MONDO:0019234

[PMID:7685145] [SUPPORT] Because peroxisomes are involved in the metabolism of lipids critical to the functioning of the nervous system, many of the peroxisomal disorders manifest with significant degrees of progressive psychomotor dysfunction. --- Explanation: The literature indicates that peroxisomal disorders, which include Peroxisome Biogenesis Disorders (PBDs), frequently present with progressive psychomotor dysfunction, supporting the statement that developmental delay is a very frequent neurologic phenotype.

[PMID:36293220] [SUPPORT] The clinical presentation of PBDs may range from severe, lethal multisystemic disorders to milder, late-onset disease. The vast majority of PBDs belong to Zellweger Spectrum Disordes (ZSDs) and represents a continuum of overlapping clinical symptoms. --- Explanation: Although this does not explicitly mention developmental delay, the overall description implies a frequent occurrence of neurologic dysfunction, which is often tied to developmental delays.

[PMID:11769739] [SUPPORT] Distinctive external features are variable among these three disorders, and neurologic deficit has its onset at birth or in infancy. --- Explanation: The article describes neurologic deficits appearing early in life, which aligns with developmental delays being a very frequent phenotype.

[PMID:38409970] [SUPPORT] Zellweger syndrome is an autosomal recessive disease within the spectrum of peroxisome biogenesis disorder manifesting in the neonatal period with profound dysfunction of the central nervous system, liver and kidney. --- Explanation: The mention of the neonatal onset of CNS dysfunction supports the frequent presence of developmental delays.

[PMID:24172221] [SUPPORT] Neurodevelopmental deficits and age-related occurrence of seizures are characteristic of RCDP and are related to the rest-activity in plasmalogen biosynthesis. --- Explanation: RCDP is a type of peroxisomal disorder, and its characteristic neurodevelopmental deficits support the statement about developmental delay being a common phenotype in PBDs.


MONDO:0019234


MONDO:0019234

[PMID:31005404] [PARTIAL] Inherited metabolic diseases account for about one third of pediatric patients with hepatomegaly, acute liver failure, cirrhosis or cholestasis. --- Explanation: The reference states that inherited metabolic diseases, which include peroxisome biogenesis disorders, account for a substantial portion of pediatric hepatomegaly cases but does not specify the frequency as 'frequent.'

[PMID:22978395] [PARTIAL] Liver pathology is a frequent finding in patients affected by a peroxisomal disorder. --- Explanation: The reference mentions liver pathology as frequent but does not specifically state hepatomegaly.

[PMID:26615381] [NO_EVIDENCE] ZS is a peroxisomal disorder with a multiple congenital anomalies, characterized by stereotypical facies, profound hypotonia, organ involvement including cerebral, retinal, hepatic, and renal. --- Explanation: The reference discusses organ involvement including hepatic involvement but does not specify hepatomegaly as frequent.


MONDO:0019234

[PMID:31884631] [SUPPORT] Retinopathy is a recurrent feature in both the severely and mildly affected patients, which can be accompanied with other ophthalmological pathologies. --- Explanation: The study states that retinopathy is a recurrent feature in patients with peroxisomal disorders, supporting the statement that visual phenotypes, specifically retinopathy, are frequent.

[PMID:12473763] [SUPPORT] Common to these three disorders are liver disease, variable neurodevelopmental delay, retinopathy, and perceptive deafness. --- Explanation: The study indicates that retinopathy is common in peroxisome biogenesis disorders like Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease, supporting the frequent occurrence of retinopathy as a visual phenotype.

[PMID:35227579] [SUPPORT] Retinal degeneration with or without optic atrophy is the most frequent phenotype, followed by oculomotor problems, involvement of the cornea and lens, and refractive errors. --- Explanation: The study states that retinal degeneration is the most frequent ocular phenotype observed in inherited metabolic disorders, which includes peroxisome biogenesis disorders, thereby supporting the frequent occurrence of retinopathy.

[PMID:31254513] [SUPPORT] Retinopathy leading to blindness is one of the major untreatable handicaps faced by patients with ZSD but is not well characterized. --- Explanation: The study highlights that retinopathy leading to blindness is a significant issue in patients with Zellweger Spectrum Disorder, a type of peroxisome biogenesis disorder, supporting the frequency of retinopathy as a visual phenotype.


MONDO:0019234

[PMID:34534157] [SUPPORT] The majority of PBD-ZSD patients in this study presented with moderately-severe to severe hearing loss. --- Explanation: This study characterizes hearing loss as a common phenotype in patients with Peroxisome Biogenesis Disorder within the Zellweger Spectrum.

[PMID:36291074] [SUPPORT] Peroxisome biogenesis disorders (due to PEX gene mutations) are associated with symptoms that range in severity and can lead to early childhood death, but a common feature is hearing impairment. --- Explanation: This study also confirms hearing impairment as a frequent phenotype in Peroxisome Biogenesis Disorders, further supporting the statement.

[PMID:33417209] [SUPPORT] Heimler syndrome is a rare syndrome associating sensorineural hearing loss with retinal dystrophy and amelogenesis imperfecta due to PEX1 or PEX6 biallelic pathogenic variations. This syndrome is one of the less severe forms of peroxisome biogenesis disorders. --- Explanation: Heimler syndrome, a less severe form of peroxisome biogenesis disorders, frequently presents with sensorineural hearing loss, further supporting the frequent association of hearing loss with these disorders.


MONDO:0019234

[PMID:36649687] [SUPPORT] Primary adrenal insufficiency is common in patients with PD. Based on our data, patients with the compound heterozygous PEX1 pathogenic variants of exon 13 (c.2097dupT and c.2528G>A) tend to have adrenal insufficiency. --- Explanation: The study indicates that primary adrenal insufficiency is frequent in patients with peroxisomal disorders, specifically those with PEX1 pathogenic variants.

[PMID:25179809] [SUPPORT] Primary adrenal insufficiency was found in 7/24 patients examined, with 4/7 being asymptomatic. Systematic evaluation of adrenal function, through a Synacthen test, should be included in the clinical management of these patients. --- Explanation: The study highlights a high prevalence of primary adrenal insufficiency in patients with Zellweger spectrum disorders, which are a type of peroxisome biogenesis disorder.


MONDO:0019234

[PMID:27941306] [NO_EVIDENCE] Peroxisome is a single-membrane-bounded ubiquitous organelle containing a hundred different enzymes that catalyze various metabolic pathways such as beta-oxidation of very long-chain fatty acids and synthesis of plasmalogens. --- Explanation: The provided literature does not mention thrombocytopenia or any hematologic symptoms in relation to Peroxisome Biogenesis Disorders.

[PMID:31884631] [NO_EVIDENCE] Peroxisomal disorders are a group of inherited metabolic diseases, which can be incompatible with life in the postnatal period or allow survival into adulthood. Retinopathy is a recurrent feature in both the severely and mildly affected patients, which can be accompanied with other ophthalmological pathologies. --- Explanation: This reference discusses peroxisomal disorders but does not mention thrombocytopenia or other hematologic conditions.


MONDO:0019234

[PMID:25465824] [PARTIAL] CI in MIDs includes cardiomyopathy, arrhythmias, heart failure, pulmonary hypertension, dilation of the aortic root, pericardial effusion, coronary heart disease, autonomous nervous system dysfunction, congenital heart defects, or sudden cardiac death. --- Explanation: The literature confirms that cardiomyopathy and heart failure are associated with mitochondrial disorders (MIDs), which are a type of metabolic disorder. However, it does not specifically mention peroxisome biogenesis disorders (PBDs) in this context.

[PMID:36870438] [NO_EVIDENCE] Paediatric cardiomyopathies form a heterogeneous group of disorders characterized by structural and electrical abnormalities of the heart muscle, commonly due to a gene variant of the myocardial cell structure. --- Explanation: This reference provides an overview of pediatric cardiomyopathies but does not specifically mention peroxisome biogenesis disorders (PBDs) as a cause.


MONDO:0019234

[PMID:33417206] [INDIRECT EVIDENCE] [SUPPORT] Impaired peroxisome biogenesis, including defects of membrane assembly, import of peroxisomal matrix proteins, and division of peroxisome, causes peroxisome biogenesis disorders (PBDs). --- Explanation: This reference highlights that mutations affecting peroxisome biogenesis lead to dysfunction of peroxisomes and consequently to metabolic impairments.

[PMID:28409474] [INDIRECT EVIDENCE] [SUPPORT] More than a dozen complementation groups of animal somatic mutant cells defective in peroxisome biogenesis have been successfully isolated in Chinese hamster ovary (CHO) cells and used as a model system reflecting fatal human severe genetic disorders named peroxisome biogenesis disorders (PBD). --- Explanation: Defective peroxisome biogenesis due to mutations in PEX genes supports the statement about peroxisomal disorders and impaired metabolic processes.

[PMID:28320181] [INDIRECT EVIDENCE] [SUPPORT] Peroxisome biogenesis factor 10 (PEX10) is involved in the import of peroxisomal matrix proteins, and the mutation of this gene causes 3 subtypes of peroxisome biogenesis disorders... --- Explanation: The reference details how mutations in PEX10 affect peroxisomal import, aligning with the statement's assertion about disrupted peroxisome function.

[PMID:36249295] [INDIRECT EVIDENCE] [SUPPORT] Peroxisomal biogenesis disorders (PBDs) represent a spectrum of conditions that result in vision loss, sensorineural hearing loss, neurologic dysfunction, and other abnormalities resulting from aberrant peroxisomal function caused by mutations in PEX genes. --- Explanation: The study confirms that mutations in PEX genes disrupt peroxisomal functions, leading to various metabolic and physiological impairments.

[PMID:34804114] [INDIRECT EVIDENCE] [SUPPORT] Pathogenic variants in the PEX26 gene lead to peroxisomal disorders of the full Zellweger spectrum continuum. --- Explanation: PEX26 mutations, which lead to peroxisomal biogenesis disorders, confirm the link between PEX gene defects and impaired peroxisomal function.

[PMID:9458170] [INDIRECT EVIDENCE] [SUPPORT] Neurological dysfunction is a prominent feature of most peroxisomal disorders. Enormous progress in defining their gene defects has been achieved. The genes and gene products, peroxins (PEX), in five of the complementation groups have been defined. --- Explanation: This reference illustrates the role of PEX genes in peroxisomal disorders, supporting the claim of their involvement in cellular and metabolic disruption.


MONDO:0019234

[PMID:19933170] [INDIRECT EVIDENCE] [PARTIAL] Peroxisomes are vital eukaryotic organelles that participate in lipid metabolism, in particular the metabolism of very-long-chain fatty acids (VLCFA)... including impaired peroxisomal protein import, elevated VLCFA levels and growth retardation. --- Explanation: The reference supports the accumulation of VLCFAs as part of the pathophysiology of Peroxisome Biogenesis Disorders but does not mention bile acid intermediates or phytanic acid.

[PMID:3119940] [INDIRECT EVIDENCE] [PARTIAL] In patients with cerebro-hepato-renal (Zellweger) syndrome, the absence of peroxisomes results in an impairment of metabolic processes... These include the catabolism of very long chain (greater than C22) fatty acids... the catabolism of phytanic acid and the catabolism of pipecolic acid. --- Explanation: This reference supports the accumulation of VLCFAs and phytanic acid in peroxisomal disorders but does not mention bile acid intermediates.

[PMID:22978395] [INDIRECT EVIDENCE] [PARTIAL] By comparing the different peroxisomal disorders, we provide evidence suggesting that the main hepatotoxic metabolites responsible for the liver pathology found in patients, are the bile acid synthesis intermediates di- and trihydroxycholestanoic acid (DHCA and THCA). --- Explanation: This reference supports the accumulation of bile acid intermediates in peroxisomal disorders but does not mention VLCFAs or phytanic acid.


