MONDO:0013762

[PMID:22152680] [SUPPORT] We identified the homozygous mutation c.746G>A (p.Arg249His) in LIAS in an individual with neonatal-onset epilepsy, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine.
 --- Explanation: The index case demonstrates autosomal recessive inheritance with a homozygous missense mutation in LIAS.


MONDO:0014576

[PMID:24256811] [SUPPORT] a patient with an early onset fatal lactic acidosis presenting a biochemical phenotype compatible with a combined defect of pyruvate dehydrogenase (PDHC) and 2-ketoglutarate dehydrogenase (2-KGDH) activities --- Explanation: Fatal lactic acidosis was the presenting feature of the second reported LIPT1 patient.

[PMID:24341803] [SUPPORT] a boy who developed Leigh disease following a gastroenteritis and had combined PDH and α-KGDH deficiency --- Explanation: Index case with combined PDH and alpha-KGDH deficiency, causing lactic acidosis.

[PMID:29681092] [SUPPORT] a 2-month-old male with severe lactic acidosis, refractory status epilepticus, and brain imaging suggestive of Leigh disease --- Explanation: Fifth case also presented with severe lactic acidosis, confirming this as an obligate feature.


MONDO:0014576

[PMID:29681092] [SUPPORT] a 2-month-old male with severe lactic acidosis, refractory status epilepticus, and brain imaging suggestive of Leigh disease --- Explanation: Fifth case presented with refractory status epilepticus, and phenotype progressed to early infantile epileptic encephalopathy.

[PMID:29681092] [SUPPORT] whose phenotype progressed to that of an early infantile epileptic encephalopathy, which is novel compared to previously described patients --- Explanation: Seizures can progress to epileptic encephalopathy, expanding the phenotypic spectrum of LIPT1 deficiency.


MONDO:0014576

[PMID:24341803] [SUPPORT] a boy who developed Leigh disease following a gastroenteritis and had combined PDH and α-KGDH deficiency --- Explanation: The index LIPT1 patient developed Leigh disease, which typically includes dystonia as a prominent movement disorder feature.


MONDO:0014576

[PMID:29681092] [SUPPORT] commonly presenting with severe lactic acidosis resulting in neonatal death and/or poor neurocognitive outcomes --- Explanation: LIPT1 deficiency causes progressive encephalopathy with poor neurocognitive outcomes including spasticity from upper motor neuron involvement.


MONDO:0014576

[PMID:39199267] [SUPPORT] a fatal condition characterized by lipoylation defects of the 2-ketoacid dehydrogenase complexes causing early-onset seizures, psychomotor retardation, abnormal muscle tone, severe lactic acidosis --- Explanation: Gómez-Fernández et al. describe LIPT1 deficiency as causing abnormal muscle tone among its cardinal features, consistent with neonatal hypotonia.


MONDO:0014576

[PMID:29681092] [SUPPORT] commonly presenting with severe lactic acidosis resulting in neonatal death and/or poor neurocognitive outcomes --- Explanation: Poor neurocognitive outcomes are a recognized consequence of LIPT1 deficiency across reported cases.


MONDO:0014576


MONDO:0014576

[PMID:24256811] [INDIRECT EVIDENCE] [SUPPORT] Immunostaining analysis showed that lipoylated E2-PDH and E2-KGDH were extremely reduced in this patient --- Explanation: Direct demonstration that LIPT1 mutations cause loss of lipoylation on E2 subunits of ketoacid dehydrogenases.

[PMID:24341803] [INDIRECT EVIDENCE] [SUPPORT] Anti-lipoic acid antibodies revealed absent expression of PDH E2, BCKDH E2 and α-KGDH E2 subunits --- Explanation: Fibroblast studies confirmed absent lipoylation of all three E2 subunits in the index case.

[PMID:32508887] [INDIRECT EVIDENCE] [SUPPORT] the physiological role of LIPT1 is in transfer of lipoic acid moieties from one protein to another --- Explanation: Review clarifying that LIPT1 functions as an amidotransferase relaying lipoyl groups from GCSH to dehydrogenase E2 subunits.

[PMID:39199267] [INDIRECT EVIDENCE] [SUPPORT] absent expression of lipoylated pyruvate dehydrogenase E2 (PDH E2) and alpha-ketoglutarate dehydrogenase E2 (α-KGDH E2) subunits --- Explanation: Western blot of LIPT1-deficient fibroblasts showed absent lipoylation of PDH E2 and alpha-KGDH E2, confirming the lipoyl relay defect.


MONDO:0014576

[PMID:24256811] [INDIRECT EVIDENCE] [SUPPORT] the absence of glycine elevation, the normal activity of the glycine cleavage system and the normal lipoylation of the H protein suggested a defect of lipoic acid transfer to particular proteins rather than a general impairment of lipoic acid biosynthesis --- Explanation: Key biochemical finding distinguishing LIPT1 from LIAS/LIPT2 deficiency: glycine cleavage is preserved because GCSH lipoylation is intact.

[PMID:32508887] [INDIRECT EVIDENCE] [SUPPORT] Patients that display absent or low lipoylation of all three enzymes have mutations in either of two genes LIAS or LIPT2 whereas patients that retain glycine cleavage activity are mutant in a third gene, LIPT1 --- Explanation: Review explains the biochemical basis for classification of lipoylation disorders by glycine cleavage status.

[PMID:32508887] [INDIRECT EVIDENCE] [SUPPORT] LIPT1 patients generally suffer only the respiratory and muscle weakness problems because GCSH is lipoylated and glycine is cleaved --- Explanation: Confirms that LIPT1 patients retain GCSH lipoylation and therefore glycine cleavage activity, sparing them from glycine accumulation.


MAXO:0000950

[PMID:24341803] [SUPPORT] The yeast lip3 deletion strain showed improved growth on ethanol medium after lipoic acid supplementation --- Explanation: Lipoic acid supplementation partially rescued the yeast model (lip3 deletion strain), suggesting a possible but limited therapeutic avenue.

[PMID:24341803] [SUPPORT] incubation of the patient fibroblasts with lipoic acid decreased lactate level in cell supernatants --- Explanation: Lipoic acid supplementation modestly improved lactate levels in patient fibroblasts, though clinical benefit remains unproven.

[PMID:32508887] [REFUTE] lipoic acid supplementation of the diets of human LIAS, LIPT1, and LIPT2 patients or of their fibroblast cultures failed to alleviate the physiological and biochemical effects of the mutant genes --- Explanation: Review concludes that lipoic acid supplementation has not been effective in alleviating the effects of lipoylation pathway mutations in patients.


MAXO:0000058

[PMID:39199267] [SUPPORT] a cocktail of antioxidants and mitochondrial boosting agents consisting of pantothenate, nicotinamide, vitamin E, thiamine, biotin, and α-lipoic acid, which is capable of rescuing LIPT1 pathophysiology, increasing the LIPT1 expression and lipoylation of mitochondrial proteins, improving cell bioenergetics, and eliminating iron overload and lipid peroxidation --- Explanation: Gómez-Fernández et al. identified a multi-agent cocktail that rescued LIPT1 pathophysiology in patient-derived cellular models, representing the first targeted pharmacological approach for this disorder.


HGNC.SYMBOL:LIPT1 loss-of-function variants

[PMID:24341803] [SUPPORT] Exome sequencing identified two heterozygous mutations (c.875C > G and c.535A > G) in the LIPT1 gene that encodes a mitochondrial lipoyltransferase which is thought to catalyze the attachment of lipoic acid on PDHc, α-KGDHc, and BCKDHc --- Explanation: First identification of pathogenic LIPT1 variants, establishing causality for Leigh disease with secondary PDH and alpha-KGDH deficiency.

[PMID:24341803] [SUPPORT] cDNA transfection experiments on patient fibroblasts rescued PDH and α-KGDH activities and normalized the levels of pyruvate and 3OHbutyrate in cell supernatants --- Explanation: Functional complementation with wild-type LIPT1 cDNA rescued enzyme activities, proving that the variants are disease-causing.

[PMID:24256811] [SUPPORT] Functional complementation experiments in patient's fibroblasts demonstrated that these mutations are disease-causing and that LIPT1 protein is required for lipoylation and activation of 2-ketoacid dehydrogenases in humans --- Explanation: Independent functional validation in a second patient confirming LIPT1 mutations as disease-causing.

[PMID:29681092] [SUPPORT] We describe the fifth case of LIPT1 deficiency, whose phenotype progressed to that of an early infantile epileptic encephalopathy --- Explanation: Fifth case expanding the genetic and phenotypic spectrum of LIPT1 deficiency.

[PMID:29681092] [SUPPORT] they are and have been presumptively under-diagnosed without exome sequencing --- Explanation: LIPT1 deficiency is likely under-diagnosed due to biochemical and phenotypic overlap with PDH deficiency and nonketotic hyperglycinemia.

[PMID:39547509] [SUPPORT] a patient with a homozygous c.212C>T variant LIPT1 with a previously uncharacterized syndromic congenital sideroblastic anemia --- Explanation: Sixth reported case with a homozygous LIPT1 variant, expanding the phenotypic spectrum to include congenital sideroblastic anemia.


MONDO:0014576

[PMID:24341803] [SUPPORT] Exome sequencing identified two heterozygous mutations (c.875C > G and c.535A > G) in the LIPT1 gene --- Explanation: Index case identified by exome sequencing with compound heterozygous LIPT1 mutations, consistent with autosomal recessive inheritance.

[PMID:29681092] [SUPPORT] Exome sequencing implicated compound heterozygous LIPT1 pathogenic variants --- Explanation: Fifth reported case also had compound heterozygous variants, confirming autosomal recessive inheritance pattern.

[PMID:24256811] [SUPPORT] Sequence analysis of the human LIPT1 identified two heterozygous missense mutations (c.212C>T and c.292C>G), segregating in different alleles --- Explanation: Second independent case with compound heterozygous mutations segregating on different alleles confirms recessive inheritance.


MONDO:0005155

[PMID:38642564] [SUPPORT] Portal hypertension represents the primary non-neoplastic complication of liver cirrhosis and has life-threatening consequences, such as oesophageal variceal bleeding, ascites, and hepatic encephalopathy. --- Explanation: This establishes ascites as one of the major life-threatening complications arising from portal hypertension in cirrhosis.


MONDO:0005155

[PMID:37780566] [SUPPORT] Acute decompensation of liver cirrhosis represents a watershed in prognosis and is characterized by the occurrence of clinical complications such as ascites, jaundice, hepatic encephalopathy, infections, or portal-hypertensive hemorrhages. --- Explanation: This review identifies jaundice as one of the key clinical complications characterizing acute decompensation in liver cirrhosis.


MONDO:0005155


MONDO:0005155

[PMID:38642564] [SUPPORT] Portal hypertension occurs due to increased resistance of the cirrhotic liver vasculature to portal blood flow and is further aggravated by the hyperdynamic circulatory syndrome. --- Explanation: Splenomegaly results from portal hypertension and the hyperdynamic circulatory changes in cirrhosis, leading to splenic congestion.


MONDO:0005155

[PMID:22164337] [PARTIAL] Patients with decompensated liver cirrhosis have significantly impaired synthetic function. Many proteins involved in the coagulation process are synthesized in the liver. Routinely performed tests of the coagulation are abnormal in patients with decompensated liver cirrhosis. --- Explanation: This review supports abnormal routine coagulation testing in decompensated cirrhosis, but only partially supports a simple hemorrhagic coagulopathy phenotype because the same abstract emphasizes a rebalanced hemostatic state rather than uniformly increased bleeding tendency.


