acids, isoleucine, and valine to achieve sustained net protein synthesis in tissues. --- Explanation: Confirms acute crisis management involves delivering calories, insulin, and amino acids to promote anabolism.


MAXO:0000058

[PMID:21098507] [SUPPORT] In vivo phenylbutyrate increases the proportion of active hepatic enzyme and unphosphorylated form over the inactive phosphorylated form of the E1α subunit of the branched-chain α-keto acid dehydrogenase complex (BCKDC). --- Explanation: Demonstrates phenylbutyrate activates BCKDH by inhibiting kinase-mediated inactivation.


MAXO:0000058

[PMID:27373929] [SUPPORT] Metformin-treatment significantly reduced levels of KIC in the muscle (by 69%) and serum (by 56%) isolated from iMSUD mice, and restored levels of mitochondrial metabolites --- Explanation: Preclinical evidence supports metformin as potential therapeutic strategy for MSUD.


MAXO:0001001

[PMID:35672312] [SUPPORT] BCKDHA gene transfer rescued the lethal phenotype. While the use of a ubiquitous promoter fully and sustainably rescued the disease (long-term survival, normal phenotype and correction of biochemical abnormalities), liver-specific expression of BCKDHA led to partial, though sustained rescue. --- Explanation: Demonstrates efficacy of AAV8 gene therapy for MSUD in a mouse model with complete rescue using ubiquitous expression.


HGNC.SYMBOL:BCKDHA

[PMID:35672312] [SUPPORT] We establish and characterize the Bckdha (branched chain keto acid dehydrogenase a)-/- mouse that exhibits a lethal neonatal phenotype mimicking human MSUD. --- Explanation: Confirms BCKDHA mutations cause MSUD.


HGNC.SYMBOL:BCKDHB

[PMID:27373929] [SUPPORT] MSUD is classified as type I, II or III based on mutations that occur in the E1, E2, or E3 complexes of BCKDH, respectively. --- Explanation: Confirms BCKDHB (E1-beta) mutations cause Type I MSUD.


HGNC.SYMBOL:DBT

[PMID:27373929] [SUPPORT] MSUD is classified as type I, II or III based on mutations that occur in the E1, E2, or E3 complexes of BCKDH, respectively. --- Explanation: Confirms DBT (E2) mutations cause Type II MSUD.


HGNC.SYMBOL:DLD

[PMID:27373929] [SUPPORT] MSUD is classified as type I, II or III based on mutations that occur in the E1, E2, or E3 complexes of BCKDH, respectively. --- Explanation: Confirms DLD (E3) mutations cause Type III MSUD.


HGNC.SYMBOL:BCKDK

[DOI:10.1002/jmd2.12419] [SUPPORT] heterozygous gain‐of‐function variants in BCKDK may represent a novel biochemical phenotype of MSUD with a benign clinical course --- Explanation: Identifies BCKDK gain-of-function as a cause of a biochemical MSUD phenotype following autosomal dominant inheritance.


HGNC.SYMBOL:PPM1K

[PMID:23086801] [SUPPORT] This article describes a hitherto unreported involvement of the phosphatase PP2Cm, a recently described member of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, in maple syrup urine disease (MSUD). --- Explanation: First report of PPM1K (PP2Cm) mutation causing MSUD, confirming the regulatory role of this phosphatase in BCKDH complex activity.


MONDO:0007947

[PMID:21797750] [SUPPORT] MFS is one of the most common inherited connective tissue disorders affecting 1 in 5000 individuals. Although the phenotype of MFS can be quite variable, aneurysmal dilation of the aortic root and consecutive acute aortic dissection is the leading cause of death in this patient population. --- Explanation: This reference confirms that aortic aneurysm and aortic dissection are frequent cardiovascular manifestations in Marfan Syndrome.

[PMID:36058493] [SUPPORT] Early Onset Marfan Syndrome is at the severe end of the Marfan syndrome spectrum and is frequently associated with variants in exons 24-32 of the FBN1 gene. --- Explanation: The literature discusses the severe cardiovascular manifestations of Marfan Syndrome, supporting the frequent occurrence of aortic aneurysm and dissection.