MONDO:0019234

[PMID:36720320] [INDIRECT EVIDENCE] [SUPPORT] The absence of plasmalogens in several organs of patients with deficiency in peroxisome biogenesis suggests that de novo synthesis of plasmalogens contributes significantly to plasmalogen homeostasis in humans. --- Explanation: The literature indicates that plasmalogen biosynthesis is significantly affected in patients with peroxisome biogenesis disorders, which supports the statement regarding impaired synthesis of plasmalogens disrupting normal cellular functions.

[PMID:32165495] [INDIRECT EVIDENCE] [SUPPORT] The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid beta-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. --- Explanation: This study reinforces that impaired peroxisome function, including the biosynthesis of plasmalogens, leads to a broad spectrum of cellular dysfunctions.

[PMID:33417206] [INDIRECT EVIDENCE] [SUPPORT] Peroxisomes are presented in all eukaryotic cells and play essential roles in many of lipid metabolic pathways, including beta-oxidation of fatty acids and synthesis of ether-linked glycerophospholipids, such as plasmalogens. --- Explanation: The abstract confirms that peroxisomes are crucial for the synthesis of plasmalogens and that their dysfunction could disrupt normal cellular functions.


MONDO:0019234

[PMID:15868469] [INDIRECT EVIDENCE] [SUPPORT] Peroxisome biogenesis disorders, of which Zellweger syndrome is the most severe, result in severe neurological dysfunction associated with abnormal CNS neuronal migrations due to the lack of functional peroxisomes. --- Explanation: The reference specifies that a lack of functional peroxisomes leads to severe neurological dysfunction, including demyelination and defects in neuronal migration, which aligns with the statement's content.

[PMID:33417206] [INDIRECT EVIDENCE] [SUPPORT] Impaired peroxisome biogenesis, including defects of membrane assembly, import of peroxisomal matrix proteins, and division of peroxisome, causes peroxisome biogenesis disorders (PBDs). --- Explanation: This reference describes PBDs leading to significant neurodegeneration and psychomotor dysfunction, consistent with the statement on neurological dysfunction due to the disorder.

[PMID:22978395] [INDIRECT EVIDENCE] [PARTIAL] Liver pathology is a frequent finding in patients affected by a peroxisomal disorder. ... we provide evidence suggesting that the main hepatotoxic metabolites responsible for the liver pathology found in patients, are the bile acid synthesis intermediates di- and trihydroxycholestanoic acid (DHCA and THCA). --- Explanation: While this reference supports the role of toxic metabolites, it focuses on liver pathology rather than CNS-specific features like demyelination and neuronal migration defects.

[PMID:7685145] [INDIRECT EVIDENCE] [SUPPORT] Because peroxisomes are involved in the metabolism of lipids critical to the functioning of the nervous system, many of the peroxisomal disorders manifest with significant degrees of progressive psychomotor dysfunction. --- Explanation: The reference acknowledges the impact on the nervous system and describes psychomotor dysfunction, supporting the idea of neurological dysfunction.

[PMID:30739266] [INDIRECT EVIDENCE] [PARTIAL] The importance of functional peroxisomes for cellular metabolism is demonstrated by the marked brain and systemic organ abnormalities occuring in peroxisome biogenesis disorders and peroxisomal enzyme deficiencies --- Explanation: This reference highlights general brain abnormalities due to peroxisomal dysfunction but does not specifically describe demyelination and neuronal migration defects. Partial support is given as it indicates a broad CNS impact.


MONDO:0019234

[PMID:12473763] [INDIRECT EVIDENCE] [SUPPORT] Common to these three disorders are liver disease, variable neurodevelopmental delay, retinopathy, and perceptive deafness. --- Explanation: The study mentions liver disease as a common symptom of peroxisome biogenesis disorder (PBD), supporting hepatic dysfunction.

[PMID:22978395] [INDIRECT EVIDENCE] [SUPPORT] The main hepatotoxic metabolites responsible for the liver pathology found in patients, are the bile acid synthesis intermediates di- and trihydroxycholestanoic acid (DHCA and THCA). --- Explanation: This reference supports the accumulation of bile acid intermediates causing liver pathology in PBDs.

[PMID:29282281] [INDIRECT EVIDENCE] [SUPPORT] They are caused by mutations of peroxisomal biogenesis factors encoded by Pex genes, and result in childhood lethality --- Explanation: This reference indirectly supports the statement by discussing the lethal and severe impact of PBDs, including liver dysfunction.

[PMID:8184191] [INDIRECT EVIDENCE] [SUPPORT] Zellweger disease or cerebro-hepato-renal syndrome is characterized clinically by... liver damage leading to cirrhosis. --- Explanation: This confirms hepatic dysfunction including fibrosis in PBDs.

[PMID:8729109] [INDIRECT EVIDENCE] [SUPPORT] Abnormally high levels of very long-chain fatty acids (VLCFA) are a feature in...peroxisomal disorders. --- Explanation: Supports the accumulation of VLCFAs as part of the pathophysiology.

[PMID:17682975] [INDIRECT EVIDENCE] [SUPPORT] Nine recognized inborn errors of bile acid metabolism have been identified that lead to enzyme deficiencies and impaired bile acid synthesis in infants, children, and adults. --- Explanation: This reference supports the accumulation of bile acid intermediates, contributing to hepatic dysfunction.


MONDO:0019234

[PMID:10904262] [INDIRECT EVIDENCE] [SUPPORT] Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and rhizomelic chondrodysplasia punctata are progressive disorders characterized by loss of multiple peroxisomal metabolic functions. --- Explanation: The context indicates that rhizomelic chondrodysplasia punctata (a type of peroxisome biogenesis disorder) results from peroxisomal dysfunction, supporting the connection between plasmalogen deficiency and skeletal abnormalities, including rhizomelic shortening of limbs and chondrodysplasia punctata.

[PMID:10972423] [INDIRECT EVIDENCE] [SUPPORT] The case of a Yemeni girl with isolated peroxisomal acyl-CoA:dihydroxyacetonephosphate acyltransferase (DHAPAT) deficiency is reported. She had rhizomelic chondrodysplasia punctata, microcephaly, failure to thrive, delayed motor and mental development, and spastic quadriplegia. --- Explanation: The document discusses a case where plasmalogen biosynthesis deficiency leads to rhizomelic chondrodysplasia punctata, supporting the statement.

[PMID:8507680] [INDIRECT EVIDENCE] [SUPPORT] The results have clearly shown an indispensable role for peroxisomes in the total process of ether lipid synthesis as evidenced by a description of the cellular topography of this process. --- Explanation: The paper supports the importance of peroxisomes in lipid synthesis, including plasmalogens, which are associated with diseases like rhizomelic chondrodysplasia punctata that impact bone and cartilage formation.

[PMID:24172221] [INDIRECT EVIDENCE] [SUPPORT] Rhizomelic chondrodysplasia punctata (RCDP); a peroxisomal disorder clinically characterized by skeletal abnormalities, congenital cataracts, severe growth and developmental impairments and immobility of joints. Defective plasmalogen biosynthesis is the main biochemical feature. --- Explanation: This clearly supports the notion that defective plasmalogen biosynthesis leads to skeletal abnormalities characteristic of rhizomelic chondrodysplasia punctata, including rhizomelic shortening of limbs and chondrodysplasia punctata.


MAXO:0000011

[PMID:11060787] [PARTIAL] Treatment of PBD patients has generally involved only supportive care and symptomatic therapy. --- Explanation: The statement about supportive care and symptomatic therapy is accurate but does not explicitly mention physical therapy for hypotonia and seizure management.

[PMID:38409970] [PARTIAL] Despite an absence of treatment options, prompt diagnosis of Zellweger syndrome is important for providing appropriate symptomatic care. --- Explanation: The statement supports symptomatic care but does not detail specific treatments such as physical therapy for hypotonia or seizure management.


MAXO:0000088

[PMID:11060787] [SUPPORT] A number of experimental therapies have been evaluated to determine whether or not correction of biochemical abnormalities through dietary supplementation and/or modification is of clinical benefit to PBD patients. --- Explanation: This snippet indicates that dietary supplementation and/or modification has been evaluated to manage biochemical abnormalities in PBD patients, supporting the statement that specialized diet and supplements can be a treatment strategy.

[PMID:18758655] [SUPPORT] The most important measures used to manage the intoxication present in many inborn errors of intermediate metabolism were presented (restriction of substrate build-up by means of diet or enzymatic inhibition, removal of toxic products, stimulation of residual enzyme activity, replacement of the deficient product). --- Explanation: This reference discusses the use of diet as a measure to manage biochemical abnormalities in metabolic disorders, including peroxisomal diseases, which supports the statement.

[PMID:16819396] [NO_EVIDENCE] Bile-acid therapy using oral cholic acid has proven effective in most of these bile acid synthetic defects making early diagnosis crucial to optimum clinical prognosis. --- Explanation: While this reference discusses a specific bile-acid therapy, it does not provide evidence about dietary or supplemental approaches for managing biochemical abnormalities in PBDs.


MAXO:0010039

[PMID:35331403] [SUPPORT] Most of these disorders are currently treated by liver transplantation as standard of care. --- Explanation: The reference indicates that liver transplantation is the standard of care for congenital inherited hepatic disorders, which includes peroxisomal disorders like Peroxisome Biogenesis Disorder (PBD), supporting that liver transplant is considered in severe cases with significant liver dysfunction.

[PMID:26615381] [PARTIAL] ZS should be considered in the list of differential diagnosis in infants with stereotypical phenotype, neurodevelopmental delay, and severe hypotonia in association with liver and other organs involvement. --- Explanation: While this reference confirms liver involvement in Peroxisome Biogenesis Disorders such as Zellweger Syndrome, it does not specifically mention liver transplantation as a treatment.

[PMID:22974902] [PARTIAL] When none of the liver parenchyma is spared, or kidney insufficiency is marked, the only potentially curable treatment is liver transplantation (LT). --- Explanation: This reference supports the use of liver transplantation in severe liver conditions, though it does not directly mention Peroxisome Biogenesis Disorder.


MAXO:0000079

[PMID:14619605] [SUPPORT] Genetic counseling has developed as a discipline in response to the need to educate patients, families and professionals about genetic mechanisms and their application in health care. ... Genetic counseling is a process of medical education based upon empathy, patient autonomy and confidentiality in an atmosphere of empathy, support and understanding. --- Explanation: The literature describes genetic counseling as a discipline developed to educate patients, families, and professionals about genetic mechanisms and their application in healthcare, which supports the statement about providing information and support to families regarding inheritance and implications.

[PMID:30237433] [SUPPORT] Furthermore, it is also important to identify pre-symptomatic patients by family analysis of probands by providing appropriate disease information and genetic counseling, which will also lead to early intervention. --- Explanation: The literature discusses the importance of providing disease information and genetic counseling to families, supporting the statement about providing information and support to families regarding inheritance and implications in the context of peroxisomal diseases.


HGNC.SYMBOL:PEX1

[PMID:33955040] [SUPPORT] Zellweger syndrome (ZS) is the foremost common and severe phenotype within the heterogeneous ZSD. However, missense mutations encode proteins with residual functions, which are associated with phenotypes that are milder than ZS. Mutations in the PEX1 gene are among the most prevalent. --- Explanation: The statement is supported as it mentions that mutations in the PEX1 gene are among the most prevalent causes of Zellweger syndrome, which is a type of PBD.