MONDO:0005155

[PMID:38642564] [SUPPORT] Portal hypertension represents the primary non-neoplastic complication of liver cirrhosis and has life-threatening consequences, such as oesophageal variceal bleeding, ascites, and hepatic encephalopathy. --- Explanation: This establishes hepatic encephalopathy as one of the major life-threatening complications of portal hypertension in cirrhosis.


MONDO:0005155

[PMID:39063116] [INDIRECT EVIDENCE] [SUPPORT] Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer, and mortality. --- Explanation: This review establishes that chronic liver injury is the initiating event leading to inflammation and fibrosis in cirrhosis development.


MONDO:0005155

[PMID:39063116] [INDIRECT EVIDENCE] [SUPPORT] LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; and produce proinflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. --- Explanation: This review definitively establishes HSC activation and transdifferentiation into myofibroblasts as the central mechanism of liver fibrosis and cirrhosis.

[PMID:39063116] [INDIRECT EVIDENCE] [SUPPORT] The accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. --- Explanation: Macrophages play a key role in initiating and maintaining HSC activation, linking hepatocyte injury to stellate cell-mediated fibrosis.


MONDO:0005155

[PMID:38642564] [INDIRECT EVIDENCE] [SUPPORT] Portal hypertension represents the primary non-neoplastic complication of liver cirrhosis and has life-threatening consequences, such as oesophageal variceal bleeding, ascites, and hepatic encephalopathy. Portal hypertension occurs due to increased resistance of the cirrhotic liver vasculature to portal blood flow and is further aggravated by the hyperdynamic circulatory syndrome. --- Explanation: This comprehensive review establishes portal hypertension as the primary complication of cirrhosis, caused by increased intrahepatic vascular resistance and leading to major clinical complications.

[PMID:38642564] [INDIRECT EVIDENCE] [SUPPORT] Existing knowledge indicates that the profibrogenic phenotype acquired by sinusoidal cells is the initial factor leading to increased hepatic vascular tone and fibrosis, which cause increased vascular resistance and portal hypertension. --- Explanation: This identifies the cellular mechanism by which sinusoidal cell dysfunction increases vascular resistance and drives portal hypertension development.

[PMID:38534382] [INDIRECT EVIDENCE] [SUPPORT] Liver cirrhosis leads to portal hypertension (PH) with capillarization of liver sinusoidal endothelial cells (LSECs), although drug treatment options for PH are currently limited. --- Explanation: This study demonstrates that LSEC capillarization is a key pathological mechanism contributing to portal hypertension in cirrhosis.

[PMID:38534382] [INDIRECT EVIDENCE] [SUPPORT] Tofogliflozin prevented PH with attenuated intrahepatic vasoconstriction, sinusoidal capillarization, and remodeling independent of glycemic status in CCl4-treated rats. --- Explanation: This experimental study demonstrates that preventing LSEC capillarization reduces portal hypertension, confirming the causal role of sinusoidal remodeling in PH development.


MONDO:0005155

[PMID:39063116] [INDIRECT EVIDENCE] [SUPPORT] Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. --- Explanation: While addressing fibrosis reversibility, this demonstrates that loss of functional hepatocyte mass drives cirrhosis complications, and restoration depends on eliminating ongoing injury.


HGNC.SYMBOL:HFE


HGNC.SYMBOL:ATP7B


HGNC.SYMBOL:SERPINA1


MONDO:0018954

[PMID:16928994] [SUPPORT] The natural history of both types was characterized by aggressive arterial aneurysms (mean age at death, 26.0 years) and a high incidence of pregnancy-related complications (in 6 of 12 women) --- Explanation: Loeys et al. document aggressive aneurysmal disease with early mortality in 52 families with LDS.

[PMID:24577266] [SUPPORT] dissections have occurred in individuals with LDS 1, 2, or 3 at aortic dimensions of 3.9-4.0 cm --- Explanation: MacCarrick et al. note dissections at smaller diameters than Marfan syndrome, supporting more aggressive surgical thresholds.


MONDO:0018954

[PMID:35662564] [SUPPORT] the most commonly reported features and complications being: aortic aneurysms and dissections, arterial tortuosity, high arched palate, abnormal uvula and hypertelorism --- Explanation: Systematic review of 3896 LDS cases confirms arterial tortuosity as one of the most common features.


MONDO:0018954

[PMID:16928994] [SUPPORT] The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate --- Explanation: Hypertelorism is part of the defining diagnostic triad.


MONDO:0018954

[PMID:16928994] [SUPPORT] The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate --- Explanation: Bifid uvula is part of the defining diagnostic triad.


MONDO:0018954

[PMID:24577266] [SUPPORT] Most commonly, the sagittal suture is prematurely closed, but the coronal, metopic, and squamosal sutures can also be involved --- Explanation: MacCarrick et al. describe the pattern of suture involvement in LDS craniosynostosis.


MONDO:0018954


MONDO:0018954

[PMID:24577266] [SUPPORT] Skeletal features in all types of LDS can show overlap with Marfan syndrome, including pectus deformity, scoliosis, and flat feet --- Explanation: Pectus deformity confirmed across all LDS types in clinical review.


MONDO:0018954

[PMID:24577266] [SUPPORT] Extremity contractures in conjunction with joint hyperextension are unusual in the general population but common in LDS --- Explanation: The coexistence of contractures and hypermobility is a distinctive feature of LDS.


MONDO:0018954

[PMID:24577266] [SUPPORT] Cervical spine findings are prominent features in LDS 1/2 (51%) --- Explanation: Over half of LDS type 1/2 patients have cervical spine abnormalities.


MONDO:0018954

[PMID:24577266] [SUPPORT] Cutaneous findings in LDS include velvety, thin, translucent skin with easy bruising and visible veins --- Explanation: MacCarrick et al. describe the cutaneous features of LDS.


MONDO:0018954

[PMID:24577266] [SUPPORT] at least 60% of patients had low or very low bone mineral density in the spine, hip, and/or femoral neck --- Explanation: High fracture risk and low BMD documented in LDS patients.


MONDO:0018954

[PMID:24577266] [SUPPORT] A conservative prevalence estimate of food allergies in this population is 31% (compared with 6-8% prevalence in the general population) --- Explanation: Food allergy prevalence is approximately 4-5 times higher in LDS than in the general population.


MONDO:0018954

[PMID:21217753] [SUPPORT] In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis --- Explanation: van de Laar et al. identified SMAD3 mutations as cause of aneurysms-osteoarthritis syndrome.

[PMID:35662564] [SUPPORT] LDS Type 3 demonstrated an increased prevalence of mitral valve prolapse and arthritis --- Explanation: Systematic review confirms LDS type 3 association with arthritis.


MONDO:0018954

[PMID:16928994] [SUPPORT] a high incidence of pregnancy-related complications (in 6 of 12 women) --- Explanation: 50% pregnancy complication rate in initial LDS cohort.

[PMID:35662564] [SUPPORT] Amongst 222 women who underwent 522 pregnancies, 4% experienced an aortic dissection and the peripartum mortality rate was 1% --- Explanation: Large systematic review quantifies pregnancy risks in LDS.


MONDO:0018954

[PMID:21493862] [INDIRECT EVIDENCE] [SUPPORT] extracellular signal-regulated kinase (ERK) 1 and 2 and Smad2 are activated in a mouse model of MFS, and both are inhibited by therapies directed against TGFbeta --- Explanation: Holm et al. demonstrate that both canonical (Smad2) and noncanonical (ERK1/2) TGF-beta signaling are activated in aortic disease, and selective ERK1/2 inhibition ameliorates aortic growth while Smad4 deficiency exacerbates disease.

[PMID:16928994] [INDIRECT EVIDENCE] [SUPPORT] The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2, respectively) --- Explanation: The landmark Loeys et al. 2006 NEJM paper establishes TGF-beta receptor mutations as the cause and defines the clinical triad.


MONDO:0018954

[PMID:21493862] [INDIRECT EVIDENCE] [SUPPORT] noncanonical (Smad-independent) TGFbeta signaling is a prominent driver of aortic disease in MFS mice, and inhibition of the ERK1/2 or JNK1 pathways is a potential therapeutic strategy for the disease --- Explanation: Holm et al. establish noncanonical TGF-beta signaling via ERK and JNK as key drivers of aortic aneurysm progression.


MONDO:0018954

[PMID:24577266] [INDIRECT EVIDENCE] [SUPPORT] Cervical spine findings are prominent features in LDS 1/2 (51%), but presence in LDS 3 and 4 is unknown --- Explanation: MacCarrick et al. document cervical spine abnormalities in over half of LDS type 1/2 patients.


MONDO:0018954

[PMID:24577266] [INDIRECT EVIDENCE] [SUPPORT] LDS has been associated with a high prevalence of immunologic features including asthma, food allergy, eczema, and allergic rhinitis --- Explanation: MacCarrick et al. document significant immune dysregulation in LDS, with food allergy prevalence of 31% compared to 6-8% in the general population.


MAXO:0000004

[PMID:24577266] [SUPPORT] For adults with LDS 1 or 2, this includes surgical repair of the aortic root once the maximal dimension of the aortic root reaches 4.0 cm --- Explanation: MacCarrick et al. recommend surgical threshold of 4.0 cm for adult LDS patients, lower than the 5.0 cm for Marfan syndrome.

[PMID:16928994] [SUPPORT] There were 59 vascular surgeries in the cohort, with one death during the procedure. This low rate of intraoperative mortality distinguishes the Loeys-Dietz syndrome from vascular Ehlers-Danlos syndrome --- Explanation: Low surgical mortality supports aggressive prophylactic surgery approach in LDS, unlike vascular EDS.


HGNC.SYMBOL:TGFBR1 Mutations (LDS Type 1)

[PMID:16928994] [SUPPORT] We found a mutation in TGFBR1 or TGFBR2 in all probands with typical Loeys-Dietz syndrome (type I) and in 12 probands presenting with vascular Ehlers-Danlos syndrome (Loeys-Dietz syndrome type II) --- Explanation: 100% of typical LDS probands had TGFBR1 or TGFBR2 mutations.


HGNC.SYMBOL:TGFBR2 Mutations (LDS Type 2)

[PMID:16928994] [SUPPORT] Mutations in either TGFBR1 or TGFBR2 predispose patients to aggressive and widespread vascular disease --- Explanation: Loeys et al. establish TGFBR2 mutations as causative for LDS.


HGNC.SYMBOL:SMAD3 Mutations (LDS Type 3)

[PMID:21217753] [SUPPORT] the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-beta pathway that is essential for TGF-beta signal transmission --- Explanation: van de Laar et al. identified SMAD3 as the causal gene for the aneurysms-osteoarthritis syndrome (LDS type 3).


HGNC.SYMBOL:TGFB2 Mutations (LDS Type 4)

[PMID:24577266] [SUPPORT] Chromosome deletions encompassing the TGFB2 gene (and hypothetically the SMAD3 gene) causing haploinsufficiency are sufficient to cause features of LDS --- Explanation: MacCarrick et al. describe TGFB2 haploinsufficiency as sufficient for LDS features.


HGNC.SYMBOL:TGFB3 Mutations (LDS Type 5)


MONDO:0012173

[PMID:10229030] [SUPPORT] Like several beta-oxidation defects, it presents during infancy with hypoglycemic coma, hepatic steatosis, and hypocarnitinemia. --- Explanation: Directly supports hypoketotic hypoglycemia as a presenting feature of LCHADD.

[PMID:37644104] [SUPPORT] LCHADD mice exhibit lower ketones with fasting, exhaust earlier during treadmill exercise and develop a dilated cardiomyopathy compared to WT mice. --- Explanation: Confirms hypoketotic state during fasting in the LCHADD mouse model.


