MONDO:0009290

[PMID:39020349] [SUPPORT] Functional tests revealed motor development delay, generalized hypotonia, and positive anti-recombinant human acid alpha-glucosidase IgG antibody titers --- Explanation: Castellar-Leones et al. case report documents motor development delay as a feature of early-onset Pompe disease.


MONDO:0009290

[PMID:32745073] [INDIRECT EVIDENCE] [SUPPORT] GAA catalyzes the hydrolysis of α-1,4 and α-1,6-glucosidic bonds of glycogen and its deficiency leads to lysosomal storage of glycogen in several tissues, particularly in muscle. --- Explanation: Taverna et al. review confirms that GAA deficiency leads to lysosomal glycogen storage predominantly in muscle tissue.

[PMID:18929906] [INDIRECT EVIDENCE] [SUPPORT] acid alpha-glucosidase deficiency leading to lysosomal glycogen storage --- Explanation: The Lancet review establishes the core pathogenic mechanism of GAA deficiency causing lysosomal glycogen accumulation.


MONDO:0009290


MONDO:0009290

[PMID:20040311] [INDIRECT EVIDENCE] [SUPPORT] In the GAA-knockout mouse model, progressive accumulation of autophagic vesicles is restricted to Type II-rich muscle fibers. Not only does this build-up of autophagosomes disrupt the contractile apparatus in the muscle fibers, it also interferes with enzyme replacement therapy by acting as a sink for the recombinant enzyme and preventing its efficient delivery to the lysosomes. --- Explanation: Shea and Raben demonstrated in GAA-knockout mice that autophagic buildup disrupts muscle architecture and impairs ERT efficacy by preventing enzyme delivery to lysosomes.

[PMID:38785980] [INDIRECT EVIDENCE] [SUPPORT] In this review, we discuss the basics of autophagy and describe its involvement in the pathogenesis of muscle damage in Pompe disease. --- Explanation: Do, Meena, and Raben review confirms the role of autophagy failure in the pathogenesis of muscle damage in Pompe disease.


MAXO:0000058

[PMID:17151339] [SUPPORT] All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. --- Explanation: The landmark Kishnani et al. clinical trial demonstrated that rhGAA ERT reduced risk of death by 99% in infantile-onset Pompe disease compared to untreated historical controls.

[PMID:20393176] [SUPPORT] At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). --- Explanation: The van der Ploeg et al. NEJM randomized controlled trial showed that alglucosidase alfa significantly improved walking distance and stabilized pulmonary function in late-onset Pompe disease.

[PMID:34800399] [SUPPORT] We consider that this study provides evidence of clinically meaningful improvement with avalglucosidase alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported. --- Explanation: The COMET phase 3 trial demonstrated that avalglucosidase alfa provided clinically meaningful improvements in respiratory function over alglucosidase alfa in late-onset Pompe disease.


MAXO:0000950


MAXO:0000011


MAXO:0000088


HGNC.SYMBOL:GAA gene mutations

[PMID:32745073] [SUPPORT] Currently, more than 560 mutations spread throughout GAA gene have been reported. --- Explanation: Taverna et al. review confirms the large number of pathogenic variants reported in the GAA gene.


MONDO:0009290

[PMID:18929906] [SUPPORT] It is a pan-ethnic autosomal recessive trait characterised by acid alpha-glucosidase deficiency leading to lysosomal glycogen storage. --- Explanation: The Lancet review by van der Ploeg and Reuser establishes Pompe disease as an autosomal recessive trait.


MONDO:0011479

[PMID:31412221] [SUPPORT] Postural orthostatic tachycardia syndrome (POTS) is a clinically heterogeneous disorder with multiple contributing pathophysiologic mechanisms manifesting as symptoms of orthostatic intolerance in the setting of orthostatic tachycardia (increase in heart rate by at least 30 beats per minute upon assuming an upright position) without orthostatic hypotension. --- Explanation: Defines the diagnostic criterion of 30 bpm heart rate increase upon standing without orthostatic hypotension.


MONDO:0011479

[PMID:30372565] [SUPPORT] The most common complaints are dizziness, weakness, rapid heartbeat and palpitation on standing. --- Explanation: Identifies palpitations as one of the most common complaints in POTS patients.


MONDO:0011479

[PMID:30372565] [SUPPORT] The most common complaints are dizziness, weakness, rapid heartbeat and palpitation on standing. --- Explanation: Identifies dizziness as one of the most common complaints in POTS patients.


MONDO:0011479

[PMID:36055438] [SUPPORT] Postural Orthostatic Tachycardia Syndrome (POTS) is a variant of autonomic cardiovascular disorder characterized by an excessive increase in heart rate upon standing associated with light-headedness, headaches, chest pain, shortness of breath, and brain fog. --- Explanation: Identifies brain fog as a characteristic symptom of POTS.


MONDO:0011479

[PMID:30372565] [SUPPORT] patients often report physical deconditioning and reduced exercise capacity as well as headache, 'brain fog', dyspnoea, gastrointestinal disorders and musculoskeletal pain. --- Explanation: Identifies headache as a commonly reported symptom in POTS.


MONDO:0011479

[PMID:31495251] [SUPPORT] Our patients had a multitude of comorbidities, were predominantly young females, and reported viral-like symptoms preceding episodes of syncope. --- Explanation: Reports syncope episodes in POTS patients.


MONDO:0011479

[PMID:34144933] [SUPPORT] Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. --- Explanation: NIH expert consensus identifies fatigue as a typical symptom of POTS.


MONDO:0011479

[PMID:34144933] [SUPPORT] Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. --- Explanation: NIH expert consensus identifies exercise intolerance as a typical symptom of POTS.

[PMID:30372565] [SUPPORT] patients often report physical deconditioning and reduced exercise capacity --- Explanation: Confirms reduced exercise capacity as a commonly reported feature of POTS.


MONDO:0011479

[PMID:34144933] [PARTIAL] Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. --- Explanation: The abstract mentions gastrointestinal distress broadly, which includes nausea, but does not specifically name nausea.


MONDO:0011479

[PMID:36055438] [SUPPORT] Postural Orthostatic Tachycardia Syndrome (POTS) is a variant of autonomic cardiovascular disorder characterized by an excessive increase in heart rate upon standing associated with light-headedness, headaches, chest pain, shortness of breath, and brain fog. --- Explanation: Lists shortness of breath as a characteristic symptom of POTS.


MONDO:0011479

[PMID:36055438] [SUPPORT] Postural Orthostatic Tachycardia Syndrome (POTS) is a variant of autonomic cardiovascular disorder characterized by an excessive increase in heart rate upon standing associated with light-headedness, headaches, chest pain, shortness of breath, and brain fog. --- Explanation: Lists chest pain as a characteristic associated symptom of POTS.


MONDO:0011479


MONDO:0011479

[PMID:30372565] [SUPPORT] The aetiology of POTS is largely unknown and three main hypotheses include an autoimmune disorder, abnormally increased sympathetic activity and catecholamine excess, and sympathetic denervation leading to central hypovolaemia and reflex tachycardia. --- Explanation: Describes the three main hypothesized autonomic mechanisms underlying POTS.


MONDO:0011479

[PMID:36055438] [INDIRECT EVIDENCE] [SUPPORT] The 3 major hypotheses about the pathophysiology of POTS are autoimmunity, abnormally increased sympathetic activity, and sympathetic denervation leading to central hypovolemia and reflex tachycardia. --- Explanation: Identifies sympathetic denervation as a major pathophysiology hypothesis in POTS.

[PMID:24647968] [INDIRECT EVIDENCE] [SUPPORT] A subset of neuropathic POTS patients may harbor mild small fiber neuropathy with abnormalities of unmyelinated nerve fibers in the skin associated with reduced myocardial postganglionic sympathetic innervation. --- Explanation: Demonstrates sympathetic denervation affecting both skin nerve fibers and cardiac postganglionic sympathetic innervation.


MONDO:0011479

[PMID:30001836] [INDIRECT EVIDENCE] [SUPPORT] Recent research has demonstrated that cardiovascular deconditioning (i.e., cardiac atrophy and hypovolemia) contributes significantly to the Postural Orthostatic Tachycardia Syndrome (POTS) and its functional disability. --- Explanation: Establishes that hypovolemia and cardiac atrophy contribute to reduced preload and the POTS phenotype.

[PMID:31412221] [INDIRECT EVIDENCE] [SUPPORT] Stockings, abdominal binders, and vasoconstrictors are used to enhance venous return in partial neuropathic POTS. --- Explanation: Treatments targeting venous pooling confirm its role in the pathophysiology.


MONDO:0011479

[PMID:30372565] [INDIRECT EVIDENCE] [SUPPORT] Postural orthostatic tachycardia syndrome (POTS) is a variant of cardiovascular autonomic disorder characterized by an excessive heart rate increase on standing and orthostatic intolerance. --- Explanation: Defines POTS as characterized by excessive heart rate increase on standing.

[PMID:34144933] [INDIRECT EVIDENCE] [SUPPORT] A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted. --- Explanation: NIH expert consensus confirms the tachycardia response involves multiple contributing pathophysiologic mechanisms.


MONDO:0011479

[PMID:30372565] [INDIRECT EVIDENCE] [SUPPORT] The aetiology of POTS is largely unknown and three main hypotheses include an autoimmune disorder, abnormally increased sympathetic activity and catecholamine excess, and sympathetic denervation leading to central hypovolaemia and reflex tachycardia. --- Explanation: Identifies abnormally increased sympathetic activity and catecholamine excess as a main pathophysiological hypothesis in POTS.

[PMID:19687359] [INDIRECT EVIDENCE] [SUPPORT] Postural tachycardia syndrome (POTS) induces disabling chronic orthostatic intolerance with an excessive increase in heart rate on standing. --- Explanation: Describes the excessive heart rate increase characteristic of POTS.


MONDO:0011479

[PMID:31495251] [INDIRECT EVIDENCE] [SUPPORT] We detected a significant number of patients with elevated levels of autoantibodies against the adrenergic alpha 1 receptor (89%) and against the muscarinic acetylcholine M4 receptor (53%). --- Explanation: Demonstrates elevated G-protein coupled receptor autoantibodies in POTS patients, supporting an autoimmune mechanism involving B cell-produced autoantibodies.


MONDO:0011479

[PMID:30001836] [INDIRECT EVIDENCE] [SUPPORT] Recent research has demonstrated that cardiovascular deconditioning (i.e., cardiac atrophy and hypovolemia) contributes significantly to the Postural Orthostatic Tachycardia Syndrome (POTS) and its functional disability. --- Explanation: Establishes cardiovascular deconditioning as a significant contributor to POTS pathophysiology and disability.


MAXO:0000011

[PMID:30001836] [SUPPORT] physical reconditioning with exercise training and volume expansion via increased salt and fluid intake should be initiated early in the course of treatment for patients with POTS if possible. The use of horizontal exercise (e.g., rowing, swimming, recumbent bike, etc.) at the beginning is a critical strategy, allowing patients to exercise while avoiding the upright posture that elicits their POTS symptoms. --- Explanation: Describes the rationale and approach for graded exercise training as a primary treatment for POTS.


MAXO:0000088

[PMID:30001836] [SUPPORT] physical reconditioning with exercise training and volume expansion via increased salt and fluid intake should be initiated early in the course of treatment for patients with POTS if possible. --- Explanation: Recommends volume expansion via salt and fluid intake as an early intervention in POTS treatment.

