CHEBI:66903

[PMID:22670904] [INDIRECT EVIDENCE] [SUPPORT] Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. --- Explanation: Randomized trial evidence for efficacy in NBCCS-associated BCC prevention and shrinkage.

[PMID:22670904] [INDIRECT EVIDENCE] [PARTIAL] The adverse events associated with treatment led to discontinuation in over half of treated patients. --- Explanation: Documents long-term tolerability limits that affect treatment strategy.


MAXO:0000058

[PMID:37887561] [PARTIAL] Vismodegib or sonidegib represent promising treatment options. --- Explanation: Supports sonidegib use as a pathway-targeted option in Gorlin-associated BCC.


CHEBI:90863

[PMID:37887561] [INDIRECT EVIDENCE] [PARTIAL] Vismodegib or sonidegib represent promising treatment options. --- Explanation: Supports sonidegib use as a pathway-targeted option in Gorlin-associated BCC.


MAXO:0000004

[PMID:19032739] [SUPPORT] Keratocysts are treated by surgical removal. Surgery for BBCs is indicated when the number of lesions is limited; other treatments include laser ablation, photodynamic therapy and topical chemotherapy. --- Explanation: Supports surgery as a core local-control treatment in NBCCS.


MAXO:0000055

[PMID:19032739] [SUPPORT] Patients with NBCCS should strictly avoid an excessive sun exposure. --- Explanation: Supports UV-avoidance counseling as a preventive management measure.


MAXO:0000079

[PMID:19032739] [SUPPORT] Genetic counseling is mandatory. --- Explanation: Supports routine genetic counseling for affected families.


HGNC.SYMBOL:PTCH1

[PMID:28596197] [SUPPORT] Heterozygous germline variants in PTCH1 and SUFU encoding components of the Sonic hedgehog pathway explain the majority of cases. --- Explanation: Supports PTCH1 as the principal causal locus in genotype-positive Gorlin syndrome.


MONDO:0007804

[PMID:24736735] [SUPPORT] PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis --- Explanation: Hypothalamic hamartoma is a cardinal feature of PHS since original description.


MONDO:0007804

[PMID:24736735] [SUPPORT] postaxial or central polydactyly, anal atresia and bifid epiglottis --- Explanation: Postaxial/central polydactyly is the characteristic limb pattern in PHS.

[PMID:28224613] [SUPPORT] four separate entities; each characterized by a specific pattern of polydactyly --- Explanation: PHS has a distinct polydactyly pattern (postaxial) from GCPS (preaxial).


MONDO:0007804

[PMID:24736735] [SUPPORT] hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis --- Explanation: Bifid epiglottis is one of the cardinal features in the original PHS description.


MONDO:0007804

[PMID:24736735] [SUPPORT] hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis --- Explanation: Anal atresia is a cardinal feature of PHS.


MONDO:0007804

[PMID:15739154] [INDIRECT EVIDENCE] [SUPPORT] In contrast, PHS was caused only by frameshift/nonsense and splicing mutations --- Explanation: Only truncating mutations cause PHS, supporting the constitutive repressor model.

[PMID:15739154] [INDIRECT EVIDENCE] [SUPPORT] among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation --- Explanation: Positional specificity of truncating mutations determines GCPS vs PHS phenotype.

[PMID:10375510] [INDIRECT EVIDENCE] [SUPPORT] C-terminal sequences are required for positive inducing activity --- Explanation: Loss of C-terminal transactivation domain explains why middle-third truncations produce a constitutive repressor.

[PMID:10693759] [INDIRECT EVIDENCE] [SUPPORT] The high relative abundance and potency of Gli3 repressor suggest specialization of Gli3 and its products for negative Hedgehog pathway regulation --- Explanation: GLI3 is specialized for repressor function, explaining why truncated repressor proteins cause disease.


MONDO:0007804

[PMID:10375510] [INDIRECT EVIDENCE] [SUPPORT] provide a molecular basis for the human Polydactyly type A and Pallister-Hall Syndrome phenotypes, derived from the deregulated production of C-terminally truncated GLI3 proteins --- Explanation: Truncated GLI3 directly causes the polydactyly phenotype in PHS.


MAXO:0000004


HGNC.SYMBOL:GLI3 Mutations (Truncating, Middle Third)

[PMID:15739154] [SUPPORT] Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities --- Explanation: Establishes GLI3 as causative for both GCPS and PHS as allelic disorders.

[PMID:15739154] [SUPPORT] These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis --- Explanation: Robust genotype-phenotype correlation across 135-patient cohort.

[PMID:20672375] [SUPPORT] A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene --- Explanation: Expanded cohort confirms GLI3 as the causative gene for PHS.

[PMID:24736735] [SUPPORT] 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases) --- Explanation: Additional large cohort confirming GLI3 genotype-phenotype correlations.


MONDO:0005184

[PMID:32593337] [SUPPORT] Pancreatic cancer is a highly fatal disease with a 5-year survival rate of approximately 10% in the USA, and it is becoming an increasingly common cause of cancer mortality. --- Explanation: The Lancet seminar confirms pancreatic cancer as a highly fatal malignancy with approximately 10% 5-year survival.


MONDO:0005184

[PMID:32593337] [SUPPORT] Patients typically present with advanced disease due to lack of or vague symptoms when the cancer is still localised. --- Explanation: The Lancet review notes that patients present with advanced disease due to vague early symptoms, consistent with abdominal pain as a common late presentation.


MONDO:0005184


MONDO:0005184

[PMID:28507210] [SUPPORT] most patients with PDAC report weight loss rather than weight gain. The clinical features of deteriorating glycemic control in conjunction with weight loss that accompanies PDAC prior to its diagnosis are atypical for T2DM --- Explanation: Andersen et al. note that weight loss is a characteristic clinical feature of PDAC, distinguishing it from typical T2DM presentation.


MONDO:0005184

[PMID:28507210] [SUPPORT] The relationships between diabetes and pancreatic ductal adenocarcinoma (PDAC) are complex. Longstanding type 2 diabetes (T2DM) is a risk factor for pancreatic cancer, but increasing epidemiological data point to PDAC as also a cause of diabetes due to unknown mechanisms. --- Explanation: Andersen et al. establish that PDAC causes new-onset diabetes through unknown mechanisms, demonstrating the bidirectional relationship between PDAC and diabetes.


MONDO:0005184

[PMID:32593337] [SUPPORT] Surgical resection represents the only chance for cure, and advancements in adjuvant chemotherapy have improved long-term outcomes in these patients. --- Explanation: The Lancet seminar describes PDAC staging categories including metastatic disease, for which surgery is not curative, consistent with the high frequency of hepatic metastases in advanced disease.


MONDO:0005184

[DOI:10.3389/fmed.2024.1369136] [INDIRECT EVIDENCE] [SUPPORT] In the case of pancreatic ductal adenocarcinomas (PDAC), 90-92% harbor mutations in the oncogene KRAS, triggering canonical MAPK signaling. --- Explanation: This review confirms that 90-92% of PDAC harbor KRAS mutations that trigger canonical MAPK signaling, supporting the central role of KRAS in PDAC pathogenesis.

[DOI:10.1093/carcin/bgae064] [INDIRECT EVIDENCE] [SUPPORT] PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving PanIN initiation. Key additional mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control and genomic stability, crucial for PanIN progression from low-grade to high-grade dysplasia. --- Explanation: This review confirms KRAS mutations as the initiating event in PanIN development, with additional tumor suppressor losses driving progression to invasive carcinoma.


MONDO:0005184

[PMID:18772397] [INDIRECT EVIDENCE] [SUPPORT] This list includes the classic tumor suppressor genes CDKN2A (p16), SMAD4, and TP53, as well as genes that had not previously been implicated in pancreatic cancer development. --- Explanation: The landmark Jones et al. genomic analysis identified CDKN2A, SMAD4, and TP53 as core tumor suppressor genes in pancreatic cancer through global sequencing of 24 advanced pancreatic adenocarcinomas.


MONDO:0005184

[DOI:10.3390/cancers16162876] [INDIRECT EVIDENCE] [SUPPORT] Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells' metabolism, inhibit drug delivery, enhance immune suppression mechanisms and finally develop resistance to chemotherapy and immunotherapy. --- Explanation: This review confirms that the PDAC TME inhibits drug delivery and enhances immune suppression, consistent with the role of the desmoplastic stroma in treatment resistance.

[DOI:10.1146/annurev-pathmechdis-031621-024600] [INDIRECT EVIDENCE] [SUPPORT] Pancreatic ductal adenocarcinoma (PDAC) features a prominent stromal microenvironment with remarkable cellular and spatial heterogeneity that meaningfully impacts disease biology and treatment resistance. --- Explanation: This review describes the prominent stromal microenvironment in PDAC and its role in treatment resistance, supporting the desmoplastic stroma mechanism.


MONDO:0005184

[DOI:10.1186/s12943-023-01813-y] [INDIRECT EVIDENCE] [SUPPORT] Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. --- Explanation: This review establishes immunosuppression as a hallmark of PDAC that contributes to metastasis and poor survival, supporting the immune evasion mechanism.

[DOI:10.1186/s12943-023-01813-y] [INDIRECT EVIDENCE] [SUPPORT] Following chemokine and exosomal guidance, these cells metastasize to the organ-specific pre-metastatic niches (PMNs) constituted by local resident cells, stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated macrophages, neutrophils, and myeloid-derived suppressor cells. --- Explanation: This describes the immune cell populations in PDAC metastatic niches including macrophages, neutrophils, and MDSCs that constitute the immunosuppressive microenvironment.


MAXO:0000004

[PMID:28129987] [SUPPORT] Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). --- Explanation: The ESPAC-4 trial enrolled patients who underwent complete macroscopic resection for PDAC, confirming surgical resection as a standard treatment approach with adjuvant chemotherapy improving outcomes.


MAXO:0000647

[PMID:30575490] [SUPPORT] Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. --- Explanation: The PRODIGE 24 trial demonstrated that adjuvant modified FOLFIRINOX significantly improved disease-free and overall survival compared to gemcitabine in resected PDAC patients.


MAXO:0000647

[PMID:24131140] [SUPPORT] nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. --- Explanation: The Von Hoff et al. phase 3 trial demonstrated that nab-paclitaxel plus gemcitabine significantly improved overall survival (8.5 vs 6.7 months) in metastatic pancreatic adenocarcinoma.


MAXO:0000058

[PMID:31157963] [SUPPORT] We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. --- Explanation: The POLO trial demonstrated that maintenance olaparib significantly prolonged progression-free survival in germline BRCA-mutated metastatic pancreatic cancer patients who had not progressed on platinum-based chemotherapy.


HGNC.SYMBOL:KRAS

[DOI:10.3389/fmed.2024.1369136] [SUPPORT] In the case of pancreatic ductal adenocarcinomas (PDAC), 90-92% harbor mutations in the oncogene KRAS, triggering canonical MAPK signaling. The smooth structure of the altered KRAS protein without a binding pocket and its affinity for GTP have, in the past, hampered drug development. --- Explanation: Confirms KRAS mutations in 90-92% of PDAC and describes the structural challenges that have historically hampered therapeutic targeting of KRAS.