[PMID:20364556] [SUPPORT] The majority of those individuals had significant organ involvement including dilatation of ascending aorta (78%). --- Explanation: This study indicates a high frequency of aortic dilation, a precursor to aortic aneurysm, among Marfan Syndrome patients.

[PMID:32290873] [SUPPORT] Marfan syndrome is an autosomal dominant disorder of the connective tissue, whose cardinal features affect eyes, musculoskeletal, and cardiovascular system. --- Explanation: The study highlights the cardiovascular system as a primary area affected in Marfan Syndrome, supporting the frequent occurrence of aortic aneurysms and dissection.

[PMID:7911041] [SUPPORT] The relation between Marfan syndrome and fibrillin mutations and that between supravalvular aortic stenosis and William syndromes and elastin mutations are reviewed. --- Explanation: This reference discusses the genetic basis of cardiovascular issues in Marfan Syndrome, supporting the frequent occurrence of aortic aneurysm and dissection.


MONDO:0007947

[PMID:28846673] [SUPPORT] Boys and girls from the MFS group were significantly taller than those in the non-MFS group and in the reference group at all ages (P<0.0001). --- Explanation: The study found that children with Marfan syndrome were significantly taller than their non-MFS counterparts at all ages, supporting the statement that tall stature is a very frequent musculoskeletal diagnostic feature of Marfan syndrome.

[PMID:36058493] [SUPPORT] Early Onset Marfan Syndrome is at the severe end of the Marfan syndrome spectrum and is frequently associated with variants in exons 24-32 of the FBN1 gene... presented with tall stature. --- Explanation: The report mentions that tall stature is frequently associated with Early Onset Marfan Syndrome, supporting the statement.

[PMID:31751304] [SUPPORT] We selected 42 patients with tall stature after exclusion of pathologies in GH/IGF1 axis and divided them into syndromic (n = 30) and non-syndromic (n = 12) subgroups... FBN1 = 3... --- Explanation: The genetic investigation identified FBN1 mutations, which are associated with Marfan syndrome, in patients with tall stature, supporting the statement.


MONDO:0007947

[PMID:34021688] [SUPPORT] Arachnodactyly, a term used since 1902 to describe abnormally long (spider-like) fingers, is a pathologic feature of several heritable conditions, notably the Marfan syndrome... --- Explanation: The literature states that arachnodactyly is a notable feature of Marfan syndrome.

[PMID:23478494] [SUPPORT] Arachnodactyly literally means spidery fingers, and describes the long, slender fingers typical of patients with Marfan syndrome (MFS). --- Explanation: This reference confirms that arachnodactyly is a typical feature of Marfan syndrome.


MONDO:0007947

[PMID:28902582] [SUPPORT] Marfan's Syndrome with Ectopia Lentis. --- Explanation: The title directly links Marfan Syndrome with ectopia lentis.

[PMID:24853997] [SUPPORT] In this strictly defined MFS group fulfilling the Ghent-1 criteria, the prevalence of EL was 62.1%. --- Explanation: The study reports a high prevalence (62.1%) of ectopia lentis in individuals with Marfan Syndrome, supporting the statement that it is a frequent ocular diagnostic feature.

[PMID:18090894] [SUPPORT] The mechanisms implicated in the clinical manifestations of zonular diseases, especially ectopia lentis, are reviewed. --- Explanation: The abstract mentions ectopia lentis as a clinical manifestation of zonular diseases, which includes Marfan Syndrome.

[PMID:17134646] [SUPPORT] Marfan syndrome is a widespread disorder of connective tissue. It is characterized by systemic and ocular features due to mutations in the fibrillin gene. --- Explanation: This reference supports the ocular diagnostic aspect of Marfan Syndrome.

[PMID:11705149] [SUPPORT] Marfan syndrome, homocystinuria, trauma, and simple ectopia lentis are the most common causes of pediatric lens subluxation. --- Explanation: This reference supports the association of Marfan Syndrome with ectopia lentis.

[PMID:6984233] [SUPPORT] Ectopia lentis may cause a marked reduction in visual acuity, which varies with the type and degree of dislocation and the presence of other ocular abnormalities. --- Explanation: This reference provides information on the clinical significance of ectopia lentis.