[PMID:34144933] [SUPPORT] Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. --- Explanation: NIH expert consensus confirms non-pharmacologic treatments as first-line management.


MAXO:0000058

[PMID:19687359] [SUPPORT] Low-dose oral propranolol significantly attenuated tachycardia and improved symptoms in POTS. Higher-dose propranolol did not further improve, and may worsen, symptoms. --- Explanation: Randomized crossover trial demonstrating that low-dose propranolol improves POTS symptoms while higher doses may be counterproductive.

[PMID:23616163] [SUPPORT] Low-dose propranolol improved VO2max in patients with POTS (24.5 +/- 0.7 placebo vs 27.6 +/- 1.0 mL/min/kg propranolol; p = 0.024), but not healthy subjects. --- Explanation: Randomized study showing low-dose propranolol improved exercise capacity in POTS patients.


CHEBI:8499

[PMID:19687359] [INDIRECT EVIDENCE] [SUPPORT] Low-dose oral propranolol significantly attenuated tachycardia and improved symptoms in POTS. Higher-dose propranolol did not further improve, and may worsen, symptoms. --- Explanation: Randomized crossover trial demonstrating that low-dose propranolol improves POTS symptoms while higher doses may be counterproductive.

[PMID:23616163] [INDIRECT EVIDENCE] [SUPPORT] Low-dose propranolol improved VO2max in patients with POTS (24.5 +/- 0.7 placebo vs 27.6 +/- 1.0 mL/min/kg propranolol; p = 0.024), but not healthy subjects. --- Explanation: Randomized study showing low-dose propranolol improved exercise capacity in POTS patients.


MAXO:0000058

[PMID:31412221] [PARTIAL] Stockings, abdominal binders, and vasoconstrictors are used to enhance venous return in partial neuropathic POTS. --- Explanation: Mentions vasoconstrictors generically for neuropathic POTS but does not specifically name midodrine.


CHEBI:6933

[PMID:31412221] [INDIRECT EVIDENCE] [PARTIAL] Stockings, abdominal binders, and vasoconstrictors are used to enhance venous return in partial neuropathic POTS. --- Explanation: Mentions vasoconstrictors generically for neuropathic POTS but does not specifically name midodrine.


MAXO:0000058

[PMID:31412221] [PARTIAL] Exercise and volume expansion are the main treatment strategies for hypo-volemic POTS. --- Explanation: Mentions volume expansion as a strategy for hypovolemic POTS but does not specifically name fludrocortisone.


CHEBI:50885

[PMID:31412221] [INDIRECT EVIDENCE] [PARTIAL] Exercise and volume expansion are the main treatment strategies for hypo-volemic POTS. --- Explanation: Mentions volume expansion as a strategy for hypovolemic POTS but does not specifically name fludrocortisone.


MAXO:0000950

[PMID:30001836] [SUPPORT] reduction in venous pooling during orthostasis by lower body compression garments extending at least to the xiphoid or with an abdominal binder --- Explanation: Describes compression garments as a non-pharmacological intervention to reduce venous pooling in POTS.

[PMID:31412221] [SUPPORT] Stockings, abdominal binders, and vasoconstrictors are used to enhance venous return in partial neuropathic POTS. --- Explanation: Confirms stockings and abdominal binders as treatments for neuropathic POTS.


MONDO:0005312

[PMID:40240062] [NO_EVIDENCE] Pouchitis, defined as inflammation of the ileal pouch, is the most common complication following restorative proctocolectomy for refractory ulcerative colitis.
 --- Explanation: Establishes pouchitis as an inflammatory condition of the ileal pouch, which manifests clinically with diarrhea as a cardinal symptom of inflammation.


MONDO:0005312


MONDO:0005312

[PMID:40240062] [NO_EVIDENCE] Pouchitis, defined as inflammation of the ileal pouch, is the most common complication following restorative proctocolectomy for refractory ulcerative colitis.
 --- Explanation: Rectal bleeding is a direct manifestation of mucosal inflammation and ulceration in the ileal pouch characteristic of pouchitis.


MONDO:0005312

[PMID:20845425] [INDIRECT EVIDENCE] [SUPPORT] UCP samples exhibited significantly more TRFLP peaks matching Clostridium and Eubacterium genera compared to HUC and FAP pouches and fewer peaks matching Lactobacillus and Streptococcus genera compared to FAP.
 --- Explanation: Demonstrates distinct microbiome alterations in UC-associated pouchitis with increased Clostridium/Eubacterium and decreased Lactobacillus/Streptococcus, supporting the dysbiosis mechanism.

[PMID:25110406] [INDIRECT EVIDENCE] [SUPPORT] there is evidence that a dysbiosis characterized by decreased gut microbiota diversity in UC-IPAA patients may, in genetically predisposed subjects, lead to aberrant mucosal immune regulation triggering an inflammatory process.
 --- Explanation: Review confirming that microbiome dysbiosis with decreased diversity is central to pouchitis pathogenesis, leading to aberrant immune regulation and inflammation.


MONDO:0005312

[PMID:40240062] [INDIRECT EVIDENCE] [PARTIAL] we outline the putative mechanisms of pouchitis, including genetic predisposition, microbiome alterations, dysfunction of the intestinal barrier and the immune system
 --- Explanation: Comprehensive review establishing that immune system dysfunction is a core pathogenic mechanism in pouchitis alongside barrier and microbiome alterations.

[PMID:7634977] [INDIRECT EVIDENCE] [SUPPORT] Cytokine production in pouchitis is similar to that in ulcerative colitis.
 --- Explanation: Demonstrates that the cytokine profile in pouchitis resembles that of ulcerative colitis, supporting shared inflammatory mechanisms between these conditions.


MONDO:0005312

[PMID:25222658] [INDIRECT EVIDENCE] [SUPPORT] In patients with UC with pouchitis, epithelial expression of ZO-1 and claudin 1 were reduced
 --- Explanation: Demonstrates reduced expression of barrier-forming tight junction proteins (ZO-1 and claudin-1) in pouchitis, directly supporting epithelial barrier dysfunction as a pathogenic mechanism.

[PMID:25222658] [INDIRECT EVIDENCE] [SUPPORT] Increased epithelial expression of the "pore-forming" TJP claudin 2, and DC expression of gut-homing markers CCR 9 and integrin β7, occurred early after ileostomy closure.
 --- Explanation: Shows early upregulation of claudin-2, a pore-forming protein that increases permeability, indicating that barrier dysfunction may be an initiating event in pouchitis development.


MAXO:0000061


MAXO:0000058


MAXO:0000169


MONDO:0005388

[PMID:35704252] [PARTIAL] Pruritus was reported in 170 patients (81%), with those reporting clinically significant pruritus (30%) scoring worse across each domain of the PBC-40 and 5-D itch, more frequently having cirrhosis, and having significantly greater levels of fatigue. --- Explanation: This real-world cohort study demonstrates that pruritus is highly prevalent in PBC (81%), with clinically significant pruritus associated with worse quality of life, more advanced disease, and greater fatigue.


MONDO:0005388

[PMID:35704252] [PARTIAL] Pruritus was reported in 170 patients (81%), with those reporting clinically significant pruritus (30%) scoring worse across each domain of the PBC-40 and 5-D itch, more frequently having cirrhosis, and having significantly greater levels of fatigue. --- Explanation: This study shows that fatigue is significantly elevated in PBC patients, particularly in those with clinically significant pruritus.


MONDO:0005388


MONDO:0005388

[PMID:26953925] [INDIRECT EVIDENCE] [PARTIAL] Primary biliary cholangitis (PBC) is an autoimmune hepatobiliary disease characterized by immune mediated destruction of the intrahepatic small bile ducts and the presence of antimitochondrial antibodies (AMAs). The mitochondrial autoantigens have been identified as the E2 subunits of the 2-oxo-acid dehydrogenase complex, including the E2 subunits of pyruvate dehydrogenase, branched-chain 2-oxo acid dehydrogenase complex, oxoglutarate dehydrogenase complex, E3 binding protein and PDC E1 alpha subunit. --- Explanation: This paper confirms that AMAs targeting PDC-E2 and related E2 subunits are characteristic of PBC and are associated with immune-mediated bile duct destruction.

[PMID:39329760] [INDIRECT EVIDENCE] [PARTIAL] Although the pathogenesis of the disease is multifactorial, there is a consensus that individuals with a genetic predisposition develop the disease in the presence of specific environmental triggers. A dysbiosis of intestinal microbiota is increasingly considered among the potential pathogenic factors. --- Explanation: This review highlights the multifactorial pathogenesis of PBC, including genetic predisposition and environmental triggers that lead to AMA production and disease development.


MONDO:0005388

[PMID:24556277] [INDIRECT EVIDENCE] [PARTIAL] In vitro cholangiocyte cytotoxicity assays demonstrated significantly increased numbers of cytotoxic hepatic dnTGFβRII KLRG1(+) CD8 cells compared to B6. Protection from disease by B6 Tregs was associated with elimination of hepatic dnTGFβRII CD8 mediated cholangiocyte cytotoxicity. These results emphasize that autoimmune cholangitis requires defects in both the T effector and regulatory compartments. --- Explanation: This study demonstrates that cytotoxic CD8+ T cells directly target and destroy cholangiocytes in experimental PBC, supporting the role of T cell- mediated cytotoxicity in bile duct epithelial cell destruction.

[PMID:39329760] [INDIRECT EVIDENCE] [SUPPORT] Cholangiocytes, the epithelial cells lining the bile ducts, are the main target of a dysregulated immune response, and cholangiocytes senescence has been recognized as a driving mechanism, leading to impaired bile duct function, in disease progression. --- Explanation: This review confirms that cholangiocytes are the primary cellular targets of immune attack in PBC, with senescent cholangiocytes driving disease progression through impaired bile duct function.


MONDO:0005388

[PMID:37047635] [INDIRECT EVIDENCE] [PARTIAL] In recent years, several studies have shown that, in case of a change in gut bacterial homeostasis or impairment of intestinal barrier functions, cholangiocytes, which are the epithelial cells lining the bile ducts, activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Intestinal dysbiosis or impaired intestinal barrier functions cause cholangiocytes to be exposed to an increasing amount of microorganisms that can reactivate inflammatory responses, thus inducing the onset of liver fibrosis. --- Explanation: This review demonstrates that cholangiocyte injury and bile duct destruction in PBC are promoted by gut-derived bacterial products reaching the liver, which trigger inflammatory responses that induce liver fibrosis and progressive disease.

[PMID:39329760] [INDIRECT EVIDENCE] [PARTIAL] Bile acids are also recognized as playing an important role, both in disease development and therapy. Thus, while bile acid-based therapies, specifically ursodeoxycholic acid and obeticholic acid, have been the cornerstone of therapy in PBC, novel therapeutic approaches have been developed in recent years. --- Explanation: This review highlights the central role of bile acids in PBC pathogenesis, noting that bile acid accumulation contributes to disease progression and that bile acid modulation is a key therapeutic strategy.