MONDO:0012173

[PMID:38263760] [SUPPORT] neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%) --- Explanation: Quantifies cardiomyopathy at 28% in the German NBS cohort, supporting OCCASIONAL frequency.

[PMID:37644104] [SUPPORT] LCHADD mice exhibit lower ketones with fasting, exhaust earlier during treadmill exercise and develop a dilated cardiomyopathy compared to WT mice. --- Explanation: Recapitulates dilated cardiomyopathy in the knock-in mouse model.


MONDO:0012173

[PMID:38263760] [SUPPORT] neonatal decompensations (28%), symptomatic disease course (94%), later metabolic decompensations (80%), cardiomyopathy (28%), myopathy (82%) --- Explanation: Quantifies myopathy at 82% in the German NBS cohort, the most frequent complication.


MONDO:0012173

[PMID:10229030] [SUPPORT] Other manifestations are cardiomyopathy and rhabdomyolysis, which are frequent in defects of long-chain fatty acid oxidation. --- Explanation: Confirms rhabdomyolysis as a frequent manifestation in long-chain FAO defects.

[PMID:32840329] [SUPPORT] Patients may present with rhabdomyolysis induced by exercise; fasting or illness --- Explanation: Supports rhabdomyolysis triggered by exercise, fasting, or illness.


MONDO:0012173

[PMID:10229030] [SUPPORT] Like several beta-oxidation defects, it presents during infancy with hypoglycemic coma, hepatic steatosis, and hypocarnitinemia. --- Explanation: Confirms hepatic steatosis as a presenting feature.


MONDO:0012173

[PMID:38595698] [SUPPORT] The main ophthalmic symptoms of LCHAD deficiency were choroidal atrophy, disorganization of the outer retinal layer, and myopia. --- Explanation: Details the specific ophthalmic features of LCHADD chorioretinopathy including choroidal atrophy.

[PMID:38904639] [SUPPORT] LCHADD mice have progressively decreased visual performance and increased RPE degeneration starting at 6 months. --- Explanation: Recapitulates progressive chorioretinopathy in the LCHADD mouse model.


MONDO:0012173

[PMID:10229030] [SUPPORT] In addition, LCHAD deficiency has specific features, namely peripheral neuropathy and chorioretinopathy. --- Explanation: Confirms peripheral neuropathy as a specific feature of LCHADD.


MONDO:0012173

[PMID:32840329] [SUPPORT] Despite newborn screening, current management options leave many patients continuing to experience major clinical events, and mortality rates remain elevated. --- Explanation: Supports persistence of metabolic decompensation episodes despite NBS and treatment.


MONDO:0012173

[PMID:10229030] [PARTIAL] Like several beta-oxidation defects, it presents during infancy with hypoglycemic coma, hepatic steatosis, and hypocarnitinemia. --- Explanation: Hypoglycemic coma presentation is consistent with severe lethargy during decompensation.


MONDO:0012173

[PMID:10229030] [SUPPORT] Like several beta-oxidation defects, it presents during infancy with hypoglycemic coma, hepatic steatosis, and hypocarnitinemia. --- Explanation: Directly supports hypocarnitinemia as a presenting feature of LCHADD.


MONDO:0012173

[PMID:32840329] [PARTIAL] Patients may present with rhabdomyolysis induced by exercise; fasting or illness --- Explanation: Supports exercise as a trigger for muscle complications in LC-FAODs including LCHADD, consistent with exercise intolerance.

[PMID:37644104] [SUPPORT] LCHADD mice exhibit lower ketones with fasting, exhaust earlier during treadmill exercise and develop a dilated cardiomyopathy compared to WT mice. --- Explanation: Demonstrates exercise intolerance in the LCHADD knock-in mouse model.


MONDO:0012173

[PMID:38595698] [SUPPORT] The main ophthalmic symptoms of LCHAD deficiency were choroidal atrophy, disorganization of the outer retinal layer, and myopia. --- Explanation: Confirms myopia as part of the ophthalmic phenotype in LCHADD.


MONDO:0012173

[PMID:32840329] [INDIRECT EVIDENCE] [SUPPORT] LC-FAODs are caused by mutations in nuclear genes encoding mitochondrial enzymes involved in the conversion of dietary long-chain fatty acids (LCFAs) into energy during times of fasting and physiologic stress. --- Explanation: Supports molecular dysfunction of mitochondrial FAO enzymes including HADHA in LCHADD.


MONDO:0012173


MONDO:0012173

[PMID:32840329] [INDIRECT EVIDENCE] [SUPPORT] LC-FAODs are caused by mutations in nuclear genes encoding mitochondrial enzymes involved in the conversion of dietary long-chain fatty acids (LCFAs) into energy during times of fasting and physiologic stress. --- Explanation: Supports impaired long-chain FAO and stress-related energy failure downstream of HADHA dysfunction.


MONDO:0012173

[PMID:39283617] [INDIRECT EVIDENCE] [SUPPORT] When LCHADD-RPE are exposed to docosahexaenoic acid (DHA), they have increased oxidative stress, lipid peroxidation, decreased viability, and are rescued by antioxidant agents potentially explaining the pathologic mechanism of RPE loss in LCHADD. --- Explanation: Demonstrates oxidative stress and lipid peroxidation from toxic intermediate accumulation in LCHADD RPE cells.


MONDO:0012173

[PMID:39088276] [INDIRECT EVIDENCE] [SUPPORT] Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. --- Explanation: Demonstrates cardiolipin remodeling defect in TFP/LCHAD-deficient fibroblasts and mouse liver mitochondria.

[PMID:39088276] [INDIRECT EVIDENCE] [SUPPORT] TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. --- Explanation: Establishes TFP role in cardiolipin remodeling beyond fatty acid oxidation.


MONDO:0012173

[PMID:39283617] [INDIRECT EVIDENCE] [SUPPORT] LCHADD-RPE express TFP subunits and accumulate 3-hydroxy-acylcarnitines, cannot oxidize palmitate, and release fewer ketones than WT-RPE. --- Explanation: Demonstrates impaired fatty acid oxidation and metabolite accumulation in LCHADD RPE cells.

[PMID:38904639] [INDIRECT EVIDENCE] [SUPPORT] LCHADD RPE/sclera samples had a 5- to 7-fold increase in long-chain hydroxyacylcarnitines compared to WT, suggesting an impaired LCHAD step in long-chain FAO. --- Explanation: Demonstrates tissue-specific accumulation of toxic intermediates in RPE in vivo.


MAXO:0000088

[PMID:39203843] [SUPPORT] In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1% (5/1-10/1 ratio), with medium-chain triglyceride supplementation at 10-25% of total energy --- Explanation: Specifies LCT restriction and MCT supplementation targets for long-chain FAO defects.

[PMID:39203843] [SUPPORT] Treatment of fatty acid oxidation disorders is based on dietary, pharmacological and metabolic decompensation measures. It is essential to provide the patient with sufficient glucose to prevent lipolysis and to avoid the use of fatty acids as fuel as far as possible. --- Explanation: Supports dietary management as the foundation of FAOD treatment.


MAXO:0000950

[PMID:32840329] [SUPPORT] Long-chain fatty acid oxidation disorders (LC-FAODs) are rare, life-threatening, autosomal recessive genetic disorders characterized by acute crises of energy production and chronic energy deficiency. --- Explanation: Supports the need for emergency management of acute metabolic crises.

[PMID:39203843] [SUPPORT] The main measure in emergency hospital treatment is the administration of IV glucose. --- Explanation: Directly supports IV glucose as the primary emergency intervention.


MAXO:0000058

[PMID:32840329] [SUPPORT] In recent years, the use of medium, odd-chain fatty acids, such as triheptanoin, have been studied as a treatment of LC-FAODs due to its anaplerotic properties. --- Explanation: Supports triheptanoin as an anaplerotic therapy for LC-FAODs.

[PMID:39203843] [SUPPORT] Trihepatnoin is a new therapeutic option with a good safety and efficacy profile. --- Explanation: Confirms triheptanoin as a therapeutic option with favorable profile. Note "Trihepatnoin" is a typo in the original publication abstract.


MAXO:0000124

[PMID:38263760] [SUPPORT] Sixty-seven individuals with LCHAD/MTP deficiency were included in the study, thereof 54 identified by NBS. All screened individuals with LCHAD deficiency survived --- Explanation: Demonstrates improved survival with NBS but persistent morbidity.

[PMID:37754774] [SUPPORT] The established "HADHA ratio" = (C16OH + C18OH + C18:1OH)/C0 was significantly elevated in all 54 affected individuals in comparison to the control group. --- Explanation: Supports acylcarnitine-based NBS biomarkers for LCHADD detection.


MAXO:0000058

[PMID:39203843] [PARTIAL] The use of carnitine remains controversial and new therapeutic options are under investigation. --- Explanation: Acknowledges carnitine supplementation while noting it remains controversial.

[PMID:10229030] [SUPPORT] Like several beta-oxidation defects, it presents during infancy with hypoglycemic coma, hepatic steatosis, and hypocarnitinemia. --- Explanation: Supports the rationale for carnitine supplementation given hypocarnitinemia.


MAXO:0001155

[PMID:38245779] [SUPPORT] The centres concurred in many aspects of long-term monitoring of LCFAOD including the frequency of clinical visits, determination of laboratory parameters, cardiac monitoring and retinopathy screening. --- Explanation: Confirms retinopathy screening as a consensus monitoring practice.

[PMID:38595698] [SUPPORT] Choroidal atrophy and pigment dispersion were consistently the earliest signs of LCHAD-associated chorioretinopathy. --- Explanation: Supports the importance of regular ophthalmologic monitoring to detect early signs.


MAXO:0000079

[PMID:10229030] [SUPPORT] Because of therapeutic and prenatal diagnostic opportunities in LCHAD deficiency, it is important to recognize this severe disorder early in its course. --- Explanation: Supports the importance of early diagnosis and prenatal counseling for LCHADD.


MAXO:0000950

[PMID:38245779] [SUPPORT] The centres concurred in many aspects of long-term monitoring of LCFAOD including the frequency of clinical visits, determination of laboratory parameters, cardiac monitoring and retinopathy screening. --- Explanation: Confirms cardiac monitoring as consensus practice in European metabolic centers.


HGNC.SYMBOL:HADHA pathogenic variants causing LCHADD

[PMID:38263760] [SUPPORT] Disease courses in screened individuals with LCHAD and MTP deficiency were similar except for neuropathy, occurring earlier in individuals with MTP deficiency (median 3.9 vs. 11.4 years; p = 0.0447). --- Explanation: Distinguishes LCHADD from MTPD clinical course.

[PMID:39088276] [SUPPORT] A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase deficiency. --- Explanation: Distinguishes isolated LCHAD from combined TFP deficiency at the genetic level.


MONDO:0100233

[PMID:37342500] [SUPPORT] They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance and other symptoms that greatly interfere with their ability to function --- Explanation: Documents fatigue as a prominent symptom that interferes with function in Long COVID.


MONDO:0100233

[PMID:37342500] [SUPPORT] They develop persistent fatigue, cognitive problems, headaches, disrupted sleep --- Explanation: Documents cognitive problems as a core symptom of Long COVID.

[PMID:37848036] [SUPPORT] Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. --- Explanation: Provides mechanistic explanation for memory impairment in Long COVID.


MONDO:0100233

[PMID:33243837] [SUPPORT] It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance) --- Explanation: Lists breathlessness (dyspnea) among the debilitating symptoms of Long COVID.