HGNC.SYMBOL:PEX6

[PMID:17055079] [SUPPORT] Defects in PEX genes impair peroxisome assembly and multiple metabolic pathways confined to this organelle, thus providing the biochemical and molecular bases of the peroxisome biogenesis disorders (PBD). --- Explanation: This statement indicates that mutations in PEX genes, including PEX6, are foundational to the development of peroxisome biogenesis disorders.

[PMID:15858711] [SUPPORT] Matsumoto and colleagues recently identified PEX26 as the gene responsible for complementation group 8 of the peroxisome biogenesis disorders... Here, we identify new PEX26 disease alleles, localize the PEX6-binding domain to the N-terminal half of the protein (aa 29-174), and show that, at the cellular level, PEX26 deficiency impairs peroxisomal import of both PTS1- and PTS2-targeted matrix proteins. --- Explanation: This paper discusses PEX26 in detail but also underscores the critical function of PEX6 in peroxisome biogenesis.

[PMID:36980088] [SUPPORT] Genetic testing revealed a mutation of the PEX6 (Peroxisomal Biogenesis Factor 6) gene, and the metabolic profile was consistent with the diagnosis. --- Explanation: This case report directly links pathogenic variants in PEX6 to a specific case of peroxisome biogenesis disorder.

[PMID:33955040] [SUPPORT] Autosomal recessive disorder of the Zellweger spectrum (ZSD) is a major subset of peroxisome biogenesis disorders (PBDs) that can be caused by mutations in any of the 14 PEX genes. ... Mutations in the PEX1 gene are among the most prevalent. PEX1 and PEX6 proteins, belonging to the AAA family of ATPases, form a hexameric complex, which is associated with peroxisome membranes and essential for peroxisome biology. --- Explanation: This paper confirms that mutations in PEX6, similar to those in PEX1, are linked to peroxisome biogenesis disorders.

[PMID:10408779] [SUPPORT] The PEX6 (peroxisome assembly factor-2, PAF-2) gene... restores peroxisome assembly in fibroblasts from peroxisome biogenesis disorder patients belonging to complementation group C (group 4 in the United States). --- Explanation: This research clarifies the structure and mutations of PEX6, noting its role in peroxisome biogenesis disorders.


HGNC.SYMBOL:PEX13


HGNC.SYMBOL:PEX26


HGNC.SYMBOL:PEX2


HGNC.SYMBOL:PEX10


HGNC.SYMBOL:PEX12


HGNC.SYMBOL:PEX5


HGNC.SYMBOL:PEX7


HGNC.SYMBOL:Other PEX Genes

[PMID:10904262] [SUPPORT] Recent studies have identified the PEX genes that are mutated in 11 of the 12 known complementation groups of PBD patients. --- Explanation: This reference indicates that pathogenic variants in other PEX genes are associated with Peroxisome Biogenesis Disorder (PBD).

[PMID:32399598] [SUPPORT] For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome... PEX6 encodes a peroxisomal biogenesis factor. --- Explanation: Although this reference primarily discusses Perrault syndrome, it confirms that variants in PEX genes such as PEX6 are associated with peroxisomal biogenesis disorders.

[PMID:34804114] [SUPPORT] Pathogenic variants in the PEX26 gene lead to peroxisomal disorders of the full Zellweger spectrum continuum. --- Explanation: This reference highlights PEX26 gene variants contributing to peroxisomal disorders which fall under the broader category of peroxisome biogenesis disorders.

[PMID:29070486] [SUPPORT] The biogenesis of peroxisomes requires a category of proteins named peroxins, which are encoded by the PEX genes. --- Explanation: The reference supports that PEX genes are crucial for peroxisome biogenesis, implying that pathogenic variants can lead to related disorders.


MONDO:0006365

[PMID:37892343] [SUPPORT] The management of pediatric Peutz-Jeghers Syndrome (PJS) focuses on the prevention of intussusception complicating small intestinal (SI) polyposis --- Explanation: Confirms small intestinal polyposis as a hallmark manifestation of PJS


MONDO:0006365

[PMID:20301443] [SUPPORT] GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception requiring repeated laparotomy and bowel resection --- Explanation: Establishes chronic gastrointestinal bleeding from polyps as a major complication of PJS


MONDO:0006365

[PMID:20301443] [SUPPORT] GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception --- Explanation: Intussusception from Peutz-Jeghers polyps causes abdominal pain and obstruction


MONDO:0006365

[PMID:20301443] [SUPPORT] Mucocutaneous hyperpigmentation presents in childhood as dark blue to dark brown macules around the mouth, eyes, and nostrils, in the perianal area, and on the buccal mucosa --- Explanation: Oral and mucocutaneous pigmentation is a characteristic diagnostic feature of PJS, often appearing before GI polyps


MONDO:0006365

[PMID:36970589] [SUPPORT] Peutz-Jeghers syndrome (PJS) is a clinically rare disease with pigmented spots on the lips and mucous membranes and extremities, scattered gastrointestinal polyps, and susceptibility to tumors --- Explanation: This cohort description identifies lip pigmentation as a characteristic feature of PJS.


MONDO:0006365

[PMID:20301443] [SUPPORT] Individuals with PJS are at increased risk for a wide variety of epithelial malignancies (colorectal, gastric, pancreatic, breast, and ovarian cancers) --- Explanation: PJS patients have substantially elevated lifetime cancer risk across multiple organ systems

[PMID:33513864] [SUPPORT] The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to update the previous guideline from 2010 and formulate a revised practical guideline for colleagues managing PJS patients --- Explanation: European hereditary tumor group recognizes comprehensive cancer risk across multiple organ systems as defining feature requiring multisystem management


MONDO:0006365

[PMID:37054692] [INDIRECT EVIDENCE] [SUPPORT] Peutz-Jeghers syndrome (PJS) is a rare disease characterized by the presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation. It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance --- Explanation: Establishes STK11 germline variants as the driver of hamartomatous polyposis in PJS.


MONDO:0006365


MONDO:0006365

[PMID:19541609] [INDIRECT EVIDENCE] [SUPPORT] Among mitogenic signaling pathways, the mammalian-target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in tissues and tumors derived from LKB1-deficient mice. --- Explanation: Demonstrates mTORC1 pathway hyperactivation in LKB1-deficient PJS models.

[PMID:19541609] [INDIRECT EVIDENCE] [SUPPORT] Importantly, we demonstrate that polyps from human Peutz-Jeghers patients similarly exhibit up-regulated mTORC1 signaling, HIF-1alpha, and GLUT1 levels. --- Explanation: Confirms mTORC1 signaling is upregulated in human PJS polyps.


MONDO:0006365

[PMID:36998347] [INDIRECT EVIDENCE] [SUPPORT] The resected specimen showed a branching bundle of smooth muscle fibers covered by hyperplastic mucosa, consistent with a hamartomatous polyp --- Explanation: Histologic description supports the arborizing smooth muscle core in PJS polyps.


MAXO:0000130

[PMID:20301443] [SUPPORT] Routine endoscopic surveillance with polypectomy decreases the frequency of emergency laparotomy and bowel loss resulting from intussusception --- Explanation: Endoscopic polyp removal is the standard therapeutic approach to prevent complications from Peutz-Jeghers polyps


MAXO:0000004

[PMID:34928720] [SUPPORT] The patient underwent exploratory laparotomy during which right hemicolectomy and small bowel resection were performed --- Explanation: Surgical resection is indicated for intussusception and polyps with neoplastic transformation


MAXO:0000079

[PMID:36998347] [SUPPORT] Endoscopic resection was conducted for a definitive diagnosis and treatment. The resected specimen showed a branching bundle of smooth muscle fibers covered by hyperplastic mucosa, consistent with a hamartomatous polyp --- Explanation: Genetic counseling for at-risk family members and molecular testing are critical given the autosomal dominant inheritance pattern and health implications of STK11 mutations


HGNC.SYMBOL:STK11 (Serine/threonine kinase 11, also called LKB1)

[PMID:37054692] [SUPPORT] It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance --- Explanation: Confirms germline STK11 mutations as the causative genetic basis for Peutz-Jeghers syndrome


HGNC.SYMBOL:PTEN (Phosphatase and tensin homolog)

[PMID:37377590] [SUPPORT] Among 19 patients with no detectable STK11 mutations, six had no pathogenic germline mutations of other genes, while 13 had other genetic mutations --- Explanation: Alternative genetic mutations including PTEN can account for STK11-negative PJS-like presentations


MONDO:0006365

[PMID:38036954] [SUPPORT] The results showed dysbiosis in the gut microbiota of patients with PJS, and decreased synthesis of short-chain fatty acids. --- Explanation: This study reports reduced short-chain fatty acid synthesis in PJS.

[PMID:38036954] [SUPPORT] Furthermore, the butyric acid level was negatively correlated with the frequency of endoscopic surgeries. --- Explanation: Lower butyric acid levels associate with higher polyp-related intervention burden.


MONDO:0007043

[PMID:29019756] [SUPPORT] premature fusion of cranial sutures and deviated broad thumbs and toes in PS --- Explanation: Identifies craniosynostosis as a key diagnostic feature of Pfeiffer syndrome.


MONDO:0007043

[PMID:29019756] [SUPPORT] premature fusion of cranial sutures and deviated broad thumbs and toes in PS --- Explanation: Broad thumbs are a hallmark feature of Pfeiffer syndrome.


MONDO:0007043

[PMID:29019756] [SUPPORT] premature fusion of cranial sutures and deviated broad thumbs and toes in PS --- Explanation: Broad toes are a hallmark feature of Pfeiffer syndrome.


MONDO:0007043


MONDO:0007043

[PMID:29019756] [INDIRECT EVIDENCE] [SUPPORT] FGFR1, FGFR2, and FGFR3 are crucial for both chondrogenesis and osteogenesis. Mutations in the genes encoding FGFRs, types 1-3, are responsible for various skeletal dysplasias and craniosynostosis syndromes. --- Explanation: Establishes FGFR1 role in skeletal development and craniosynostosis.


MAXO:0000004


hgnc:3688

[PMID:29019756] [SUPPORT] Skeletal disorders caused by type 1 mutations include Pfeiffer syndrome (PS) and osteoglophonic dysplasia --- Explanation: Confirms FGFR1 (type 1) mutations as a cause of Pfeiffer syndrome.


MONDO:0007043

[PMID:29019756] [SUPPORT] Most of these mutations are inherited in an autosomal dominant fashion and are gain-of-function-type mutations. --- Explanation: Confirms autosomal dominant inheritance and GOF mechanism for FGFR-related skeletal disorders including Pfeiffer syndrome.


MONDO:0004947


MONDO:0004947

[PMID:41251904] [INDIRECT EVIDENCE] [SUPPORT] Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by the BCR::ABL1 fusion gene resulting from the translocation t(9;22). --- Explanation: This abstract directly links Ph+ ALL to the BCR::ABL1 fusion from t(9;22), matching the described mechanism.


MAXO:0000058


CHEBI:49375


CHEBI:45783


CHEBI:78543


NCIT:C62528


MAXO:0000747


MAXO:0001002


HGNC.SYMBOL:BCR-ABL1 Fusion


HGNC.SYMBOL:IKZF1 Deletion


MONDO:0004947

[PMID:25408859] [SUPPORT] Acute lymphoblastic leukemia (ALL) is a disseminated malignancy of B- or --- Explanation: Abstract defines ALL as a malignancy of B- or T-lymphoblasts.


MONDO:0011652

[PMID:22670140] [SUPPORT] this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia --- Explanation: Phelan and McDermid's review identifies global developmental delay as a core neurological feature of PMS.