HGNC.SYMBOL:HLA-DRB1*08


HGNC.SYMBOL:IL12A


HGNC.SYMBOL:IL12RB2


MONDO:0008919

[PMID:38585546] [SUPPORT] Cardiomyopathy associated with PCD often presents with life-threatening heart failure. --- Explanation: Directly supports cardiomyopathy as a frequent life-threatening manifestation.

[PMID:39091928] [SUPPORT] Dilated cardiomyopathy (DCM) is a prevalent symptom associated with this condition, and episodes of metabolic disturbance may lead to sudden death. --- Explanation: Confirms DCM as a prevalent feature of PCD.


MONDO:0008919

[PMID:39691889] [SUPPORT] Primary carnitine deficiency may mimic hypertrophic cardiomyopathy and be mistakenly attributed to genotype-negative sarcomeric protein dysfunction in hypertrophic cardiomyopathy. --- Explanation: Directly supports HCM as a phenocopy presentation of PCD.

[PMID:38166572] [SUPPORT] Clinical evaluations, echocardiography, and cardiac magnetic resonance imaging findings revealed hypertrophic cardiomyopathy as a clinical presentation of PCD. --- Explanation: Confirms HCM as a clinical presentation in a confirmed PCD case.


MONDO:0008919

[PMID:38585546] [SUPPORT] Carnitine deficiency can result in acute metabolic decompensation or, in a more insidious presentation, cardiomyopathy. --- Explanation: Supports metabolic decompensation as a clinical presentation, which includes hypoketotic hypoglycemia.

[PMID:40406429] [SUPPORT] Carnitine deficiency is associated with various types of inherited disorders related to low levels of carnitine. --- Explanation: Supports carnitine deficiency as the underlying cause of metabolic decompensation features.


MONDO:0008919

[PMID:40406429] [SUPPORT] A strong correlation exists between the insufficiency of carnitine and the occurrence of HE. --- Explanation: Supports the link between carnitine deficiency and hyperammonemia/encephalopathy.

[PMID:38585546] [SUPPORT] Carnitine deficiency can result in acute metabolic decompensation or, in a more insidious presentation, cardiomyopathy. --- Explanation: Metabolic decompensation in PCD includes hyperammonemia.


MONDO:0008919

[PMID:38585546] [SUPPORT] This presentation also usually includes skeletal muscle myopathy. --- Explanation: Directly supports skeletal myopathy as a frequent accompanying feature.


MONDO:0008919

[PMID:38585546] [SUPPORT] This presentation also usually includes skeletal muscle myopathy. --- Explanation: Skeletal myopathy presentation is consistent with hypotonia as a feature.


MONDO:0008919


MONDO:0008919

[PMID:38166572] [SUPPORT] We herein describe an 8-year-old boy with symptoms of weakness and lethargy diagnosed with PCD through clinical evaluations, lab tests, echocardiography, and cardiac magnetic resonance imaging. --- Explanation: Directly reports lethargy as a presenting symptom in a confirmed PCD patient. Frequency based on limited case reports.


MONDO:0008919

[PMID:39091928] [SUPPORT] episodes of metabolic disturbance may lead to sudden death. --- Explanation: Directly states that metabolic disturbance episodes in PCD can lead to sudden death.


MONDO:0008919

[PMID:40406429] [SUPPORT] A strong correlation exists between the insufficiency of carnitine and the occurrence of HE. --- Explanation: Supports encephalopathy risk in severe carnitine deficiency through association with hepatic encephalopathy.


MONDO:0008919

[PMID:38961493] [INDIRECT EVIDENCE] [SUPPORT] Primary carnitine deficiency (PCD) is a rare autosomal recessive fatty acid oxidation disorder caused by variants in SLC22A5, with its prevalence and SLC22A5 gene mutation spectrum varying across races and regions. --- Explanation: Confirms autosomal recessive etiology with SLC22A5 variants across populations.


MONDO:0008919

[PMID:38585546] [INDIRECT EVIDENCE] [PARTIAL] Carnitine deficiency can result in acute metabolic decompensation or, in a more insidious presentation, cardiomyopathy. --- Explanation: Supports systemic carnitine depletion as the proximal biochemical state linked to the clinical syndrome.


MONDO:0008919

[PMID:39091928] [INDIRECT EVIDENCE] [SUPPORT] Primary Carnitine Deficiency (PCD) is a potentially life-threatening autosomal recessive monogenic disorder arising from mutations in the organic cation transporter 2 (OCTN2) gene. Dilated cardiomyopathy (DCM) is a prevalent symptom associated with this condition, and episodes of metabolic disturbance may lead to sudden death. --- Explanation: Links OCTN2 mutations to cardiomyopathy and metabolic disturbance, supporting impaired fatty acid oxidation as a central mechanism.

[PMID:38585546] [INDIRECT EVIDENCE] [SUPPORT] Carnitine deficiency can result in acute metabolic decompensation or, in a more insidious presentation, cardiomyopathy. --- Explanation: Confirms that carnitine depletion leads to both metabolic crises and cardiomyopathy.


MONDO:0008919

[PMID:39091928] [INDIRECT EVIDENCE] [SUPPORT] OCTN2-deficient cardiomyocytes displayed transcriptomic alterations indicative of reduced contractility, developmental abnormalities, and fibrosis. --- Explanation: Directly supports cardiac remodeling with reduced contractility and fibrosis in PCD.


MONDO:0008919

[PMID:40406429] [INDIRECT EVIDENCE] [SUPPORT] Carnitine acts as a vital component in facilitating the transport of long-chain fatty acids into the mitochondria, thereby enabling their oxidation for the generation of energy. Carnitine additionally assumes a crucial role in the functionality of the brain. Carnitine deficiency is associated with various types of inherited disorders related to low levels of carnitine. --- Explanation: Supports carnitine's role in hepatic fatty acid oxidation and brain function, linking deficiency to encephalopathy.

[PMID:38585546] [INDIRECT EVIDENCE] [SUPPORT] Carnitine deficiency can result in acute metabolic decompensation or, in a more insidious presentation, cardiomyopathy. --- Explanation: Confirms acute metabolic decompensation as a presentation of PCD.


MAXO:0000058

[PMID:38585546] [SUPPORT] Early recognition of this disorder and treatment with carnitine can avoid life-threatening complications related to cardiomyopathy. --- Explanation: Supports the critical importance of early carnitine treatment.


MAXO:0000088

[PMID:38585546] [SUPPORT] Carnitine deficiency can result in acute metabolic decompensation or, in a more insidious presentation, cardiomyopathy. --- Explanation: Prevention of metabolic decompensation through dietary management is a standard approach.


MAXO:0000950

[PMID:38585546] [SUPPORT] Carnitine deficiency can result in acute metabolic decompensation or, in a more insidious presentation, cardiomyopathy. --- Explanation: Acute metabolic decompensation requires emergency supportive management.

[PMID:40406429] [SUPPORT] If a deficiency of carnitine is identified through clinical symptoms or laboratory results in patients with liver dysfunction, treatment with carnitine replacement therapy is recommended. --- Explanation: Supports carnitine replacement as treatment during acute episodes.


MAXO:0000124

[PMID:36810318] [SUPPORT] This disease is of high complexity to screen, due to its pathophysiology and wide clinical spectrum. --- Explanation: Confirms the complexity and importance of NBS for PCD.

[PMID:39248612] [SUPPORT] The PPV reached 20% after combining with second-tier NGS. --- Explanation: Demonstrates improved screening performance with NGS second-tier testing.


MAXO:0000058

[PMID:38585546] [SUPPORT] Cardiomyopathy associated with PCD often presents with life-threatening heart failure. --- Explanation: Heart failure presentation necessitates cardiac pharmacotherapy.


MAXO:0000079

[PMID:38961493] [SUPPORT] Primary carnitine deficiency (PCD) is a rare autosomal recessive fatty acid oxidation disorder caused by variants in SLC22A5 --- Explanation: Autosomal recessive etiology mandates genetic counseling for affected families.


MAXO:0000058

[PMID:40406429] [SUPPORT] the administration of acetyl-L-carnitine in patients with HE can improve their mental and psychological conditions. --- Explanation: Directly supports acetyl-L-carnitine as treatment for carnitine-associated encephalopathy.


HGNC.SYMBOL:SLC22A5 (OCTN2) pathogenic variants

[PMID:39201429] [SUPPORT] A plethora of missense variants with uncertain clinical significance are reported both in the dbSNP and the Catalogue of Somatic Mutations in Cancer (COSMIC) databases for both genes. --- Explanation: Confirms the large number of SLC22A5 variants and their clinical importance.


MONDO:0016575

[PMID:27258773] [SUPPORT] Primary ciliary dyskinesia (PCD) is a rare, heterogeneous, recessive, genetic disorder of motile cilia, leading to chronic upper and lower respiratory symptoms. --- Explanation: The statement is supported because PCD leads to chronic respiratory symptoms, including chronic cough.

[PMID:17142159] [SUPPORT] Primary ciliary dyskinesia is an autosomal recessive genetic disease that results in impaired mucociliary clearance causing progressive involvement of the upper and lower respiratory tract, characterized by airway obstruction and recurrent infections of the lungs, middle ear and paranasal sinuses. --- Explanation: The statement is supported because PCD causes progressive involvement of the respiratory tract, which includes chronic cough.


MONDO:0016575

[PMID:39069333] [SUPPORT] This review article explores the respiratory aspects of primary ciliary dyskinesia (PCD), a rare, heterogenous, genetic disorder characterized by impaired motile ciliary function. It discusses the clinical diagnosis and management strategies for PCD-related respiratory disease, including chronic sinusitis, otitis media with effusion, recurrent pneumonia, and bronchiectasis. --- Explanation: The article discusses recurrent respiratory diseases as a significant aspect of PCD, supporting the statement that recurrent respiratory infections are very frequent in PCD.

[PMID:36214320] [SUPPORT] Ninety-two children with chronic respiratory symptoms were divided into 4 groups: 18 children with refractory asthma, 10 with bronchiectasis without dextrocardia, 18 with dextrocardia and 46 with recurrent respiratory tract infections. --- Explanation: The study highlights recurrent respiratory tract infections in children with chronic respiratory symptoms, supporting the statement that recurrent respiratory infections are very frequent in PCD.

[PMID:31430425] [SUPPORT] The objective of this study was to evaluate the prevalence of chronic rhinosinusitis (CRS) and its characteristics in bronchiectasis patients suspected of harboring ciliary dyskinesia. --- Explanation: The study mentions chronic rhinosinusitis and bronchiectasis in patients suspected of ciliary dyskinesia, indicating frequent respiratory issues.

[PMID:25370419] [SUPPORT] The sinuses should be considered as a bacterial reservoir and a target for surgery and antibiotic treatment in patients with primary ciliary dyskinesia (PCD). --- Explanation: The study discusses sinus infections as a common issue in PCD, supporting the statement about frequent respiratory infections.


MONDO:0016575

[PMID:10894096] [SUPPORT] Patients with primary ciliary dyskinesia could potentially develop recurrent sinotrachrobronchitis, bronchiectasis, serous otitis media, hydrocephalus, and male infertility. --- Explanation: The article mentions bronchiectasis as one of the potential conditions that patients with PCD could develop.

[PMID:36344229] [SUPPORT] Typical manifestations include bronchiectasis, secretory otitis media, sinusitis, situs inversus, and infertility. --- Explanation: The article lists bronchiectasis as a typical manifestation of primary ciliary dyskinesia.