HGNC.SYMBOL:TP53

[PMID:37404765] [SUPPORT] the KRAS mutated group had a significantly higher percentage of TP53 (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001) --- Explanation: Foundation Medicine genomic profiling of 9,444 advanced PDAC cases showed TP53 mutations in 80.2% of KRAS-mutated PDAC.


HGNC.SYMBOL:SMAD4

[PMID:37404765] [SUPPORT] SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001) --- Explanation: Foundation Medicine profiling showed SMAD4 mutations in 26.8% of KRAS-mutated PDAC. Higher rates reported in other studies reflect inclusion of homozygous deletions not captured by all assays.


HGNC.SYMBOL:CDKN2A

[PMID:37404765] [SUPPORT] CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001) --- Explanation: Foundation Medicine profiling showed CDKN2A alterations in 56.2% of KRAS-mutated PDAC. Higher rates in other studies include epigenetic silencing.


HGNC.SYMBOL:BRCA2

[PMID:31157963] [SUPPORT] Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. --- Explanation: The POLO trial confirmed that BRCA-mutated PDAC patients represent a distinct subgroup that responds to PARP inhibition, validating the clinical relevance of BRCA2 mutations in PDAC.


MONDO:0018523

[PMID:20043327] [SUPPORT] Mucinous cystic neoplasms typically arise in the body or tail of the pancreas of middle-aged women and demonstrate a septated cyst without dilatation of the main pancreatic duct. --- Explanation: Describes the characteristic cystic presentation of MCNs as septated cysts in the body or tail of the pancreas.


MONDO:0018523

[PMID:21128317] [PARTIAL] The majority of MCNs are slow growing and asymptomatic. --- Explanation: While most MCNs are asymptomatic, abdominal pain is the most common presenting symptom when symptoms do occur, as noted across clinical series.


MONDO:0018523

[PMID:28416122] [SUPPORT] MCNs presented almost exclusively in middle-aged women (median 47.5 years, 96.5% female) as solitary (100%), macrocystic (94.2%) lesions in the distal pancreas (92.1%). --- Explanation: Large single-institution series of 142 MCNs demonstrates that MCNs are macrocystic (94.2%) and large (median 4.2 cm), consistent with presentation as a palpable abdominal mass.


MONDO:0018523

[PMID:21128317] [SUPPORT] MCNs are pancreatic mucin-producing cysts with a distinctive ovarian-type stroma localized in the body-tail of the gland and occurring in middle-aged females. --- Explanation: MCNs present as discrete pancreatic masses localized in the body-tail of the pancreas.


MONDO:0018523

[PMID:29574408] [PARTIAL] Resection is also recommended for MCN which are symptomatic or have risk factors (ie, mural nodule) irrespective of their size --- Explanation: European guidelines recognize symptomatic MCNs as indication for resection. Weight loss is a known nonspecific symptom but is not named in this snippet.


MONDO:0018523

[PMID:29574408] [PARTIAL] Resection is also recommended for MCN which are symptomatic or have risk factors (ie, mural nodule) irrespective of their size --- Explanation: European guidelines recognize that MCNs can be symptomatic, supporting nausea as a possible symptom, though nausea is not named specifically.


MONDO:0018523

[PMID:29574408] [PARTIAL] Resection is also recommended for MCN which are symptomatic or have risk factors (ie, mural nodule) irrespective of their size --- Explanation: European guidelines recognize that MCNs can be symptomatic, indirectly supporting vomiting as a possible symptom, though not named specifically.


MONDO:0018523

[PMID:29574408] [PARTIAL] Resection is also recommended for MCN which are symptomatic or have risk factors (ie, mural nodule) irrespective of their size --- Explanation: European guidelines recognize symptomatic MCNs; back pain from retroperitoneal body/tail lesions is a known symptom but not named here.


MONDO:0018523

[PMID:29574408] [PARTIAL] MCN ≥40 mm should undergo surgical resection. Resection is also recommended for MCN which are symptomatic or have risk factors (ie, mural nodule) irrespective of their size --- Explanation: The MCN-specific section of European guidelines references symptomatic MCNs as an indication for resection without enumerating individual symptoms. New-onset diabetes mellitus is a recognized symptom of pancreatic cystic neoplasms but is not specifically named in the MCN management section.


MONDO:0018523

[PMID:29574408] [PARTIAL] MCN ≥40 mm should undergo surgical resection. Resection is also recommended for MCN which are symptomatic or have risk factors (ie, mural nodule) irrespective of their size --- Explanation: The MCN-specific section of European guidelines references symptomatic MCNs as an indication for resection without enumerating individual symptoms. Pancreatitis is a recognized symptom of pancreatic cystic neoplasms but is not specifically named in the MCN management section.


MONDO:0018523

[PMID:29574408] [PARTIAL] MCN ≥40 mm should undergo surgical resection. Resection is also recommended for MCN which are symptomatic or have risk factors (ie, mural nodule) irrespective of their size --- Explanation: The MCN-specific section of European guidelines references symptomatic MCNs as an indication for resection without enumerating individual symptoms. Jaundice is a recognized symptom of pancreatic cystic neoplasms but is not specifically named in the MCN management section.


MONDO:0018523

[PMID:21128317] [INDIRECT EVIDENCE] [SUPPORT] MCNs are pancreatic mucin-producing cysts with a distinctive ovarian-type stroma localized in the body-tail of the gland and occurring in middle-aged females. --- Explanation: Systematic review confirming the defining features of MCNs including mucin-producing cysts and body-tail location.

[PMID:20043327] [INDIRECT EVIDENCE] [SUPPORT] Mucinous cystic neoplasms typically arise in the body or tail of the pancreas of middle-aged women and demonstrate a septated cyst without dilatation of the main pancreatic duct. --- Explanation: Describes the characteristic mucinous epithelial cystic presentation of MCNs.


MONDO:0018523


MONDO:0018523

[PMID:24746205] [INDIRECT EVIDENCE] [SUPPORT] All cases of PMC and HBC demonstrated nuclear reactivity for FOXL2 in the subepithelial stromal cells. Ninety percent of MEST demonstrated nuclear FOXL2 positivity. Estrogen receptor nuclear positivity was demonstrated in 57% of PMC, 77% of HBC, and 80% of MEST. Progesterone receptor nuclear positivity was present in 67% of PMC, 100% of HBC, and 90% of MEST. --- Explanation: Demonstrates that ovarian-type stroma in pancreatic mucinous cystic neoplasms expresses FOXL2 and hormone receptors, confirming the ovarian-type stromal differentiation pathophysiology.

[PMID:28416122] [INDIRECT EVIDENCE] [SUPPORT] Mucinous cystic neoplasms (MCNs) are rare pancreas tumors distinguished from intraductal papillary mucinous neoplasms (IPMNs) by the presence of ovarian-type stroma. --- Explanation: Large clinical series confirming ovarian-type stroma as the defining diagnostic feature distinguishing MCNs from IPMNs.


MONDO:0018523

[PMID:10721805] [INDIRECT EVIDENCE] [SUPPORT] Partial resection should be avoided as evidence suggests that mucinous cystic neoplasms can progress from adenomas to borderline lesions to carcinomas in situ to invasive carcinomas over time; partial resection should be avoided if possible. --- Explanation: Describes the stepwise progression model from adenoma through borderline and in situ carcinoma to invasive carcinoma in mucinous cystic neoplasms.

[PMID:28570009] [INDIRECT EVIDENCE] [SUPPORT] KRAS mutations were uncommon in cases of low-grade dysplasia (1/20, 5%), whereas KRAS was mutated in all cases of higher grades, except for one liver MCN with intermediate-grade dysplasia (4/5, 80%; P = 0.002). --- Explanation: Demonstrates that KRAS mutations are strongly associated with higher-grade dysplasia in MCNs, supporting the role of KRAS as a driver in adenoma-carcinoma progression.


MONDO:0018523

[PMID:28570009] [INDIRECT EVIDENCE] [SUPPORT] KRAS mutations appear to be major driver genetic alterations in both liver and pancreatic MCNs. As identical KRAS mutations were present in low-grade and higher-grade areas in individual cases, KRAS mutations occurring in low-grade MCNs may lead to tumour progression. --- Explanation: Establishes KRAS as the primary oncogenic driver in pancreatic MCNs through molecular analysis of 25 surgical cases, showing clonal progression from low-grade to higher-grade dysplasia.

[PMID:35066614] [INDIRECT EVIDENCE] [SUPPORT] MCNs frequently harbored KRAS mutations, at rates of 100% in HG/INV lesions and 50% in LG lesions of HG/INV and LG cases. --- Explanation: Study of 106 MCN cases quantifies grade-dependent KRAS mutation rates, establishing 50% in low-grade and 100% in high-grade/invasive lesions.

[PMID:34099908] [INDIRECT EVIDENCE] [SUPPORT] We also discuss the most prevalent genetic alterations in these precancerous lesions, including somatic mutations in the oncogenes KRAS and GNAS as well as tumour suppressor genes CDKN2A, TP53 and SMAD4. --- Explanation: Review confirms KRAS as one of the most prevalent genetic alterations in pancreatic precancerous lesions including mucinous cystic neoplasms.


MONDO:0018523

[PMID:35066614] [INDIRECT EVIDENCE] [SUPPORT] The frequency of RNF43 mutations was significantly higher in HG/INV cases than in LG cases. Furthermore, HG/INV lesions (56%) and LG lesions (33%) of HG/INV cases possessed RNF43 mutation, whereas no such mutation was detected in any LG cases. --- Explanation: Study of 106 MCN cases directly demonstrates RNF43 mutations are enriched in high-grade/invasive lesions, supporting RNF43 loss as a driver of Wnt pathway dysregulation in MCN progression.

[PMID:28570009] [INDIRECT EVIDENCE] [PARTIAL] KRAS, GNAS, RNF43 and PIK3CA were sequenced in 25 surgical cases of hepatopancreatic MCN. Molecular features were correlated with clinicopathological and immunohistochemical findings. KRAS mutations were identified in five cases (20%), whereas GNAS, RNF43 and PIK3CA were wild-type in all cases. --- Explanation: This smaller study of 25 cases did not find RNF43 mutations, likely due to sample size and enrichment for low-grade lesions. Confirms GNAS is absent in MCNs, distinguishing them from IPMNs.


MONDO:0018523

[PMID:34099908] [INDIRECT EVIDENCE] [SUPPORT] We also discuss the most prevalent genetic alterations in these precancerous lesions, including somatic mutations in the oncogenes KRAS and GNAS as well as tumour suppressor genes CDKN2A, TP53 and SMAD4. --- Explanation: Identifies TP53, CDKN2A, and SMAD4 as key tumor suppressor genes altered in pancreatic precancerous lesions including MCNs, supporting the progressive accumulation of genetic alterations model.


MAXO:0000448

[PMID:10721805] [SUPPORT] Completely removed mucinous cystadenomas, borderline mucinous cystic neoplasms, and mucinous cystic neoplasms with in situ carcinoma follow benign courses. Partial resection should be avoided as evidence suggests that mucinous cystic neoplasms can progress from adenomas to borderline lesions to carcinomas in situ to invasive carcinomas over time; partial resection should be avoided if possible. --- Explanation: Demonstrates that complete resection is curative for non-invasive MCNs and that partial resection risks leaving tissue that may progress to carcinoma.