MONDO:0011652

[PMID:23758760] [SUPPORT] only five (19%) used some words spontaneously to communicate --- Explanation: Soorya et al. prospectively evaluated 32 PMS patients and found that only 19% used any spontaneous words, confirming severe speech impairment as a hallmark.

[PMID:12920066] [SUPPORT] all patients showed some degree of mental retardation and severe delay or absence of expressive speech, regardless of deletion size --- Explanation: Wilson et al. found universal speech delay/absence across all deletion sizes in 56 patients.


MONDO:0011652

[PMID:23758760] [SUPPORT] Most patients (77%) exhibited severe to profound intellectual disability --- Explanation: Soorya et al. prospectively assessed cognitive function in 32 PMS patients and found the majority had severe to profound intellectual disability.


MONDO:0011652

[PMID:22670140] [SUPPORT] this syndrome is characterized by neurological deficits which include global developmental delay, moderate to severe intellectual impairment, absent or severely delayed speech, and neonatal hypotonia --- Explanation: Neonatal hypotonia is listed as one of the four core neurological features in the definitive PMS review.


MONDO:0011652

[PMID:23758760] [SUPPORT] The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. --- Explanation: Soorya et al. used ADOS and ADI-R gold-standard instruments to establish a high ASD prevalence in PMS.

[PMID:22670140] [SUPPORT] more than 50% of patients show autism or autistic-like behavior, and therefore it can be classified as a syndromic form of autism spectrum disorders (ASD) --- Explanation: Phelan and McDermid noted >50% ASD prevalence across >600 documented cases.


MONDO:0011652

[PMID:24481935] [SUPPORT] the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age --- Explanation: Sarasua et al. documented increasing seizure prevalence with age in 201 PMS patients.

[PMID:24481935] [SUPPORT] Seizures were reported three times more often among patients with a de novo deletion of the maternal rather than paternal chromosome 22. --- Explanation: Parent-of-origin effect on seizure susceptibility in PMS, with maternal deletions conferring higher risk.


MONDO:0011652

[PMID:35741804] [SUPPORT] The scientific literature suggests that up to 40% of individuals with PMS have kidney disorders, yet little research has been conducted on the renal system to assess candidate genes attributed to these disorders. --- Explanation: McCoy et al. systematically reviewed kidney disorders in PMS, finding up to 40% prevalence and identifying candidate renal genes in the 22q13 region.

[PMID:29719671] [SUPPORT] renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3 --- Explanation: De Rubeis et al. found that renal anomalies were not observed in SHANK3 point mutation patients, suggesting other deleted genes in 22q13.3 are responsible.


MONDO:0011652

[PMID:24481935] [SUPPORT] the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age --- Explanation: Sarasua et al. documented lymphedema as an age-related feature in the 201-patient PMS cohort.


MONDO:0011652

[PMID:31879555] [SUPPORT] we conducted a systematic literature review and identified 56 PMS cases showing signs of behavioral and neurologic decompensation in adolescence or adulthood --- Explanation: Kolevzon et al. systematically documented neuropsychiatric decompensation and skill loss in 56 PMS cases, establishing this as a recognized feature of the syndrome.

[PMID:29719671] [SUPPORT] Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems. --- Explanation: De Rubeis et al. confirmed regression occurs in SHANK3 point mutation patients as well, demonstrating that SHANK3 haploinsufficiency alone is sufficient.


MONDO:0011652

[PMID:22670140] [INDIRECT EVIDENCE] [SUPPORT] Almost all of these deletions include the gene SHANK3 which encodes a scaffold protein in the postsynaptic densities of excitatory synapses, connecting membrane-bound receptors to the actin cytoskeleton. --- Explanation: Phelan and McDermid's comprehensive review establishes SHANK3's role as a postsynaptic scaffold protein and its centrality to PMS neurological features.

[PMID:12920066] [INDIRECT EVIDENCE] [SUPPORT] Our analysis therefore supports haploinsufficiency of the gene SHANK3, which codes for a structural protein of the postsynaptic density, as a major causative factor in the neurological symptoms of 22q13 deletion syndrome. --- Explanation: Wilson et al. found that all 45 testable patients were deleted for SHANK3, supporting its role as the critical gene.

[PMID:11431708] [INDIRECT EVIDENCE] [SUPPORT] ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses. --- Explanation: First paper linking SHANK3 (ProSAP2) disruption to 22q13.3 deletion syndrome, via a balanced translocation that disrupted the gene.


MONDO:0011652


MONDO:0011652

[PMID:24132240] [INDIRECT EVIDENCE] [SUPPORT] We show that PMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission. --- Explanation: Shcheglovitov et al. used iPSC-derived neurons from PMS patients to demonstrate selective excitatory synaptic deficits, providing direct human cellular evidence for E/I imbalance.

[PMID:21423165] [INDIRECT EVIDENCE] [SUPPORT] Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. --- Explanation: Peca et al. showed cortico-striatal circuit defects in Shank3 knockout mice, supporting disrupted neural circuit function.


hgnc:14290

[PMID:12920066] [SUPPORT] all 45 cases that could be specifically tested for the terminal region at the site of SHANK3 were deleted for this gene --- Explanation: Wilson et al. demonstrated that SHANK3 deletion is universal in the 22q13 deletion syndrome, establishing it as the critical gene.

[PMID:17173049] [SUPPORT] we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders --- Explanation: Durand et al. in Nature Genetics showed that SHANK3 point mutations alone cause language and social communication disorders, independent of larger deletions.

[PMID:29719671] [SUPPORT] All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). --- Explanation: De Rubeis et al. confirmed the full PMS phenotype in individuals with SHANK3 point mutations, with 100% ID and 73% ASD.


MONDO:0009861

[PMID:34017006] [SUPPORT] If untreated, this brain dysfunction results in severe intellectual disability, epilepsy and behavioural problems. --- Explanation: The Nature Reviews Primer confirms severe intellectual disability as a key untreated phenotype.

[PMID:38907189] [PARTIAL] Adult patients with PKU showed significantly lower performance than HC in Full Scale IQ --- Explanation: Even early-treated adults show lower IQ compared to healthy controls.


MONDO:0009861

[PMID:29025426] [SUPPORT] If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. --- Explanation: European guidelines confirm epilepsy as a major untreated manifestation.


MONDO:0009861

[PMID:17092471] [SUPPORT] In addition to well-known findings such as mental retardation, autistic features, microcephaly, and tremor, motor retardation was common and responded promptly to dietary treatment. --- Explanation: Pediatric PKU case series documents microcephaly among established neurologic manifestations.

[PMID:35854334] [SUPPORT] Untreated PKU, also known as PAH deficiency, results in severe and irreversible intellectual disability, epilepsy, behavioral disorders, and clinical features such as acquired microcephaly, seizures, psychological signs, and generalized hypopigmentation of skin (including hair and eyes). --- Explanation: Review abstract independently supports acquired microcephaly in untreated PKU.


MONDO:0009861

[PMID:17092471] [SUPPORT] Hypotonia and diminished reflexes were more frequent findings than hypertonia. --- Explanation: Confirms hypertonia occurs in PKU while indicating lower relative frequency.

[PMID:2516176] [SUPPORT] Dietary therapy reduced serum phenylalanine levels, improved symptoms of hypertonicity, and cerebrospinal fluid neurotransmitter metabolites became normal. --- Explanation: Adult PKU report supports clinically significant hypertonicity as a neurologic manifestation.


MONDO:0009861

[PMID:35854334] [SUPPORT] Untreated PKU, also known as PAH deficiency, results in severe and irreversible intellectual disability, epilepsy, behavioral disorders, and clinical features such as acquired microcephaly, seizures, psychological signs, and generalized hypopigmentation of skin (including hair and eyes). --- Explanation: Supports generalized skin, hair, and eye hypopigmentation as a PKU phenotype.

[PMID:30570999] [SUPPORT] These signs can include musty odor from skin and urine, fair skin, eczema, seizures, tremors, and hyperactivity. --- Explanation: Fair skin in PKU is consistent with clinical hypopigmentation.


MONDO:0009861

[PMID:30570999] [SUPPORT] These signs can include musty odor from skin and urine, fair skin, eczema, seizures, tremors, and hyperactivity. --- Explanation: Clinical overview explicitly lists eczema among PKU manifestations.


MONDO:0009861

[PMID:30570999] [SUPPORT] These signs can include musty odor from skin and urine, fair skin, eczema, seizures, tremors, and hyperactivity. --- Explanation: Clinical overview directly supports musty body odor as a characteristic PKU sign.


MONDO:0009861

[PMID:29025426] [INDIRECT EVIDENCE] [SUPPORT] Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. --- Explanation: Defines PAH deficiency as the primary molecular lesion in PKU.


MONDO:0009861


MONDO:0009861

[PMID:24385074] [INDIRECT EVIDENCE] [SUPPORT] Phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood of affected individuals and was the first inborn error of metabolism to be identified through population screening. --- Explanation: Clinical guideline abstract confirms blood phenylalanine accumulation in PKU.

[PMID:21216643] [INDIRECT EVIDENCE] [SUPPORT] Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase gene (PAH) with consequent elevation of blood phenylalanine (Phe), reduction in tyrosine (Tyr) and elevation of Phe/Tyr ratio (P/T). --- Explanation: Independent clinical study confirms elevated blood phenylalanine in PKU.


MONDO:0009861

[PMID:29025426] [INDIRECT EVIDENCE] [SUPPORT] Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. --- Explanation: Impaired conversion from phenylalanine to tyrosine implies substrate deficiency downstream.

[PMID:21216643] [INDIRECT EVIDENCE] [SUPPORT] Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase gene (PAH) with consequent elevation of blood phenylalanine (Phe), reduction in tyrosine (Tyr) and elevation of Phe/Tyr ratio (P/T). --- Explanation: Human PKU cohort data directly reports reduced tyrosine associated with hyperphenylalaninemia.


MONDO:0009861

[PMID:987768] [INDIRECT EVIDENCE] [SUPPORT] The LNAA group of amino acids--phenylalanine, tyrosine, tryptophan, leucine, isoleucine, and valine--compete with each other for entry into brain by a common transport mechanism. --- Explanation: Provides mechanistic support for competitive BBB amino acid transport.


MONDO:0009861

[PMID:6119011] [INDIRECT EVIDENCE] [SUPPORT] In classical PKU, the serotonin and dopamine biosynthesis is inhibited by high L-phenylalanine in blood and tissues. --- Explanation: Human PKU data support reduced serotonin synthesis under high phenylalanine conditions.


MONDO:0009861

[PMID:6119011] [INDIRECT EVIDENCE] [SUPPORT] In classical PKU, the serotonin and dopamine biosynthesis is inhibited by high L-phenylalanine in blood and tissues. --- Explanation: Human PKU data support reduced dopamine synthesis under high phenylalanine conditions.


MONDO:0009861

[PMID:34017006] [INDIRECT EVIDENCE] [SUPPORT] Phenylketonuria (PKU; also known as phenylalanine hydroxylase (PAH) deficiency) is an autosomal recessive disorder of phenylalanine metabolism, in which especially high phenylalanine concentrations cause brain dysfunction. --- Explanation: Confirms high phenylalanine concentrations as a direct driver of brain dysfunction.


MONDO:0009861

[PMID:37265600] [INDIRECT EVIDENCE] [SUPPORT] In conclusion, our findings demonstrate that white matter alterations in early-treated phenylketonuria persist into adulthood, are most prominent in the posterior white matter and are likely to be driven by axonal damage. --- Explanation: Supports persistent white matter injury in adults with early-treated PKU.