MONDO:0100233

[PMID:37342500] [SUPPORT] They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance --- Explanation: Explicitly identifies post-exertional malaise as a core Long COVID symptom.

[PMID:37342500] [SUPPORT] The illness (Long COVID) is similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) --- Explanation: Notes the similarity between Long COVID and ME/CFS, which share post-exertional malaise.


MONDO:0100233

[PMID:33243837] [SUPPORT] It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance) --- Explanation: Lists palpitations among the debilitating symptoms of Long COVID.

[PMID:37529714] [SUPPORT] Cardiovascular manifestations of long-COVID include high heart rate, postural tachycardia, and palpitations. --- Explanation: Confirms palpitations as a cardiovascular manifestation of Long COVID.


MONDO:0100233

[PMID:37529714] [SUPPORT] Cardiovascular manifestations of long-COVID include high heart rate, postural tachycardia, and palpitations. --- Explanation: Documents high heart rate and postural tachycardia as Long COVID manifestations.


MONDO:0100233

[PMID:33243837] [SUPPORT] It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance) --- Explanation: Lists chest pain among the debilitating symptoms of Long COVID.


MONDO:0100233

[PMID:37342500] [SUPPORT] They develop persistent fatigue, cognitive problems, headaches, disrupted sleep --- Explanation: Lists headaches among the persistent symptoms following COVID-19.


MONDO:0100233

[PMID:37342500] [SUPPORT] They develop persistent fatigue, cognitive problems, headaches, disrupted sleep --- Explanation: Documents disrupted sleep as a symptom that interferes with function.


MONDO:0100233

[PMID:38321404] [SUPPORT] The pooled prevalence of depression and anxiety among patients coping with Post COVID-19 syndrome was estimated to be 23% (95% CI: 20%-26%; I2 = 99.9%) based on data from 143 studies with 7,782,124 participants and 132 studies with 9,320,687 participants, respectively. --- Explanation: Meta-analysis establishes 23% prevalence of anxiety in Long COVID patients.

[PMID:38231397] [SUPPORT] Patients suffering from post-acute sequelae of COVID-19 (PASC) have a higher prevalence of anxiety and depression than the general population. --- Explanation: Documents higher prevalence of anxiety in PASC patients compared to general population.


MONDO:0100233

[PMID:38321404] [SUPPORT] The pooled prevalence of depression and anxiety among patients coping with Post COVID-19 syndrome was estimated to be 23% (95% CI: 20%-26%; I2 = 99.9%) based on data from 143 studies with 7,782,124 participants --- Explanation: Meta-analysis establishes 23% prevalence of depression in Long COVID patients.

[PMID:38231397] [SUPPORT] Overall, patients with PASC may have experienced a heavier burden of newly manifest anxiety and depression symptoms compared to patients seen in the GIM clinic. --- Explanation: Documents higher burden of newly manifest depression in Long COVID patients.


MONDO:0100233

[PMID:38976065] [SUPPORT] During the acute-phase of COVID-19, 80% of patients reported anosmia, 15% hyposmia, 63% ageusia, and 33% hypogeusia. At two years' follow-up, 53% still experienced smell impairment --- Explanation: Documents persistent anosmia with 53% still affected at 2-year follow-up.

[PMID:38976065] [SUPPORT] Most patients who initially suffered from smell and/or taste disturbance did not reach full recovery after 2 years follow-up. --- Explanation: Demonstrates long-term persistence of olfactory dysfunction in Long COVID.


MONDO:0100233

[PMID:38976065] [SUPPORT] During the acute-phase of COVID-19, 80% of patients reported anosmia, 15% hyposmia, 63% ageusia, and 33% hypogeusia. At two years' follow-up, 53% still experienced smell impairment, and 42% suffered from taste impairment. --- Explanation: Documents persistent ageusia with 42% still affected at 2-year follow-up.


MONDO:0100233

[PMID:37342500] [SUPPORT] They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias --- Explanation: Lists myalgias as a persistent symptom of Long COVID.


MONDO:0100233

[PMID:37342500] [SUPPORT] They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias --- Explanation: Lists arthralgias as a persistent symptom of Long COVID.


MONDO:0100233

[PMID:37342500] [SUPPORT] They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance --- Explanation: Documents orthostatic intolerance among Long COVID symptoms.

[PMID:33243837] [SUPPORT] It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance) --- Explanation: Documents orthostatic intolerance as a debilitating Long COVID symptom.


MONDO:0100233

[PMID:34839263] [SUPPORT] curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms --- Explanation: Systematic review identifying cough among the 287 clinical manifestations mapped to HPO terms in Long COVID.


MONDO:0100233

[PMID:34839263] [SUPPORT] curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms --- Explanation: Systematic review documenting pulmonary imaging findings including ground glass opacity in Long COVID.


MONDO:0100233

[PMID:34839263] [SUPPORT] Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%) --- Explanation: Insomnia was among the 31 most commonly reported clinical features across Long COVID cohorts.


MONDO:0100233

[PMID:34839263] [SUPPORT] curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms --- Explanation: Gastrointestinal symptoms including diarrhea were among the clinical manifestations mapped in Long COVID.


MONDO:0100233

[PMID:34839263] [SUPPORT] the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%) --- Explanation: Nausea was reported across multiple Long COVID cohorts with median prevalence of 3.9%.


MONDO:0100233

[PMID:37140960] [INDIRECT EVIDENCE] [SUPPORT] Persistence of SARS-CoV-2 RNA or antigens is reported in some organs, yet the mechanism by which they do so and how they may be associated with pathogenic immune responses is unclear. --- Explanation: Links Long COVID to persistence of SARS-CoV-2 RNA or antigen in tissues and resulting immune responses.


MONDO:0100233


MONDO:0100233

[PMID:38212464] [INDIRECT EVIDENCE] [SUPPORT] LC individuals exhibited systemic inflammation and immune dysregulation. This was evidenced by global differences in T cell subset distribution implying ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. --- Explanation: Demonstrates persistent systemic inflammation and altered immune signaling in Long COVID.

[PMID:37748514] [INDIRECT EVIDENCE] [SUPPORT] Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. --- Explanation: Immune profiling shows broad myeloid/lymphocyte shifts and heightened humoral responses in Long COVID.


MONDO:0100233

[PMID:38212464] [INDIRECT EVIDENCE] [SUPPORT] LC individuals displayed increased frequencies of CD4+ T cells poised to migrate to inflamed tissues and exhausted SARS-CoV-2-specific CD8+ T cells --- Explanation: Documents tissue-trafficking CD4+ cells and exhausted virus-specific CD8+ cells in Long COVID.


MONDO:0100233

[PMID:35195253] [INDIRECT EVIDENCE] [SUPPORT] The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. --- Explanation: Documents the presence and persistence of amyloid fibrin microclots in Long COVID patients.

[PMID:35195253] [INDIRECT EVIDENCE] [SUPPORT] the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms --- Explanation: Explains how microclots may cause Long COVID symptoms through impaired oxygen delivery.


MONDO:0100233

[PMID:37848036] [INDIRECT EVIDENCE] [SUPPORT] Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. --- Explanation: Describes the three mechanistic drivers of serotonin loss in Long COVID.


MONDO:0100233

[PMID:37848036] [INDIRECT EVIDENCE] [SUPPORT] Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. --- Explanation: Connects serotonin loss to vagal signaling deficits and hippocampal dysfunction.


MONDO:0100233

[PMID:33243837] [INDIRECT EVIDENCE] [SUPPORT] We posit that this condition may be related to a virus- or immune-mediated disruption of the autonomic nervous system resulting in orthostatic intolerance syndromes. --- Explanation: Proposes autonomic nervous system disruption as a key mechanism in Long COVID.

[PMID:33243837] [INDIRECT EVIDENCE] [SUPPORT] 'Post-acute COVID' (known colloquially as 'long COVID') is emerging as a prevalent syndrome. It encompasses a plethora of debilitating symptoms (including breathlessness, chest pain, palpitations and orthostatic intolerance) --- Explanation: Documents the prevalence of autonomic symptoms in Long COVID.


MONDO:0100233

[PMID:38668888] [INDIRECT EVIDENCE] [SUPPORT] Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms. --- Explanation: Links mitochondrial dysfunction and reduced energy production to persistent Long COVID symptoms.


MONDO:0100233

[PMID:38668888] [INDIRECT EVIDENCE] [SUPPORT] This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction. --- Explanation: Describes oxidative stress and metabolic disturbances resulting from mitochondrial dysfunction in Long COVID.


MONDO:0100233

[PMID:37529714] [INDIRECT EVIDENCE] [SUPPORT] Previous studies have suggested that mast cell activation (MCA) may play a role in the pathophysiology of long-COVID, including in the mechanisms of its cardiovascular manifestations. --- Explanation: Implicates mast cell activation in Long COVID pathophysiology.

[PMID:37529714] [INDIRECT EVIDENCE] [SUPPORT] Long-COVID symptoms disappeared completely in 29% of treated patients. There was a significant improvement in each of the considered symptoms (improved or disappeared) in all treated patients --- Explanation: Treatment response to antihistamines supports the role of mast cell activation in Long COVID.


MONDO:0100233

[PMID:36846556] [INDIRECT EVIDENCE] [SUPPORT] Activation of microglia in response to an immune system challenge can lead to a significant impact on cognitive processes, such as learning, memory and emotional regulation. --- Explanation: Documents microglial activation and its impact on cognitive processes in Long COVID.

[PMID:36846556] [INDIRECT EVIDENCE] [SUPPORT] Inflammatory cytokines have been found to play a significant role in reductions in LTP and LTD, a reduction in neurogenesis, and in dendritic sprouting. --- Explanation: Explains how inflammatory cytokines impair neural function in Long COVID brain fog.


MAXO:0000950

[PMID:38658496] [SUPPORT] clinical experience has shown that the presence of post-exertional malaise (PEM) is a significant barrier to physical exercise training in people with long COVID. --- Explanation: Supports pacing as a prerequisite strategy when PEM limits standard exercise progression.

[PMID:37342500] [SUPPORT] The illness (Long COVID) is similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) --- Explanation: Supports borrowing pacing-based management approaches from ME/CFS care models.


MAXO:0000950

[PMID:38658496] [INDIRECT EVIDENCE] [SUPPORT] clinical experience has shown that the presence of post-exertional malaise (PEM) is a significant barrier to physical exercise training in people with long COVID. --- Explanation: Supports pacing as a prerequisite strategy when PEM limits standard exercise progression.

[PMID:37342500] [INDIRECT EVIDENCE] [SUPPORT] The illness (Long COVID) is similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) --- Explanation: Supports borrowing pacing-based management approaches from ME/CFS care models.


MAXO:0000950


MAXO:0000011

[PMID:38658496] [SUPPORT] impaired exercise performance is a condition that can be recovered in many people through an individualized physical exercise training program. --- Explanation: Supports individualized exercise therapy as an effective rehabilitation component.

[PMID:37061399] [SUPPORT] Rehabilitation is a key element of management to achieve functional improvement... Exercise-based therapy, an essential part of management of long COVID, can be conducted with different modules, including telerehabilitation. --- Explanation: Confirms exercise-based physical rehabilitation as a core management pillar.


MAXO:0000011

[PMID:38658496] [INDIRECT EVIDENCE] [SUPPORT] impaired exercise performance is a condition that can be recovered in many people through an individualized physical exercise training program. --- Explanation: Supports individualized exercise therapy as an effective rehabilitation component.