[PMID:29574408] [SUPPORT] MCN ≥40 mm should undergo surgical resection. Resection is also recommended for MCN which are symptomatic or have risk factors (ie, mural nodule) irrespective of their size --- Explanation: 2018 European evidence-based guidelines specify size-based criteria for surgical resection of MCNs, superseding earlier recommendations for universal resection.

[PMID:21128317] [PARTIAL] Surgery is indicated for all MCNs. --- Explanation: 2010 systematic review recommended surgery for all MCNs; this has been superseded by 2018 European guidelines allowing surveillance for MCNs <40 mm without risk features.


MAXO:0001492

[PMID:29574408] [SUPPORT] MCN measuring <40 mm without a mural nodule or symptoms may undergo surveillance with MRI, EUS, or a combination of both. --- Explanation: European evidence-based guidelines recommend surveillance with MRI and/or EUS for MCNs <40mm without concerning features.

[PMID:29574408] [SUPPORT] Surveillance is recommended every 6 months for the first year, then annually if no changes are observed. Patients with an MCN measuring <40 mm and with no concerning features or symptoms should have lifelong surveillance as long as they are fit for surgery --- Explanation: Specifies the surveillance interval and duration for small asymptomatic MCNs.


hgnc:6407

[PMID:28570009] [SUPPORT] KRAS mutations were identified in five cases (20%), whereas GNAS, RNF43 and PIK3CA were wild-type in all cases. KRAS mutations were uncommon in cases of low-grade dysplasia (1/20, 5%), whereas KRAS was mutated in all cases of higher grades, except for one liver MCN with intermediate-grade dysplasia (4/5, 80%; P = 0.002). --- Explanation: Molecular analysis of 25 MCN cases establishing KRAS mutation rates across different dysplasia grades.


hgnc:18505

[PMID:35066614] [SUPPORT] These results suggest that RNF43 mutations may be involved in and predictive of malignant transformation from an early stage of MCN. --- Explanation: Study of 106 MCN cases demonstrating RNF43 mutations in 56% of high-grade/ invasive lesions, with RNF43 loss correlating with aberrant Wnt signaling.


hgnc:11998

[PMID:34099908] [SUPPORT] We also discuss the most prevalent genetic alterations in these precancerous lesions, including somatic mutations in the oncogenes KRAS and GNAS as well as tumour suppressor genes CDKN2A, TP53 and SMAD4. --- Explanation: Identifies TP53 as one of the key tumor suppressor genes altered during malignant progression of pancreatic precancerous lesions.


hgnc:6770

[PMID:34099908] [SUPPORT] We also discuss the most prevalent genetic alterations in these precancerous lesions, including somatic mutations in the oncogenes KRAS and GNAS as well as tumour suppressor genes CDKN2A, TP53 and SMAD4. --- Explanation: Identifies SMAD4 as a key tumor suppressor gene altered in pancreatic precancerous lesion progression including MCNs.


hgnc:1787

[PMID:34099908] [SUPPORT] We also discuss the most prevalent genetic alterations in these precancerous lesions, including somatic mutations in the oncogenes KRAS and GNAS as well as tumour suppressor genes CDKN2A, TP53 and SMAD4. --- Explanation: Identifies CDKN2A as a key tumor suppressor gene altered during malignant progression of pancreatic precancerous lesions.


MONDO:0019954

[PMID:21252315] [SUPPORT] Pancreatic neuroendocrine tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. --- Explanation: The landmark genomics study confirms pNETs as a clinically important form of pancreatic neoplasia.


MONDO:0019954


MONDO:0019954

[PMID:21252315] [SUPPORT] Nonfunctional PanNETs grow silently and patients often present with either an asymptomatic abdominal mass or symptoms of abdominal pain secondary to compression by a large tumor. --- Explanation: The Jiao et al. paper confirms that non-functional pNETs commonly present with abdominal pain from tumor compression.


MONDO:0019954

[PMID:21252315] [INDIRECT EVIDENCE] [SUPPORT] 44% of the tumors had somatic inactivating mutations in MEN1, which encodes menin, a component of a histone methyltransferase complex --- Explanation: Jiao et al. whole-exome sequencing study established MEN1 mutation frequency at 44% in sporadic pNETs and identified its role in chromatin remodeling.

[PMID:21252315] [INDIRECT EVIDENCE] [SUPPORT] Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. --- Explanation: Despite being the most common driver mutation, MEN1 mutations were associated with better prognosis in the Jiao et al. cohort.


MONDO:0019954

[PMID:21252315] [INDIRECT EVIDENCE] [SUPPORT] 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain-associated protein) and ATRX --- Explanation: Jiao et al. discovered DAXX/ATRX as the second most commonly mutated pathway in pNETs at 43%, with mutual exclusivity between the two genes.

[PMID:21252315] [INDIRECT EVIDENCE] [SUPPORT] Recently, it has been shown that DAXX is an H3.3-specific histone chaperone --- Explanation: The paper cites evidence that DAXX functions as a histone H3.3 chaperone, explaining the mechanistic basis of chromatin remodeling deficiency.


MONDO:0019954

[PMID:21252315] [INDIRECT EVIDENCE] [SUPPORT] We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors. --- Explanation: Jiao et al. identified mTOR pathway mutations at 14% frequency and proposed their use for patient stratification for mTOR inhibitor therapy.

[PMID:21306238] [INDIRECT EVIDENCE] [SUPPORT] Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. --- Explanation: The RADIANT-3 trial demonstrated that targeting the mTOR pathway with everolimus significantly improves PFS in advanced pNETs, validating the therapeutic relevance of this pathway.


MONDO:0019954

[PMID:41794038] [INDIRECT EVIDENCE] [SUPPORT] Functional studies in pNET cell models demonstrate that BEND2 fusions drive transcriptional reprogramming, promoting a shift from ASCL1+ endocrine states toward neurodevelopmental, mesenchymal, and immune-related gene programs. --- Explanation: Lu et al. used cell models to functionally validate that BEND2 fusions drive transcriptional plasticity in pNETs.

[PMID:41794038] [INDIRECT EVIDENCE] [SUPPORT] BEND2 gene fusions occur in 5% of pNETs, all belonging to the Gastrin-high subtype, which shows activation of the late endocrine progenitor FEV regulon. --- Explanation: Clinical characterization showed BEND2 fusions exclusively in the Gastrin-high subtype with FEV regulon activation.


MONDO:0019954

[PMID:41794038] [INDIRECT EVIDENCE] [SUPPORT] Single-nucleus analysis reveals complex multicellular ecosystems, with NOTCH3-mediated signaling between tumor cells and myofibroblasts emerging as a potential therapeutic vulnerability. --- Explanation: Single-nucleus RNA-seq analysis identified NOTCH3-mediated tumor-stromal crosstalk as a novel therapeutic target in pNETs.


MONDO:0019954

[PMID:41794038] [INDIRECT EVIDENCE] [SUPPORT] Gastrin-high tumors exhibit CD8+ T cell infiltration alongside PD-1/PD-L1 upregulation, suggesting potential responsiveness to immune checkpoint blockade. --- Explanation: The molecular taxonomy study revealed an immunologically active microenvironment in Gastrin-high pNETs that could be targeted with checkpoint inhibitors.


MAXO:0000448

[PMID:21252315] [SUPPORT] Surgical resection is the treatment of choice, but many patients present with unresectable tumors or extensive metastatic disease --- Explanation: The landmark genomic study confirms surgical resection as the primary treatment for pNETs, noting the challenge of unresectable or metastatic disease.


MAXO:0000058

[PMID:25014687] [SUPPORT] Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). --- Explanation: The CLARINET phase 3 trial demonstrated lanreotide's antiproliferative effect in metastatic enteropancreatic NETs with a 53% reduction in risk of progression.


MAXO:0000058

[PMID:21306238] [SUPPORT] Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. --- Explanation: The RADIANT-3 phase 3 trial established everolimus as standard treatment for advanced progressive pNETs with significant PFS improvement.


MAXO:0000058

[PMID:21306237] [SUPPORT] Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. --- Explanation: The phase 3 sunitinib trial demonstrated significant improvement in PFS and overall survival for patients with advanced well-differentiated pNETs.


MAXO:0000014

[PMID:30566620] [SUPPORT] Treatment with 177Lu-DOTATATE is a safe and effective therapy resulting in radiological, symptomatic and biochemical response in a high percentage of patients with metastatic functioning pNETs. --- Explanation: Zandee et al. demonstrated 177Lu-DOTATATE efficacy directly in functioning pNETs (n=34), with 59% response rate and 18.1 month median PFS.


MAXO:0000647

[PMID:36260828] [SUPPORT] The combination of capecitabine/temozolomide was associated with a significant improvement in PFS compared with temozolomide alone in patients with advanced pancreatic NETs. --- Explanation: The E2211 randomized phase II trial demonstrated that CAPTEM significantly improved PFS compared to temozolomide monotherapy in advanced pNETs.


HGNC.SYMBOL:MEN1

[PMID:21252315] [SUPPORT] 44% of the tumors had somatic inactivating mutations in MEN1, which encodes menin, a component of a histone methyltransferase complex --- Explanation: Jiao et al. exome sequencing established MEN1 as the most frequently mutated gene in sporadic pNETs at 44%.


HGNC.SYMBOL:DAXX

[PMID:21252315] [SUPPORT] somatic mutations in MEN1, DAXX, ATRX, PTEN, TSC2, and PIK3CA were identified in 44.1%, 25%, 17.6%, 7.3%, 8.8%, and 1.4% PanNETs, respectively --- Explanation: DAXX mutations were found in 25% of pNETs in the combined discovery and validation cohorts.


HGNC.SYMBOL:ATRX

[PMID:21252315] [SUPPORT] somatic mutations in MEN1, DAXX, ATRX, PTEN, TSC2, and PIK3CA were identified in 44.1%, 25%, 17.6%, 7.3%, 8.8%, and 1.4% PanNETs, respectively --- Explanation: ATRX mutations were found in 17.6% of pNETs, mutually exclusive with DAXX.


HGNC.SYMBOL:PTEN

[PMID:21252315] [SUPPORT] somatic mutations in MEN1, DAXX, ATRX, PTEN, TSC2, and PIK3CA were identified in 44.1%, 25%, 17.6%, 7.3%, 8.8%, and 1.4% PanNETs, respectively --- Explanation: PTEN was mutated in 7.3% of pNETs in the Jiao et al. cohort.


HGNC.SYMBOL:TSC2

[PMID:21252315] [SUPPORT] somatic mutations in MEN1, DAXX, ATRX, PTEN, TSC2, and PIK3CA were identified in 44.1%, 25%, 17.6%, 7.3%, 8.8%, and 1.4% PanNETs, respectively --- Explanation: TSC2 was mutated in 8.8% of pNETs.


HGNC.SYMBOL:PIK3CA

[PMID:21252315] [SUPPORT] somatic mutations in MEN1, DAXX, ATRX, PTEN, TSC2, and PIK3CA were identified in 44.1%, 25%, 17.6%, 7.3%, 8.8%, and 1.4% PanNETs, respectively --- Explanation: PIK3CA was mutated in 1.4% of pNETs in the Jiao et al. cohort.