[PMID:38907189] [INDIRECT EVIDENCE] [SUPPORT] Moreover, these patients showed reduced global white matter volume as well as reductions in the volume of several subcortical grey matter structures, which might be related to the existence of underlying neurodevelopmental alterations. --- Explanation: Independently confirms white matter and subcortical structural abnormalities.


MONDO:0009861

[PMID:38907189] [INDIRECT EVIDENCE] [SUPPORT] Adult patients with early-treated PKU showed significantly lower global intelligence than HC. --- Explanation: Demonstrates measurable cognitive impairment in early-treated adult PKU cohorts.


MONDO:0009861

[PMID:30570999] [INDIRECT EVIDENCE] [SUPPORT] These signs can include musty odor from skin and urine, fair skin, eczema, seizures, tremors, and hyperactivity. --- Explanation: Fair skin in PKU is consistent with reduced pigmentation downstream of tyrosine deficit.


MONDO:0009861

[PMID:21565303] [INDIRECT EVIDENCE] [SUPPORT] The urinary metabolic marker compounds, namely phenylpyruvic acid (PPA), 2-hydroxyphenylacetic acid (oOPAA), 4-hydroxyphenylacetic acid (pOPAA), phenyllactic acid (PLA) and phenylacetic acid (PAA) of phenylketonuric individuals were detected --- Explanation: Confirms phenylketone metabolite accumulation in PKU urine profiles.


MAXO:0000088

[PMID:34017006] [SUPPORT] Dietary restriction of phenylalanine has been the mainstay of treatment for over 60 years and has been highly successful, although outcomes are still suboptimal and patients can find the treatment difficult to adhere to. --- Explanation: Confirms diet as the primary and long-standing treatment approach.

[PMID:21555948] [SUPPORT] The mainstay of treatment for hyperphenylalaninemia involves a low-protein diet and use of a phenylalanine-free medical formula. --- Explanation: Independent clinical review confirms low-protein dietary treatment as standard of care.


MAXO:0000088

[PMID:21555948] [SUPPORT] The mainstay of treatment for hyperphenylalaninemia involves a low-protein diet and use of a phenylalanine-free medical formula. --- Explanation: Directly supports phenylalanine-free medical formula as standard PKU therapy.

[PMID:35854334] [SUPPORT] Dietary treatment, including natural protein restriction and Phe-free supplements, must be used to maintain blood Phe concentrations of 120-360 μmol/L throughout the life span. --- Explanation: Independent review confirms ongoing use of Phe-free supplementation in PKU management.


MAXO:0000058

[PMID:34017006] [SUPPORT] Pharmacological treatments are available, such as tetrahydrobiopterin, which is effective in only a minority of patients (usually those with milder PKU) --- Explanation: Confirms sapropterin (BH4) effectiveness in a subset of patients with milder disease.

[PMID:17693179] [SUPPORT] In some patients with phenylketonuria who are responsive to BH4, sapropterin treatment to reduce blood phenylalanine could be used as an adjunct to a restrictive low-phenylalanine diet, and might even replace the diet in some instances. --- Explanation: Phase III trial evidence supports sapropterin efficacy in BH4-responsive PKU.


CHEBI:59560

[PMID:34017006] [INDIRECT EVIDENCE] [SUPPORT] Pharmacological treatments are available, such as tetrahydrobiopterin, which is effective in only a minority of patients (usually those with milder PKU) --- Explanation: Confirms sapropterin (BH4) effectiveness in a subset of patients with milder disease.

[PMID:17693179] [INDIRECT EVIDENCE] [SUPPORT] In some patients with phenylketonuria who are responsive to BH4, sapropterin treatment to reduce blood phenylalanine could be used as an adjunct to a restrictive low-phenylalanine diet, and might even replace the diet in some instances. --- Explanation: Phase III trial evidence supports sapropterin efficacy in BH4-responsive PKU.


MAXO:0000058

[PMID:34017006] [PARTIAL] pegylated phenylalanine ammonia lyase, which requires daily subcutaneous injections and causes adverse immune responses --- Explanation: Confirms pegvaliase as an available treatment, noting its route and immunogenicity concerns.

[PMID:29628378] [SUPPORT] Results from this study confirmed the efficacy of pegvaliase in maintaining reduced blood Phe concentrations with a manageable safety profile for most participants. --- Explanation: Pivotal Phase 3 trial independently supports pegvaliase efficacy and tolerability profile.


NCIT:C174744

[PMID:34017006] [INDIRECT EVIDENCE] [PARTIAL] pegylated phenylalanine ammonia lyase, which requires daily subcutaneous injections and causes adverse immune responses --- Explanation: Confirms pegvaliase as an available treatment, noting its route and immunogenicity concerns.

[PMID:29628378] [INDIRECT EVIDENCE] [SUPPORT] Results from this study confirmed the efficacy of pegvaliase in maintaining reduced blood Phe concentrations with a manageable safety profile for most participants. --- Explanation: Pivotal Phase 3 trial independently supports pegvaliase efficacy and tolerability profile.


MAXO:0000088

[PMID:987768] [SUPPORT] Increasing the serum concentrations of amino acids competitive with phenylalanine for transport across the blood brain barrier might form an alternative approach to effective dietary treatment of PKU. --- Explanation: Supports LNAA supplementation rationale as an adjunctive PKU dietary strategy.

[PMID:35854334] [SUPPORT] Additional treatments include the casein glycomacropeptide (GMP), which contains very limited aromatic amino acids and may improve immunological function, and large neutral amino acid (LNAA) supplementation to prevent plasma Phe transport into the brain. --- Explanation: Human PKU review independently supports LNAA supplementation as an adjunctive treatment strategy.


hgnc:8582

[PMID:35854334] [SUPPORT] PKU, an autosomal recessive disease, is an inborn error of phenylalanine (Phe) metabolism caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. --- Explanation: Directly supports PAH as the causative gene in classical PKU.

[PMID:35952926] [SUPPORT] Thirty-three PAH variants and five PTS variants were detected in HPA patients; 80.6 % PAH variants and 100 % PTS variants were classified as pathogenic or likely pathogenic. --- Explanation: Provides cohort-level evidence for multiple pathogenic PAH variants in HPA/PKU.


MONDO:0009861

[PMID:21555948] [SUPPORT] Phenylalanine hydroxylase deficiency is an autosomal recessive disorder that results in intolerance to the dietary intake of the essential amino acid phenylalanine. --- Explanation: Confirms autosomal recessive inheritance for PAH deficiency (PKU).


MONDO:0035540

[PMID:17156452] [SUPPORT] An increase in the production of catecholamines causes symptoms (mainly headaches, palpitations and excess sweating) and signs (mainly hypertension, weight loss and diabetes) reflecting the effects of epinephrine and norepinephrine on alpha- and beta-adrenergic receptors. --- Explanation: Abstract lists hypertension among catecholamine-related signs.


MONDO:0035540


MONDO:0035540

[PMID:33112834] [INDIRECT EVIDENCE] [SUPPORT] SDHx mutations lead to the accumulation of succinate, which acts as an oncometabolite by inhibiting iron(II) and alpha-ketoglutarate-dependent dioxygenases thereby regulating the cell's hypoxic response and epigenetic processes. --- Explanation: This abstract connects SDHx mutations to succinate accumulation and dioxygenase inhibition, matching the described mechanism.


MONDO:0035540

[PMID:32617052] [INDIRECT EVIDENCE] [SUPPORT] The majority of PCC and sympathetic PGL are endocrine active tumors causing clinical symptoms by secreting excess catecholamines (norepinephrine, epinephrine, dopamine) and their metabolites. --- Explanation: Abstract notes catecholamine-secreting tumors causing clinical symptoms.


MAXO:0000004

[PMID:24893135] [SUPPORT] We recommend minimally invasive adrenalectomy for most pheochromocytomas with open resection for most paragangliomas. --- Explanation: Endocrine Society clinical practice guideline recommending surgical resection as primary treatment.


MAXO:0000058

[PMID:24893135] [SUPPORT] All patients with functional PPGLs should undergo preoperative blockade to prevent perioperative complications. --- Explanation: Endocrine Society guideline recommending preoperative alpha blockade for all functional PPGLs.


MAXO:0000014


MAXO:0000647


MAXO:0000058


CHEBI:38940


HGNC.SYMBOL:SDHB

[PMID:15328326] [SUPPORT] SDHB mutation carriers have an increased frequency of malignant disease (11/32 vs 0/34, P<.001). --- Explanation: JAMA study demonstrating significantly increased malignancy risk in SDHB mutation carriers compared to SDHD.


HGNC.SYMBOL:SDHD

[PMID:15328326] [SUPPORT] Head and neck paragangliomas (10/32 vs 27/34, respectively, P<.001) and multifocal (9/32 vs 25/34, respectively, P<.001) tumors were more frequent in carriers of SDHD mutations. --- Explanation: JAMA study demonstrating SDHD mutations predispose to head and neck and multifocal paragangliomas.


HGNC.SYMBOL:VHL


HGNC.SYMBOL:RET

[PMID:32388798] [SUPPORT] Multiple endocrine neoplasia type 2 (MEN2) is a rare hereditary syndrome due to mutations of the proto-oncogene REarranged during Transfection (RET), defined by the association of medullary thyroid carcinoma (MTC) in almost 100% cases, and pheochromocytoma in roughly 50% --- Explanation: Review establishing RET mutations in MEN2 cause pheochromocytoma in approximately 50% of patients.


HGNC.SYMBOL:NF1


MONDO:0035540

[PMID:32617052] [SUPPORT] Pheochromocytomas (PCC) and paragangliomas (PGL) are rare neuroendocrine tumors. --- Explanation: Abstract characterizes PCC/PGL as rare neuroendocrine tumors.


MONDO:0008243

[PMID:30537913] [PARTIAL] Patients with bvFTD often have perseverative, stereotyped, or compulsive-ritualistic behavior as an early aspect of their disorder. --- Explanation: The reference discusses the presence of repetitive behaviors in frontotemporal dementia (bvFTD), which includes Pick's disease. However, the emphasis is more on impulsive behaviors rather than strictly compulsive behaviors as seen in OCD.


MONDO:0008243

[PMID:9059759] [SUPPORT] Primary progressive aphasia is an important recently emphasized clinical syndrome that is a common early manifestation of Pick's disease and Pick complex pathology. --- Explanation: The reference states that primary progressive aphasia is a common early manifestation of Pick's disease, supporting the claim that aphasia is a frequent neurological symptom of Pick's disease.

[PMID:36925418] [SUPPORT] Frontotemporal Dementia, also known by the name Pick's disease, is a rare form of dementia that can run for several generations. The two key characteristics are argyrophilic, spherical intraneuronal inclusions, which most frequently impact the frontal and temporal poles, and localized cortical atrophy (Pick bodies). --- Explanation: This reference confirms the association of Pick's disease with frontotemporal dementia, which includes language difficulties such as aphasia.

[PMID:37276800] [SUPPORT] His frontal and temporal forms of aphasia foreshadowed what are now called the nonfluent/agrammatic and semantic variants of primary progressive aphasia. Moreover, aphasic symptoms may occur with frontal degeneration (what used to be called 'Pick's disease') that yields personality changes and behavioral disturbances, now called the behavioral variant of frontotemporal dementia. --- Explanation: The reference supports the statement by indicating that aphasic symptoms are associated with Pick's disease, particularly its frontal and temporal forms.