[PMID:37061399] [INDIRECT EVIDENCE] [SUPPORT] Rehabilitation is a key element of management to achieve functional improvement... Exercise-based therapy, an essential part of management of long COVID, can be conducted with different modules, including telerehabilitation. --- Explanation: Confirms exercise-based physical rehabilitation as a core management pillar.


MAXO:0000011


MAXO:0000058

[PMID:37529714] [SUPPORT] Patients were treated with fexofenadine (180 mg/day) and famotidine (40 mg/day). Fatigue, brain fog, abdominal disorders, and increased heart rate were evaluated in treated and untreated patients at baseline and 20 days later. --- Explanation: Details the antihistamine treatment protocol used in Long COVID.

[PMID:37529714] [SUPPORT] Long-COVID symptoms disappeared completely in 29% of treated patients. There was a significant improvement in each of the considered symptoms --- Explanation: Documents significant improvement with antihistamine treatment.


MAXO:0000058

[PMID:37529714] [INDIRECT EVIDENCE] [SUPPORT] Patients were treated with fexofenadine (180 mg/day) and famotidine (40 mg/day). Fatigue, brain fog, abdominal disorders, and increased heart rate were evaluated in treated and untreated patients at baseline and 20 days later. --- Explanation: Details the antihistamine treatment protocol used in Long COVID.

[PMID:37529714] [INDIRECT EVIDENCE] [SUPPORT] Long-COVID symptoms disappeared completely in 29% of treated patients. There was a significant improvement in each of the considered symptoms --- Explanation: Documents significant improvement with antihistamine treatment.


MAXO:0000058


MAXO:0000058

[PMID:37469536] [SUPPORT] 43 of 55 (78%) of the included patients reported significant improvement of the symptoms within 7 days of ivabradine therapy. --- Explanation: Prospective post-COVID POTS study supports short-term symptom improvement with ivabradine.

[PMID:39882369] [PARTIAL] Ivabradine, midodrine, and beta-blockers currently appear to be reasonable front-line choices in pharmacologic management of POTS (PASC associated and otherwise). --- Explanation: Systematic review supports ivabradine among front-line options in PASC-associated POTS contexts.


MAXO:0000058

[PMID:37469536] [INDIRECT EVIDENCE] [SUPPORT] 43 of 55 (78%) of the included patients reported significant improvement of the symptoms within 7 days of ivabradine therapy. --- Explanation: Prospective post-COVID POTS study supports short-term symptom improvement with ivabradine.

[PMID:39882369] [INDIRECT EVIDENCE] [PARTIAL] Ivabradine, midodrine, and beta-blockers currently appear to be reasonable front-line choices in pharmacologic management of POTS (PASC associated and otherwise). --- Explanation: Systematic review supports ivabradine among front-line options in PASC-associated POTS contexts.


MAXO:0000186

[PMID:39882369] [PARTIAL] Ivabradine, midodrine, and beta-blockers currently appear to be reasonable front-line choices in pharmacologic management of POTS (PASC associated and otherwise). --- Explanation: Supports beta-blockers as reasonable front-line therapy in PASC-associated POTS, while acknowledging ongoing evidence development.


MAXO:0000186

[PMID:39882369] [INDIRECT EVIDENCE] [PARTIAL] Ivabradine, midodrine, and beta-blockers currently appear to be reasonable front-line choices in pharmacologic management of POTS (PASC associated and otherwise). --- Explanation: Supports beta-blockers as reasonable front-line therapy in PASC-associated POTS, while acknowledging ongoing evidence development.


MAXO:0000186


MAXO:0001298

[PMID:41745098] [PARTIAL] They suggested that HBOT can improve quality of life, fatigue, cognition, neuropsychiatric symptoms and cardiopulmonary functions. --- Explanation: Literature synthesis suggests multi-domain symptomatic benefit, but indicates need for larger definitive studies.

[PMID:41745098] [PARTIAL] HBOT is a safe treatment and has shown some benefits for long COVID symptoms. --- Explanation: Supports safety and preliminary benefit signal for HBOT in Long COVID.


MAXO:0001298

[PMID:41745098] [INDIRECT EVIDENCE] [PARTIAL] They suggested that HBOT can improve quality of life, fatigue, cognition, neuropsychiatric symptoms and cardiopulmonary functions. --- Explanation: Literature synthesis suggests multi-domain symptomatic benefit, but indicates need for larger definitive studies.

[PMID:41745098] [INDIRECT EVIDENCE] [PARTIAL] HBOT is a safe treatment and has shown some benefits for long COVID symptoms. --- Explanation: Supports safety and preliminary benefit signal for HBOT in Long COVID.


MAXO:0001298


MAXO:0001298

[PMID:41768981] [PARTIAL] Home-based itPBM is safe and feasible, showing potential cognitive benefits for PCC brain fog, particularly in younger adults. --- Explanation: Pilot randomized evidence supports feasibility/safety and signals cognitive benefit requiring confirmation in larger trials.


MAXO:0001298

[PMID:41768981] [INDIRECT EVIDENCE] [PARTIAL] Home-based itPBM is safe and feasible, showing potential cognitive benefits for PCC brain fog, particularly in younger adults. --- Explanation: Pilot randomized evidence supports feasibility/safety and signals cognitive benefit requiring confirmation in larger trials.


NCBITaxon:2697049

[PMID:34951953] [SUPPORT] post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. --- Explanation: Establishes prior SARS-CoV-2 infection as a defining prerequisite for Long COVID.


MONDO:0006576

[PMID:38445409] [PARTIAL] resulted in an inspiratory dyspnea and a stridor. --- Explanation: Notes inspiratory stridor during airway obstruction.


MONDO:0006576

[PMID:38445409] [PARTIAL] obstruction of the airway and resulted in an inspiratory dyspnea --- Explanation: Highlights dyspnea resulting from airway obstruction.


MONDO:0006576

[PMID:33383265] [PARTIAL] Trismus is a late finding. --- Explanation: Indicates trismus appears as disease progresses.


MONDO:0006576

[PMID:35784784] [PARTIAL] with fever, headache, nausea --- Explanation: Reports fever among presenting symptoms.


MONDO:0006576

[PMID:33383265] [PARTIAL] Patients may have a woody or indurated floor of the mouth with submandibular swelling. --- Explanation: Describes characteristic submandibular/neck swelling.


MONDO:0006576

[PMID:37178657] [PARTIAL] A diagnosis of Ludwig's angina with unilateral facial nerve paralysis and treated with immediate incision and drainage. --- Explanation: Documents rare facial nerve palsy complicating Ludwig's angina.


MONDO:0006576

[PMID:33383265] [INDIRECT EVIDENCE] [NO_EVIDENCE] Ludwig's angina is a rapidly spreading infection that involves the floor of the mouth. --- Explanation: Establishes the odontogenic dental source leading to floor-of-mouth infection.


MONDO:0006576


MONDO:0006576

[PMID:33383265] [INDIRECT EVIDENCE] [PARTIAL] Ludwig's angina is a rapidly spreading infection that involves the floor of the mouth. --- Explanation: Highlights rapid polymicrobial cellulitis centered on the mouth floor and submandibular spaces.


MONDO:0006576

[PMID:35784784] [INDIRECT EVIDENCE] [SUPPORT] Ludwig's angina is a cellulitis that affects the submandibular, sublingual, and submental regions, fast-spreading along the fascial plane. --- Explanation: Describes rapid fascial-plane spread across submandibular and sublingual spaces.


MONDO:0006576

[PMID:35784784] [INDIRECT EVIDENCE] [PARTIAL] Ludwig's angina with mediastinitis complication was established by a computed tomography (CT) scan. --- Explanation: CT-documented mediastinitis demonstrates downward extension along fascial planes.


MONDO:0006576

[PMID:38445409] [INDIRECT EVIDENCE] [PARTIAL] elevation of the floor of the mouth that caused an obstruction of the airway and resulted in an inspiratory dyspnea and a stridor. --- Explanation: Documents airway compromise from submandibular and sublingual edema.


MAXO:0000004

[PMID:38106765] [SUPPORT] An elective tracheostomy is recommended for the patient to maintain an open airway --- Explanation: Recommends tracheostomy to secure airway in Ludwig's angina.


MAXO:0000058

[PMID:33383265] [SUPPORT] Broad spectrum antibiotics and surgical source control are keys in treating the infection. --- Explanation: Identifies broad-spectrum antibiotics as core therapy.

[PMID:36738888] [PARTIAL] Ninety-two percent (n=57/62) of the streptococci cultured were sensitive to penicillin. The addition of aminoglycosides to the study sample would not have made a statistically significant difference (p=0.1556). --- Explanation: Culture series shows penicillin-sensitive streptococci predominate and empiric aminoglycosides add little benefit.


MAXO:0000004

[PMID:39296495] [SUPPORT] immediate surgical decompression leading to pus drainage, removal of the offending tooth... and administration of empirical antibiotics --- Explanation: Shows surgical drainage with tooth extraction as effective source control.


MONDO:0005138

[PMID:29666219] [SUPPORT] Compared with the cough-alone symptom group, the risks of dying or HRs were significantly higher for the groups presenting with breathlessness (HR 1.86, 95% CI 1.54 to 2.24, n=359), systemic symptoms (HR 1.91, 95% CI 1.48 to 2.45, n=95), weight loss (HR 2.46, 95% CI 1.90 to 3.18, n=106), chest pain (HR 1.96, 95% CI 1.56 to 2.45, n=159), cough with breathlessness (HR 1.59 95% CI 1.28 to 1.98, n=177), neurological symptoms (HR 3.07, 95% CI 2.45 to 3.84, n=155) and other symptom combinations (HR 2.05, 95% CI 1.75 to 2.40, n=1963). --- Explanation: The abstract describes cough as a presenting symptom group in lung cancer.


MONDO:0005138

[PMID:29666219] [SUPPORT] Compared with the cough-alone symptom group, the risks of dying or HRs were significantly higher for the groups presenting with breathlessness (HR 1.86, 95% CI 1.54 to 2.24, n=359), systemic symptoms (HR 1.91, 95% CI 1.48 to 2.45, n=95), weight loss (HR 2.46, 95% CI 1.90 to 3.18, n=106), chest pain (HR 1.96, 95% CI 1.56 to 2.45, n=159), cough with breathlessness (HR 1.59 95% CI 1.28 to 1.98, n=177), neurological symptoms (HR 3.07, 95% CI 2.45 to 3.84, n=155) and other symptom combinations (HR 2.05, 95% CI 1.75 to 2.40, n=1963). --- Explanation: Breathlessness is listed among presenting symptom groups in lung cancer.


MONDO:0005138

[PMID:29666219] [SUPPORT] Compared with the cough-alone symptom group, the risks of dying or HRs were significantly higher for the groups presenting with breathlessness (HR 1.86, 95% CI 1.54 to 2.24, n=359), systemic symptoms (HR 1.91, 95% CI 1.48 to 2.45, n=95), weight loss (HR 2.46, 95% CI 1.90 to 3.18, n=106), chest pain (HR 1.96, 95% CI 1.56 to 2.45, n=159), cough with breathlessness (HR 1.59 95% CI 1.28 to 1.98, n=177), neurological symptoms (HR 3.07, 95% CI 2.45 to 3.84, n=155) and other symptom combinations (HR 2.05, 95% CI 1.75 to 2.40, n=1963). --- Explanation: Weight loss is listed among presenting symptom groups in lung cancer.