[PMID:36670079] [SUPPORT] Congenital ectopia lentis (EL) refers to the congenital dysplasia or weakness of the lens suspensory ligament, resulting in an abnormal position of the crystalline lens, which can appear as isolated EL or as an ocular manifestation of a syndrome, such as the Marfan syndrome. --- Explanation: This reference supports the statement by linking ectopia lentis as an ocular manifestation of Marfan Syndrome.

[PMID:38088571] [SUPPORT] Ectopia lentis is a hallmark of Marfan syndrome (MFS), a genetic connective tissue disorder affecting 1/5000 to 1/10 000 individuals worldwide. --- Explanation: This reference supports the statement by identifying ectopia lentis as a hallmark of Marfan Syndrome.


MONDO:0007947

[PMID:9076882] [SUPPORT] The data on all patients seen at one institution who had Marfan syndrome and scoliosis by age three were reviewed. --- Explanation: The study documents cases of scoliosis in patients with Marfan syndrome, supporting the statement that scoliosis is a frequent musculoskeletal diagnostic in Marfan syndrome.

[PMID:37270806] [SUPPORT] A large cross-sectional study revealed a 63% prevalence of scoliosis among patients with MFS. --- Explanation: This study provides statistical evidence of a high prevalence of scoliosis in Marfan syndrome patients, reinforcing that scoliosis is frequent in this condition.

[PMID:34916231] [SUPPORT] Among the several musculoskeletal manifestations in patients with Marfan syndrome, spinal deformity causes pain and respiratory impairment and is a great hindrance to patients' daily activities. --- Explanation: This study highlights scoliosis as one of the significant musculoskeletal manifestations in Marfan syndrome, supporting its frequent occurrence.

[PMID:35248143] [SUPPORT] One out of six with Marfan syndrome was registered with scoliosis (HR: 36.7 (27.5-48.9). --- Explanation: The nationwide epidemiological study confirms that scoliosis is a common musculoskeletal diagnosis in Marfan syndrome patients.


MONDO:0007947

[PMID:31883816] [SUPPORT] Though cardiovascular, skeletal and ophthalmological manifestations are the most frequent features, the respiratory system can also be involved. --- Explanation: The reference mentions that Marfan syndrome can involve the respiratory system, including pneumothorax.

[PMID:25765122] [SUPPORT] Marfan's syndrome is a rare genetic disorder...but minor diagnostic criteria also include pulmonary manifestations. Pneumothorax, frequently relapsing, affects 5 to 11% of patients. --- Explanation: The reference states that pneumothorax affects 5 to 11% of patients with Marfan syndrome, supporting the statement that it occurs occasionally.

[PMID:33896616] [SUPPORT] Pneumothorax often develops in patients with Marfan syndrome. --- Explanation: The reference confirms that pneumothorax is a common occurrence in patients with Marfan syndrome.

[PMID:21252480] [SUPPORT] Increased risk of spontaneous pneumothorax has been described in patients with Marfan syndrome. --- Explanation: The reference supports the statement by indicating an increased risk of pneumothorax in Marfan syndrome patients.


MONDO:0007947

[PMID:21797750] [SUPPORT] MFS is one of the most common inherited connective tissue disorders affecting 1 in 5000 individuals. Although the phenotype of MFS can be quite variable, aneurysmal dilation of the aortic root and consecutive acute aortic dissection is the leading cause of death in this patient population. --- Explanation: This reference directly states that aortic dissection is the leading cause of death in Marfan syndrome patients.

[PMID:16321689] [SUPPORT] Aortic dissection occurred more frequently in group R (7 patients, 47%) than in group S (0%, P < 0.001). --- Explanation: This study demonstrates that aortic dissection is a frequent complication in patients with rapid aortic root dilation.


MONDO:0007947


MAXO:0000186

[PMID:36939732] [PARTIAL] Beta-blockers remain the mainstay of therapy as they have proven to slow aortic enlargement. Angiotensin receptor blockers are a useful alternative and with proven benefit as an add-on therapy to limit aortic growth. --- Explanation: Beta-blockers are used to slow aortic enlargement, which indirectly reduces stress on the aorta. However, they do not prevent aortic enlargement entirely.