MONDO:0008243

[PMID:11402143] [NO_EVIDENCE] The clinical presentation in frontotemporal dementia (FTD) reflects the distribution of the pathologic changes rather than the exact histologic subtype of the disease. Three major clinical syndromes can be identified: 1) frontal variant FTD (dementia of frontal type) in which changes in social behavior and personality predominate, reflecting the orbitobasal frontal lobe focus of the pathology. Traditional cognitive tests are insensitive, but more specific measures are under development; 2) semantic dementia (progressive fluent aphasia) in which there is a breakdown in the conceptual database which underlies language production and comprehension, although deficits in nonverbal semantic knowledge can also be shown on neuropsychologic testing. Patients with semantic dementia have asymmetric anterolateral temporal atrophy with relative sparing of the hippocampal formation, which is typically worse on the left side. A variant of this syndrome affecting the right temporal lobe presents with progressive prosopagnosia; 3) progressive nonfluent aphasia in which the phonologic and syntactic components of language are affected in association with left peri-Sylvian atrophy. The assessment of patients with potential FTD involves a multidisciplinary approach. The development of comprehensive caregiver-based neuropsychiatric instruments, neuropsychologic tasks sensitive to semantic memory and other key cognitive impairments, and functional (hexamethyly-propyleneamine-SPECT) and structural (MRI) brain imaging represent significant advances in the field. --- Explanation: The provided literature does not mention parkinsonism or extrapyramidal signs such as rigidity, bradykinesia, and postural instability in the context of Pick's disease (Frontotemporal dementia).


MONDO:0008243

[PMID:16317256] [PARTIAL] What was once called Pick's disease has three major anatomic variants. With all three, frontotemporal brain is selectively injured whereas posterior cortical regions are spared. --- Explanation: The reference discusses the clinical features of Pick's disease (now considered a type of frontotemporal dementia) but does not specifically mention seizures as a typical feature. However, it does not refute the possibility of seizures occurring in advanced stages.

[PMID:17076146] [NO_EVIDENCE] Pick's disease. --- Explanation: This reference only provides the title "Pick's disease" and does not contain any information about seizures or their frequency in Pick's disease.


MONDO:0008243


MONDO:0008243

[PMID:20487487] [INDIRECT EVIDENCE] [SUPPORT] Pick's disease is a rare and incurable type of dementia that is associated with atrophy of the frontal and temporal lobes of the brain over time as a result of accumulation of tau protein fibres known as Pick's bodies. --- Explanation: The accumulation of tau proteins in the brain is mentioned as a central feature of Pick's disease, supporting the statement.

[PMID:26583316] [INDIRECT EVIDENCE] [SUPPORT] Pick disease tau neuropathology may originate in limbic/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau-mediated neurodegeneration. --- Explanation: This study outlines how tau pathology progresses and leads to neuron damage, supporting the statement's claim about the mechanism.

[PMID:30158706] [INDIRECT EVIDENCE] [SUPPORT] Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer's disease, which contain both 3R and 4R tau... Here we determine the structures of tau filaments from patients with Pick's disease, a neurodegenerative disorder characterized by frontotemporal dementia. --- Explanation: The mechanistic understanding of tau filaments in Pick's disease supports the idea that tau protein accumulation leads to neuron damage and brain dysfunction.

[PMID:37351604] [INDIRECT EVIDENCE] [SUPPORT] Two siblings with deletion mutation ∆K281 in MAPT developed frontotemporal dementia. At autopsy, numerous inclusions of hyperphosphorylated 3R Tau were present in neurons and glial cells of neocortex and some subcortical regions, including hippocampus, caudate/putamen and globus pallidus. --- Explanation: Genetic mutation leading to the accumulation of tau proteins and subsequent neuron damage supports the statement.


MONDO:0008243

[PMID:27025090] [INDIRECT EVIDENCE] [SUPPORT] Pick's disease is a type of frontotemporal lobar degeneration (FTLD) with circumscribed atrophy in the frontotemporal lobe. --- Explanation: The literature states that Pick's disease involves atrophy in the frontotemporal lobe, which aligns with neuronal loss in the frontal and temporal lobes as described.

[PMID:38521060] [INDIRECT EVIDENCE] [SUPPORT] Here, we report a high-resolution, comparative single-cell molecular atlas of the human primary motor and dorsolateral prefrontal cortices and their transcriptional alterations in sporadic and familial ALS and FTLD. --- Explanation: While discussing FTLD, which includes Pick Disease, literature supports degeneration in the frontal areas of the brain.

[PMID:11809165] [INDIRECT EVIDENCE] [SUPPORT] The area of the substantia nigra was significantly reduced in PiD with PB... The pigmented and nonpigmented neuron counts in PiD with PB were not statistically different from those in controls. --- Explanation: Although the literature specifies a reduction in neuron size rather than number, it aligns with the idea of neuronal degradation in PiD.


MAXO:0000950

[PMID:12080867] [PARTIAL] Pick's disease is a progressive illness that affects brain function, eventually causing loss of verbal skills and problem-solving abilities --- Explanation: The reference discusses the management of Pick's disease by addressing symptoms, but does not explicitly mention the use of medications to manage behavior and support cognitive function. Hence, it provides partial support.


MAXO:0000011


MAXO:0001351


MAXO:0000930


MAXO:0000077

[PMID:12080867] [SUPPORT] Nurses have the responsibility of educating the primary caregiver about nutrition, skin protection, incontinence care, safety, and end-of-life decisions. --- Explanation: This reference discusses the responsibilities of nurses to educate caregivers, aligning with the statement that education and resources for caregivers are part of the treatments for Pick's disease.

[PMID:18090424] [PARTIAL] Clinical and biologic evidence in favor the entity is discussed. The changing and proliferating knowledge and terminology requires the integration of several levels of descriptions, while keeping the work in the past in sight. --- Explanation: This reference provides clinical and biological descriptions of Pick's disease and does not explicitly mention caregiver support or education, thus only partially supporting the statement.


HGNC.SYMBOL:MAPT

[PMID:37351604] [SUPPORT] Two siblings with deletion mutation ∆K281 in MAPT developed frontotemporal dementia. At autopsy, numerous inclusions of hyperphosphorylated 3R Tau were present in neurons and glial cells of neocortex and some subcortical regions, including hippocampus, caudate/putamen and globus pallidus. --- Explanation: This establishes that MAPT ΔK281 mutation causes familial Pick's disease with characteristic 3R tau pathology.


HGNC.SYMBOL:MAPT

[PMID:38631765] [SUPPORT] The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 ... p=0·0021) --- Explanation: This demonstrates a genetic risk factor for sporadic Pick's disease through MAPT haplotype variation.


HGNC.SYMBOL:GRN

[PMID:28890134] [PARTIAL] Heterozygous loss-of-function (LOF) mutations in the human progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. --- Explanation: GRN mutations cause FTLD which can clinically mimic Pick's disease, though the pathology differs (TDP-43 vs tau).


MONDO:0000979

[PMID:23332859] [SUPPORT] Mal del pinto is a dermatological disease characterized by discoloured patches of skin on the face and body. --- Explanation: The abstract describes discoloured patches of skin in pinta.


MAXO:0000058

[PMID:26304920] [SUPPORT] All stages of pinta are treatable with a single intramuscular injection of penicillin. --- Explanation: The abstract states that penicillin injection treats pinta.


MONDO:0019095


MONDO:0019095

[PMID:30940874] [SUPPORT] allowing unrestricted bacterial replication in lymph nodes (bubonic plague) and in lungs (pneumonic plague) --- Explanation: Confirms lung involvement as a primary site in pneumonic plague.


MONDO:0019095

[PMID:30940874] [INDIRECT EVIDENCE] [SUPPORT] Plague is a vector-borne disease caused by Yersinia pestis. Transmitted by fleas from rodent reservoirs, Y. pestis emerged <6000 years ago from an enteric bacterial ancestor through events of gene gain and genome reduction. --- Explanation: Establishes flea-mediated vector transmission as the primary route of Y. pestis infection.


MONDO:0019095

[PMID:24198067] [INDIRECT EVIDENCE] [SUPPORT] Within the host cell, the Yop effector proteins function to inhibit bacterial phagocytosis and to suppress the production of pro-inflammatory cytokines. --- Explanation: Describes the T3SS-delivered Yop effectors and their functions within host cells.

[PMID:30940874] [INDIRECT EVIDENCE] [SUPPORT] A complex set of virulence determinants, including the Yersinia outer-membrane proteins (Yops), the broad-range protease Pla, pathogen-associated molecular patterns (PAMPs), and iron capture systems play critical roles in the molecular strategies that Y. pestis employs to subvert the human immune system --- Explanation: Confirms the multi-factorial virulence strategy including Yops and Pla protease.


MONDO:0019095

[PMID:10922034] [INDIRECT EVIDENCE] [SUPPORT] YopH is a powerful phosphotyrosine phosphatase playing an antiphagocytic role by dephosphorylating several focal adhesion proteins. YopE and YopT contribute to antiphagocytic effects by inactivating GTPases controlling cytoskeleton dynamics. YopP/YopJ plays an anti-inflammatory role by preventing the activation of the transcription factor NF-kappaB. --- Explanation: Details the specific molecular mechanisms of each Yop effector in immune evasion.


MONDO:0019095

[PMID:30940874] [INDIRECT EVIDENCE] [SUPPORT] allowing unrestricted bacterial replication in lymph nodes (bubonic plague) and in lungs (pneumonic plague) --- Explanation: Confirms that lymph nodes are a primary site of Y. pestis replication in bubonic plague.

[PMID:12951845] [INDIRECT EVIDENCE] [SUPPORT] Yersinia pestis is the cause of plague, an illness that may manifest in bubonic, pneumonic, or septicemic form. Plague has killed an estimated 200 million humans throughout history --- Explanation: Establishes that bubonic form involves lymph node involvement and that plague has been historically devastating.


MONDO:0019095

[PMID:10922034] [INDIRECT EVIDENCE] [SUPPORT] YopP/YopJ plays an anti-inflammatory role by preventing the activation of the transcription factor NF-kappaB. It also induces rapid apoptosis of macrophages. --- Explanation: Yop-mediated macrophage apoptosis contributes to uncontrolled bacterial dissemination and systemic disease.

[PMID:15207311] [INDIRECT EVIDENCE] [SUPPORT] Bubonic disease, pneumonic plague, and septicemic plague are seen in addition to a number of other less common manifestations. --- Explanation: Confirms the clinical spectrum including septicemic plague.


MONDO:0019095

[PMID:30940874] [INDIRECT EVIDENCE] [SUPPORT] the rapid onset of death in the absence of antibiotic treatment (less than a week for bubonic plague and <48 h for pneumonic plague) --- Explanation: Confirms the extreme lethality and rapidity of pneumonic plague without treatment.

[PMID:24198067] [INDIRECT EVIDENCE] [SUPPORT] Yersinia pestis, the etiologic agent of plague, utilizes a type III secretion system (T3SS) to subvert the defenses of its mammalian hosts. --- Explanation: T3SS-mediated immune evasion applies to pulmonary infection as well.


MONDO:0019095

[PMID:36261521] [INDIRECT EVIDENCE] [SUPPORT] The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages. --- Explanation: Directly demonstrates that ERAP2 rs2549794 was selected during the Black Death and confers functional immune advantage against Y. pestis.

[PMID:36261521] [INDIRECT EVIDENCE] [SUPPORT] we show that protective variants overlap with alleles that are today associated with increased susceptibility to autoimmune diseases, providing empirical evidence for the role played by past pandemics in shaping present-day susceptibility to disease. --- Explanation: Demonstrates antagonistic pleiotropy where plague-protective alleles now increase autoimmune disease risk.