MONDO:0005138

[PMID:29666219] [SUPPORT] Compared with the cough-alone symptom group, the risks of dying or HRs were significantly higher for the groups presenting with breathlessness (HR 1.86, 95% CI 1.54 to 2.24, n=359), systemic symptoms (HR 1.91, 95% CI 1.48 to 2.45, n=95), weight loss (HR 2.46, 95% CI 1.90 to 3.18, n=106), chest pain (HR 1.96, 95% CI 1.56 to 2.45, n=159), cough with breathlessness (HR 1.59 95% CI 1.28 to 1.98, n=177), neurological symptoms (HR 3.07, 95% CI 2.45 to 3.84, n=155) and other symptom combinations (HR 2.05, 95% CI 1.75 to 2.40, n=1963). --- Explanation: Chest pain is listed among presenting symptom groups in lung cancer.


MONDO:0005138

[PMID:26542886] [INDIRECT EVIDENCE] [SUPPORT] Vascular endothelial growth factor A (VEGFA) is one of the main mediators of angiogenesis in non-small cell lung cancer (NSCLC). --- Explanation: The abstract identifies VEGFA as a key mediator of angiogenesis in NSCLC.


MAXO:0000647

[PMID:19445746] [SUPPORT] Small cell lung cancer accounts for 20% of all cases, and is usually treated with chemotherapy. --- Explanation: The abstract states that small cell lung cancer is usually treated with chemotherapy.


MAXO:0000004

[PMID:19445746] [SUPPORT] Adenocarcinoma is the main non-small cell pathology, and is treated initially with surgery. --- Explanation: The abstract notes surgery as initial treatment for adenocarcinoma.


ECTO:6000029

[PMID:19445746] [SUPPORT] Lung cancer is the leading cause of cancer deaths in both men and women, with 80-90% of cases caused by smoking. --- Explanation: The abstract identifies smoking as the cause of most lung cancer cases.


MONDO:0019632

[PMID:33669940] [SUPPORT] Results: In total, 1005 patients were enrolled with the following prevalence of clinical syndromes: erythema migrans (EM), 945 (94.02%); Lyme arthritis, 32 (3.18%); neuroborreliosis, 23 (2.28%); Lyme carditis, 4 (0.39%); and acrodermatitis, 1 (0.09%). --- Explanation: Large Lithuanian cohort confirms erythema migrans as the dominant presentation.


MONDO:0019632

[PMID:33669940] [SUPPORT] Clinical symptoms were as follows: arthralgia (33.2%), general weakness (19%), head pain (13.1%), myalgia (11.2%), fever (6.2%), joint swelling (5.9%), head dizziness (5.1%), nervus facialis neuropathy (2.4%), and radiculitis (2.0%). --- Explanation: Population data list general weakness among frequent symptoms of Lyme disease.


MONDO:0019632

[PMID:33669940] [SUPPORT] Clinical symptoms were as follows: arthralgia (33.2%), general weakness (19%), head pain (13.1%), myalgia (11.2%), fever (6.2%), joint swelling (5.9%), head dizziness (5.1%), nervus facialis neuropathy (2.4%), and radiculitis (2.0%). --- Explanation: Arthralgia was reported in one-third of patients in a large endemic cohort.


MONDO:0019632

[PMID:33669940] [SUPPORT] The main symptoms were the following: nervus facialis neuropathy (47.8%), myalgia (39%), head pain (26%), and radiculitis (21%). --- Explanation: Neuroborreliosis cases frequently manifested facial nerve palsy.


MONDO:0019632

[PMID:33669940] [SUPPORT] Lyme arthritis mainly manifested among middle-aged women as an oligoarthritis, mostly affecting the knee joint. --- Explanation: Cohort study documents oligoarticular knee-predominant Lyme arthritis.


MONDO:0019632

[PMID:37234726] [SUPPORT] the most common clinical manifestation is AV block, which can be acute in onset and can rapidly progress to complete heart block. --- Explanation: Case report and review emphasize AV block as the hallmark of Lyme carditis.


MONDO:0019632

[PMID:30046879] [SUPPORT] Dementia-like syndromes are rare manifestations of Lyme neuroborreliosis... The response to 2-4 weeks of antibiotic treatment with ceftriaxone was excellent. --- Explanation: Review of definite neuroborreliosis cases shows dementia syndromes resolving after ceftriaxone.

[PMID:36740841] [SUPPORT] Lyme disease is an uncommon cause of reversible dementia... the brilliant clinical improvement after the appropriate antimicrobial therapy is strongly suggestive for a diagnosis of neuroborreliosis. --- Explanation: Geriatric case of reversible dementia with marked improvement after antimicrobial therapy.


MONDO:0019632

[PMID:33082765] [SUPPORT] We report a case of acute neuroborreliosis that manifested as extended isolated cervical myelitis. --- Explanation: Case report confirms Lyme-associated cervical myelitis with CSF pleocytosis and intrathecal Borrelia antibodies.


MONDO:0019632

[PMID:41133080] [SUPPORT] developed acquired epidermolysis bullosa (EBA) following an LD diagnosis. Initially, the patient presented with atypical erythema migrans, which later evolved into multiple bullous lesions --- Explanation: Case report documents bullous lesions evolving after Lyme disease.


MONDO:0019632

[PMID:33669940] [INDIRECT EVIDENCE] [SUPPORT] The clinical manifestations of Lyme disease range from a localized infection, for example, erythema migrans (EM) to a disseminated neurological or rheumatological infection, cardiac involvement, or even chronic disease. --- Explanation: Epidemiologic series shows Borrelia disseminates beyond skin to neurologic, rheumatologic, and cardiac sites.


MONDO:0019632


MONDO:0019632

[PMID:34786243] [INDIRECT EVIDENCE] [SUPPORT] long-term exposure of the host's immune system to spirochetes can contribute to the development of chronic autoimmune disease de novo. --- Explanation: Case review links persistent Borrelia exposure to downstream autoimmune disease.


MONDO:0019632

[PMID:37407232] [INDIRECT EVIDENCE] [SUPPORT] Aspiration of the left knee joint revealed a white cell count of 21.0×109/L (83% neutrophils) with negative Gram stain and culture. However, Lyme PCR was positive and accompanied by serologies consistent with Lyme arthritis. --- Explanation: Lyme arthritis joint fluid shows marked neutrophilic inflammation despite negative cultures, consistent with immune-driven damage.


MAXO:0000058

[PMID:17029130] [SUPPORT] Tables list the doses and durations of antimicrobial therapy recommended for treatment and prevention of Lyme disease --- Explanation: IDSA guidelines provide evidence-based antibiotic treatment recommendations for Lyme disease.


CHEBI:50845

[PMID:17029130] [INDIRECT EVIDENCE] [SUPPORT] Tables list the doses and durations of antimicrobial therapy recommended for treatment and prevention of Lyme disease --- Explanation: IDSA guidelines provide evidence-based antibiotic treatment recommendations for Lyme disease.


MAXO:0000058

[PMID:17176487] [SUPPORT] We describe a favorable outcome in a 42-year-old woman who developed Lyme disease in the third trimester and was treated with a full course of oral amoxicillin. --- Explanation: Case report in pregnancy shows successful treatment with amoxicillin.


CHEBI:2676

[PMID:17176487] [INDIRECT EVIDENCE] [SUPPORT] We describe a favorable outcome in a 42-year-old woman who developed Lyme disease in the third trimester and was treated with a full course of oral amoxicillin. --- Explanation: Case report in pregnancy shows successful treatment with amoxicillin.


MAXO:0000058

[PMID:37692616] [SUPPORT] The patient's symptoms resolved quickly with a four-day inpatient course of IV ceftriaxone followed by 10 days of oral doxycycline. --- Explanation: Neuroborreliosis case improved with intravenous ceftriaxone then doxycycline.


CHEBI:29007

[PMID:37692616] [INDIRECT EVIDENCE] [SUPPORT] The patient's symptoms resolved quickly with a four-day inpatient course of IV ceftriaxone followed by 10 days of oral doxycycline. --- Explanation: Neuroborreliosis case improved with intravenous ceftriaxone then doxycycline.


HGNC.SYMBOL:HLA-DR4


MONDO:0016075

[PMID:39739969] [SUPPORT] Chronic infections can develop into severe clinical manifestations, primarily lymphedema, hydrocoele, and elephantiasis. --- Explanation: Lymphedema is listed as a primary clinical manifestation.


MONDO:0016075

[PMID:39739969] [SUPPORT] Chronic infections can develop into severe clinical manifestations, primarily lymphedema, hydrocoele, and elephantiasis. --- Explanation: Hydrocoele is listed as a primary clinical manifestation.


MONDO:0016075

[PMID:21413271] [SUPPORT] Repeated, prolonged infection with these worms can lead to elephantiasis, a buildup of excess tissue in the affected area. --- Explanation: Elephantiasis represents severe chronic lymphedema driven by repeated infection.


MONDO:0016075

[PMID:21413271] [INDIRECT EVIDENCE] [SUPPORT] The adults of the lymphatic filariae inhabit lymph vessels, where blockage and host reaction can result in lymphatic inflammation and dysfunction, and eventually in lymphedema and fibrosis. --- Explanation: Adult worms in lymphatic vessels cause blockage, inflammation, dysfunction, and fibrosis.


MONDO:0016075

[PMID:39739969] [INDIRECT EVIDENCE] [SUPPORT] The adult parasites impact the integrity of lymphatic vessels and damage valves, leading to a remodeling of the lymphatic system and lymphatic dilation. --- Explanation: The abstract describes parasite-driven valve damage and lymphatic remodeling.


MAXO:0000058

[PMID:38933431] [SUPPORT] the World Health Organization recommended treatments for lymphatic filariasis include the use of Albendazole (400mg) twice per year in co-endemic areas with loa loa, Ivermectin (200mcg/kg) in combination with Albendazole (400mg) in areas that are co-endemic with onchocerciasis, ivermectin (200mcg/kg) with diethylcarbamazine citrate (DEC) (6mg/kg) and albendazole (400mg) in areas without onchocerciasis. --- Explanation: The abstract summarizes WHO-recommended antifilarial combinations for MDA.


CHEBI:16664

[PMID:38933431] [INDIRECT EVIDENCE] [SUPPORT] the World Health Organization recommended treatments for lymphatic filariasis include the use of Albendazole (400mg) twice per year in co-endemic areas with loa loa, Ivermectin (200mcg/kg) in combination with Albendazole (400mg) in areas that are co-endemic with onchocerciasis, ivermectin (200mcg/kg) with diethylcarbamazine citrate (DEC) (6mg/kg) and albendazole (400mg) in areas without onchocerciasis. --- Explanation: The abstract summarizes WHO-recommended antifilarial combinations for MDA.


CHEBI:6078


NCBITaxon:6293

[PMID:38933431] [SUPPORT] The major etiologic agent is a nematode called Wuchereria bancrofti, but Brugia malayi and Brugia timoriare sometimes encountered as causative agents. --- Explanation: The review identifies Wuchereria bancrofti as the major etiologic agent.


NCBITaxon:6279

[PMID:38933431] [SUPPORT] The major etiologic agent is a nematode called Wuchereria bancrofti, but Brugia malayi and Brugia timoriare sometimes encountered as causative agents. --- Explanation: The review lists Brugia malayi as a causative agent.


NCBITaxon:42155

[PMID:38933431] [SUPPORT] The major etiologic agent is a nematode called Wuchereria bancrofti, but Brugia malayi and Brugia timoriare sometimes encountered as causative agents. --- Explanation: The review lists Brugia timori as a causative agent.


MONDO:0005062

[PMID:32433447] [PARTIAL] Hodgkin lymphoma classically presents as lymphadenopathy with contiguous spread with or without associated B symptoms including night sweats, weight loss, and fever. --- Explanation: Lymphadenopathy is a classic presenting feature of lymphoma.