[PMID:17845137] [PARTIAL] Traditional medical therapies, such as beta-adrenergic receptor blockade, are used to slow pathologic aortic growth and decrease the risk of aortic dissection by decreasing hemodynamic stress. --- Explanation: Beta-blockers are used to slow aortic growth and decrease hemodynamic stress, but they do not completely prevent aortic enlargement.

[PMID:17376944] [PARTIAL] Medical treatment with beta-blockers is probably helpful in most children with aortic root dilatation. --- Explanation: Beta-blockers are helpful in slowing the progression of aortic root dilatation, but they do not completely prevent it.


MAXO:0000058


MAXO:0000004

[PMID:26586198] [SUPPORT] To prevent such catastrophic aortic events, a lower threshold has been recommended for prophylactic interventions on the aortic root. --- Explanation: The literature mentions that prophylactic aortic root replacement is recommended to prevent severe aortic events such as dissections.

[PMID:29948025] [SUPPORT] Few data exist regarding predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome (MFS). --- Explanation: The study investigates predictors for referral for aortic surgery in patients with Marfan syndrome, indicating that surgery is recommended for severe aortic dilation.


MAXO:0000004

[PMID:11961443] [SUPPORT] The authors recommend arthrodesing both the primary and secondary curves in all patients with Marfan syndrome. --- Explanation: The study discusses surgical treatment of scoliosis in Marfan syndrome and provides guidelines for successful outcomes through orthopedic interventions.

[PMID:11880731] [SUPPORT] The major orthopedic manifestations of Marfan syndrome include scoliosis, chest wall deformity, dural ectasia, joint hypermobility, and acetabular protrusion. --- Explanation: This review highlights the orthopedic aspects of Marfan syndrome, including treatments for scoliosis and other skeletal abnormalities.

[PMID:34916231] [SUPPORT] We elucidated the genetic risk factors for the development of severe scoliosis in patients with Marfan syndrome. --- Explanation: The study investigates the genetic risk factors for severe scoliosis in Marfan syndrome, which is relevant to orthopedic interventions.

[PMID:17945136] [SUPPORT] Kyphoscoliosis, spondylolisthesis, and atlantoaxial subluxation are common spinal deformities in Marfan syndrome... Surgical correction is associated with complications, such as failure of fixation and additional deformity; however good results are possible when consideration is given to the unique challenges presented by patients who have Marfan syndrome. --- Explanation: The article discusses common spinal deformities in Marfan syndrome and the complexities of surgical correction, supporting the statement on orthopedic interventions.

[PMID:26130954] [SUPPORT] Patients with Marfan syndrome (MFS) presents with primary skeletal manifestations such as tall stature, chest wall abnormality, and scoliosis. --- Explanation: This study covers the primary skeletal manifestations of Marfan syndrome, including scoliosis, which require orthopedic interventions.


MAXO:0000004

[PMID:24698610] [SUPPORT] Anterior lensectomy and limited vitrectomy with aphakic correction is safe and provides a consistent visual outcome in patients with lens subluxation secondary to Marfan syndrome. --- Explanation: The study discusses surgical management of ectopia lentis in Marfan syndrome patients, which supports the statement about managing ocular issues with surgery.

[PMID:23661206] [SUPPORT] The ocular features were ectopia lentis in 92.3% of the patients... The best corrected visual acuity in 4 out of 5 patients who had cataract extraction at 8 weeks post op. was 6/60 to 6/12. --- Explanation: This study highlights the use of surgical intervention for vision correction in Marfan syndrome patients with ectopia lentis.

[PMID:30260057] [SUPPORT] Our study indicates that even though EL typically occurs at an early stage in most MFS patients, there is still a risk of developing EL in adulthood. --- Explanation: The study confirms the management of ectopia lentis (EL) in Marfan syndrome, indicating the necessity for vision correction, which can include glasses or surgery.


HGNC.SYMBOL:FBN1

[PMID:31163209] [SUPPORT] FBN1 gene mutations lead to MFS and related connective tissue disorders. --- Explanation: The abstract directly states that FBN1 gene mutations are associated with Marfan syndrome and related disorders.