MAXO:0000058

[PMID:32435802] [SUPPORT] Treatment with aminoglycosides such as streptomycin or gentamicin is effective when initiated early in illness but can have serious side effects. --- Explanation: Confirms aminoglycosides as effective first-line treatment for plague.

[PMID:32435800] [SUPPORT] Tetracyclines, chloramphenicol, and aminoglycosides were associated with the lowest case fatality rates of all antimicrobials used for treatment of plague. --- Explanation: Aggregate data confirms aminoglycosides among the most effective treatments for plague.


MAXO:0000058

[PMID:32435800] [SUPPORT] Tetracyclines, chloramphenicol, and aminoglycosides were associated with the lowest case fatality rates of all antimicrobials used for treatment of plague. --- Explanation: Confirms tetracyclines among the most effective plague treatments.


MAXO:0000950


hgnc:17910

[PMID:36261521] [SUPPORT] The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages. --- Explanation: ERAP2 rs2549794 was under positive selection during the Black Death and provides functional immune advantage.


NCBITaxon:632

[PMID:12951845] [SUPPORT] Yersinia pestis is the cause of plague, an illness that may manifest in bubonic, pneumonic, or septicemic form. --- Explanation: Establishes Y. pestis as the causative agent of all forms of plague.


MONDO:0000288

[PMID:33553405] [SUPPORT] Computed tomography of the abdomen revealed a huge polycystic lesion in left liver lobe, without reinforcement after enhanced scanning and sized about 16.9 cm × 12.2 cm, which was considered a type II hydatid cyst. --- Explanation: The CT finding documents a large hepatic polycystic hydatid lesion consistent with the phenotype.


MONDO:0000288

[PMID:41431593] [SUPPORT] We describe a rural patient with hepatitis B virus (HBV)-related cirrhosis and neotropical echinococcosis who developed a hepatic abscess that fistulized into the right hemithorax. --- Explanation: The report documents hepatic abscess formation as a complication of neotropical echinococcosis.


MONDO:0000288

[PMID:41431593] [SUPPORT] We describe a rural patient with hepatitis B virus (HBV)-related cirrhosis and neotropical echinococcosis who developed a hepatic abscess that fistulized into the right hemithorax. --- Explanation: The case describes a transdiaphragmatic fistula leading to a thoracic abscess, aligning with a lung abscess complication.


MONDO:0000288

[PMID:33553405] [INDIRECT EVIDENCE] [SUPPORT] Computed tomography of the abdomen revealed a huge polycystic lesion in left liver lobe, without reinforcement after enhanced scanning and sized about 16.9 cm × 12.2 cm, which was considered a type II hydatid cyst. --- Explanation: The CT finding localizes the polycystic hydatid lesion to hepatic parenchyma, consistent with metacestode implantation.


MONDO:0000288

[PMID:33553405] [INDIRECT EVIDENCE] [SUPPORT] Computed tomography of the abdomen revealed a huge polycystic lesion in left liver lobe, without reinforcement after enhanced scanning and sized about 16.9 cm × 12.2 cm, which was considered a type II hydatid cyst. --- Explanation: The multilocular hepatic mass on imaging reflects proliferating daughter cysts and associated matrix remodeling.


MONDO:0000288


MONDO:0000288

[PMID:33553405] [INDIRECT EVIDENCE] [SUPPORT] Computed tomography of the abdomen revealed a huge polycystic lesion in left liver lobe, without reinforcement after enhanced scanning and sized about 16.9 cm × 12.2 cm, which was considered a type II hydatid cyst. --- Explanation: The large polycystic hepatic lesion demonstrates mass effect consistent with local compression and invasive growth.


MAXO:0000058

[PMID:34034501] [SUPPORT] Treatment with albendazole, whether combined or not with praziquantel, is useful for smaller, uncomplicated cysts (< 5 cm). --- Explanation: Review guidance highlights albendazole as standard medical therapy for hydatid cysts.


MAXO:0000004

[PMID:33553405] [SUPPORT] According to Romic classification, the case belongs to type IIb, and radical left hemi-hepatectomy was performed. --- Explanation: The case demonstrates radical liver resection as operative management for polycystic echinococcosis.


NCBITaxon:6213

[PMID:40705460] [SUPPORT] We describe a case of E. vogeli echinococcosis in a woman, diagnosed through PCR, mitochondrial DNA sequencing, and molecular characterization. --- Explanation: Molecular confirmation links human infection to Echinococcus vogeli.


MONDO:0020642

[PMID:29105594] [SUPPORT] the vasopressin V2-receptor antagonist tolvaptan slowed the growth in total kidney volume --- Explanation: REPRISE trial confirms PKD as a cystic kidney disease defined by progressive kidney volume increase.

[PMID:40126492] [SUPPORT] Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development of kidney cysts --- Explanation: JAMA review describes ADPKD as a progressive cystic kidney disease.


MONDO:0020642

[PMID:40126492] [SUPPORT] Hypertension affects 70% to 80% of patients with ADPKD --- Explanation: JAMA review confirms very high prevalence of hypertension in ADPKD patients.

[PMID:40126492] [SUPPORT] Optimal management of ADPKD includes systolic blood pressure lower than 120 mm Hg for most patients --- Explanation: Tight blood pressure targets underscore hypertension as a central clinical issue in ADPKD.

[PMID:40371605] [SUPPORT] Comorbidities include hypertension, flank pain, and bacterial infections. --- Explanation: Proteomic study lists hypertension as a common comorbidity in ADPKD cohorts.


MONDO:0020642

[PMID:29105594] [SUPPORT] The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m2 --- Explanation: Trial demonstrates progressive GFR decline in PKD patients.

[PMID:40126492] [SUPPORT] Approximately 50% of individuals with ADPKD require kidney replacement therapy by 62 years of age --- Explanation: High rate of kidney replacement therapy highlights progression to advanced CKD in ADPKD.


MONDO:0020642

[PMID:40126492] [SUPPORT] More than 90% of patients older than 35 years have hepatic cysts --- Explanation: JAMA review confirms hepatic cysts as a very common manifestation in ADPKD.

[PMID:40126492] [SUPPORT] More than 90% of patients older than 35 years have hepatic cysts, which may cause abdominal discomfort and occasionally require medical or surgical intervention --- Explanation: Describes prevalence plus symptomatic burden and intervention needs from hepatic cysts in ADPKD.


MONDO:0020642

[PMID:40126492] [SUPPORT] approximately 9% to 14% develop intracranial aneurysms --- Explanation: JAMA review confirms intracranial aneurysms occur in 9-14% of ADPKD patients.


MONDO:0020642

[PMID:40371605] [SUPPORT] Comorbidities include hypertension, flank pain, and bacterial infections. --- Explanation: Proteomic study notes flank pain as a common comorbidity in ADPKD patients.


MONDO:0020642

[PMID:29105594] [INDIRECT EVIDENCE] [SUPPORT] the vasopressin V2-receptor antagonist tolvaptan slowed the growth in total kidney volume --- Explanation: Tolvaptan’s effect on kidney volume underscores vasopressin/cAMP signaling as a key driver of cyst expansion.


MONDO:0020642


MONDO:0020642

[PMID:29105594] [INDIRECT EVIDENCE] [SUPPORT] slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate --- Explanation: Dampening kidney volume growth parallels slower GFR loss, linking cyst epithelial proliferation to functional decline.


MONDO:0020642

[PMID:29105594] [INDIRECT EVIDENCE] [SUPPORT] the vasopressin V2-receptor antagonist tolvaptan slowed the growth in total kidney volume --- Explanation: Reduction of cyst growth via V2 receptor blockade underscores cAMP-mediated ciliary signaling as a driver of cystogenesis.


MONDO:0020642

[PMID:40126492] [INDIRECT EVIDENCE] [SUPPORT] ADPKD accounts for 5% to 10% of kidney failure in the US and Europe --- Explanation: High kidney failure burden reflects cumulative nephron loss from cyst-driven injury and interstitial fibrosis.


MAXO:0000058

[PMID:29105594] [SUPPORT] Tolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. --- Explanation: REPRISE trial demonstrated tolvaptan efficacy in slowing GFR decline in PKD patients.


CHEBI:32246

[PMID:29105594] [INDIRECT EVIDENCE] [SUPPORT] Tolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. --- Explanation: REPRISE trial demonstrated tolvaptan efficacy in slowing GFR decline in PKD patients.


MAXO:0000058

[PMID:40126492] [SUPPORT] First-line treatment includes blood pressure control, dietary and weight management, and adequate hydration. --- Explanation: JAMA review confirms blood pressure control as first-line treatment for ADPKD.


MAXO:0000601

[PMID:40126492] [SUPPORT] Approximately 50% of individuals with ADPKD require kidney replacement therapy by 62 years of age. --- Explanation: JAMA review confirms high rate of kidney replacement therapy (dialysis/transplant) in ADPKD.


MAXO:0010039


HGNC.SYMBOL:PKD1 Mutations

[PMID:40126492] [SUPPORT] ADPKD is typically diagnosed in individuals aged 27 to 42 years and is primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%) genes. --- Explanation: JAMA review quantifies PKD1 as the predominant cause of ADPKD.


HGNC.SYMBOL:PKD2 Mutations

[PMID:40126492] [SUPPORT] ADPKD is typically diagnosed in individuals aged 27 to 42 years and is primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%) genes. --- Explanation: JAMA review documents PKD2 as a minority but established cause of ADPKD.


HGNC.SYMBOL:PKHD1 Mutations

[PMID:41467628] [SUPPORT] Autosomal recessive polycystic kidney disease (ARPKD) is a rare disorder mainly caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene. --- Explanation: Clin Nephrol study states PKHD1 mutations as the primary cause of ARPKD.


MONDO:0008487

[PMID:14671196] [SUPPORT] We hypothesize that an increased AMH tone within the cohort could be involved in the follicular arrest of PCOS, by interacting negatively with FSH at the time of selection. --- Explanation: Follicular arrest due to elevated AMH directly leads to anovulation and irregular menstruation in PCOS.


MONDO:0008487

[PMID:38152131] [SUPPORT] Compelling evidence suggests that hyperandrogenism is not just a primary feature of PCOS. Instead, it may be a causative factor for this condition. --- Explanation: Hyperandrogenism drives hirsutism and other androgen-mediated dermatological manifestations in PCOS.


MONDO:0008487


MONDO:0008487

[PMID:14671196] [SUPPORT] Because PCOS is associated with a 2- to 3-fold increase in growing FN, we investigated whether an increased AMH serum level correlates to other hormonal and/or U/S features of PCOS. --- Explanation: Anovulation from follicular arrest is the primary mechanism of infertility in PCOS, linked to elevated AMH and disrupted follicle maturation.


MONDO:0008487

[PMID:38152131] [INDIRECT EVIDENCE] [SUPPORT] Compelling evidence suggests that hyperandrogenism is not just a primary feature of PCOS. Instead, it may be a causative factor for this condition. --- Explanation: This review establishes hyperandrogenism as potentially causative rather than merely symptomatic in PCOS pathophysiology.

[PMID:24014605] [INDIRECT EVIDENCE] [SUPPORT] LHCGR and 17α-hydroxylase/17-20-lyase (CYP17A1) protein levels are increased in polycystic ovaries (PCOs). --- Explanation: Direct evidence of increased androgen biosynthetic machinery (CYP17A1) in PCOS ovaries, supporting intrinsic theca cell abnormality.