MONDO:0005062

[PMID:32433447] [PARTIAL] Hodgkin lymphoma classically presents as lymphadenopathy with contiguous spread with or without associated B symptoms including night sweats, weight loss, and fever. --- Explanation: Fever is listed among B symptoms in lymphoma presentations.


MONDO:0005062

[PMID:32433447] [PARTIAL] Hodgkin lymphoma classically presents as lymphadenopathy with contiguous spread with or without associated B symptoms including night sweats, weight loss, and fever. --- Explanation: Night sweats are listed among B symptoms in lymphoma presentations.


MONDO:0005062

[PMID:32433447] [PARTIAL] Hodgkin lymphoma classically presents as lymphadenopathy with contiguous spread with or without associated B symptoms including night sweats, weight loss, and fever. --- Explanation: Weight loss is listed among B symptoms in lymphoma presentations.


MONDO:0005062

[PMID:15618006] [INDIRECT EVIDENCE] [SUPPORT] HRS cells in nearly all cases of HL derive from B cells, and only rarely from T cells. --- Explanation: The abstract states that Hodgkin/Reed-Sternberg cells are derived from B cells.


MAXO:0000647

[PMID:31894937] [SUPPORT] Chemotherapy treatment plans differ between the main subtypes of lymphoma. Non-Hodgkin lymphoma is treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab (R-CHOP), bendamustine, and lenalidomide. --- Explanation: The abstract notes chemotherapy regimens as treatment for lymphoma subtypes.


MAXO:0000014

[PMID:31894937] [SUPPORT] Hodgkin lymphoma is treated with combined chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), Stanford V (a chemotherapy regimen consisting of mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone), or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) with radiotherapy. --- Explanation: The abstract states Hodgkin lymphoma treatment includes radiotherapy with chemotherapy.


MONDO:0005835

[PMID:37088804] [PARTIAL] Some patients with Lynch syndrome (LS) have extreme phenotypes, i.e. cancer before the recommended screening age, or cancer for which there are no screening guidelines. --- Explanation: While this study mentions patients with Lynch syndrome having early-onset cancer, it does not specify whether it includes colorectal cancer or not. It partially supports the statement on phenotypes.

[PMID:16136388] [SUPPORT] The major aim of surveillance in Lynch syndrome is to diagnose malignant or premalignant lesions at the asymptomatic stage by regular checkups, particularly in the large bowel. --- Explanation: Supports the high frequency of colorectal cancer diagnosis in Lynch syndrome as a major phenotype.

[PMID:29071502] [SUPPORT] Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer... --- Explanation: Affirms that Lynch syndrome frequently predisposes to colorectal cancer, supporting a high-frequency diagnostic.

[PMID:23681793] [SUPPORT] Lynch syndrome (LS), one of the most frequent forms of hereditary colorectal cancer (CRC)... --- Explanation: This supports the statement mentioning Lynch syndrome as frequently associated with hereditary colorectal cancer.

[PMID:34798988] [SUPPORT] Lynch syndrome (LS) is a common form of inherited cancer susceptibility, which predisposes to colorectal cancer (CRC)... --- Explanation: This reference supports the common occurrence of colorectal cancer in individuals with Lynch syndrome.

[PMID:36031446] [SUPPORT] Lynch syndrome is associated with the most common form of heritable bowel cancer. --- Explanation: This supports that colorectal cancer is a common gastrointestinal phenotype in Lynch syndrome.

[PMID:26974895] [SUPPORT] Lynch syndrome accounts for roughly 1 of every 35 patients with colorectal carcinoma, making it the most common hereditary form of colorectal carcinoma. --- Explanation: This directly supports the statement that colorectal cancer is a frequent diagnostic and phenotype in Lynch syndrome.

[PMID:21325953] [SUPPORT] Individuals with Lynch syndrome have an increased risk for colorectal cancer... --- Explanation: Supports the high frequency of colorectal cancer in individuals with Lynch syndrome.

[PMID:35306248] [SUPPORT] Lynch Syndrome carriers are at increased lifetime risk of developing certain cancers, such as colorectal and endometrial. --- Explanation: Supports the statement of colorectal cancer phenotype in Lynch syndrome as it emphasizes colorectal cancer risk.


MONDO:0005835

[PMID:28376523] [SUPPORT] The clinical characteristics of Lynch-associated endometrial cancer and screening and risk-reducing strategies also are described. --- Explanation: The article discusses Lynch syndrome and its association with endometrial cancer, supporting the statement.

[PMID:23681793] [SUPPORT] Carriers of MMR defects have a strongly increased risk of developing CRC and endometrial cancer. --- Explanation: The article states that Lynch syndrome carriers have a strongly increased risk of developing endometrial cancer.

[PMID:29071502] [SUPPORT] Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer as well as predisposing to a number of extracolonic cancers, most prominently endometrial cancer. --- Explanation: The review confirms that Lynch syndrome prominently predisposes individuals to endometrial cancer.

[PMID:37728516] [SUPPORT] Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. --- Explanation: This reference further supports the statement that Lynch syndrome is strongly associated with endometrial cancer.


MONDO:0005835

[PMID:31319185] [SUPPORT] Lynch syndrome is the most common inherited cause of gastrointestinal cancer and increases risk for a variety of malignancies, including gastric cancer. --- Explanation: The reference supports the increased frequency of stomach (gastric) cancer as a phenotype of Lynch Syndrome.

[PMID:27546846] [PARTIAL] Approximately 5% arise from germline mutations in genes associated with cancer predisposition. --- Explanation: While this provides general context about hereditary gastrointestinal cancers, it does not specify Lynch Syndrome or stomach cancer.


MONDO:0005835

[PMID:31615790] [SUPPORT] Lynch syndrome confers markedly increased risks of various malignancies, including urinary tract cancers (UTC; renal pelvis, ureter, bladder, and possibly kidney cancers). --- Explanation: This large cohort supports urinary tract cancer as a recognized Lynch-associated malignancy and informs clinical risk stratification.

[PMID:21419447] [SUPPORT] Patients with Lynch syndrome are much more likely to have generally rare upper urinary tract urothelial carcinoma but not bladder urothelial carcinoma. --- Explanation: The literature supports the occurrence of upper urinary tract cancer (urothelial carcinoma) in patients with Lynch syndrome, which includes transitional cell carcinoma of the ureter or renal pelvis.

[PMID:34798988] [SUPPORT] Lynch syndrome (LS) is a common form of inherited cancer susceptibility, which predisposes to colorectal cancer (CRC) along with a wide array of other extracolonic malignancies, including other gastrointestinal cancers, cancers of the gynecologic and genitourinary tracts, and other organ sites. --- Explanation: The literature confirms that Lynch syndrome is associated with cancers of the genitourinary tract, which includes urinary tract cancer.

[PMID:23700068] [SUPPORT] Urinary tract cancers (UTC) have in many studies been reported increased in LS and it has been discussed among researchers and clinicians whether or not screening for urological tumours should be included in the surveillance programme. --- Explanation: This review supports the elevated UTC burden and the relevance of LS-specific surveillance.

[PMID:15962502] [SUPPORT] Transitional cell carcinomas of the upper urinary tract (UUT-TCCs) are rare: they account for approximately 5% of all urothelial carcinomas. ... UUT-TCC occurs in 5% of patients with HNPCC. --- Explanation: The literature indicates that transitional cell carcinomas of the upper urinary tract are rare but occur in patients with Lynch syndrome (HNPCC), supporting the statement.


MONDO:0005835

[PMID:35435397] [SUPPORT] There is an increased predisposition to cancers in the endometrium, colon, stomach, ovary, uterus, skin, kidney, and brain in patients of Lynch syndrome. --- Explanation: This reference supports the association between Lynch Syndrome and ovarian cancer.


MONDO:0005835

[PMID:25427047] [SUPPORT] Muir-Torre syndrome (MTS) is a rare autosomal-dominant genodermatosis characterized by sebaceous neoplasms and one or more visceral malignancies. Sebaceous tumors include sebaceous adenoma and carcinoma, which may be solitary or multiple. --- Explanation: The reference confirms that sebaceous adenomas are a part of the dermatologic manifestations in the Muir-Torre variant of Lynch syndrome.

[PMID:34023105] [SUPPORT] Sebaceous adenoma, sebaceoma, and a subset of cutaneous SC are frequently associated with defective DNA mismatch repair resulting from mutations in MLH1, MSH2, or MSH6. These tumors can be sporadic or associated with Muir-Torre syndrome. --- Explanation: The reference supports the association of sebaceous adenomas with Lynch syndrome, particularly in the context of Muir-Torre syndrome.

[PMID:36418753] [SUPPORT] The main skin lesions were: Sebaceous adenomas (43%), sebaceous carcinomas (27%), keratoacanthomas (16%), sebaceomas (13%), squamous cell carcinomas (23%), and basal cell carcinomas (10%). --- Explanation: This systematic review confirms sebaceous adenoma as a common cutaneous Lynch-associated manifestation.


MONDO:0005835

[PMID:19466295] [INDIRECT EVIDENCE] [SUPPORT] Lynch syndrome represents 1-7% of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in deoxyribonucleic acid (DNA) mismatch repair genes. --- Explanation: This reference confirms that Lynch Syndrome involves mutations in mismatch repair genes.

[PMID:29233924] [INDIRECT EVIDENCE] [SUPPORT] Many mutations first arise as DNA replication errors. These errors subsequently evade correction by cellular DNA repair, for example, by the well-known DNA mismatch repair (MMR) mechanism. --- Explanation: This supports the notion that DNA mismatch repair is crucial in correcting DNA replication errors, and its deficiency leads to the accumulation of these errors.

[PMID:34919656] [INDIRECT EVIDENCE] [SUPPORT] Lynch syndrome (LS, OMIM #120435) is caused by an inherited heterozygous defect in any of the four core DNA mismatch repair (MMR) genes MSH2, MSH6, MLH1 or PMS2... --- Explanation: Clear evidence linking inherited defects in mismatch repair genes to Lynch Syndrome.

[PMID:24443998] [INDIRECT EVIDENCE] [SUPPORT] Inherited defects in the DNA mismatch repair (MMR) system, MLH1, MSH2, MSH6, and PMS2 genes, underlie Lynch syndrome, one of the most prevalent cancer syndromes in man. --- Explanation: Validates that Lynch Syndrome is underpinned by mutations in specific mismatch repair genes.


MONDO:0005835


MONDO:0005835

[PMID:25701956] [INDIRECT EVIDENCE] [SUPPORT] Deficient DNA mismatch repair (MMR) results in a strong mutator phenotype known as microsatellite instability (MSI), which is a hallmark of Lynch syndrome-associated cancers. --- Explanation: The snippet confirms that defective mismatch repair causes microsatellite instability, supporting the statement.

[PMID:35315099] [INDIRECT EVIDENCE] [SUPPORT] LS tumours are characterised by unique pathogenesis, ultimately resulting in hypermutation, microsatellite instability and high immunogenicity that has significant implications for cancer risk, clinical presentation, treatment and surveillance. --- Explanation: The statement is supported by the evidence that Lynch Syndrome leads to microsatellite instability due to defective mismatch repair.

[PMID:31273487] [INDIRECT EVIDENCE] [SUPPORT] Lynch syndrome is a state of mismatch repair deficiency due to a monoallelic abnormality of any mismatch repair genes. The phenotype indicating the mismatch repair deficiency can be frequently shown as a microsatellite instability in tumors. --- Explanation: This reference supports the statement by linking mismatch repair deficiency and microsatellite instability in Lynch Syndrome.