HGNC.SYMBOL:BEND2

[PMID:41794038] [SUPPORT] BEND2 gene fusions occur in 5% of pNETs, all belonging to the Gastrin-high subtype, which shows activation of the late endocrine progenitor FEV regulon. --- Explanation: Lu et al. discovered BEND2 fusions as a novel oncogenic driver in pNETs, restricted to the Gastrin-high molecular subtype.


MONDO:0005180

[PMID:17955331] [SUPPORT] Participants are screened in the baseline and follow-up examinations for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia or impaired postural reflexes). --- Explanation: This identifies resting tremor as a cardinal sign used to detect parkinsonism, supporting it as a core PD phenotype.


MONDO:0005180

[PMID:17955331] [SUPPORT] Participants are screened in the baseline and follow-up examinations for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia or impaired postural reflexes). --- Explanation: This lists bradykinesia among the cardinal signs of parkinsonism, supporting its central role in PD.


MONDO:0005180

[PMID:17955331] [SUPPORT] Participants are screened in the baseline and follow-up examinations for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia or impaired postural reflexes). --- Explanation: This confirms rigidity as a cardinal sign of parkinsonism relevant to PD.


MONDO:0005180

[PMID:17955331] [SUPPORT] Participants are screened in the baseline and follow-up examinations for cardinal signs of parkinsonism (resting tremor, rigidity, bradykinesia or impaired postural reflexes). --- Explanation: This supports postural instability as a cardinal parkinsonian sign captured in PD assessments.


MONDO:0005180

[PMID:24136244] [SUPPORT] Hyposmia, identified as reduced sensitivity to odor, is a common non-motor symptom of Parkinson's disease (PD) that antedates the typical motor symptoms by several years. It occurs in ∼90% of early-stage cases of PD. --- Explanation: This establishes hyposmia as a highly prevalent prodromal symptom that precedes motor symptoms, supporting its importance as an early marker of PD.


MONDO:0005180

[PMID:7845407] [SUPPORT] We investigated the role of anorectal manometry in evaluating constipation and anorectal function in 15 patients with Parkinson's disease (PD) and compared results with those of 9 patients with idiopathic constipation (IC) and 8 control (C) subjects. --- Explanation: This study directly evaluates constipation in PD patients, supporting constipation as a common non-motor symptom.


MONDO:0005180

[PMID:41301797] [SUPPORT] Depressive symptoms were similar across groups, but in prodromal PD, higher GDS scores were associated with worse UPDRS III scores (p = 0.02), as well as higher freezing and fall scores. --- Explanation: This indicates depressive symptoms are present and clinically relevant in PD, supporting depression as a non-motor phenotype.


MONDO:0005180

[PMID:37048085] [INDIRECT EVIDENCE] [SUPPORT] Tremor, shaking, movement problems, and difficulty with balance and coordination are among the hallmarks, and dopaminergic neuronal loss in substantia nigra pars compacta of the brain and aggregation of intracellular protein α-synuclein are the pathological characterizations. --- Explanation: This review confirms that dopaminergic neuronal loss in the substantia nigra pars compacta is a pathological hallmark of Parkinson's disease, supporting the core mechanism of dopaminergic neuron degeneration.


MONDO:0005180


MONDO:0005180

[PMID:38245249] [INDIRECT EVIDENCE] [SUPPORT] Parkinson's disease is a progressive neurodegenerative condition associated with the deposition of aggregated α-synuclein. --- Explanation: This authoritative Lancet review establishes that aggregated α-synuclein deposition is a defining feature of Parkinson's disease pathogenesis.

[PMID:38245249] [INDIRECT EVIDENCE] [SUPPORT] Biochemical studies, investigation of transplanted neurons in patients with Parkinson's disease, and cell and animal model studies suggest that abnormal aggregation of α-synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson's disease. --- Explanation: This provides direct evidence for the prion-like spreading mechanism of α-synuclein pathology across neural networks, supporting the mechanism of trans-neuronal propagation.

[PMID:36598534] [INDIRECT EVIDENCE] [SUPPORT] Parkinson's disease (PD) is the second most common neurodegenerative disease, and is characterized by accumulation of α-synuclein (α-syn). --- Explanation: Confirms that α-synuclein accumulation is a key pathological characterization of PD, reinforcing the central role of protein aggregation in disease pathology.


MONDO:0005180

[PMID:38245249] [INDIRECT EVIDENCE] [SUPPORT] At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson's disease, suggesting multiple potential treatment approaches. --- Explanation: This establishes that mitochondrial dysfunction is a common cellular feature across both genetic and sporadic forms of PD, supporting its central role in disease pathogenesis.

[PMID:25611507] [INDIRECT EVIDENCE] [SUPPORT] Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in Parkinson's disease. --- Explanation: This directly supports the role of PINK1 and Parkin genes in mitochondrial quality control and confirms that mitochondrial damage is involved in PD pathogenesis.

[PMID:27911343] [INDIRECT EVIDENCE] [SUPPORT] For the past 30 years, mitochondrial dysfunction has been hypothesized to play a central role in the pathobiology of this devastating neurodegenerative disease. The identifications of mutations in genes encoding PINK1 (PTEN-induced kinase 1) and Parkin (E3 ubiquitin ligase) in familial PD and their functional association with mitochondrial quality control provided further support to this hypothesis. --- Explanation: This review confirms the long-standing central role of mitochondrial dysfunction in PD and validates the connection between PINK1/Parkin mutations and mitochondrial quality control defects.


MONDO:0005180

[PMID:38245249] [INDIRECT EVIDENCE] [SUPPORT] Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson's disease. --- Explanation: This establishes that maladaptive immune and inflammatory responses play an active role in accelerating PD pathogenesis, supporting the neuroinflammation mechanism.

[PMID:37048085] [INDIRECT EVIDENCE] [SUPPORT] Neuroinflammation has emerged as an involving mechanism at the initiation and development of PD. It is a complex network of interactions comprising immune and non-immune cells in addition to mediators of the immune response. Microglia, the resident macrophages in the CNS, take on the leading role in regulating neuroinflammation and maintaining homeostasis. --- Explanation: This directly supports the role of microglia-mediated neuroinflammation in PD initiation and progression, confirming the importance of microglial activation in disease pathology.

[PMID:36598534] [INDIRECT EVIDENCE] [SUPPORT] Neuroinflammation driven by microglia is an important pathological manifestation of PD. α-Syn is a crucial marker of PD, and its accumulation leads to microglia M1-like phenotype polarization, activation of NLRP3 inflammasomes, and impaired autophagy and phagocytosis in microglia. --- Explanation: This links α-synuclein accumulation to microglial activation and pro-inflammatory M1 phenotype polarization, supporting the mechanism by which neuroinflammation contributes to neurodegeneration in PD.


MONDO:0005180

[PMID:31761667] [INDIRECT EVIDENCE] [SUPPORT] In recent years, multiple lines of evidence from human genetic and molecular studies have highlighted the importance of the autophagy lysosomal pathway (ALP) in Parkinson's disease (PD). Genes such as GBA and LRRK2, which harbor some of the most common mutations associated with PD, have essential roles in the ALP. --- Explanation: This review establishes the genetic basis for autophagy-lysosome dysfunction in PD, identifying key genes and their mechanistic roles.


MONDO:0005180

[PMID:38098067] [INDIRECT EVIDENCE] [SUPPORT] Various microorganisms inhabiting the gastrointestinal tract can profoundly influence the physiopathology of the central nervous system through neurological, endocrine, and immune system pathways involved in the microbiota-gut-brain axis. --- Explanation: This review establishes the gut microbiota-brain connection in PD pathophysiology.

[PMID:37449597] [INDIRECT EVIDENCE] [SUPPORT] The vagus nerve, the main component of the parasympathetic nervous system, is involved in the regulation of immune response, digestion, heart rate, and control of mood. --- Explanation: Establishes the vagus nerve as the key anatomical connection mediating gut-brain communication in PD.


MONDO:0005180

[PMID:37303175] [INDIRECT EVIDENCE] [SUPPORT] Reactive oxygen species (ROS)-induced oxidative stress triggers the vicious cycle leading to the degeneration of dopaminergic neurons in the nigra pars compacta. --- Explanation: This review directly describes the mechanism by which oxidative stress drives dopaminergic neurodegeneration.


MONDO:0005180

[PMID:35339179] [INDIRECT EVIDENCE] [SUPPORT] Calcium (Ca2+) plays a central role in regulating many cellular processes and influences cell survival. --- Explanation: This review establishes the fundamental role of calcium channel dysregulation in PD pathogenesis.


MONDO:0005180

[PMID:38026955] [INDIRECT EVIDENCE] [SUPPORT] Accumulating evidence shows that endoplasmic reticulum (ER) stress occurring in the SNpc DA neurons is an early event in the development of PD. --- Explanation: This review establishes ER stress as an early and central event in PD pathogenesis.


MONDO:0005180

[PMID:38595283] [INDIRECT EVIDENCE] [SUPPORT] Notably, several of these genes are linked to the synaptic vesicle recycling process, particularly the clathrin-mediated endocytosis pathway. This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease --- Explanation: Establishes synaptic vesicle endocytosis dysfunction as an early feature of PD.


MONDO:0005180

[PMID:39218077] [INDIRECT EVIDENCE] [SUPPORT] Parkinson's disease (PD) is a prevalent and advancing age-related neurodegenerative disorder, distinguished by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Iron regional deposit in SNpc is a significant pathological characteristic of PD. --- Explanation: This review establishes iron accumulation as a significant pathological characteristic and mechanistic driver of PD.


MONDO:0005180

[PMID:39075566] [INDIRECT EVIDENCE] [SUPPORT] There is increasing evidence for blood-brain barrier (BBB) alterations in Parkinson's disease (PD), the second most common neurodegenerative disorder with rapidly rising prevalence. --- Explanation: This comprehensive 2024 review establishes BBB dysfunction as an emerging mechanism in PD pathogenesis.


MAXO:0000058

[PMID:27577098] [SUPPORT] The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. --- Explanation: This review identifies L-Dopa as a core pharmacotherapy for PD motor symptoms.


CHEBI:15765

[PMID:27577098] [INDIRECT EVIDENCE] [SUPPORT] The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. --- Explanation: This review identifies L-Dopa as a core pharmacotherapy for PD motor symptoms.


CHEBI:3395


MAXO:0000058

[PMID:27577098] [SUPPORT] The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. --- Explanation: This review identifies dopamine agonists as part of standard pharmacotherapy for PD.


MAXO:0000058

[PMID:27577098] [SUPPORT] The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. --- Explanation: This review lists MAO-B inhibitors among standard PD pharmacotherapies.


MAXO:0000058

[PMID:27577098] [SUPPORT] The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. --- Explanation: This review lists COMT inhibitors among standard PD pharmacotherapies.


MAXO:0000004

[PMID:27577098] [SUPPORT] The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. --- Explanation: This review identifies deep brain stimulation as a standard symptomatic therapy for PD.


MAXO:0000011

[PMID:27577098] [SUPPORT] The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. --- Explanation: This review lists physiotherapy as part of symptomatic treatment for PD.