[PMID:25673230] [SUPPORT] Primary ciliary dyskinesia (PCD) is a rare disease, characterised by chronic airway infection. --- Explanation: The article discusses the relationship between functional and structural abnormalities in PCD, including bronchiectasis.

[PMID:21680564] [SUPPORT] A review is presented of key clinical papers published in Thorax and elsewhere between 2008 and April 2011 which have advanced our understanding of cystic fibrosis (CF), primary ciliary dyskinesia and non-CF bronchiectasis. --- Explanation: The article discusses primary ciliary dyskinesia and non-CF bronchiectasis, implying a connection between PCD and bronchiectasis.

[PMID:31430425] [SUPPORT] The objective of this study was to evaluate the prevalence of chronic rhinosinusitis (CRS) and its characteristics in bronchiectasis patients suspected of harboring ciliary dyskinesia. --- Explanation: The study evaluates bronchiectasis in patients suspected of having ciliary dyskinesia, indicating a frequent association.

[PMID:37278553] [SUPPORT] Primary ciliary dyskinesia as a common cause of bronchiectasis in the Canadian Inuit population. --- Explanation: The article explicitly states that PCD is a common cause of bronchiectasis in a specific population.

[PMID:33895745] [SUPPORT] Primary ciliary dyskinesia (PCD) is a rare genetic disorder which requires a complex diagnostic workup. Thus, an easy and widely available screening method would be helpful to identify patients who need a further diagnostic workup for PCD. --- Explanation: The article discusses the need for diagnostic workup for PCD in patients with bronchiectasis, indicating a frequent association.

[PMID:23181248] [SUPPORT] Mucociliary clearance is a primary defence mechanism of the airway that can be altered in congenital diseases such as primary ciliary dyskinesia and cystic fibrosis, as well as acquired conditions. --- Explanation: The article focuses on primary ciliary dyskinesia and its impact on mucociliary clearance, which is related to bronchiectasis.

[PMID:37852905] [NO_EVIDENCE] Bardet-Biedl Syndrome: An Uncommon Cause of Bronchiectasis. --- Explanation: The article discusses Bardet-Biedl Syndrome as a cause of bronchiectasis, not primary ciliary dyskinesia.


MONDO:0016575

[PMID:29135867] [SUPPORT] All 15 patients showed ciliary ultrastructural abnormalities on electron microscopy and/or biallelic mutations in genes associated with ciliary function or structure. All 30 eardrums examined showed certain abnormalities. Fourteen patients had otitis media with effusion or its sequelae. The remaining patient had chronic otitis media. --- Explanation: The study found that patients with primary ciliary dyskinesia (PCD) frequently exhibited otologic issues, including chronic otitis media.

[PMID:19796826] [SUPPORT] Primary ciliary dyskinesia is an autosomal recessively inherited group of disorders of ciliary ultrastructure. Otolaryngologists are frequently involved in the management of some of the most common symptoms of primary ciliary dyskinesia including chronic rhinitis, sinusitis and otitis media with effusion. --- Explanation: This reference supports that chronic otitis media and other otologic issues are common in patients with primary ciliary dyskinesia.


MONDO:0016575

[PMID:29287859] [REFUTE] Slight to mild CHL and all types of otitis media are prevalent among patients with PCD, and some of these children have sensorineural hearing loss (SNHL). --- Explanation: The study indicates that hearing loss is a prevalent condition among patients with primary ciliary dyskinesia (PCD), not occasional.

[PMID:9222635] [REFUTE] All children (11 patients) had bilateral otitis media with effusion. Of the five adults, three had tympanosclerosis; one had bilateral cholesteatoma; and one patient had bilateral keratosis obturans in combination with tympanosclerosis. --- Explanation: The study describes otological manifestations including hearing loss as a prominent feature in patients with PCD, suggesting it is not occasional but rather common.

[PMID:33844744] [NO_EVIDENCE] In this group of patients with OI, 30% had hearing loss and among those ears with normal hearing, 13% did not have an acoustic stapedial reflex. --- Explanation: This study discusses hearing loss in osteogenesis imperfecta (OI), not primary ciliary dyskinesia (PCD).


MONDO:0016575

[PMID:16036877] [PARTIAL] Total immotility of the cilia should therefore result in random asymmetry of the body that is situs inversus in 50% of the cases. It has also been claimed that 50% of cases with PCD have situs inversus. --- Explanation: The literature indicates that situs inversus, including situs inversus totalis, occurs in approximately 50% of primary ciliary dyskinesia (PCD) cases. This suggests that it is not merely 'occasional' but rather relatively common in PCD patients.

[PMID:36342963] [PARTIAL] Results: Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively; heterotaxy, defined as situs ambiguus with complex cardiovascular defects, was present in 14 (2.5%) --- Explanation: The data indicates that situs inversus totalis occurs in 38.5% of PCD cases, which is more frequent than 'occasional.'

[PMID:38072392] [PARTIAL] The remaining 355 participants did not have SA, including 152 with SIT and 203 with SS. --- Explanation: Situs inversus totalis (SIT) is present in a significant portion of PCD cases, indicating it is more common than 'occasional.'


MONDO:0016575


MONDO:0016575

[PMID:19818430] [INDIRECT EVIDENCE] [SUPPORT] Primary ciliary dyskinesia is a genetically inherited syndrome characterized by cilia immotility or dysmotility. Deficiency in mucociliary clearance produces chronic respiratory infections since birth. --- Explanation: The reference confirms that defects in the structure and function of motile cilia impair mucociliary clearance, supporting the statement.

[PMID:20525503] [INDIRECT EVIDENCE] [SUPPORT] Ciliary dysfunction may be primary, the result of genetic mutations resulting in abnormal cilia structure, or secondary, the result of environmental, infectious or inflammatory stimuli that disrupt normal motility or coordination. --- Explanation: This reference supports the statement by indicating that primary ciliary dyskinesia results from genetic mutations affecting cilia structure and function, leading to impaired mucociliary clearance.

[PMID:17059358] [INDIRECT EVIDENCE] [SUPPORT] The most prominent genetic abnormality involving motile cilia (and the respiratory tract) is primary ciliary dyskinesia (PCD). PCD is a rare, usually autosomal recessive, genetically heterogeneous disorder characterized by sino-pulmonary disease, laterality defects, and male infertility. --- Explanation: The reference supports the statement by describing PCD as a disorder involving motile cilia defects, which leads to respiratory issues due to impaired mucociliary clearance.

[PMID:15750039] [INDIRECT EVIDENCE] [SUPPORT] Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by recurrent infections of the airways and situs inversus in half of the affected offspring. The most frequent genetic defects comprise recessive mutations of DNAH5 and DNAI1, which encode outer dynein arm (ODA) components. --- Explanation: This reference supports the statement by listing DNAH5 and DNAI1 as genes involved in PCD, which is characterized by defects in motile cilia leading to impaired mucociliary clearance.

[PMID:32185794] [INDIRECT EVIDENCE] [SUPPORT] Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by defects in the function or structure of motitle cilia --- Explanation: The reference supports the statement by confirming that PCD involves defects in the structure and function of motile cilia, which impair mucociliary clearance.


MONDO:0016575

[PMID:11376511] [INDIRECT EVIDENCE] [SUPPORT] Failure to keep the airways sterile by MCC results in a host inflammatory response to the persistent microorganisms which, if it becomes chronic, causes damage to the airway wall and upregulation of mucus production manifest clinically as bronchiectasis, sinusitis and otitis. --- Explanation: The literature supports that primary ciliary dyskinesia (PCD) leads to impaired mucociliary clearance, which results in chronic respiratory infections, sinusitis, and otitis media.

[PMID:17142159] [INDIRECT EVIDENCE] [SUPPORT] Primary ciliary dyskinesia is an autosomal recessive genetic disease that results in impaired mucociliary clearance causing progressive involvement of the upper and lower respiratory tract, characterized by airway obstruction and recurrent infections of the lungs, middle ear and paranasal sinuses. --- Explanation: The literature supports that primary ciliary dyskinesia leads to impaired mucociliary clearance and downstream chronic respiratory infections, sinusitis, and otitis media.

[PMID:15917207] [INDIRECT EVIDENCE] [SUPPORT] Disruption of 9+2 cilia, which move mucus across respiratory epithelia, leads to rhinitis, sinusitis and bronchiectasis. --- Explanation: The literature supports that disruption of motile cilia, as seen in primary ciliary dyskinesia, leads to impaired mucociliary clearance and resultant respiratory conditions such as sinusitis and bronchiectasis.

[PMID:29490941] [INDIRECT EVIDENCE] [SUPPORT] We hypothesised that olfactory function could be impaired in primary ciliary dyskinesia (PCD). Olfaction, nasal nitric oxide (nNO) and sinus CT were assessed in patients with PCD and non-PCD sinus disease, and healthy controls (no CT scan). PCD and non-PCD patients had similar severity of sinus disease. --- Explanation: The literature supports that primary ciliary dyskinesia leads to impaired mucociliary clearance and associated conditions such as sinusitis.


MONDO:0016575

[PMID:16036877] [INDIRECT EVIDENCE] [PARTIAL] The normal left-right asymmetry of the body is thought to be due to the beating of the cilia in the embryonic (Hensen's) node. Total immotility of the cilia should therefore result in random asymmetry of the body that is situs inversus in 50% of the cases. It has also been claimed that 50% of cases with PCD have situs inversus. --- Explanation: The statement is partially supported. The literature confirms that primary ciliary dyskinesia (PCD) can lead to situs inversus due to ciliary dysfunction during embryonic development, and it is claimed that 50% of PCD cases have situs inversus. However, the phrase 'abnormal placement of internal organs' is more general and could include other forms of laterality defects, not just situs inversus.

[PMID:36342963] [INDIRECT EVIDENCE] [PARTIAL] Results: Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively; heterotaxy, defined as situs ambiguus with complex cardiovascular defects, was present in 14 (2.5%) --- Explanation: The statement is partially supported. The data shows that 38.5% of PCD cases have situs inversus totalis, which is close to but not exactly 50%. Additionally, there are other laterality defects like situs ambiguus, which are not covered by the statement.


MAXO:0000011

[PMID:28408202] [SUPPORT] Airway clearance techniques (ACTs) are commonly recommended for patients with PCD to facilitate mucus clearance, despite a lack of evidence in this group. --- Explanation: The reference acknowledges the use of airway clearance techniques in patients with Primary Ciliary Dyskinesia (PCD) to help clear mucus from the lungs.

[PMID:38861625] [SUPPORT] Airway clearance techniques (ACTs) are critical in managing respiratory conditions characterized by mucus hypersecretion and impaired clearance, such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), and various neuromuscular disorders. --- Explanation: The reference discusses the importance of ACTs in managing conditions with mucus hypersecretion and impaired clearance, which aligns with the use of these techniques in PCD.

[PMID:11376511] [SUPPORT] There are three principal disorders of MCC. Firstly, primary ciliary dyskinesia (PCD)... --- Explanation: The reference mentions PCD and discusses airway hygiene and mucociliary clearance, supporting the relevance of airway clearance techniques in PCD.