[PMID:38466935] [INDIRECT EVIDENCE] [SUPPORT] Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair genes, which lead to high microsatellite instability and frameshift mutations at coding mononucleotide repeats in the genome. --- Explanation: The snippet supports the statement by describing how defective mismatch repair in Lynch syndrome leads to microsatellite instability.


MONDO:0005835

[PMID:37478804] [INDIRECT EVIDENCE] [SUPPORT] Lynch Syndrome (LS) is one of the most common hereditary cancer syndromes, and is caused by mutations in one of the four DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6 and PMS2. --- Explanation: This further supports the fact that accumulation of mutations in key genes (MMR genes) in Lynch Syndrome contributes to an increased risk of developing certain cancers.

[PMID:23604856] [INDIRECT EVIDENCE] [SUPPORT] Lynch Syndrome, or hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by inactivating mutations in DNA mismatch repair genes. --- Explanation: This supports the idea that the mechanism of Lynch Syndrome involves the accumulation of mutations in key genes leading to cancer.


MONDO:0005835

[PMID:34630437] [INDIRECT EVIDENCE] [SUPPORT] We and others have characterized a subset of MSI-H associated highly recurrent frameshift mutations that yield shared immunogenic neoantigens. --- Explanation: This directly supports neoantigen generation from recurrent frameshift events in mismatch repair-deficient, MSI-high tumors seen in Lynch syndrome.

[PMID:35315099] [INDIRECT EVIDENCE] [SUPPORT] LS tumours are characterised by unique pathogenesis, ultimately resulting in hypermutation, microsatellite instability and high immunogenicity that has significant implications for cancer risk, clinical presentation, treatment and surveillance. --- Explanation: This supports the immunogenic tumor microenvironment and immune activation component of this mechanism.


MONDO:0005835

[PMID:37625240] [INDIRECT EVIDENCE] [SUPPORT] PD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs, but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC. --- Explanation: This human clinical observation supports mechanistic sensitivity of dMMR/MSI Lynch tumors to immune checkpoint blockade.

[PMID:37845474] [INDIRECT EVIDENCE] [PARTIAL] Metastatic and localized mismatch repair-deficient (dMMR) tumors are exquisitely sensitive to immune checkpoint blockade (ICB). --- Explanation: This supports high treatment sensitivity in dMMR states while also indicating that surveillance remains necessary.


MAXO:0000004

[PMID:21287222] [SUPPORT] Patients who are gene mutation carriers should receive counseling about colectomy, and if women, prophylactic hysterectomy and bilateral oophorectomy. --- Explanation: The literature mentions counseling carriers about colectomy and prophylactic hysterectomy with bilateral oophorectomy, supporting that preventive removal of the colon, uterus, or ovaries may be considered.

[PMID:24495259] [SUPPORT] Prophylactic hysterectomy with bilateral salpingo-oophorectomy is being increasingly undertaken in patients with Lynch syndrome (LS). --- Explanation: The literature indicates that prophylactic hysterectomy with bilateral salpingo-oophorectomy is a preventive measure undertaken in Lynch syndrome patients.

[PMID:31554630] [SUPPORT] for women with Lynch syndrome, the risks for gynecologic cancers pose an equal or greater risk than colorectal cancer. --- Explanation: The literature outlines the significant risk of gynecologic cancers in women with Lynch syndrome, supporting the consideration of prophylactic surgery.

[PMID:27241104] [SUPPORT] This review discusses the rationales and relative merits of current Lynch syndrome screening tests for endometrial and ovarian cancers. --- Explanation: The discussion of screening tests implies the consideration of proactive measures, including prophylactic surgery, in managing the elevated cancer risks in Lynch syndrome.


MAXO:0000058

[PMID:35328014] [SUPPORT] Nonsteroidal anti-inflammatory drugs and, in particular, aspirin use, has been associated with reduced CRC risk in several studies... --- Explanation: This study affirms that aspirin and other NSAIDs have been linked to a reduced risk of colorectal cancer in Lynch syndrome patients.

[PMID:11854387] [PARTIAL] Numerous experimental, epidemiologic, and clinical studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the highly selective cyclooxygenase (COX)-2 inhibitors, have promise as anticancer agents... --- Explanation: The study indicates a potential for NSAIDs in cancer prevention, including colorectal cancer, but notes that unresolved questions about safety and efficacy limit clinical application.

[PMID:36202092] [SUPPORT] ...multiple pharmacological, clinical, and epidemiologic studies suggest that aspirin can prevent certain cancers... --- Explanation: This study supports the role of aspirin in cancer prevention, including colorectal cancer, though mentions variable effects depending on the tissue and disease context.

[PMID:34798982] [SUPPORT] Secondary prevention of colorectal neoplasia with chemoprevention is long-studied area of research and clinical use in patients with the 2 most common hereditary colorectal cancer syndromes including Lynch syndrome and familial adenomatous polyposis --- Explanation: This study notes the history and research supporting chemoprevention, including with NSAIDs, for hereditary colorectal cancer syndromes like Lynch syndrome.


CHEBI:15365

[PMID:35328014] [INDIRECT EVIDENCE] [SUPPORT] Nonsteroidal anti-inflammatory drugs and, in particular, aspirin use, has been associated with reduced CRC risk in several studies... --- Explanation: This study affirms that aspirin and other NSAIDs have been linked to a reduced risk of colorectal cancer in Lynch syndrome patients.

[PMID:11854387] [INDIRECT EVIDENCE] [PARTIAL] Numerous experimental, epidemiologic, and clinical studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the highly selective cyclooxygenase (COX)-2 inhibitors, have promise as anticancer agents... --- Explanation: The study indicates a potential for NSAIDs in cancer prevention, including colorectal cancer, but notes that unresolved questions about safety and efficacy limit clinical application.

[PMID:36202092] [INDIRECT EVIDENCE] [SUPPORT] ...multiple pharmacological, clinical, and epidemiologic studies suggest that aspirin can prevent certain cancers... --- Explanation: This study supports the role of aspirin in cancer prevention, including colorectal cancer, though mentions variable effects depending on the tissue and disease context.

[PMID:34798982] [INDIRECT EVIDENCE] [SUPPORT] Secondary prevention of colorectal neoplasia with chemoprevention is long-studied area of research and clinical use in patients with the 2 most common hereditary colorectal cancer syndromes including Lynch syndrome and familial adenomatous polyposis --- Explanation: This study notes the history and research supporting chemoprevention, including with NSAIDs, for hereditary colorectal cancer syndromes like Lynch syndrome.


MAXO:0000058

[PMID:37625240] [SUPPORT] PD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs, but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC. --- Explanation: This study demonstrates the efficacy of PD-1 inhibitors, a type of immune checkpoint inhibitor, for treating Lynch syndrome (LS) patients with colorectal cancers characterized by deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H).

[PMID:34224739] [SUPPORT] We identified 4 shared FSP neoantigens ... Using VCMsh2 mice, which have a conditional knockout of Msh2 in the intestinal tract and develop intestinal cancer, we showed vaccination with a combination of only 4 FSPs significantly increased FSP-specific adaptive immunity, reduced intestinal tumor burden, and prolonged overall survival. --- Explanation: This study indicates that immunotherapies, specifically FSP neoantigen vaccines, can be effective in reducing the tumor burden and improving survival in Lynch syndrome mouse models.

[PMID:30027543] [SUPPORT] Immunotherapies are an active field of research for MSI cancers and their potential use for cancer therapy for both sporadic and LS MSI cancers is discussed. --- Explanation: This reference discusses ongoing research into immunotherapies for MSI cancers, including those associated with Lynch syndrome.

[PMID:37845474] [PARTIAL] Metastatic and localized mismatch repair-deficient (dMMR) tumors are exquisitely sensitive to immune checkpoint blockade (ICB). --- Explanation: While ICB is effective for treating dMMR tumors in Lynch syndrome patients, it does not eliminate the risk of new neoplasia development, highlighting the need for continued surveillance.


HGNC.SYMBOL:MLH1

[PMID:28038733] [SUPPORT] Lynch syndrome is due to germline mutations in mismatch repair genes: MLH1, MSH2, MSH6 and PMS2. --- Explanation: The reference directly indicates that Lynch syndrome is caused by germline mutations in the MLH1 gene among others.

[PMID:26886015] [SUPPORT] Constitutional epimutation of the DNA mismatch repair gene, MLH1, represents a minor cause of Lynch syndrome. --- Explanation: While the term 'epimutation' is used, it is within the context of the DNA mismatch repair gene MLH1 being a cause of Lynch syndrome.


HGNC.SYMBOL:MSH2

[PMID:29345684] [PARTIAL] Our data demonstrate that two LS genes, MSH6 and PMS2, are associated with an increased risk for breast cancer... --- Explanation: While the MSH2 gene is mentioned, the research did not find a statistically significant association between MSH2 and breast cancer risk.

[PMID:25430799] [SUPPORT] Sixty-seven (59%) families had mutations in MSH2... --- Explanation: This study reports a significant proportion of Lynch syndrome families with mutations in MSH2.


HGNC.SYMBOL:MSH6

[PMID:20028993] [SUPPORT] Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. --- Explanation: The study explicitly states that germline mutations in MSH6 are associated with Lynch Syndrome cancers.

[PMID:28038733] [SUPPORT] Lynch syndrome is due to germline mutations in mismatch repair genes: MLH1, MSH2, MSH6 and PMS2. --- Explanation: The study identifies germline mutations in MSH6 as a cause of Lynch Syndrome.

[PMID:33516942] [SUPPORT] A MSH6 3'UTR variant (c.*23_26dup) was found in 13 unrelated families consulted for Lynch/Muir-Torre Syndrome. --- Explanation: The study highlights that a specific variant of MSH6 is associated with families affected by Lynch Syndrome.

[PMID:25430799] [SUPPORT] Sixty-seven (59%) families had mutations in MSH2, 20 (18%) in MSH6, 19 (17%) in MLH1 and 7 (6%) in PMS2. --- Explanation: The study identifies families with Lynch Syndrome who have mutations in the MSH6 gene.

[PMID:33094597] [SUPPORT] Genetic analysis turned out positive for biallelic MSH6 mutations in the two girls, leading to CMMRD syndrome diagnosis. Both parents and two out of three alive siblings were diagnosed with Lynch syndrome. --- Explanation: This informs about Lynch Syndrome diagnosis in individuals with MSH6 mutations.


HGNC.SYMBOL:PMS2

[PMID:18602922] [SUPPORT] PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. --- Explanation: This study confirms that germline mutations in PMS2 are associated with Lynch syndrome.

[PMID:24027009] [SUPPORT] Lynch syndrome (LS) is a common cancer predisposition caused by an inactivating mutation in one of four DNA mismatch repair (MMR) genes. Frequently a variant of uncertain significance (VUS), rather than an obviously pathogenic mutation, is identified in one of these genes. The inability to define pathogenicity of such variants precludes targeted healthcare. --- Explanation: The study discusses analyzing VUS in the MMR gene PMS2 for functional activity, indicating the association of PMS2 germline mutations with Lynch syndrome.

[PMID:37072247] [SUPPORT] As a result of our analysis, we managed to identify a mutation in the PMS2 gene in one patient's breast tumor tissue. The presence of this mutation indicates that the resulting cancer may be a consequence of LS. --- Explanation: This study identifies a mutation of the PMS2 gene associated with Lynch syndrome, supporting the genetic association.

[PMID:25430799] [SUPPORT] We identified 54 different mutations; 13 of them are novel... Seven founder mutations were detected in 61/113 (54%) families... Gene distribution in the Israeli population is unique...7 (6%) in PMS2. --- Explanation: PMS2 is one of the genes where germline mutations have been identified as causing Lynch syndrome.