HGNC.SYMBOL:SNCA

[PMID:9197268] [SUPPORT] A mutation was identified in the alpha-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. --- Explanation: This landmark 1997 Science paper identified the first SNCA mutations in familial PD with autosomal dominant inheritance, establishing SNCA as a causative gene for Parkinson's disease.


HGNC.SYMBOL:LRRK2

[PMID:19945904] [SUPPORT] The LRRK2 G2019S mutation is the most frequent known cause of familial and sporadic Parkinson's disease. --- Explanation: This systematic review establishes that LRRK2 G2019S is the most common genetic cause of both familial and sporadic PD, supporting its role as the major genetic risk factor.


HGNC.SYMBOL:GBA

[PMID:30097731] [SUPPORT] DLB shares risk loci with AD, in the APOE E4 allele, and with PD, in variation at GBA and SNCA. --- Explanation: This identifies GBA as a genetic risk locus shared with PD, supporting its role as a PD risk factor.


HGNC.SYMBOL:PARK2

[PMID:25611507] [SUPPORT] Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in Parkinson's disease. --- Explanation: This establishes Parkin (PARK2) as a gene mutated in autosomal recessive parkinsonism, supporting its causative role.


HGNC.SYMBOL:PINK1

[PMID:25611507] [SUPPORT] Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in Parkinson's disease. --- Explanation: This identifies PINK1 mutations in autosomal recessive parkinsonism, supporting its causative role in PD.


MONDO:0011644

[PMID:27051493] [SUPPORT] The most common presenting symptoms are floaters and blurred vision. --- Explanation: Blurred vision is a core presenting symptom reported in pars planitis.


MONDO:0011644

[PMID:27051493] [SUPPORT] The most common presenting symptoms are floaters and blurred vision. --- Explanation: Floaters are among the predominant presenting symptoms of pars planitis.


MONDO:0011644

[PMID:27051493] [SUPPORT] Although pars planitis is known to be a benign form of uveitis in most cases, it may become a potentially blinding disease due to complications including cataract, cystoid macular edema, vitreous opacities and optic disc edema. --- Explanation: Chronic inflammation can lead to complications that threaten vision if not controlled.


MONDO:0011644

[PMID:27051493] [SUPPORT] Diffuse vitreous cells, haze, snowballs and snowbanks are typical findings of pars planitis. --- Explanation: Vitreous opacities such as snowballs are typical inflammatory findings in pars planitis.


MONDO:0011644

[PMID:27051493] [SUPPORT] Cystoid macular edema is the most common cause of visual morbidity. --- Explanation: Macular edema represents a significant complication that can lead to permanent vision loss.


MONDO:0011644

[PMID:27051493] [SUPPORT] Peripheral retinal vasculitis, optic disc edema and anterior segment inflammation are other well-known findings. --- Explanation: Optic disc edema is a recognized complication of pars planitis.


MONDO:0011644

[PMID:30200907] [SUPPORT] Progressive, intraretinal bone crepuscule pigmentation developed in his left retina during the following three months. --- Explanation: Describes bone spicule-like pigmentation emerging after bilateral pars planitis, mimicking retinitis pigmentosa.


MONDO:0011644

[PMID:26438050] [INDIRECT EVIDENCE] [SUPPORT] Clinical and histopathological findings suggest an autoimmune etiology, most likely as a reaction to endogenous antigen of unknown source, with T cells predominant in both vitreous and pars plana infiltrations. --- Explanation: Shows T-cell predominance in ocular infiltrates supporting autoimmune pathogenesis.

[PMID:37976519] [INDIRECT EVIDENCE] [SUPPORT] It is thought to be a T-cell mediated disease with a genetic predisposition. --- Explanation: Confirms T-cell mediated immunopathogenesis and genetic susceptibility in pars planitis.


MONDO:0011644


MONDO:0011644

[PMID:27051493] [INDIRECT EVIDENCE] [SUPPORT] Diffuse vitreous cells, haze, snowballs and snowbanks are typical findings of pars planitis. --- Explanation: Documents vitreous cell infiltration and haze as defining inflammatory findings.

[PMID:28389773] [INDIRECT EVIDENCE] [SUPPORT] Vitreous inflammation (100%), vitreous haze (92.6%), snowballs (74.1%), snowbanks (66.7%)...were the most common presentations. --- Explanation: Confirms high prevalence of vitreous inflammation and snowballs in clinical cohorts.


MONDO:0011644

[PMID:28389773] [INDIRECT EVIDENCE] [SUPPORT] Vitreous inflammation (100%), vitreous haze (92.6%), snowballs (74.1%), snowbanks (66.7%)...were the most common presentations. --- Explanation: Shows snowbanks as a frequent structural manifestation of pars planitis at the pars plana.


MONDO:0011644

[PMID:27051493] [INDIRECT EVIDENCE] [SUPPORT] Peripheral retinal vasculitis, optic disc edema and anterior segment inflammation are other well-known findings. --- Explanation: Notes peripheral retinal vasculitis as a recognized manifestation in pars planitis.

[PMID:28389773] [INDIRECT EVIDENCE] [SUPPORT] ...peripheral retinal vascular sheathing (48.1%) were the most common presentations. --- Explanation: Confirms high frequency of peripheral vascular sheathing in clinical series.


MONDO:0011644

[PMID:27188332] [INDIRECT EVIDENCE] [SUPPORT] The cut-off value of CFT for initiating systemic treatment was determined at 215.5 μm in a post hoc analysis (sensitivity 62.5 %, specificity 96.4 %). --- Explanation: Shows that macular thickening beyond a threshold prompts treatment due to risk of vision loss in intermediate uveitis.

[PMID:33559832] [INDIRECT EVIDENCE] [SUPPORT] According to multivariate linear regression analysis, the presence of DME, and loss of normal foveal contour appearance at baseline were the independent factors associated with BCVA at the final examination. --- Explanation: OCT-defined diffuse macular edema and foveal contour loss predict worse visual acuity, underscoring the impact of macular thickening.


MAXO:0000058

[PMID:27051493] [SUPPORT] A stepladder approach including corticosteroids, immunosupressive agents, anti-tumor necrosis factor-alpha and pars plana vitrectomy and/or laser photocoagulation is the most commonly used method for treatment of pars planitis. --- Explanation: Corticosteroids form the foundation of treatment for pars planitis.


MAXO:0000058

[PMID:27051493] [SUPPORT] Methotrexate is the most widely used first-line immunosuppressive agent in children with chronic non-infectious uveitis because of its long-term safety record and well tolerance. --- Explanation: Immunosuppressive agents, particularly methotrexate, provide steroid-sparing control for chronic cases.


MAXO:0000058

[PMID:34568953] [SUPPORT] ADA was initiated in 23 patients (38.9%) due to refractory uveitis and adverse effects to the corticosteroid and helped control intraocular inflammation and decrease the use of systemic steroids/immunosuppressives in 22 of 23 (95%) of patients who received ADA. --- Explanation: TNF-alpha inhibition with adalimumab controlled inflammation and enabled steroid-sparing in refractory cases.


MAXO:0000004

[PMID:27051493] [SUPPORT] A stepladder approach including corticosteroids, immunosupressive agents, anti-tumor necrosis factor-alpha and pars plana vitrectomy and/or laser photocoagulation is the most commonly used method for treatment of pars planitis. --- Explanation: Surgical intervention may be necessary for cases with severe vitreous involvement or complications.


HGNC.SYMBOL:HLA-DR15

[PMID:27051493] [SUPPORT] Associations between pars planitis and HLA-DR2, -DR15, -B51 and -DRB1*0802 haplotypes have been described suggesting an immunogenetic predisposition. --- Explanation: HLA-DR15 has been linked to immunogenetic susceptibility in pars planitis.


HGNC.SYMBOL:HLA-B51

[PMID:27051493] [SUPPORT] Associations between pars planitis and HLA-DR2, -DR15, -B51 and -DRB1*0802 haplotypes have been described suggesting an immunogenetic predisposition. --- Explanation: HLA-B51 is reported among haplotypes associated with pars planitis, supporting a genetic component.


MONDO:0006544

[PMID:9595838] [SUPPORT] Arthropathy is known to occur in children and adults with acute parvovirus B19 infection. In adults, the arthropathy is common and is usually brief and self-limited, although a chronic arthropathy due to HPV B19 infections can occur rarely. --- Explanation: The reference confirms that arthropathy is a common manifestation in adults with acute parvovirus B19 infection.

[PMID:27511498] [PARTIAL] The highest positivity for IgG alone was found in musculoskeletal system and connective tissue diseases (55.9%)... The highest positivity for IgG was seen in rheumatoid arthritis (72.2%) and pregnancy (52.6%). --- Explanation: The reference indicates a high prevalence of parvovirus B19 antibodies in musculoskeletal diseases, but does not specifically mention arthropathy.

[PMID:29512949] [SUPPORT] Arthritis and arthralgia during a viral infection are often polyarticular and symmetric and can mimic rheumatoid arthritis. ... Worldwide most common germs are Parvovirus B19, hepatitis B and C, HIV and alphavirus. --- Explanation: The reference supports that arthritis and arthralgia, which can be associated with parvovirus B19, are common.

[PMID:32510300] [SUPPORT] We report here a small outbreak of B19V infection among physicians and family members in an adult rheumatology practice that occurred after providing care for a patient with B19V arthropathy. --- Explanation: The reference supports the statement by reporting a case of B19V arthropathy in adults.

[PMID:33944819] [SUPPORT] Typical clinical manifestations are: short lived fever accompanied by asthenia, myalgias and pharyngodynia; symmetrical acute polyarthritis. --- Explanation: The reference supports that symmetrical acute polyarthritis, a form of arthropathy, is a typical manifestation of parvovirus B19.

[PMID:19480999] [SUPPORT] B19 infection-associated joint symptoms occur most frequently in adults, usually presenting as a self-limited, acute symmetric polyarthritis affecting the small joints of the hands, wrists, and knees. --- Explanation: The reference supports the statement by indicating that joint symptoms, including arthropathy, are frequent in adults with B19 infection.

[PMID:25965702] [SUPPORT] Arthralgias and arthritis, with or without rash, are common manifestations of B19V infection in adults. --- Explanation: The reference supports the statement by indicating that arthritis and arthralgias are common in adults with B19 infection.


MONDO:0006544

[PMID:21502743] [SUPPORT] Fetal hydrops caused by anemia from parvovirus B19 infection (FH-B19) is rare. --- Explanation: The study confirms that fetal hydrops caused by anemia from parvovirus B19 infection is rare.

[PMID:9095492] [SUPPORT] Fetal infection by Parvovirus B 19 is a common cause of fetal anemia and nonimmune hydrops fetalis and may result in fetal death. --- Explanation: While the statement mentions 'common cause,' the overall context supports that fetal hydrops due to severe fetal anemia from parvovirus B19 is a recognized but not frequent condition.

[PMID:30124157] [SUPPORT] Parvovirus B-19 is a common childhood illness; the virus can cause fetal anemia, non-immune fetal hydrops, and spontaneous abortion and might lead to fetal demise. --- Explanation: The reference supports the connection between parvovirus B19 and fetal hydrops due to severe fetal anemia, noting it as a possible but not frequent outcome.