[PMID:24014605] [INDIRECT EVIDENCE] [SUPPORT] A significant increase in the intensity of immunostaining for CYP17A1 was identified in antral follicles in sections of PCO compared with ovaries from normal women (P = 0.04). --- Explanation: Quantitative demonstration of elevated CYP17A1 protein in polycystic ovaries compared to controls.

[PMID:24014605] [INDIRECT EVIDENCE] [SUPPORT] A higher proportion of theca cells from anovulatory PCO expressed LHCGR protein when compared with control ovaries (P = 0.01). --- Explanation: Increased LH receptor expression in theca cells explains heightened LH-driven androgen production in PCOS.


MONDO:0008487

[PMID:40013621] [INDIRECT EVIDENCE] [SUPPORT] Hyperinsulinemia (i.e., elevated insulin without hypoglycemia) is a common metabolic feature of PCOS that worsens its reproductive symptoms by exacerbating pituitary hormone imbalances and increasing levels of bioactive androgens. --- Explanation: Demonstrates the direct mechanistic link between hyperinsulinemia and worsening of reproductive and androgenic features in PCOS.

[PMID:40013621] [INDIRECT EVIDENCE] [SUPPORT] However, it is challenging to define the sequential relationship between insulin sensitivity and insulin secretion, as they are tightly interlinked, and evidence suggests that hyperinsulinemia can alternatively precede insulin resistance. --- Explanation: Challenges traditional causality and suggests hyperinsulinemia may be primary rather than compensatory in some PCOS cases.

[PMID:40013621] [INDIRECT EVIDENCE] [SUPPORT] Notably, other drivers of hyperinsulinemia (outside of insulin resistance) may be highly relevant in the context of PCOS. For instance, high androgen levels can augment both hyperinsulinemia and insulin resistance, generating a self-perpetuating cycle of reproductive and metabolic dysfunction. --- Explanation: Describes the vicious cycle where androgens exacerbate both hyperinsulinemia and insulin resistance in PCOS.


MONDO:0008487

[PMID:14671196] [INDIRECT EVIDENCE] [SUPPORT] Because PCOS is associated with a 2- to 3-fold increase in growing FN, we investigated whether an increased AMH serum level correlates to other hormonal and/or U/S features of PCOS. --- Explanation: Documents the 2-3 fold increase in small growing follicle number characteristic of PCOS polycystic morphology.

[PMID:14671196] [INDIRECT EVIDENCE] [SUPPORT] Mean serum AMH level was markedly increased in the PCOS group (47.1 +/- 22.9 vs. 20.8 +/- 11.6 pmol/liter in controls; P < 0.0001), an increase in the same order of magnitude as the one of the FN in the 2- to 5-mm range at U/S (12.8 +/- 8.3 vs. 4.8 +/- 1.9; P < 0.0001, respectively). --- Explanation: Shows parallel elevation of AMH levels and small antral follicle count in PCOS, implicating AMH in follicular arrest.

[PMID:14671196] [INDIRECT EVIDENCE] [SUPPORT] We hypothesize that an increased AMH tone within the cohort could be involved in the follicular arrest of PCOS, by interacting negatively with FSH at the time of selection. --- Explanation: Proposes mechanism by which elevated AMH interferes with FSH action to prevent dominant follicle selection in PCOS.


MONDO:0008487

[PMID:39036884] [INDIRECT EVIDENCE] [SUPPORT] Polycystic ovarian syndrome (PCOS) is related to pro-apoptotic and pro-inflammatory conditions generated by Endoplasmic reticulum (ER) stress. --- Explanation: Establishes the link between ER stress, inflammation, and apoptotic pathways in PCOS pathophysiology.

[PMID:39036884] [INDIRECT EVIDENCE] [SUPPORT] The levels of TNF-α (p = 0.009), IL-18 (p = 0.003), IL-6 (p = 0.013) and active caspase-3 (p = 0.012) were also statistically significant lower in the therapy group. --- Explanation: Clinical trial evidence demonstrating elevated TNF-α, IL-18, and IL-6 levels in PCOS patients at baseline, confirming chronic inflammatory state.


HGNC.SYMBOL:DENND1A


HGNC.SYMBOL:THADA


HGNC.SYMBOL:LHCGR


HGNC.SYMBOL:FSHR


MONDO:0009891


MONDO:0009891

[PMID:41580684] [INDIRECT EVIDENCE] [PARTIAL] Polycythemia vera (PV) is a myeloproliferative neoplasm, characterized by trilineage hypercellularity, which increases the risk of thrombosis. --- Explanation: This abstract states that PV is an MPN with increased thrombosis risk, supporting the thrombotic mechanism described.


MAXO:0000002


MAXO:0000058


CHEBI:15365


CHEBI:44423


CHEBI:66919


HGNC.SYMBOL:JAK2


MONDO:0009891

[PMID:40246933] [SUPPORT] PV is typically characterized by erythrocytosis and often --- Explanation: Abstract states that PV is typically characterized by erythrocytosis.


MONDO:0019127

[PMID:31257434] [SUPPORT] The level of serum creatinine kinase was higher in patients with CD8+ T cells in muscle cells than those without these cells. --- Explanation: Links the presence of CD8+ T cell invasion to elevated muscle enzymes and clinical muscle damage manifestations.


MONDO:0019127


MONDO:0019127

[PMID:31257434] [INDIRECT EVIDENCE] [SUPPORT] The hallmark histopathology of PM is the presence of CD8+ T cells in the non-necrotic muscle cells. --- Explanation: Demonstrates that CD8+ T cell invasion into muscle fibers is the defining pathological feature of polymyositis.

[PMID:31257434] [INDIRECT EVIDENCE] [SUPPORT] CD8+ T cells invade into muscle cells and contribute to muscle injury in PM. --- Explanation: Confirms the direct cytotoxic role of CD8+ T cells in causing muscle fiber damage through invasion and attack.


MONDO:0019127

[PMID:15934115] [INDIRECT EVIDENCE] [SUPPORT] Up-regulation of class I MHC in skeletal muscle fibers was an early and consistent feature of human inflammatory myopathies. --- Explanation: Demonstrates that MHC class I upregulation is a hallmark feature of polymyositis pathogenesis.

[PMID:15934115] [INDIRECT EVIDENCE] [SUPPORT] Class I MHC staining in muscle fibers of myositis patients showed both cell surface and a reticular pattern of internal reactivity. --- Explanation: Shows that aberrant MHC I expression occurs both on the sarcolemma and within the endoplasmic reticulum of muscle fibers.


MONDO:0019127

[PMID:15934115] [INDIRECT EVIDENCE] [SUPPORT] The pathways of endoplasmic reticulum (ER) stress response, the unfolded protein response (glucose-regulated protein 78 pathway), and the ER overload response (NF-kappaB pathway) were significantly activated in muscle tissue of human myositis patients and in the mouse model. --- Explanation: Demonstrates that ER stress pathways are activated in polymyositis muscle tissue as a consequence of MHC I overexpression.

[PMID:15934115] [INDIRECT EVIDENCE] [SUPPORT] These results indicate that the ER stress response may be a major nonimmune mechanism responsible for skeletal muscle damage and dysfunction in autoimmune myositis. --- Explanation: Identifies ER stress as a non-immune mechanism contributing to muscle pathology, explaining why inflammation doesn't always correlate with disease severity.


MONDO:0019127

[PMID:37483632] [INDIRECT EVIDENCE] [SUPPORT] Recent studies have revealed that muscle fibers of IIMs undergo necroptosis, a newly recognized form of regulated cell death, and promote muscle inflammation and dysfunction through releasing inflammatory mediators such as damage-associated molecular patterns (DAMPs). --- Explanation: Establishes necroptosis as a key mechanism of muscle fiber death in polymyositis that perpetuates inflammation.

[PMID:37483632] [INDIRECT EVIDENCE] [SUPPORT] The research on murine model of polymyositis, a subtype of IIM, revealed that the inhibition of necroptosis or HMGB1, one of major DAMPs released from muscle fibers undergoing necroptosis, ameliorated muscle inflammation and recovered muscle weakness. --- Explanation: Demonstrates that blocking necroptosis or DAMP signaling improves both inflammation and muscle function, highlighting therapeutic potential.


MONDO:0019127

[PMID:32936839] [INDIRECT EVIDENCE] [SUPPORT] Apoptotic myonuclei were found in muscle with partial invasion, but not in the invaded fibres. Fibres with TUNEL positive nuclei were surrounded by CD8+ T-cells, granzyme B+ cells and macrophages, but lacked FAS receptor expression. --- Explanation: Shows that apoptosis occurs in polymyositis muscle fibers adjacent to those with CD8+ T cell invasion, mediated by cytotoxic mechanisms.

[PMID:32936839] [INDIRECT EVIDENCE] [SUPPORT] The findings confirm that apoptosis occurs in idiopathic inflammatory myopathies and support that it is mediated by CD8+ cytotoxic T- cells, acting in parallel to the process of partial invasion. --- Explanation: Establishes that CD8+ T cell-mediated apoptosis is a distinct pathway of muscle damage occurring alongside direct fiber invasion.


HGNC.SYMBOL:HLA-DRB1*0301


MONDO:0009290

[PMID:18929906] [SUPPORT] Cardiac hypertrophy is a key feature of classic infantile Pompe's disease. --- Explanation: The Lancet review confirms cardiac hypertrophy as a key feature of classic infantile Pompe disease.

[PMID:17151339] [SUPPORT] Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. --- Explanation: The Kishnani et al. clinical trial paper confirms cardiomyopathy as a characteristic feature of infantile-onset Pompe disease.


MONDO:0009290

[PMID:33554498] [SUPPORT] Pompe disease manifests with a broad spectrum of disease severity, ranging from severe infantile-onset diseases such as hypotonia and hypertrophic cardiomyopathy to late-onset diseases such as myopathy and respiratory compromise. --- Explanation: Davison review confirms hypotonia as a key manifestation of severe infantile-onset Pompe disease.


MONDO:0009290

[PMID:32745073] [SUPPORT] PD is a chronic and progressive pathology usually characterized by limb-girdle muscle weakness and respiratory failure. --- Explanation: Taverna et al. review confirms that Pompe disease is characterized by progressive limb-girdle muscle weakness.


MONDO:0009290

[PMID:20393176] [SUPPORT] Late-onset Pompe's disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. --- Explanation: The van der Ploeg et al. NEJM trial confirms progressive loss of respiratory function as characteristic of late-onset Pompe disease.


MONDO:0009290

[PMID:26889246] [SUPPORT] cardiac hypertrophy, hepatomegaly and elevated serum enzyme levels, which was characterized by an aspartate aminotransferase level of 95 U/l, lactate dehydrogenase level of 778 U/l and creatine kinase level of 1,299 U/l --- Explanation: Liu et al. case report documents markedly elevated creatine kinase (1,299 U/l) in an infant with Pompe disease, consistent with ongoing muscle damage.


MONDO:0009290

[PMID:26889246] [SUPPORT] a newborn who was found to have cardiac hypertrophy, hepatomegaly and elevated serum enzyme levels --- Explanation: Liu et al. case report documents hepatomegaly as a presenting feature of infantile Pompe disease.


MONDO:0009290

[PMID:39020349] [SUPPORT] presented with generalized hypotonia, macroglossia, hyporeflexia, and mild left ventricular hypertrophy --- Explanation: Castellar-Leones et al. case report documents macroglossia as a presenting feature in an infant with early-onset Pompe disease.


MONDO:0009290

[PMID:16737883] [SUPPORT] feeding difficulties (57%), and failure to thrive (53%) appeared after a median age of approximately 4.0 months --- Explanation: Kishnani et al. natural history study of 168 IOPD patients found failure to thrive in 53% of cases.