MAXO:0000058

[PMID:28552099] [SUPPORT] Non-functional airway cilia impair the mucociliary clearance (MCC), causing mucostasis, lung infections and destruction, chronic rhinosinusitis (CRS) and hearing impairment. It is of paramount importance to postpone chronic lung infection mainly with Gram-negative bacteria (GNB) in patients with an impaired MCC. When successful, lung function can be stabilized and quality of life (QoL) improved. --- Explanation: The literature mentions the importance of postponing chronic lung infection in patients with impaired MCC, which is a characteristic of PCD. This aligns with the use of long-term antibiotic therapy to manage such infections.

[PMID:26586601] [SUPPORT] Most of the treatments recommended in PCD have been extrapolated from cystic fibrosis (CF) and non-CF bronchiectasis literature. Mainstays of therapy are reviewed in detail, and should include at a minimum: regular airway clearance, routine microbiological surveillance, antibiotic treatment for pulmonary exacerbation, and health vaccinations. --- Explanation: The reference states that antibiotic treatment for pulmonary exacerbation is a mainstay of therapy for PCD, supporting the use of long-term or prophylactic antibiotics.

[PMID:19812481] [SUPPORT] Antibiotic prophylaxis is one of the mainstays of therapy of primary immunodeficiencies. --- Explanation: While the focus is on primary immunodeficiencies, the principle of using antibiotic prophylaxis can be extended to PCD due to similar needs for managing chronic infections.


MAXO:0000058

[PMID:28552099] [INDIRECT EVIDENCE] [SUPPORT] Non-functional airway cilia impair the mucociliary clearance (MCC), causing mucostasis, lung infections and destruction, chronic rhinosinusitis (CRS) and hearing impairment. It is of paramount importance to postpone chronic lung infection mainly with Gram-negative bacteria (GNB) in patients with an impaired MCC. When successful, lung function can be stabilized and quality of life (QoL) improved. --- Explanation: The literature mentions the importance of postponing chronic lung infection in patients with impaired MCC, which is a characteristic of PCD. This aligns with the use of long-term antibiotic therapy to manage such infections.

[PMID:26586601] [INDIRECT EVIDENCE] [SUPPORT] Most of the treatments recommended in PCD have been extrapolated from cystic fibrosis (CF) and non-CF bronchiectasis literature. Mainstays of therapy are reviewed in detail, and should include at a minimum: regular airway clearance, routine microbiological surveillance, antibiotic treatment for pulmonary exacerbation, and health vaccinations. --- Explanation: The reference states that antibiotic treatment for pulmonary exacerbation is a mainstay of therapy for PCD, supporting the use of long-term or prophylactic antibiotics.

[PMID:19812481] [INDIRECT EVIDENCE] [SUPPORT] Antibiotic prophylaxis is one of the mainstays of therapy of primary immunodeficiencies. --- Explanation: While the focus is on primary immunodeficiencies, the principle of using antibiotic prophylaxis can be extended to PCD due to similar needs for managing chronic infections.


MAXO:0000058

[PMID:39269762] [NO_EVIDENCE] Primary ciliary dyskinesia (PCD) is a respiratory disorder that impairs mucociliary clearance, leading to decreased lung function. --- Explanation: The reference focuses on airway clearance techniques in PCD and does not mention the use of bronchodilators.


MAXO:0000058

[PMID:19879441] [PARTIAL] Long-term treatment with corticosteroid nasal spray reduces inflammation and nasal polyp size, and improves nasal symptoms such as nasal blockage, rhinorrea, and the loss of smell. --- Explanation: While nasal steroids are used to treat nasal polyps and chronic rhinosinusitis, the statement should specify that they are used to manage symptoms rather than being a description of Primary Ciliary Dyskinesia (PCD).

[PMID:33305974] [PARTIAL] Topical nasal steroids play an important role in the treatment of CRS. --- Explanation: Nasal steroids are used in the treatment of chronic rhinosinusitis (CRS), which can be a condition associated with PCD. However, the statement should clarify that nasal steroids are for symptom management rather than a direct description of PCD.

[PMID:35312075] [PARTIAL] Our findings indicate for the first time that PCD patients with CRSwNP display a more severe disease than those with CRSsNP. --- Explanation: This reference indicates that chronic rhinosinusitis with nasal polyps (CRSwNP) is more severe in PCD patients. However, it does not directly state that nasal steroids are used to treat these conditions in the context of PCD.

[PMID:28552099] [PARTIAL] Implementing ESS with adjuvant therapy to PCD patients (I, IV) significantly ameliorated CRS symptoms. --- Explanation: This reference suggests that surgical and adjuvant therapies, including possibly nasal steroids, can ameliorate CRS symptoms in PCD patients. However, it does not explicitly state the use of nasal steroids.


MAXO:0000950

[PMID:29287859] [NO_EVIDENCE] CONCLUSIONS: Slight to mild CHL and all types of otitis media are prevalent among patients with PCD, and some of these children have sensorineural hearing loss (SNHL). --- Explanation: The study discusses the prevalence and types of hearing loss in children with PCD but does not mention the use of hearing aids or other assistive devices for management.

[PMID:22960754] [NO_EVIDENCE] This article explores factors pertaining to children's use of and attitudes toward hearing technologies, such as hearing aids, cochlear implants, teacher-worn microphones, and student-worn microphones. --- Explanation: This study focuses on the use of hearing technologies among students with hearing impairment but does not specifically address children with PCD.

[PMID:28187057] [NO_EVIDENCE] OBJECTIVE: To evaluate whether wearing auditory assistive devices can improve gait and dynamic balance. --- Explanation: The study evaluates the impact of hearing assistive devices on gait and balance in adults but does not mention their use in patients with PCD.

[PMID:30827358] [NO_EVIDENCE] Implantable auditory devices (IADs) are a viable hearing restoration option for patients with hearing loss. --- Explanation: The article discusses implantable auditory devices as a hearing restoration option but does not specifically mention hearing aids for patients with PCD.

[PMID:2062156] [NO_EVIDENCE] In patients with primary ciliary dyskinesia, a discrepancy was found between subjective ear complaints and the actual middle ear function. --- Explanation: This study discusses middle ear function in patients with PCD but does not mention the use of hearing aids or other assistive devices.


MAXO:0000079

[PMID:29800551] [NO_EVIDENCE] Our knowledge of cilia genetics and the function of the proteins encoded has led to a greater understanding of the clinical manifestations of motile ciliopathies. These advances have changed our approach toward diagnostic testing for primary ciliary dyskinesia. --- Explanation: The reference discusses advances in genetics and diagnostic testing for primary ciliary dyskinesia but does not mention genetic counseling providing information and support for affected individuals and families.

[PMID:29905515] [NO_EVIDENCE] This document presents the American Thoracic Society clinical practice guidelines for the diagnosis of primary ciliary dyskinesia (PCD). --- Explanation: The guideline focuses on diagnostic practices and does not mention genetic counseling or support for affected individuals and families.

[PMID:19410203] [NO_EVIDENCE] Newer genetic modifiers show an exciting potential for personalized medication, combining selection of patients with a common genetic mutation and a drug treatment that has been specifically designed to overcome that mutation, and will greatly enhance the therapeutic arsenal for PCD. --- Explanation: The reference discusses potential future therapies for PCD but does not mention genetic counseling or support services.

[PMID:35854386] [NO_EVIDENCE] Diagnostic delay and under-recognition of PCD remain a big issue in China, which contributes to progressive lung disease and PA infection indicating worse outcome. --- Explanation: The reference discusses diagnostic delays and clinical outcomes but does not mention genetic counseling or support services.


HGNC.SYMBOL:DNAI1

[PMID:11893720] [SUPPORT] Mutations in DNAI1 (IC78) cause primary ciliary dyskinesia. --- Explanation: This study directly links mutations in DNAI1 to the cause of primary ciliary dyskinesia.

[PMID:35869935] [SUPPORT] 13 rare variants were identified in patients with PCD, among which were three homozygous causative variants (including one splicing variant) in the PCD-associated genes CCDC40 and DNAI1. --- Explanation: The study identifies causative variants in DNAI1 associated with primary ciliary dyskinesia.

[PMID:15750039] [SUPPORT] The most frequent genetic defects comprise recessive mutations of DNAH5 and DNAI1, which encode outer dynein arm (ODA) components. --- Explanation: This study mentions DNAI1 mutations as frequent genetic defects causing primary ciliary dyskinesia.

[PMID:11231901] [SUPPORT] We identified compound heterozygous DNAI1 gene defects in three independent patients and in two of their siblings who presented with PCD and situs solitus. --- Explanation: The study links compound heterozygous DNAI1 gene defects with primary ciliary dyskinesia.


HGNC.SYMBOL:DNAH5

[PMID:31118369] [SUPPORT] A genetic examination detected compound heterozygous mutations of DNAH5 that encode ODA components. --- Explanation: The study reports a case of primary ciliary dyskinesia (PCD) with DNAH5 mutations, confirming the association between PCD and pathogenic variants in DNAH5.

[PMID:36727596] [SUPPORT] Most PCD-causing variants result in abnormal outer dynein arms (ODAs), which provide the generative force for respiratory ciliary beating and proper mucociliary clearance. --- Explanation: The study indicates that pathogenic variants causing PCD often result in abnormal ODAs, which are associated with DNAH5.


HGNC.SYMBOL:DNAH11


HGNC.SYMBOL:CCDC39


HGNC.SYMBOL:CCDC40


HGNC.SYMBOL:RSPH1


HGNC.SYMBOL:RSPH4A


HGNC.SYMBOL:RSPH9


HGNC.SYMBOL:CCNO


HGNC.SYMBOL:FOXJ1


HGNC.SYMBOL:MCIDAS


HGNC.SYMBOL:ODAD1


ECTO:8000036

[PMID:34574829] [SUPPORT] Air pollution decreases quality of life and life expectancy. It exacerbates acute and chronic respiratory symptoms in patients with chronic airway diseases, and increases the morbidity and risk of hospitalization associated with respiratory diseases. --- Explanation: The literature indicates that air pollution exacerbates respiratory symptoms in patients with chronic airway diseases, which can be inferred to include conditions like Primary Ciliary Dyskinesia (PCD).

[PMID:37147124] [SUPPORT] CONCLUSIONS: Short-term ambient NO2 and PM2.5 exposure were associated with increased odds of exacerbations in Canadians with mild to moderate COPD, further heightening the awareness of non-infectious triggers of COPD exacerbations --- Explanation: While this study focuses on COPD, it highlights the role of air pollution in exacerbating respiratory conditions, which can be extended to other chronic respiratory diseases like PCD.


MONDO:0018155

[PMID:26515619] [SUPPORT] Patients experience stiffness; decreased balance and coordination; mild weakness; and, if the bulbar region is affected, difficulty speaking and swallowing, and emotional lability. --- Explanation: Stiffness in the abstract reflects spasticity in PLS.


MONDO:0018155

[PMID:26515619] [SUPPORT] Patients experience stiffness; decreased balance and coordination; mild weakness; and, if the bulbar region is affected, difficulty speaking and swallowing, and emotional lability. --- Explanation: Difficulty speaking is consistent with dysarthria in PLS.


MONDO:0018155

[PMID:26515619] [SUPPORT] Patients experience stiffness; decreased balance and coordination; mild weakness; and, if the bulbar region is affected, difficulty speaking and swallowing, and emotional lability. --- Explanation: The abstract notes difficulty swallowing when bulbar regions are affected.