MONDO:0006544


MONDO:0006544

[PMID:9372060] [INDIRECT EVIDENCE] [SUPPORT] Human parvovirus B19 shows remarkable tropism for human erythroid progenitor cells. --- Explanation: The abstract clearly states that Parvovirus B19 has a strong preference for infecting human erythroid progenitor cells.

[PMID:26845771] [INDIRECT EVIDENCE] [SUPPORT] The pathogenic Parvovirus B19 (B19V) is characterized by a strict adaptation to erythroid progenitor cells (EPCs)... --- Explanation: The study describes the infection dynamics of Parvovirus B19 in erythroid progenitor cells, supporting the statement that the virus primarily targets these cells.

[PMID:37175911] [INDIRECT EVIDENCE] [SUPPORT] Parvovirus B19V (B19V) is a common human pathogen that infects bone marrow erythroid progenitor cells, leading to transient or persistent anemia. --- Explanation: The abstract mentions that Parvovirus B19 infects erythroid progenitor cells in the bone marrow, aligning with the statement.

[PMID:21680529] [INDIRECT EVIDENCE] [SUPPORT] Human parvovirus B19 (B19V) infection is restricted to erythroid progenitor cells of the human bone marrow. --- Explanation: The abstract confirms the restriction of Parvovirus B19 infection to erythroid progenitor cells in the bone marrow.

[PMID:28377277] [INDIRECT EVIDENCE] [SUPPORT] Parvovirus B19 (B19V) infection is restricted to erythroid progenitor cells (EPCs) of the human bone marrow, leading to transient arrest of erythropoiesis... --- Explanation: The study indicates that Parvovirus B19 infection is limited to erythroid progenitor cells and disrupts red blood cell production.

[PMID:35062288] [INDIRECT EVIDENCE] [SUPPORT] Parvovirus B19 (B19V) is a human pathogenic virus of clinical relevance, characterized by a selective tropism for erythroid progenitor cells in bone marrow. --- Explanation: The abstract highlights the selective tropism of Parvovirus B19 for erythroid progenitor cells in the bone marrow.

[PMID:12116854] [INDIRECT EVIDENCE] [SUPPORT] Parvovirus B19 is a human erythrovirus, i.e. which induces the death of erythroid progenitors. --- Explanation: The abstract states that Parvovirus B19 induces the death of erythroid progenitors, supporting the statement.


MAXO:0000950

[PMID:31323869] [SUPPORT] Presently available treatments are only supportive, symptomatic, or unspecific, such as administration of intravenous immunoglobulins, and often of limited efficacy. --- Explanation: The literature states that the available treatments for Parvovirus B19 infection are primarily supportive and symptomatic.

[PMID:8668619] [SUPPORT] Treatment ranges from analgesics and antipyretics for mild and self-limited illness to administration of commercial immunoglobulin preparations and blood transfusion for more serious conditions. --- Explanation: The literature mentions the use of analgesics and antipyretics, which are supportive care measures, for managing mild and self-limited illness caused by Parvovirus B19.

[PMID:7899371] [SUPPORT] Nonsteroid antiinflammatory drugs are generally effective. --- Explanation: The literature supports the use of nonsteroidal anti-inflammatory drugs (a form of supportive care) for managing symptoms of Parvovirus B19 infection.


MAXO:0000058

[PMID:37544998] [SUPPORT] IVIG infusion effectively treated the parvovirus B19 infection and restored erythropoiesis making the child transfusion independent. --- Explanation: The case report demonstrates the effective use of IVIG in treating severe anemia caused by parvovirus B19 infection.

[PMID:11560750] [SUPPORT] Specific antiviral therapy is not available, however, intravenous immunoglobulin produces rapid improvement in most cases. --- Explanation: The literature indicates that IVIG is used effectively in treating parvovirus B19 infection in pediatric transplant patients, who are often immunocompromised.

[PMID:33346452] [SUPPORT] In addition to blood transfusions, we administered intravenous donor immunoglobulin with a dose increase from 5000 mg to 20 000 mg per day. --- Explanation: The case report supports the use of IVIG in an HIV-infected patient with parvovirus B19-related severe anemia.

[PMID:7756792] [SUPPORT] Treatment of parvovirus infections among immunocompromised hosts using immunoglobulin has provided the clinician with a useful therapeutic tool but has also highlighted the problems concerning chronic disease states. --- Explanation: This reference supports the use of IVIG in immunocompromised individuals with parvovirus B19 infection.


NCBITaxon:10798

[PMID:25283854] [SUPPORT] Parvovirus B19 (B19V) is a small non-enveloped single-stranded DNA (ssDNA) virus of the family Parvoviridae, the subfamily Parvovirinae, the genus Erythrovirus and Human parvovirus B19 type species. --- Explanation: The reference confirms that Parvovirus B19 is a single-stranded DNA virus.

[PMID:15485533] [SUPPORT] Parvovirus B19 infections cause a wide range of clinical findings, including erythema infectiosum, 'glove-and-socks' syndrome, arthropathies, red cell aplasia, and intrauterine infections. --- Explanation: The reference supports that Parvovirus B19 causes several clinical conditions.

[PMID:33944819] [SUPPORT] Parvovirus B19 (PVB19) is a small DNA virus that causes the fifth disease in children; however it can also affect adults. --- Explanation: The reference supports that Parvovirus B19 causes clinical conditions, particularly in children.

[PMID:31850715] [SUPPORT] Parvoviruses are small DNA viruses causing erythema infectiosum, which is known as the fifth disease. --- Explanation: The reference supports that Parvovirus B19 is a single-stranded DNA virus causing clinical conditions.


MONDO:0010714

[PMID:29478609] [SUPPORT] it is characterized by pendular nystagmus, head tremor, and systemic hypotonia --- Explanation: Nystagmus is described as one of the cardinal features of prototypic PMD.


MONDO:0010714

[PMID:20301361] [SUPPORT] PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment --- Explanation: GeneReviews confirms hypotonia as a typical early manifestation of PMD.


MONDO:0010714

[PMID:20301361] [SUPPORT] the findings progress to severe spasticity and ataxia --- Explanation: GeneReviews confirms progressive spasticity as a major feature of PMD.


MONDO:0010714

[PMID:29478609] [SUPPORT] affected patients manifest some combination of mental retardation, choreoathetosis, dystonia, cerebellar ataxia and long tract signs --- Explanation: Cerebellar ataxia is listed among the neurological manifestations of PMD.


MONDO:0010714

[PMID:20301361] [SUPPORT] PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment --- Explanation: Cognitive impairment is a core feature of PMD per GeneReviews.


MONDO:0010714

[PMID:29478609] [SUPPORT] spasticity of the lower extremities that can be isolated, or co-exist with varying degrees of cognitive impairment, nystagmus, ataxia, dysarthria and spastic urinary bladder --- Explanation: Dysarthria is listed among the neurological features associated with PLP1-related disorders.


MONDO:0010714

[PMID:29478609] [SUPPORT] it is characterized by pendular nystagmus, head tremor, and systemic hypotonia --- Explanation: Head tremor (titubation) is described as a cardinal feature of prototypic PMD.


MONDO:0010714

[PMID:29478609] [SUPPORT] MRI subsequently revealed overt hypomyelination, as reflected by the failure of PMD patients to develop the expected developmental increase in T1 and decrease in T2 signals characteristic of myelin maturation --- Explanation: Describes the characteristic MRI finding of hypomyelination in PMD.


MONDO:0010714

[PMID:29478609] [SUPPORT] Classic PMD presents before the first year of age, with nystagmus, slowly acquired or unachieved motor milestones, and significant axial hypotonia --- Explanation: Delayed or unachieved motor milestones are a core feature of classic PMD.


MONDO:0010714

[PMID:29478609] [SUPPORT] affected patients manifest some combination of mental retardation, choreoathetosis, dystonia, cerebellar ataxia and long tract signs --- Explanation: Choreoathetosis is listed among the neurological manifestations of PMD.


MONDO:0010714

[PMID:29478609] [SUPPORT] Optic atrophy and seizures may occur later in the course, although seizures are uncommon, and typically treatable --- Explanation: Seizures occur but are uncommon and typically treatable in classic PMD.


MONDO:0010714

[PMID:29478609] [SUPPORT] Optic atrophy and seizures may occur later in the course, although seizures are uncommon, and typically treatable --- Explanation: Optic atrophy is described as a later-onset feature of classic PMD.


MONDO:0010714

[PMID:29478609] [SUPPORT] Babies with connatal PMD manifest extrapyramidal signs, laryngeal stridor, feeding difficulties and optic atrophy --- Explanation: Laryngeal stridor is a characteristic feature of connatal PMD.


MONDO:0010714

[PMID:20301361] [SUPPORT] individuals with scoliosis benefit from proper wheelchair seating and physical therapy; surgery may be required for severe scoliosis --- Explanation: GeneReviews describes scoliosis management as part of PMD care, confirming it as a recognized complication.


MONDO:0010714

[PMID:29478609] [SUPPORT] The PLP1 null phenotype represents another syndrome later described by Garbern and colleagues, and is characterized by complicated spastic paraplegia, with mild to moderate demyelinating peripheral neuropathy and axonal injury --- Explanation: Demyelinating peripheral neuropathy is characteristic of PLP1 null syndrome.


MONDO:0010714

[PMID:15627202] [INDIRECT EVIDENCE] [SUPPORT] Distinct types of mutations, including point mutations and genomic duplications and deletions, have been identified as causes of PMD/SPG2 that act through different molecular mechanisms --- Explanation: Reviews distinct molecular mechanisms for different PLP1 mutation types including misfolding pathways.


MONDO:0010714


MONDO:0010714

[PMID:17115121] [INDIRECT EVIDENCE] [SUPPORT] the wide range of mutations that can occur but also for the effects of PLP1 mutations on both cell autonomous and non-cell autonomous processes in myelinating cells --- Explanation: Describes how PLP1 mutations affect cell-autonomous processes including ER stress in oligodendrocytes.

[PMID:31585094] [INDIRECT EVIDENCE] [SUPPORT] Previous work showed involvement of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways --- Explanation: Directly confirms UPR and ER stress pathway involvement in PLP1-mutant oligodendrocytes.


MONDO:0010714

[PMID:29478609] [INDIRECT EVIDENCE] [SUPPORT] Accumulation in the ER leads to activation of the unfolded protein response (UPR) and consequent oligodendrocytic death --- Explanation: Directly describes UPR-triggered oligodendrocyte death from ER-retained misfolded PLP1.

[PMID:31585094] [INDIRECT EVIDENCE] [SUPPORT] reduced oligodendrocyte apoptosis and enabled myelin formation --- Explanation: Iron chelation in jimpy mice reduced oligodendrocyte apoptosis, confirming apoptosis as a key cell death mechanism.


MONDO:0010714

[PMID:29478609] [INDIRECT EVIDENCE] [SUPPORT] PLP gene duplications are the most common cause of Pelizaeus-Merzbacher disease --- Explanation: Confirms PLP1 duplications as the most common mutation type.