[PMID:34916231] [SUPPORT] We retrospectively evaluated 278 patients with pathogenic or likely pathogenic FBN1 variants. --- Explanation: The study focuses on patients with Marfan syndrome who have pathogenic FBN1 variants, supporting the association.

[PMID:32130918] [SUPPORT] Aortic risk has not been evaluated in patients with Marfan syndrome and documented pathogenic variants in the FBN1 gene. --- Explanation: The study describes aortic risks in patients with Marfan syndrome with pathogenic FBN1 variants, supporting the association.

[PMID:35419902] [SUPPORT] Different pathogenic variants in the fibrillin-1 gene (FBN1) cause Marfan syndrome and acromelic dysplasias. --- Explanation: The abstract states that pathogenic variants in FBN1 cause Marfan syndrome, supporting the association.

[PMID:36004597] [SUPPORT] Marfan syndrome is an orphan disease that is caused by a mutation in the FBN1 gene located on chromosome 15 (15q21.1). --- Explanation: The article reviews studies concerning the potential ocular manifestations of Marfan syndrome caused by FBN1 mutations.

[PMID:30485715] [SUPPORT] Pathogenic variants in FBN1 cause autosomal dominant Marfan syndrome. --- Explanation: The abstract states that pathogenic variants in FBN1 cause autosomal dominant Marfan syndrome, supporting the association.

[PMID:19059503] [SUPPORT] We report two families in which the probands have compound-heterozygous Marfan syndrome (MFS). --- Explanation: The study reports cases of Marfan syndrome associated with compound-heterozygous FBN1 mutations, supporting the association.


HGNC.SYMBOL:TGFBR1


HGNC.SYMBOL:TGFBR2


HGNC.SYMBOL:SMAD2


HGNC.SYMBOL:SMAD3


HGNC.SYMBOL:ACTA2


HGNC.SYMBOL:AGTR1


HGNC.SYMBOL:ITGAV


HGNC.SYMBOL:NOS2


HGNC.SYMBOL:VCAN


XCO:0000059

[PMID:9789865] [SUPPORT] The person with Marfan syndrome is often tall and agile and may unknowingly participate in certain physical activities and sports, putting himself or herself at risk for aortic dissection and sudden death. --- Explanation: The article suggests that physical activity restrictions are necessary to prevent aortic dissection in individuals with Marfan syndrome.

[PMID:36453629] [SUPPORT] We instructed patients to take 10 000 steps per day, tracked by an activity tracker... AoR Z score in the intervention group had a significantly lower rate of change per year compared with the controls (rate of change, -0.24 versus +0.008; P=0.01). --- Explanation: The study indicates that controlled physical activity can reduce the rate of aortic root dilation, which is associated with a lower risk of aortic dissection.

[PMID:28947563] [SUPPORT] Over the 5-month experimental period, aortic root dilation rate was significantly greater in the sedentary MF group, compared with the wild-type group (∆mm, 0.27±0.07 versus 0.13±0.02, respectively). Exercise significantly blunted the aortic root dilation rate in MF mice compared with sedentary MF littermates (∆mm, 0.10±0.04 versus 0.27±0.07, respectively). --- Explanation: Moderate dynamic exercise mitigates the progression of cardiovascular issues in Marfan syndrome, indirectly supporting the idea that physical activity restrictions can help manage aortic dissection risk.


MONDO:0007955

[PMID:8506491] [SUPPORT] Meckel's diverticula are most commonly manifested in children by painless lower gastrointestinal bleeding and in adults, as an inflammatory process or obstruction. --- Explanation: This describes the age-specific manifestations of Meckel diverticulum complications.

[PMID:17021300] [SUPPORT] It can cause complications in the form of ulceration, haemorrhage, intussusception, intestinal obstruction, perforation and, very rarely, vesicodiverticular fistulae and tumours. --- Explanation: This systematic review identifies hemorrhage as a major complication of Meckel diverticulum.

[PMID:15026601] [SUPPORT] The most common complications are hemorrhage from peptic ulceration, small intestinal obstruction, and diverticulitis. --- Explanation: This identifies hemorrhage from peptic ulceration as the most common complication.