MAXO:0000950

[PMID:26515619] [SUPPORT] Treatment is largely supportive. --- Explanation: The abstract states that management is supportive.


MONDO:0009692


MONDO:0009692

[PMID:41514563] [INDIRECT EVIDENCE] [PARTIAL] Primary myelofibrosis (PMF) is a Philadelphia chromosome (Ph)-negative myeloproliferative neoplasm (MPN) that features clonal proliferation of atypical megakaryocytes and myeloid cells, fibrosis of the bone marrow, extramedullary hematopoiesis, and increased risk of leukemic transformation to acute myeloid leukemia (AML). --- Explanation: This abstract highlights bone marrow fibrosis and atypical megakaryocyte proliferation, supporting the fibrosis mechanism described.


MAXO:0000058


CHEBI:66919


NCIT:C88293


MAXO:0000747


CHEBI:44423


CHEBI:142290


HGNC.SYMBOL:JAK2


HGNC.SYMBOL:CALR


HGNC.SYMBOL:MPL


HGNC.SYMBOL:ASXL1


MONDO:0009692

[PMID:33477816] [PARTIAL] Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by --- Explanation: Abstract describes PMF as a myeloproliferative neoplasm characterized by bone marrow fibrosis.


MONDO:0019806

[PMID:19300609] [PARTIAL] Primary progressive aphasia (PPA) is a neurodegenerative disease of insidious onset presenting with progressive isolated loss of language function, without significant impairment in other cognitive domains. --- Explanation: Progressive loss of language function defines the aphasic phenotype.


MONDO:0019806

[PMID:19300609] [SUPPORT] Current diagnostic criteria require the language dysfunction to remain isolated for at least two years, and to remain the salient feature as the disease progresses, usually to involve other domains such as behavior, executive functions, and judgment. --- Explanation: The abstract notes progression to behavioral involvement in PPA.


HGNC.SYMBOL:MAPT

[PMID:19300609] [SUPPORT] Pathogenic mutations in genes coding for the proteins tau and progranulin have been isolated. --- Explanation: The abstract cites pathogenic mutations in the tau gene (MAPT).


HGNC.SYMBOL:GRN

[PMID:19300609] [SUPPORT] Pathogenic mutations in genes coding for the proteins tau and progranulin have been isolated. --- Explanation: The abstract cites pathogenic mutations in the progranulin gene (GRN).


MONDO:0013433


MONDO:0013433

[PMID:39250501] [INDIRECT EVIDENCE] [PARTIAL] Cholangiopathies comprise a spectrum of chronic intrahepatic and extrahepatic biliary tract disorders culminating in progressive cholestatic liver injury, fibrosis, and often cirrhosis and its sequela. --- Explanation: Demonstrates that PSC involves progressive fibrosis as a core pathological feature of biliary tract disorders.

[PMID:39250501] [INDIRECT EVIDENCE] [PARTIAL] Herein, we review the pivotal role of cholangiocytes in cholestatic fibrogenesis, focusing on the crosstalk between cholangiocytes and portal fibroblasts and HSCs. --- Explanation: Confirms the central role of fibroblast-cholangiocyte crosstalk in driving periductal fibrosis in PSC.


MONDO:0013433

[PMID:39250501] [INDIRECT EVIDENCE] [PARTIAL] The crosstalk between cholangiocytes and cells of the innate (neutrophils and macrophages) and adaptive (T cells and B cells) immune systems is also examined in detail. --- Explanation: Confirms the role of adaptive immune cells, particularly T cells, in the pathogenesis of cholestatic liver diseases including PSC.


MONDO:0013433

[PMID:39250501] [INDIRECT EVIDENCE] [PARTIAL] The proclivity of these cells to undergo a senescence-associated secretory phenotype, which is proinflammatory and profibrogenic, and the intrinsic intracellular activation pathways resulting in the secretion of cytokines and chemokines are reviewed. --- Explanation: Directly supports that cholangiocytes undergo senescence-associated secretory phenotype that drives inflammation and fibrosis in cholestatic diseases.


HGNC.SYMBOL:HLA-DRB1*03


HGNC.SYMBOL:HLA-B8


MONDO:0044884

[PMID:19558906] [PARTIAL] Histopathologic study revealed 80 % to be benign and 20 % malignant. The risk factors with the strongest association were enlargement of cervical lymphatic nodes and suspicious appearance of the tonsil. --- Explanation: The reference supports that tonsillar enlargement can be a diagnostic sign for malignancies, including lymphoma, but it does not specifically state that primary tonsillar lymphoma is very frequent.

[PMID:2190267] [PARTIAL] Lymphoma is the second most common neoplasm of the head and neck region and should be considered in the differential diagnosis of any lesion in this region, especially if the typical factors for squamous cell carcinoma are not present. --- Explanation: This reference indicates that lymphoma, including primary tonsillar lymphoma, is common in the head and neck region but does not specify it as very frequent.

[PMID:34754855] [PARTIAL] Lymphomas are the second most common malignancy of the head and neck. In this region, the vast majority of extranodal lymphomas are located in the palatine tonsil, accounting for about 51%. --- Explanation: The reference supports that primary tonsillar lymphoma is common in the head and neck region but does not specify it as very frequent.

[PMID:38044117] [PARTIAL] Tonsillar Peripheral T-cell Lymphoma Detected by Esophagogastroduodenoscopy. --- Explanation: This reference indicates the occurrence of tonsillar lymphoma but does not provide information on its frequency.


MONDO:0044884

[PMID:37997620] [NO_EVIDENCE] We report a case of primary CLL/SLL of the palatine tonsil in a 51-year-old gentleman who presented with tonsillar asymmetry and obstructive sleep apnea (OSA) but lacked signs and symptoms suspicious for malignancy, including lymphadenopathy and 'B-symptoms.' --- Explanation: The case report of primary CLL/SLL of the palatine tonsil mentioned does not include fever as a symptom.

[PMID:35314548] [NO_EVIDENCE] A 52-year-old man presented with palatine tonsillar swelling caused by follicular lymphoma. His tumor burden was low, but exacerbation of snoring and dysphagia was observed. --- Explanation: Fever is not mentioned as a symptom in this case of palatine tonsillar follicular lymphoma.

[PMID:28351195] [NO_EVIDENCE] Hematolymphoid malignancy was diagnosed in 6 adults by histology/immunohistochemistry: diffuse large B-cell lymphoma (2), small B-cell lymphoma (2), concomitant follicular lymphoma and histiocytic sarcoma (1), and extraosseous plasmacytoma (1). --- Explanation: The study does not mention fever as a common symptom in cases of tonsillar hematolymphoid malignancy.

[PMID:30639969] [NO_EVIDENCE] Burkitt lymphoma (32.6%) followed by diffuse large B-cell lymphoma (DLBCL) (27.0%) were the two most common histological types of tonsillar cancers. --- Explanation: The study on pediatric tonsillar malignancies does not mention fever as a frequent symptom.

[PMID:29025800] [NO_EVIDENCE] Fever is a common sign of illness in children and is most frequently due to infection. However, when acute and chronic infections have been excluded and when the fever pattern becomes recurrent or periodic, the expanding spectrum of autoinflammatory diseases, including periodic fever syndromes, should be considered. --- Explanation: This study discusses fever in the context of infections and autoinflammatory diseases, not specifically in primary tonsillar lymphoma.


MONDO:0044884

[PMID:12643362] [REFUTE] Tuberculosis and lymphoma are diseases in which night sweats are a dominant symptom, but these are infrequently found to be the cause of night sweats in modern practice. --- Explanation: While lymphoma can cause night sweats, they are not frequently found to be the cause in modern practice, suggesting that night sweats are not a frequent systemic symptom of primary tonsillar lymphoma.

[PMID:24387945] [REFUTE] The presence of B symptoms occurred in only 16% of the patients. --- Explanation: Night sweats are considered a B symptom, and they were present in only 16% of pediatric tonsillar lymphoma cases, indicating that they are not a frequent symptom.


MONDO:0044884

[PMID:10592134] [NO_EVIDENCE] We report six cases of primary tonsillar lymphoma with a median patient age of 42 years... All patients achieved durable complete remission. --- Explanation: The literature does not mention weight loss as a frequent systemic symptom in primary tonsillar lymphoma.

[PMID:38742359] [NO_EVIDENCE] Objective: To analyze the ultrasonic features of tonsillar lymphoma to improve the diagnostic accuracy... Conclusions: The ultrasonic features of tonsillar lymphoma include hypoechoic area, clear boundary, full shape, irregular and uniform internal echo, no or low linear signal of internal blood flow. --- Explanation: The study focuses on the ultrasonic characteristics of tonsillar lymphoma and does not mention systemic symptoms such as weight loss.


MONDO:0044884

[PMID:24387945] [SUPPORT] The most common clinical manifestations found in children with lymphoma in palatine tonsils were unilateral tonsillar enlargement (72.7%), alteration in appearance of the tonsil (45.4%) and cervical lymphadenopathy (30.3%). --- Explanation: This reference supports the statement that primary tonsillar lymphoma is frequently associated with lymphadenopathy, particularly in the neck.

[PMID:2190267] [PARTIAL] The head and neck is the second most common site for extranodal lymphoma. It can involve virtually any region, including the orbit, paranasal sinuses, Waldeyer's ring, salivary glands, or thyroid. --- Explanation: This reference indicates that lymphoma can frequently involve the head and neck region, which includes the tonsils, but does not specifically mention lymphadenopathy.

[PMID:38779794] [NO_EVIDENCE] A 30-year-old female patient presented with a swelling of a cervical left lymph node measuring 1x3 cm, which had been presenting for three weeks. Lymph node excision revealed a metastasis of a malignant melanoma, but the primary tumor was not found. --- Explanation: This reference discusses lymphadenopathy in the context of metastatic melanoma, not primary tonsillar lymphoma.

[PMID:32719287] [NO_EVIDENCE] Histiocytic sarcoma (HS) is an extremely rare and aggressive hematopoietic tumor. --- Explanation: This reference is about histiocytic sarcoma, not primary tonsillar lymphoma.


MONDO:0044884

[PMID:3891063] [SUPPORT] Tonsillar and base of tongue lesions presented with sore throat and dysphagia, whereas nasopharyngeal lymphomas most commonly presented with nasal, auditory, and cranial nerve sympatomatology. --- Explanation: The study indicates that dysphagia is a common presenting symptom in tonsillar lymphoma.

[PMID:38044117] [SUPPORT] Tonsillar Peripheral T-cell Lymphoma Detected by Esophagogastroduodenoscopy. --- Explanation: Although the specific symptoms are not detailed, the detection of tonsillar lymphoma via esophagogastroduodenoscopy suggests an association with dysphagia.


MONDO:0044884


MAXO:0000647

[PMID:10592134] [SUPPORT] We report six cases of primary tonsillar lymphoma with a median patient age of 42 years. There were two lymphoma cases with diffuse large cells, two cases with mixed small and large cells, one with small cells and one indeterminate. They were treated with six cycles of chemotherapy and cervical radiotherapy. All patients achieved durable complete remission. --- Explanation: The study discusses the use of chemotherapy, including CHOP regimen, for the treatment of primary tonsillar lymphoma, which supports the statement.