MONDO:0010714

[PMID:29478609] [INDIRECT EVIDENCE] [SUPPORT] Increased levels of PLP may lead to sequestration of cholesterol in the lysosomal compartments, resulting in abnormal cellular trafficking of lipid rafts and sphingolipids that are normally sorted out of the Golgi compartments, and this in turn may result in oligodendrocyte injury and early oligodendroglial death --- Explanation: Describes the mechanism by which PLP1 overexpression leads to oligodendrocyte dysfunction through lipid trafficking defects.


MONDO:0010714

[PMID:27882623] [INDIRECT EVIDENCE] [SUPPORT] all forms of the disease result in central hypomyelination, associated in most cases with early neurological dysfunction, progressive deterioration, and ultimately death --- Explanation: Confirms that all forms of PMD share the feature of central hypomyelination.

[PMID:29478609] [INDIRECT EVIDENCE] [SUPPORT] There is a marked deficiency of myelin, particularly in deeper cerebral structures, but relative myelin preservation in areas surrounding blood vessels, providing the classic tigroid appearance of PMD histopathology --- Explanation: Describes the characteristic histopathological pattern of myelin deficiency in PMD.


MONDO:0010714

[PMID:31585094] [INDIRECT EVIDENCE] [SUPPORT] Mutant oligodendrocytes demonstrated key hallmarks of ferroptosis including lipid peroxidation, abnormal iron metabolism, and hypersensitivity to free iron --- Explanation: iPSC-derived PLP1-mutant oligodendrocytes show ferroptosis hallmarks including lipid peroxidation and abnormal iron metabolism.

[PMID:31585094] [INDIRECT EVIDENCE] [SUPPORT] systemic treatment of Plp1 mutant Jimpy mice with deferiprone, a small molecule iron chelator, reduced oligodendrocyte apoptosis and enabled myelin formation --- Explanation: Iron chelation rescues oligodendrocyte death and enables myelination in the jimpy mouse model.


MAXO:0000950

[PMID:20301361] [SUPPORT] routine management of spasticity including physical therapy, exercise, medications (baclofen, diazepam, tizanidine), orthotics, and surgery for joint contractures --- Explanation: GeneReviews describes the multidisciplinary supportive care approach for PMD management.


MAXO:0000011

[PMID:20301361] [SUPPORT] physical and occupational therapy for ataxia with adaptive devices as needed --- Explanation: GeneReviews recommends physical and occupational therapy as part of PMD management.


MAXO:0000016

[PMID:27882623] [SUPPORT] PMD and similar hypomyelinating disorders are attractive therapeutic targets for neural stem cell and glial progenitor cell transplantation, efforts at which are now underway in a number of research centers --- Explanation: Reviews the rationale and ongoing efforts for stem cell-based therapy in PMD.


MAXO:0001593

[PMID:32610343] [SUPPORT] Administration of a single dose of Plp1-targeting antisense oligonucleotides in postnatal jimpy mice fully restored oligodendrocyte numbers, increased myelination, improved motor performance, normalized respiratory function and extended lifespan up to an eight-month end point --- Explanation: Landmark Nature study demonstrating that ASO-mediated PLP1 suppression rescues the jimpy mouse model of severe PMD.


hgnc:9086

[PMID:15627202] [SUPPORT] Both PMD and SPG2 are caused by mutations in the proteolipid protein 1 (PLP1) gene, which encodes a major component of CNS myelin proteins --- Explanation: Confirms PLP1 as the causative gene for PMD.

[PMID:17115121] [SUPPORT] Pelizaeus-Merzbacher disease (PMD) and the allelic spastic paraplegia type 2 (SPG2) arise from mutations in the X-linked gene encoding myelin proteolipid protein (PLP) --- Explanation: Confirms the genetic basis of PMD in PLP1 mutations.


MONDO:0008219


MONDO:0008219

[PMID:10878487] [INDIRECT EVIDENCE] [SUPPORT] Auto-Ab against the desmosomal adhesion molecule, desmoglein 3 (Dsg3), are critical in the pathogenesis of this disease, since the transfer of serum IgG Ab reactive with Dsg3 into newborn mice induces a bullous skin disease resembling PV. --- Explanation: Passive transfer experiments demonstrate that anti-Dsg3 IgG autoantibodies are directly pathogenic and sufficient to cause pemphigus-like disease.

[PMID:39075718] [INDIRECT EVIDENCE] [PARTIAL] The most notable biomarkers trends include elevations in IL-4, IL-6, IL-17A, anti-Dsg1/3 autoantibodies, and a reduction in Treg cells and FOXP3. --- Explanation: Systematic review of 66 studies confirms that anti-Dsg1 and anti-Dsg3 autoantibodies are the most consistent biomarkers in pemphigus vulgaris.


MONDO:0008219

[PMID:10878487] [INDIRECT EVIDENCE] [PARTIAL] Antibody (Ab) binding interferes with the adhesive function of these molecules, leading to detachment and subsequently blister formation. --- Explanation: Autoantibody binding directly interferes with the adhesive function of desmogleins, resulting in keratinocyte detachment and blister formation.


MONDO:0008219

[PMID:19811408] [INDIRECT EVIDENCE] [SUPPORT] All patients with PV and PF showed significantly (p < 0.000) elevated levels of T(H)2 cytokines (IL-10 and IL-4) as compared with healthy controls. However, the mean concentration of T(H)1 cytokines (IL-2 and IFN-gamma) was significantly decreased in patients as compared to healthy individuals. --- Explanation: Cytokine profiling demonstrates a clear Th2 cytokine dominance in PV patients with elevated IL-4 and IL-10, supporting the role of Th2-mediated immune responses in disease pathogenesis.

[PMID:17377382] [INDIRECT EVIDENCE] [SUPPORT] The proportion of Treg cells in all PV patients was severely reduced, approximately ten times less than controls. These observations were further confirmed by both diminished gene and protein expression of Foxp3 in the CD4(+)CD25(+) T cell population in PV patients. --- Explanation: Severe reduction in regulatory T cells may contribute to loss of tolerance and failure to suppress autoreactive B and T cells in pemphigus vulgaris.

[PMID:39075718] [INDIRECT EVIDENCE] [SUPPORT] The results of this review support current theories of PV pathogenesis, with increased Th2 activity, increased Th17 activity, decreased Treg activity, and production of anti-Dsg1/3 autoantibodies being observed. --- Explanation: Systematic review synthesizing 66 studies confirms the Th2/Th17 skewing and Treg deficiency as core immunological features of pemphigus vulgaris.


HGNC.SYMBOL:HLA-DRB1*04

[PMID:10878487] [PARTIAL] The involvement of CD4+ T lymphocytes in PV has been suggested by the strong association with distinct HLA class II alleles. --- Explanation: Strong HLA class II associations support the role of autoreactive CD4+ T cells in recognizing desmoglein epitopes and driving autoantibody production.


HGNC.SYMBOL:HLA-DRB1*14


MONDO:0011150

[PMID:34894066] [SUPPORT] A 21-year-old male presented shortly after birth with a prematurely aged appearance with distinctive facial features and cutaneous atrophy with hypertrophic scar-like lesions. --- Explanation: Prematurely aged appearance is the hallmark feature.


MONDO:0011150

[PMID:34894066] [SUPPORT] Generalized brachydactyly with acro-osteolysis was observed. --- Explanation: Brachydactyly with acro-osteolysis is a characteristic finding.


MONDO:0011150

[PMID:34894066] [SUPPORT] Flexion contractures limited his daily activities. --- Explanation: Flexion contractures causing joint limitation are a prominent feature.


MONDO:0011150

[PMID:34894066] [SUPPORT] A 21-year-old male presented shortly after birth with a prematurely aged appearance with distinctive facial features and cutaneous atrophy with hypertrophic scar-like lesions. --- Explanation: Cutaneous atrophy is a hallmark dermatologic feature of Penttinen syndrome.


MAXO:0000058

[PMID:34894066] [SUPPORT] Imatinib, a receptor tyrosine kinase (RTK) inhibitor, has been used in Penttinen syndrome (PS) patients with good results. --- Explanation: Clinical evidence of imatinib efficacy.


MAXO:0000058

[PMID:34894066] [SUPPORT] Improved clinical response was observed after treatment with dasatinib. --- Explanation: Demonstrates clinical improvement with dasatinib after incomplete imatinib response.


hgnc:8804

[PMID:34894066] [SUPPORT] Penttinen type of premature aging syndrome is an autosomal-dominant disorder that can be caused by the c.1994T>A pVal665Ala pathogenic variant in platelet-derived growth factor receptor-B (PDGFRB). --- Explanation: Identifies the causative variant in PDGFRB.

[PMID:33449152] [SUPPORT] gain-of-function mutants are present in patients with fusiform aneurysms, Kosaki overgrowth syndrome or Penttinen premature aging syndrome. --- Explanation: Review confirms PDGFRB gain-of-function mutations cause Penttinen syndrome.


MONDO:0011150


MONDO:0005386

[PMID:38961103] [SUPPORT] The clinical manifestations of PAD which are typically not revealed until symptoms like intermittent claudication, rest pain and ischemic gangrene develop, are not present in majority of diabetes mellitus patients with PAD due to diabetic peripheral neuropathy. --- Explanation: Identifies intermittent claudication as a key clinical manifestation of PAD, though noting it may be masked in diabetic patients.


MONDO:0005386


MONDO:0005386

[PMID:38961103] [SUPPORT] The most serious long-term effects of diabetes is peripheral artery disease (PAD) which increases the chance of developing diabetic foot ulcers, gangrene and even lower limb amputation. --- Explanation: Demonstrates that PAD leads to non-healing wounds including diabetic foot ulcers and gangrene, particularly in diabetes patients.


MONDO:0005386

[PMID:38003290] [INDIRECT EVIDENCE] [SUPPORT] Peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CeVD) are characterized by atherosclerosis and inflammation as their underlying mechanisms. --- Explanation: Confirms atherosclerosis as the primary pathophysiological mechanism underlying PAD.

[PMID:37452714] [INDIRECT EVIDENCE] [SUPPORT] Atherosclerosis is a lipid-driven chronic inflammatory disease characterized by the accumulation and transformation of inflammatory cells, and smooth muscle cells in the intimal space. --- Explanation: Describes the characteristic lipid accumulation and cellular transformation in atherosclerotic plaques.

[PMID:38401035] [INDIRECT EVIDENCE] [SUPPORT] Some clinical trials have demonstrated the association between NETs and the severity and prognosis of atherosclerosis. --- Explanation: Links neutrophil activity to atherosclerotic plaque progression and severity in peripheral arteries.


MONDO:0005386

[PMID:38961103] [INDIRECT EVIDENCE] [SUPPORT] It was observed that serum IL-6, IL-8, ICAM and VCAM levels in type II diabetes mellitus (T2DM) with PAD patients were increased significantly (85.93, 597.08, 94.80 and 80.66) as compared to T2DM patients (59.52, 231.34, 56.88 and 50.19) and healthy individuals (4.81, 16.93, 5.55 and 5.16). --- Explanation: Demonstrates marked elevation of endothelial activation markers (ICAM, VCAM) in PAD patients, indicating severe endothelial dysfunction.