[PMID:19444035] [SUPPORT] Our first patient presented with massive bleeding per rectum in the first week of life, which is the only case reported so far. --- Explanation: This documents rare neonatal presentation with massive rectal bleeding in the first week of life.


MONDO:0007955

[PMID:8506491] [SUPPORT] Meckel's diverticula are most commonly manifested in children by painless lower gastrointestinal bleeding and in adults, as an inflammatory process or obstruction. --- Explanation: This describes intestinal obstruction as a common adult presentation.

[PMID:17021300] [SUPPORT] It can cause complications in the form of ulceration, haemorrhage, intussusception, intestinal obstruction, perforation and, very rarely, vesicodiverticular fistulae and tumours. --- Explanation: This systematic review identifies intestinal obstruction as a major complication.

[PMID:27492813] [SUPPORT] The major complications of Meckel's diverticulum include gastrointestinal bleeding, bowel obstruction, perforation and inflammation. --- Explanation: This identifies bowel obstruction as one of the major complications of Meckel diverticulum.

[PMID:1084202] [SUPPORT] In particular, the possiblity of an attached mesodiverticular band leading to obstruction must be stressed. --- Explanation: This highlights mesodiverticular bands as an important cause of intestinal obstruction.

[PMID:15026601] [SUPPORT] The most common complications are hemorrhage from peptic ulceration, small intestinal obstruction, and diverticulitis. --- Explanation: This identifies small intestinal obstruction as one of the three most common complications.


MONDO:0007955

[PMID:8506491] [SUPPORT] Meckel's diverticula are most commonly manifested in children by painless lower gastrointestinal bleeding and in adults, as an inflammatory process or obstruction. --- Explanation: This describes inflammatory presentations in adults.

[PMID:27492813] [SUPPORT] The major complications of Meckel's diverticulum include gastrointestinal bleeding, bowel obstruction, perforation and inflammation. --- Explanation: This identifies inflammation as a major complication.

[PMID:37769709] [SUPPORT] Diverticulitis in Meckel's diverticulum. --- Explanation: This is a case report specifically documenting diverticulitis in Meckel's diverticulum.


MONDO:0007955

[PMID:17021300] [SUPPORT] It can cause complications in the form of ulceration, haemorrhage, intussusception, intestinal obstruction, perforation and, very rarely, vesicodiverticular fistulae and tumours. --- Explanation: This systematic review identifies perforation as a complication of Meckel diverticulum.

[PMID:27492813] [SUPPORT] The major complications of Meckel's diverticulum include gastrointestinal bleeding, bowel obstruction, perforation and inflammation. --- Explanation: This identifies perforation as a major complication.

[PMID:41044867] [SUPPORT] Perforated Meckel Diverticulum Caused by Vegetal Food Entrapment: A Rare Case Report and Literature Review. --- Explanation: This case report documents perforation of Meckel diverticulum.


MONDO:0007955

[PMID:17021300] [SUPPORT] It can cause complications in the form of ulceration, haemorrhage, intussusception, intestinal obstruction, perforation and, very rarely, vesicodiverticular fistulae and tumours. --- Explanation: This systematic review identifies intussusception as a complication of Meckel diverticulum.

[PMID:37099684] [SUPPORT] There are few cases of a Meckel's diverticulum having been identified as the lead point for adult intussusception. --- Explanation: This notes that Meckel diverticulum as a lead point for intussusception is uncommon in adults.


MAXO:0000004

[PMID:8506491] [SUPPORT] All symptomatic and pathologic Meckel's diverticula should be removed with a segment of ileum. --- Explanation: This provides guidance on surgical management of symptomatic Meckel diverticula.

[PMID:31930430] [SUPPORT] Complicated Meckel's diverticulum is treated by resection. --- Explanation: This confirms resection as the treatment for complicated cases.


MAXO:0000004

[PMID:8506491] [SUPPORT] The use of stapling devices, with their ease of use and low complication rate, make it reasonable to remove any Meckel's diverticulum that easily fits in the device. If a diverticulum found incidentally is so broad-based or short that stapling cannot be done without difficulty, it is unlikely to become symptomatic and should be left undisturbed. --- Explanation: This provides specific guidance on management of incidentally discovered Meckel diverticula using stapling devices.