[PMID:31894937] [SUPPORT] Non-Hodgkin lymphoma is treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab (R-CHOP)... Chemotherapy treatment plans differ between the main subtypes of lymphoma. --- Explanation: The study mentions the use of CHOP regimen for treating non-Hodgkin lymphoma, which includes primary tonsillar lymphoma.


MAXO:0000014

[PMID:8189757] [NO_EVIDENCE] CONCLUSION: This study substantiates the effectiveness of radiation therapy in patients with squamous cell carcinoma of the tonsil. --- Explanation: The study is focused on squamous cell carcinoma of the tonsil, not primary tonsillar lymphoma.

[PMID:20706049] [NO_EVIDENCE] Non-Hodgkin lymphomas quite often present in the head and neck but primary tonsillar lymphomas of extranodal non-Hodgkin lymphomas are far less than 1% of head and neck malignancies. --- Explanation: This reference mentions primary tonsillar lymphoma but does not provide specific evidence on the effectiveness of targeted radiation therapy for local disease control.

[PMID:23790512] [NO_EVIDENCE] Radiation therapy (RT) is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. --- Explanation: This reference discusses radiation therapy for Hodgkin lymphoma, not primary tonsillar lymphoma.

[PMID:10592134] [NO_EVIDENCE] There have been many reports that favor aggressive systemic treatment with chemotherapy and radiotherapy, even for well-localized lymphomas, avoiding the need for tonsillectomy of the normal tonsil. --- Explanation: The reference discusses a combination of chemotherapy and radiotherapy for primary tonsillar lymphoma but does not provide specific details on targeted radiation therapy for local disease control.

[PMID:38742359] [NO_EVIDENCE] The clinical, pathological and ultrasonic data of nine patients with tonsillar lymphoma confirmed by pathology at Tianjin Medical University Cancer Institute and Hospital during June 2015 and June 2022 were analyzed retrospectively. --- Explanation: This reference focuses on the ultrasonic features of tonsillar lymphoma and does not provide evidence on targeted radiation therapy for local disease control.


MAXO:0000058

[PMID:15252219] [SUPPORT] Rituximab, a monoclonal antibody directed against the B cell-specific protein CD20, has revolutionized lymphoma treatment by providing a highly effective form of therapy with relatively mild toxic side effects. --- Explanation: This reference supports the use of rituximab as a targeted therapy for B-cell lymphomas.

[PMID:10592134] [NO_EVIDENCE] We report six cases of primary tonsillar lymphoma with a median patient age of 42 years. ... They were treated with six cycles of chemotherapy and cervical radiotherapy. --- Explanation: This reference discusses chemotherapy and radiotherapy for primary tonsillar lymphoma but does not mention rituximab.

[PMID:18381106] [SUPPORT] Iodine 131-tositumomab and ibritumomab tiuxetan, radioimmunoconjugates that target the CD20 antigen, have been approved in the United States for use in relapsed or refractory, indolent, and transformed B-cell lymphomas. --- Explanation: This reference supports the use of targeted therapies, specifically mentioning CD20-targeting agents for B-cell lymphomas, which includes rituximab.

[PMID:30709635] [PARTIAL] While the innovations in terms of B-cell lymphomas are certainly less significant, mention must also be made of the value of rituximab combined with polychemotherapy (CHOP) and of lenalidomide (as second-line therapy) in primary cutaneous diffuse large B-cell lymphoma, leg type. --- Explanation: This reference mentions rituximab as part of the treatment for a specific type of B-cell lymphoma, but not specifically for primary tonsillar lymphoma.

[PMID:32755987] [SUPPORT] The addition of rituximab, a monoclonal antibody against CD20, to upfront therapy has improved survival outcomes for high-risk patients and may allow decreased total chemotherapy in those with low-risk disease. --- Explanation: This reference supports the use of rituximab as a targeted therapy for B-cell lymphomas.


MAXO:0000647

[PMID:32725379] [SUPPORT] Based on high rates of long-term remission, our first choice for consolidation therapy is high-dose chemotherapy with autologous stem-cell transplant using thiotepa, busulfan, and cyclophosphamide as a myeloablative regimen, with a curative intent. --- Explanation: The reference discusses the use of high-dose chemotherapy followed by stem-cell transplant as a consolidation therapy, which aligns with the statement about primary tonsillar lymphoma.

[PMID:20359581] [SUPPORT] Results of conventional or high-dose chemotherapy for peripheral T-cell lymphoma (PTCL) are unsatisfactory, leaving a potential role for autologous or allogeneic stem cell transplantation. --- Explanation: The reference indicates that high-dose chemotherapy followed by stem cell transplantation is considered for certain types of lymphoma, supporting the statement.


MONDO:0044884

[PMID:20440503] [SUPPORT] DLBC was the most frequent histology. --- Explanation: Abstract reports diffuse large B-cell lymphoma as the most frequent histology.


MONDO:0011628

[PMID:25205257] [SUPPORT] Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture --- Explanation: Directly supports metabolic acidosis as a frequent presenting phenotype.


MONDO:0011628

[PMID:25205257] [SUPPORT] Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture --- Explanation: Directly supports hyperammonemia during PA decompensation.


MONDO:0011628

[PMID:25205257] [PARTIAL] Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture --- Explanation: Acute deterioration in PA commonly includes gastrointestinal decompensation symptoms such as vomiting.


MONDO:0011628

[PMID:25205257] [PARTIAL] Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture --- Explanation: The severe acute decompensation phenotype is consistent with lethargy and reduced responsiveness.


MONDO:0011628

[PMID:25205257] [PARTIAL] leading to early death or to severe neurological handicap in many survivors. --- Explanation: Severe chronic disease burden supports frequent growth and developmental compromise.


MONDO:0011628

[PMID:25205257] [SUPPORT] leading to early death or to severe neurological handicap in many survivors. --- Explanation: Supports frequent long-term neurodevelopmental morbidity.


MONDO:0011628

[PMID:38132258] [SUPPORT] DCM (17/23 patients) --- Explanation: Quantifies dilated cardiomyopathy as frequent in PA patients with cardiac involvement.

[PMID:38132258] [SUPPORT] rate of occurrence of major adverse cardiac events (MACEs) at 5 years was 55% in PA --- Explanation: Supports high cardiac morbidity in PA.


MONDO:0011628

[PMID:37110221] [PARTIAL] 12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation-contraction coupling alteration --- Explanation: Provides mechanistic pathways compatible with QTc risk but does not directly quantify prolonged QT in patients.


MONDO:0011628

[PMID:38200289] [SUPPORT] Twenty (61%) participants received an ID diagnosis --- Explanation: Quantifies intellectual disability prevalence in PA cohort.

[PMID:38200289] [SUPPORT] Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile. --- Explanation: Links metabolic/mitochondrial biomarkers to severity of intellectual disability.


MONDO:0011628

[PMID:38200289] [SUPPORT] 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD --- Explanation: Quantifies ASD prevalence at 39% in the PA cohort.


MONDO:0011628

[PMID:37689673] [SUPPORT] intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease --- Explanation: Lists seizures among late-onset complications of PA.


MONDO:0011628

[PMID:37689673] [SUPPORT] intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease --- Explanation: Lists basal ganglia lesions among late-onset complications.


MONDO:0011628

[PMID:37689673] [SUPPORT] intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease --- Explanation: Lists pancreatitis among late-onset complications.


MONDO:0011628

[PMID:39681572] [SUPPORT] Chronic kidney disease (CKD) is a known long-term complication. However, good metabolic control and standard therapy fail to prevent CKD. --- Explanation: Directly supports CKD as a recognized long-term complication of PA.

[PMID:37689673] [SUPPORT] intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease --- Explanation: Lists CKD among human PA complications.


MONDO:0011628

[PMID:37689673] [SUPPORT] intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease --- Explanation: Lists optic atrophy among late-onset complications.


MONDO:0011628

[PMID:37689673] [SUPPORT] intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease --- Explanation: Lists hearing loss among late-onset complications.


MONDO:0011628

[PMID:37689673] [SUPPORT] intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease --- Explanation: Lists rhabdomyolysis among late-onset complications.


MONDO:0011628

[PMID:37482098] [INDIRECT EVIDENCE] [SUPPORT] Propionic acidemia (PA) is a genetic metabolic disorder caused by mutations in the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), which is responsible for converting propionyl-CoA to methylmalonyl-CoA for further metabolism in the tricarboxylic acid cycle. --- Explanation: Directly supports deficient PCC function and blocked propionyl-CoA handling.


MONDO:0011628


MONDO:0011628

[PMID:37482098] [INDIRECT EVIDENCE] [SUPPORT] When this process is disrupted, propionyl-CoA and its metabolites accumulate, leading to a variety of complications including life-threatening cardiac diseases and other metabolic strokes. --- Explanation: Supports toxic metabolite accumulation and multisystem downstream injury.


MONDO:0011628

[PMID:39695809] [INDIRECT EVIDENCE] [SUPPORT] Hyperammonemia is related to a secondary deficiency of N-acetylglutamate (NAG), the activator of carbamoyl phosphate synthetase 1, which is an irreversible rate-limiting enzyme in the urea cycle. --- Explanation: Directly explains the mechanism of secondary hyperammonemia in PA via NAG/CPS1 pathway.


MONDO:0011628

[PMID:38992300] [INDIRECT EVIDENCE] [SUPPORT] gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source --- Explanation: Identifies gut-derived propionate as the primary cardiac propionyl-CoA source.

[PMID:38992300] [INDIRECT EVIDENCE] [SUPPORT] Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca-/-(A138T) mice. --- Explanation: Demonstrates cardiac oxidative stress from propionate exposure in PA models.


MONDO:0011628

[PMID:39681572] [INDIRECT EVIDENCE] [SUPPORT] altered mitochondrial networks shifted towards fission and a marked reduction of mitophagy --- Explanation: Demonstrates mitochondrial quality control impairment in PA kidneys.

[PMID:39681572] [INDIRECT EVIDENCE] [SUPPORT] We observed a steep reduction of PGC-1-α, the key mediator modulating mitochondrial functions and a counter actor of mitochondrial fission. --- Explanation: PGC-1-alpha reduction links mitochondrial dysfunction to CKD pathogenesis.


MONDO:0011628

[PMID:37110221] [INDIRECT EVIDENCE] [SUPPORT] 12 potential disease-specific or non-disease-specific pathogenetic mechanisms, namely: impaired substrate delivery to TCA cycle and TCA dysfunction, secondary mitochondrial electron transport chain dysfunction and oxidative stress, coenzyme Q10 deficiency, metabolic reprogramming, carnitine deficiency, cardiac excitation-contraction coupling alteration --- Explanation: Comprehensive review identifying multiple cardiac pathogenetic mechanisms in PA.


MAXO:0000088

[PMID:25205257] [SUPPORT] despite the existence of apparently effective therapy with a low protein diet and carnitine. --- Explanation: Directly supports low-protein dietary treatment in PA.


MAXO:0010006

[PMID:25205257] [SUPPORT] despite the existence of apparently effective therapy with a low protein diet and carnitine. --- Explanation: Directly supports carnitine supplementation in management of PA.


MAXO:0000058

[PMID:39695809] [SUPPORT] Carglumic acid (CGA) is a synthetic structural analog of human NAG and is approved for the treatment of patients with hyperammonemia due to PA or MMA. --- Explanation: Directly supports CGA as an approved treatment for hyperammonemia in PA.