[PMID:38182796] [INDIRECT EVIDENCE] [SUPPORT] We have previously shown that VEGF165b, an alternatively spliced anti-angiogenic VEGF-A isoform, inhibits the VEGFR-STAT3 pathway in ischemic endothelial cells (ECs) to decrease their angiogenic capacity. --- Explanation: Describes impaired angiogenic signaling in ischemic endothelial cells in PAD, contributing to endothelial dysfunction and inadequate collateral formation.


MONDO:0005386

[PMID:38401035] [INDIRECT EVIDENCE] [SUPPORT] Continuous release of NETs in response to external stimuli leads to activation of surrounding platelets and monocytes/macrophages, resulting in damage to endothelial cells (EC) and vascular smooth muscle cells (VSMC). --- Explanation: Demonstrates that neutrophil extracellular traps promote platelet activation and thrombosis in atherosclerotic vessels.

[PMID:37452714] [INDIRECT EVIDENCE] [SUPPORT] NETs not only capture pathogens in innate immunity but also respond to sterile inflammatory stimuli in atherosclerosis, such as lipoproteins and inflammatory cytokines. --- Explanation: Shows how NETs respond to atherosclerotic stimuli and contribute to prothrombotic conditions in PAD.


MONDO:0005386

[PMID:38003290] [INDIRECT EVIDENCE] [SUPPORT] Peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CeVD) are characterized by atherosclerosis and inflammation as their underlying mechanisms. --- Explanation: Establishes inflammation as a core mechanism underlying PAD pathophysiology.

[PMID:37452714] [INDIRECT EVIDENCE] [SUPPORT] Neutrophil extracellular traps (NETs) are network-like structures of chromatin filaments decorated by histones, granules, and cytoplasmic-derived proteins expelled by activated neutrophils under multiple pathogenic conditions. --- Explanation: Describes neutrophil-driven inflammatory mechanisms involving NET formation in atherosclerosis.

[PMID:38401035] [INDIRECT EVIDENCE] [SUPPORT] Continuous release of NETs in response to external stimuli leads to activation of surrounding platelets and monocytes/macrophages, resulting in damage to endothelial cells (EC) and vascular smooth muscle cells (VSMC). --- Explanation: Demonstrates how neutrophil-mediated inflammation causes vascular cell damage in atherosclerotic disease.


HGNC.SYMBOL:9p21.3 locus


HGNC.SYMBOL:PCSK9


HGNC.SYMBOL:LPA


MONDO:0010233

[PMID:26471271] [SUPPORT] Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. --- Explanation: Large cohort confirming seizures as the predominant presenting feature in FLNA-PVNH.

[PMID:26471271] [SUPPORT] a concerning median diagnostic latency of 17 to 20 years was noted between seizure onset and the genetic diagnosis --- Explanation: Highlights the significant delay between symptom onset and molecular diagnosis.


MONDO:0010233

[PMID:9883725] [SUPPORT] many neurons fail to migrate and persist as nodules lining the ventricular surface --- Explanation: Original description of the periventricular nodular heterotopia phenotype in FLNA-deficient patients.


MONDO:0010233

[PMID:26471271] [PARTIAL] 22 of 24 patients with available educational data were able to attend regular school and obtain professional education according to age --- Explanation: Most patients have normal cognition; intellectual disability is not a predominant feature.


MONDO:0010233

[PMID:9883725] [SUPPORT] Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy --- Explanation: Patent ductus arteriosus identified as part of the PVNH phenotype in the original gene discovery paper.

[PMID:20301392] [SUPPORT] congenital heart disease (patent ductus arteriosus, atrial and ventricular septal defects), valvular dystrophy --- Explanation: GeneReviews confirms PDA and other cardiac defects as part of the FLNA deficiency spectrum.


MONDO:0010233

[PMID:26471271] [SUPPORT] Distinct associated extracerebral findings have been observed and may help to establish the diagnosis including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve disease and aortic dissection --- Explanation: Large cohort confirms progressive cardiovascular complications including valvular dystrophy and aortic dissection.

[PMID:28457522] [SUPPORT] in all patients, severe ascending aortic dilation has been observed with aortic regurgitation --- Explanation: Progressive aortic dilation observed even after lung transplant, highlighting ongoing cardiovascular risk.


MONDO:0010233

[PMID:28457522] [SUPPORT] All patients had pulmonary arterial hypertension and chronic respiratory failure requiring tracheostomy and escalating levels of ventilator support before transplantation. --- Explanation: Describes severe pulmonary phenotype in FLNA-PVNH infants.

[PMID:30547349] [SUPPORT] The respiratory phenotype in the form of childhood interstitial lung disease is a recently recognised clinical consequence of loss-of-function FLNA mutation. --- Explanation: Review confirming lung disease as an emerging FLNA phenotype.


MONDO:0010233

[PMID:20301392] [SUPPORT] joint hypermobility --- Explanation: GeneReviews lists joint hypermobility as part of FLNA deficiency spectrum.


MONDO:0010233

[PMID:9883725] [SUPPORT] Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy --- Explanation: Coagulopathy identified in the original FLNA-PVNH gene discovery.

[PMID:20301392] [SUPPORT] macrothrombocytopenia --- Explanation: GeneReviews confirms macrothrombocytopenia as part of FLNA deficiency.


MONDO:0010233

[PMID:26471271] [SUPPORT] chronic constipation --- Explanation: Large PVNH cohort identifies chronic constipation as an associated feature.

[PMID:20301392] [SUPPORT] gastrointestinal dysmotility and obstruction --- Explanation: GeneReviews confirms GI dysmotility as part of FLNA deficiency.


MONDO:0010233

[PMID:9883725] [INDIRECT EVIDENCE] [SUPPORT] In the X-linked dominant human disorder periventricular heterotopia (PH), many neurons fail to migrate and persist as nodules lining the ventricular surface. --- Explanation: The landmark paper identifying FLNA (then FLN1) as the causative gene for X-linked periventricular heterotopia, demonstrating its role in neuronal migration.

[PMID:9883725] [INDIRECT EVIDENCE] [SUPPORT] We have identified the PH gene as filamin 1 (FLN1), which encodes an actin-cross-linking phosphoprotein that transduces ligand-receptor binding into actin reorganization, and which is required for locomotion of many cell types. --- Explanation: Establishes FLNA as an actin-binding protein required for cell locomotion, explaining the neuronal migration failure mechanism.

[PMID:14988809] [INDIRECT EVIDENCE] [SUPPORT] Two disorders, periventricular nodular heterotopia (PVNH) and a group of skeletal dysplasias belonging to the oto-palato-digital (OPD) spectrum, are caused by FLNA mutations. They are considered mutually exclusive because of the different presumed effects of the respective FLNA gene mutations, leading to loss of function (PVNH) and gain of function (OPD), respectively. --- Explanation: Zenker et al. 2004 describes a patient with dual PVNH and FMD phenotype from a single FLNA mutation producing both loss-of-function and gain-of-function transcripts, reinforcing the mechanistic distinction between PVNH (loss-of-function) and OPD (gain-of-function).


MONDO:0010233


MONDO:0010233

[PMID:26471271] [INDIRECT EVIDENCE] [SUPPORT] Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. --- Explanation: Large cohort study of 47 FLNA-PVNH patients confirming seizures as the most common presenting symptom.


MONDO:0010233

[PMID:9883725] [INDIRECT EVIDENCE] [SUPPORT] Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy --- Explanation: Original description establishing cardiovascular involvement (PDA) as part of the FLNA-PVNH phenotype.

[PMID:28457522] [INDIRECT EVIDENCE] [SUPPORT] in all patients, severe ascending aortic dilation has been observed with aortic regurgitation --- Explanation: Documents progressive aortic dilation in FLNA-PVNH patients who underwent lung transplantation, highlighting cardiovascular complications.


MONDO:0010233

[PMID:28457522] [INDIRECT EVIDENCE] [SUPPORT] Respiratory failure secondary to progressive obstructive lung disease during infancy may be the presenting phenotype of FLNA-associated periventricular nodular heterotopia. --- Explanation: Describes a cohort of 6 female infants with FLNA loss-of-function who presented with progressive respiratory failure requiring lung transplantation.

[PMID:30547349] [INDIRECT EVIDENCE] [SUPPORT] The respiratory phenotype in the form of childhood interstitial lung disease is a recently recognised clinical consequence of loss-of-function FLNA mutation. --- Explanation: Review confirming interstitial lung disease as an emerging phenotype of FLNA loss-of-function mutations.


MAXO:0000058

[PMID:20301392] [SUPPORT] Treatment of epilepsy generally follows principles for a seizure disorder caused by a known structural brain abnormality. --- Explanation: GeneReviews management guidance for seizure treatment.


MAXO:0000950

[PMID:20301392] [SUPPORT] Cardiology evaluations, echocardiogram, stress testing, and cardiac MRI as recommended by cardiologist. --- Explanation: GeneReviews surveillance recommendations for cardiovascular monitoring.

[PMID:26471271] [SUPPORT] intensely delaying appropriate medical surveillance for potentially life threatening cardiovascular complications --- Explanation: Emphasizes the importance of early cardiovascular surveillance after genetic diagnosis.


MAXO:0010039

[PMID:28457522] [SUPPORT] All 6 patients survived initial lung transplantation --- Explanation: Demonstrates lung transplantation as viable treatment for FLNA-associated progressive lung disease.


MAXO:0000079

[PMID:20301392] [SUPPORT] it is appropriate to evaluate the older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from echocardiogram and cardiac MRI --- Explanation: GeneReviews emphasizes cascade screening of at-risk relatives.


hgnc:3754

[PMID:26471271] [SUPPORT] Thirty-nine different FLNA mutations were observed, they are mainly truncating (37/39) and distributed throughout the entire coding region. --- Explanation: Large cohort characterizing the mutation spectrum in FLNA-PVNH.

[PMID:9883725] [SUPPORT] hemizygous males die embryonically --- Explanation: Original paper establishing prenatal male lethality with null FLNA.

[PMID:20301392] [SUPPORT] About 50% of affected females inherit the pathogenic variant from their mother and at least 50% have a de novo pathogenic variant. --- Explanation: GeneReviews confirms approximately equal de novo and inherited cases.


MONDO:0019234

[PMID:7685145] [SUPPORT] These disorders should be considered in the differential diagnosis of the infant with hypotonia and psychomotor delay... --- Explanation: The reference mentions hypotonia as a significant clinical feature in peroxisomal disorders.

[PMID:28320181] [PARTIAL] ...suggest that these PEX10 mutations involve not only cerebellar but also more multiple nervous systems... --- Explanation: While the reference primarily discusses cerebellar involvement, it indirectly supports the statement by implicating neurological systems in PEX10-related peroxisome biogenesis disorders.

[PMID:13129589] [SUPPORT] The floppy infant syndrome is a well-recognized entity for pediatricians and neonatologists. The condition refers to an infant with generalized hypotonia... --- Explanation: The reference directly supports the very frequent occurrence of hypotonia in infants with peroxisomal disorders.

[PMID:38409970] [SUPPORT] Common clinical presentations include hypotonia, seizure, hepatomegaly, craniofacial dysmorphism and early death. --- Explanation: Hypotonia is listed as one of the common clinical presentations in Zellweger syndrome, a type of peroxisome biogenesis disorder.