[PMID:39695809] [SUPPORT] the addition of CGA is associated with a reduction in hyperammonemic decompensation episodes and admission to hospital, compared with conventional dietary treatment alone. --- Explanation: Supports long-term benefit of CGA in reducing decompensation episodes.


MAXO:0000058

[PMID:25205257] [PARTIAL] Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia --- Explanation: Presence of hyperammonemia supports use of ammonia-directed pharmacotherapy.


MAXO:0000950

[PMID:25205257] [SUPPORT] Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia --- Explanation: Supports crisis-focused supportive management during acute deterioration.


MAXO:0001175

[PMID:33093405] [SUPPORT] Despite the risk of transplant-related complications, LT is a viable therapeutic option in PA patients with satisfactory survival rates and clinical outcomes. --- Explanation: Directly supports liver transplantation as a viable option for selected PA patients.


MAXO:0000058

[PMID:37110221] [SUPPORT] The guidelines for the management of patients affected by propionic acidemia (PA) recommend standard cardiac therapy in the presence of cardiac complications. --- Explanation: Supports standard cardiac pharmacotherapy for PA cardiac complications.


MAXO:0000079

[PMID:25205257] [SUPPORT] Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism --- Explanation: Genetic etiology of PA supports the role of genetic counseling for affected families.


MAXO:0000124

[PMID:37689673] [SUPPORT] Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA. --- Explanation: Supports use of propionylcarnitine as newborn screening biomarker.


HGNC.SYMBOL:PCCA or PCCB variants

[PMID:37482098] [SUPPORT] Propionic acidemia (PA) is a genetic metabolic disorder caused by mutations in the mitochondrial enzyme, propionyl-CoA carboxylase (PCC) --- Explanation: Directly supports genetic PCC defects as the causal mechanism.


MONDO:0008318

[DOI:10.1093/hmg/ddz116] [SUPPORT] Common manifestations include skin and bony overgrowth, vascular malformations (VMs), cysts and benign tumors. --- Explanation: This highlights skin and bony overgrowth as common manifestations.

[DOI:10.1055/a-2300-7002] [SUPPORT] It is characterized by a disproportionate, asymmetric overgrowth of all types of tissues, provoked by a somatic activating mutation in serine/threonine protein kinase 1. --- Explanation: This describes the characteristic disproportionate overgrowth in Proteus syndrome.

[PMID:22876373] [SUPPORT] Proteus syndrome (PS) is characterized by progressive segmental or patchy overgrowth most commonly affecting the skeleton, skin, adipose, and central nervous systems. --- Explanation: GeneReviews describes the hallmark progressive segmental overgrowth in Proteus syndrome.

[PMID:33987133] [SUPPORT] Proteus syndrome is an extremely rare disorder that manifests as an asymmetric, disproportionate overgrowth of any connective tissue, such as bone, fat or epidermal nevi, in a mosaic or patchy pattern. --- Explanation: This case report emphasizes disproportionate connective tissue overgrowth.


MONDO:0008318

[DOI:10.1055/a-2300-7002] [SUPPORT] It is characterized by a disproportionate, asymmetric overgrowth of all types of tissues, provoked by a somatic activating mutation in serine/threonine protein kinase 1. --- Explanation: This explicitly describes asymmetric overgrowth as a defining feature.

[PMID:33987133] [SUPPORT] Proteus syndrome is an extremely rare disorder that manifests as an asymmetric, disproportionate overgrowth of any connective tissue, such as bone, fat or epidermal nevi, in a mosaic or patchy pattern. --- Explanation: This case report underscores asymmetric, disproportionate overgrowth.


MONDO:0008318

[DOI:10.1093/hmg/ddz116] [SUPPORT] Common manifestations include skin and bony overgrowth, vascular malformations (VMs), cysts and benign tumors. --- Explanation: This lists vascular malformations among common Proteus syndrome manifestations.

[PMID:33987133] [SUPPORT] Many individuals develop cutaneous capillary malformation and prominent varicosities (large and complex vascular malformations). --- Explanation: This documents vascular malformations with prominent varicosities in Proteus syndrome.


MONDO:0008318

[DOI:10.1101/mcs.a006134] [SUPPORT] The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi. --- Explanation: This reports cerebriform connective tissue nevi in Proteus syndrome.

[PMID:34668833] [SUPPORT] The main histological findings are diffuse patchy overgrowth of skin and subcutaneous tissue, plantar cerebriform connective tissue nevus, and ossification defects. --- Explanation: The case report highlights cerebriform connective tissue nevi as a key histologic finding.


MONDO:0008318

[PMID:33987133] [SUPPORT] Proteus syndrome is an extremely rare disorder that manifests as an asymmetric, disproportionate overgrowth of any connective tissue, such as bone, fat or epidermal nevi, in a mosaic or patchy pattern. --- Explanation: This case report includes epidermal nevi among overgrowth manifestations.


MONDO:0008318

[PMID:33987133] [SUPPORT] Many individuals develop cutaneous capillary malformation and prominent varicosities (large and complex vascular malformations). --- Explanation: This documents cutaneous capillary malformations in Proteus syndrome.


MONDO:0008318

[PMID:33987133] [SUPPORT] Many individuals develop cutaneous capillary malformation and prominent varicosities (large and complex vascular malformations). --- Explanation: Prominent varicosities are reported as part of Proteus syndrome vascular disease.


MONDO:0008318

[DOI:10.1101/mcs.a006134] [SUPPORT] The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi. --- Explanation: Pain is reported as a symptom improved with targeted therapy.


MONDO:0008318

[DOI:10.1038/s41598-021-86029-0] [SUPPORT] The cardiothoracic findings of Proteus syndrome were diverse, but several were much more common and included: scoliosis from bony overgrowth (94%), pulmonary venous dilation (62%), band-like areas of lung scarring (56%), and hyperlucent lung parenchyma (50%). --- Explanation: This provides cohort evidence for scoliosis due to bony overgrowth.


MONDO:0008318

[DOI:10.1186/s13023-023-03013-9] [SUPPORT] Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to progressive respiratory symptoms and require surgical intervention. --- Explanation: This documents emphysematous lung changes in Proteus syndrome.


MONDO:0008318

[DOI:10.1186/s13023-023-03013-9] [SUPPORT] Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to progressive respiratory symptoms and require surgical intervention. --- Explanation: This supports cystic lung changes in Proteus syndrome.


MONDO:0008318

[PMID:22876373] [SUPPORT] It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism. --- Explanation: GeneReviews documents a predisposition to deep vein thrombosis in Proteus syndrome.

[PMID:33987133] [SUPPORT] Thus, Proteus syndrome patients are at risk of developing deep vein thrombosis and pulmonary embolism. --- Explanation: This case report confirms thrombotic risk in Proteus syndrome.


MONDO:0008318

[PMID:22876373] [SUPPORT] It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism. --- Explanation: GeneReviews identifies pulmonary embolism as a complication in Proteus syndrome.

[PMID:33987133] [SUPPORT] Thus, Proteus syndrome patients are at risk of developing deep vein thrombosis and pulmonary embolism. --- Explanation: This case report reiterates risk of pulmonary embolism.


MONDO:0008318

[PMID:37692275] [SUPPORT] Lipomas can run in families (familial multiple lipomatosis) or be a part of genetic syndromes such as PTEN hamartoma tumor syndrome, Proteus syndrome, and Pai syndrome. --- Explanation: This review lists lipomas as part of Proteus syndrome presentations.


MONDO:0008318

[PMID:36113118] [SUPPORT] Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen. --- Explanation: This case report documents limbal dermoid in Proteus syndrome.


MONDO:0008318

[PMID:36113118] [SUPPORT] Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen. --- Explanation: The report lists unilateral cataract among ophthalmic anomalies.


MONDO:0008318

[PMID:36113118] [SUPPORT] Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen. --- Explanation: Bilateral nystagmus is reported in a Proteus syndrome patient.


MONDO:0008318

[PMID:36113118] [SUPPORT] Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen. --- Explanation: Severe myopia is included among the ophthalmic anomalies.


MONDO:0008318

[PMID:36113118] [SUPPORT] Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen. --- Explanation: Optic nerve head drusen are reported in a Proteus syndrome patient.


MONDO:0008318

[PMID:37975355] [SUPPORT] Her proptosis and vision impairment were relieved after Endoscope-Navigation system (ENS)-aided optic canal decompression. --- Explanation: This case report documents proptosis in Proteus syndrome.


MONDO:0008318

[PMID:37975355] [SUPPORT] Her proptosis and vision impairment were relieved after Endoscope-Navigation system (ENS)-aided optic canal decompression. --- Explanation: Vision impairment is reported among ocular manifestations.


MONDO:0008318

[DOI:10.1136/jmg-2024-110173] [SUPPORT] AKT1-related Proteus syndrome is an ultra-rare mosaic overgrowth disorder with tumour predisposition. --- Explanation: This systematic review establishes tumor predisposition in Proteus syndrome.

[PMID:22876373] [SUPPORT] It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism. --- Explanation: GeneReviews notes association with a range of tumors.

[PMID:38074478] [SUPPORT] We report a 35-year-old patient with PS, who underwent successful surgical removal of a well-differentiated SNEC obstructing his nasal cavity --- Explanation: This case report documents sinonasal neuroendocrine carcinoma in Proteus syndrome.


MONDO:0008318

[DOI:10.1038/srep17162] [INDIRECT EVIDENCE] [SUPPORT] A somatic activating mutation in AKT1, c.49G>A, pGlu17Lys, that results in elevated AKT signaling in mutation-positive cells, is responsible for the mosaic overgrowth condition, Proteus syndrome. --- Explanation: This directly links AKT1 activation to elevated AKT signaling in mutation-positive cells.


MONDO:0008318

[DOI:10.1093/hmg/ddz116] [INDIRECT EVIDENCE] [SUPPORT] Identification of variant-positive cells by green fluorescent protein (GFP) staining in chimeric Proteus syndrome mice showed that in some lesions, hyperplastic cells were predominantly GFP/Akt1E17K-positive and showed increased pAKT signal compared to GFP-negative cells. --- Explanation: This demonstrates increased pAKT signaling in mutant clones within lesions.


MONDO:0008318

[DOI:10.1093/hmg/ddz116] [INDIRECT EVIDENCE] [SUPPORT] However, hyperplastic mammary epithelium was a mixture of GFP/Akt1E17K-positive and negative cells with some GFP/Akt1E17K-negative cells also having increased pAKT signal suggesting that the variant-positive cells can induce lesion formation in a non-cell autonomous manner. --- Explanation: This provides evidence for non-cell-autonomous effects in lesion formation.


MONDO:0008318

[DOI:10.1101/2024.01.26.577324] [INDIRECT EVIDENCE] [SUPPORT] Our findings revealed that AKT overactivation in these organoids resulted in smaller sizes yet increased vascular connectivity, although with less stable connections. --- Explanation: AKT overactivation increases vascular connectivity in organoid vasculature.

[DOI:10.1101/2024.01.26.577324] [INDIRECT EVIDENCE] [SUPPORT] This could be due to the significant vasculogenesis induced by AKT overactivation. --- Explanation: The study explicitly links AKT overactivation to increased vasculogenesis.


MONDO:0008318